Title 21 Food and Drugs Parts 300 to 499

Home , Bithionol, Candicidin, Cetalkonium chloride, Cyclomethycaine, Docusate, Dyclonine

Revised as of April 1, 2018

Containing a codification of documents of general applicability and future effect

As of April 1, 2018

Published by the Office of the Federal Register National Archives and Records Administration as a Special Edition of the Federal Register

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Page Explanation ...... v

Title 21:

Chapter I—Food and Drug Administration, Department of Health and Human Services (Continued) ...... 3

Finding Aids:

Table of CFR Titles and Chapters ...... 361

Alphabetical List of Agencies Appearing in the CFR ...... 381

List of CFR Sections Affected ...... 391

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To cite the regulations in this volume use title, part and section number. Thus, 21 CFR 300.50 refers to title 21, part 300, section 50.

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The Code of Federal Regulations is a codification of the general and permanent rules published in the Federal Register by the Executive departments and agencies of the Federal Government. The Code is divided into 50 titles which represent broad areas subject to Federal regulation. Each title is divided into chapters which usually bear the name of the issuing agency. Each chapter is further sub- divided into parts covering specific regulatory areas. Each volume of the Code is revised at least once each calendar year and issued on a quarterly basis approximately as follows: Title 1 through Title 16...... as of January 1 Title 17 through Title 27 ...... as of April 1 Title 28 through Title 41 ...... as of July 1 Title 42 through Title 50...... as of October 1 The appropriate revision date is printed on the cover of each volume. LEGAL STATUS The contents of the Federal Register are required to be judicially noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie evidence of the text of the original documents (44 U.S.C. 1510). HOW TO USE THE CODE OF FEDERAL REGULATIONS The Code of Federal Regulations is kept up to date by the individual issues of the Federal Register. These two publications must be used together to determine the latest version of any given rule. To determine whether a Code volume has been amended since its revision date (in this case, April 1, 2018), consult the ‘‘List of CFR Sections Affected (LSA),’’ which is issued monthly, and the ‘‘Cumulative List of Parts Affected,’’ which appears in the Reader Aids section of the daily Federal Register. These two lists will identify the Federal Register page number of the latest amendment of any given rule. EFFECTIVE AND EXPIRATION DATES Each volume of the Code contains amendments published in the Federal Reg- ister since the last revision of that volume of the Code. Source citations for the regulations are referred to by volume number and page number of the Federal Register and date of publication. Publication dates and effective dates are usually not the same and care must be exercised by the user in determining the actual effective date. In instances where the effective date is beyond the cut- off date for the Code a note has been inserted to reflect the future effective date. In those instances where a regulation published in the Federal Register states a date certain for expiration, an appropriate note will be inserted following the text. OMB CONTROL NUMBERS The Paperwork Reduction Act of 1980 (Pub. L. 96–511) requires Federal agencies to display an OMB control number with their information collection request.

VerDate Sep<11>2014 11:29 Jun 12, 2018 Jkt 244074 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\244074.XXX 244074 nshattuck on DSK9F9SC42PROD with CFR Many agencies have begun publishing numerous OMB control numbers as amendments to existing regulations in the CFR. These OMB numbers are placed as close as possible to the applicable recordkeeping or reporting requirements. PAST PROVISIONS OF THE CODE Provisions of the Code that are no longer in force and effect as of the revision date stated on the cover of each volume are not carried. Code users may find the text of provisions in effect on any given date in the past by using the appropriate List of CFR Sections Affected (LSA). For the convenience of the reader, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. For changes to the Code prior to the LSA listings at the end of the volume, consult previous annual editions of the LSA. For changes to the Code prior to 2001, consult the List of CFR Sections Affected compilations, published for 1949- 1963, 1964-1972, 1973-1985, and 1986-2000. ‘‘[RESERVED]’’ TERMINOLOGY The term ‘‘[Reserved]’’ is used as a place holder within the Code of Federal Regulations. An agency may add regulatory information at a ‘‘[Reserved]’’ location at any time. Occasionally ‘‘[Reserved]’’ is used editorially to indicate that a portion of the CFR was left vacant and not accidentally dropped due to a printing or computer error. INCORPORATION BY REFERENCE What is incorporation by reference? Incorporation by reference was established by statute and allows Federal agencies to meet the requirement to publish regulations in the Federal Register by referring to materials already published elsewhere. For an incorporation to be valid, the Director of the Federal Register must approve it. The legal effect of incorporation by reference is that the material is treated as if it were published in full in the Federal Register (5 U.S.C. 552(a)). This material, like any other properly issued regulation, has the force of law. What is a proper incorporation by reference? The Director of the Federal Register will approve an incorporation by reference only when the requirements of 1 CFR part 51 are met. Some of the elements on which approval is based are: (a) The incorporation will substantially reduce the volume of material published in the Federal Register. (b) The matter incorporated is in fact available to the extent necessary to afford fairness and uniformity in the administrative process. (c) The incorporating document is drafted and submitted for publication in accordance with 1 CFR part 51. What if the material incorporated by reference cannot be found? If you have any problem locating or obtaining a copy of material listed as an approved incorporation by reference, please contact the agency that issued the regulation containing that incorporation. If, after contacting the agency, you find the material is not available, please notify the Director of the Federal Register, National Archives and Records Administration, 8601 Adelphi Road, College Park, MD 20740-6001, or call 202-741-6010. CFR INDEXES AND TABULAR GUIDES A subject index to the Code of Federal Regulations is contained in a separate volume, revised annually as of January 1, entitled CFR INDEX AND FINDING AIDS. This volume contains the Parallel Table of Authorities and Rules. A list of CFR titles, chapters, subchapters, and parts and an alphabetical list of agencies publishing in the CFR are also included in this volume.

VerDate Sep<11>2014 11:29 Jun 12, 2018 Jkt 244074 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\244074.XXX 244074 nshattuck on DSK9F9SC42PROD with CFR An index to the text of ‘‘Title 3—The President’’ is carried within that volume. The Federal Register Index is issued monthly in cumulative form. This index is based on a consolidation of the ‘‘Contents’’ entries in the daily Federal Reg- ister. A List of CFR Sections Affected (LSA) is published monthly, keyed to the revision dates of the 50 CFR titles. REPUBLICATION OF MATERIAL There are no restrictions on the republication of material appearing in the Code of Federal Regulations. INQUIRIES For a legal interpretation or explanation of any regulation in this volume, contact the issuing agency. The issuing agency’s name appears at the top of odd-numbered pages. For inquiries concerning CFR reference assistance, call 202–741–6000 or write to the Director, Office of the Federal Register, National Archives and Records Administration, 8601 Adelphi Road, College Park, MD 20740-6001 or e-mail [email protected]. SALES The Government Publishing Office (GPO) processes all sales and distribution of the CFR. For payment by credit card, call toll-free, 866-512-1800, or DC area, 202-512-1800, M-F 8 a.m. to 4 p.m. e.s.t. or fax your order to 202-512-2104, 24 hours a day. For payment by check, write to: US Government Publishing Office – New Orders, P.O. Box 979050, St. Louis, MO 63197-9000. ELECTRONIC SERVICES The full text of the Code of Federal Regulations, the LSA (List of CFR Sections Affected), The United States Government Manual, the Federal Register, Public Laws, Public Papers of the Presidents of the United States, Compilation of Presi- dential Documents and the Privacy Act Compilation are available in electronic format via www.ofr.gov. For more information, contact the GPO Customer Con- tact Center, U.S. Government Publishing Office. Phone 202-512-1800, or 866-512- 1800 (toll-free). E-mail, [email protected]. The Office of the Federal Register also offers a free service on the National Archives and Records Administration’s (NARA) World Wide Web site for public law numbers, Federal Register finding aids, and related information. Connect to NARA’s web site at www.archives.gov/federal-register. The e-CFR is a regularly updated, unofficial editorial compilation of CFR material and Federal Register amendments, produced by the Office of the Federal Register and the Government Publishing Office. It is available at www.ecfr.gov.

OLIVER A. POTTS, Director, Office of the Federal Register April 1, 2018.

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Title 21—FOOD AND DRUGS is composed of nine volumes. The parts in these volumes are arranged in the following order: Parts 1–99, 100–169, 170–199, 200–299, 300–499, 500–599, 600–799, 800–1299 and 1300 to end. The first eight volumes, containing parts 1–1299, comprise Chapter I—Food and Drug Administration, Depart- ment of Health and Human Services. The ninth volume, containing part 1300 to end, includes Chapter II—Drug Enforcement Administration, Department of Jus- tice, and Chapter III—Office of National Drug Control Policy. The contents of these volumes represent all current regulations codified under this title of the CFR as of April 1, 2018.

For this volume, Susannah C. Hurley was Chief Editor. The Code of Federal Regulations publication program is under the direction of John Hyrum Martinez, assisted by Stephen J. Frattini.

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(This book contains parts 300 to 499)

Part

CHAPTER I—Food and Drug Administration, Department of Health and Human Services (Continued) ...... 300

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EDITORIAL NOTE: Nomenclature changes to chapter I appear at 59 FR 14366, Mar. 28, 1994, and 69 FR 13717, Mar. 24, 2004.

SUBCHAPTER D—DRUGS FOR HUMAN USE

Part Page 300 General ...... 5 310 New drugs...... 5 312 Investigational new drug application ...... 52 314 Applications for FDA approval to market a new drug ...... 94 315 Diagnostic radiopharmaceuticals...... 191 316 Orphan drugs...... 193 317 Qualifying pathogens...... 206 320 Bioavailability and bioequivalence requirements ... 206 328 Over-the-counter drug products intended for oral ingestion that contain alcohol ...... 221 329 Nonprescription human drug products subject to section 760 of the Federal food, drug, and cosmetic act ...... 222 330 Over-the-counter (OTC) human drugs which are generally recognized as safe and effective and not misbranded ...... 223 331 Antacid products for over-the-counter (OTC) human use ...... 243 332 Antiflatulent products for over-the-counter human use ...... 247 333 Topical antimicrobial drug products for over-the- counter human use ...... 248 335 Antidiarrheal drug products for over-the-counter human use ...... 256 336 Antiemetic drug products for over-the-counter human use ...... 258 338 Nighttime sleep-aid drug products for over-the- counter human use ...... 260 3

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Part Page 340 Stimulant drug products for over-the-counter human use ...... 261 341 Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use ...... 262 343 Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use .... 286 344 Topical otic drug products for over-the-counter human use ...... 293 346 Anorectal drug products for over-the-counter human use ...... 295 347 Skin protectant drug products for over-the-counter human use ...... 300 348 External analgesic drug products for over-the- counter human use ...... 308 349 Ophthalmic drug products for over-the-counter human use ...... 309 350 Antiperspirant drug products for over-the-counter human use ...... 315 352 Sunscreen drug products for over-the-counter human use [stayed indefinitely] ...... 317 355 Anticaries drug products for over-the-counter human use ...... 327 357 Miscellaneous internal drug products for over-the- counter human use ...... 332 358 Miscellaneous external drug products for over-the- counter human use ...... 336 361 Prescription drugs for human use generally recognized as safe and effective and not misbranded: Drugs used in research ...... 345 369 Interpretative statements re warnings on drugs and devices for over-the-counter sale ...... 350 370–499 [Reserved]

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PART 300—GENERAL presented for it, then formulation, labeling, or dosage changes may be pro- Subpart A [Reserved] posed and any resulting formulation may meet the appropriate criteria list- Subpart B—Combination Drugs ed in paragraph (a) of this section. (c) A fixed-combination prescription Sec. 300.50 Fixed-combination prescription drugs drug for humans that has been deter- for humans. mined to be effective for labeled indications by the Food and Drug Adminis- Subpart C—Substances Generally tration, based on evaluation of the Prohibited From Drugs NAS-NRC report on the combination, is considered to be in compliance with 300.100 Chlorofluorocarbon propellants. the requirements of this section. AUTHORITY: 21 U.S.C. 331, 351, 352, 355, 360b, 361, 371. [40 FR 13496, Mar. 27, 1975, as amended at 64 FR 401, Jan. 5, 1999] Subpart A [Reserved] Subpart C—Substances Generally Subpart B—Combination Drugs Prohibited From Drugs § 300.50 Fixed-combination prescrip- § 300.100 Chlorofluorocarbon propel- tion drugs for humans. lants. The Food and Drug Administration’s The use of chlorofluorocarbons in policy in administering the new-drug, human drugs as propellants in self- antibiotic, and other regulatory provi- pressurized containers is generally pro- sions of the Federal Food, Drug, and hibited except as provided by § 2.125 of Cosmetic Act regarding fixed combina- this chapter. tion dosage form prescription drugs for [43 FR 11317, Mar. 17, 1978] humans is as follows: (a) Two or more drugs may be combined in a single dosage form when PART 310—NEW DRUGS each component makes a contribution to the claimed effects and the dosage of Subpart A—General Provisions each component (amount, frequency, Sec. duration) is such that the combination 310.3 Definitions and interpretations. is safe and effective for a significant 310.4 Biologics; products subject to license patient population requiring such con- control. current therapy as defined in the label- 310.6 Applicability of ‘‘new drug’’ or safety ing for the drug. Special cases of this or effectiveness findings in drug efficacy general rule are where a component is study implementation notices and no- added: tices of opportunity for hearing to iden- (1) To enhance the safety or effec- tical, related, and similar drug products. tiveness of the principal active compo- Subpart B—Specific Administrative Rulings nent; and and Decisions (2) To minimize the potential for abuse of the principal active compo- 310.100 New drug status opinions; statement nent. of policy. (b) If a combination drug presently 310.103 New drug substances intended for the subject of an approved new-drug hypersensitivity testing. application has not been recognized as effective by the Commissioner of Food Subpart C—New Drugs Exempted From and Drugs based on his evaluation of Prescription-Dispensing Requirements the appropriate National Academy of 310.200 Prescription-exemption procedure. Sciences-National Research Council 310.201 Exemption for certain drugs limited panel report, or if substantial evidence by new drug applications to prescription of effectiveness has not otherwise been sale.

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Subpart D—Records and Reports 310.537 Drug products containing active ingredients offered over-the-counter (OTC) 310.303 Continuation of long-term studies, for oral administration for the treatment records, and reports on certain drugs for of fever blisters and cold sores. which new drug applications have been 310.538 Drug products containing active in- approved. gredients offered over-the-counter (OTC) 310.305 Records and reports concerning ad- for use for ingrown toenail relief. verse drug experiences on marketed pre- 310.540 Drug products containing active in- scription drugs for human use without gredients offered over-the-counter (OTC) approved new drug applications. for use as stomach acidifiers. 310.306 Notification of a permanent dis- 310.541 Over-the-counter (OTC) drug prod- continuance or an interruption in manu- ucts containing active ingredients of- facturing of marketed prescription drugs fered for use in the treatment of hypo- for human use without approved new phosphatemia. drug applications. 310.542 Over-the-counter (OTC) drug products containing active ingredients of- Subpart E—Requirements for Specific New fered for use in the treatment of hyper- Drugs or Devices phosphatemia. 310.543 Drug products containing active in- 310.501 Patient package inserts for oral con- gredients offered over-the-counter (OTC) traceptives. for human use in exocrine pancreatic in- 310.502 Certain drugs accorded new drug sta- sufficiency. tus through rulemaking procedures. 310.544 Drug products containing active in- 310.503 Requirements regarding certain ra- gredients offered over-the-counter (OTC) dioactive drugs. for use as a smoking deterrent. 310.509 Parenteral drug products in plastic 310.545 Drug products containing certain ac- containers. tive ingredients offered over-the-counter 310.515 Patient package inserts for estro- (OTC) for certain uses. gens. 310.546 Drug products containing active in- 310.517 Labeling for oral hypoglycemic gredients offered over-the-counter (OTC) drugs of the sulfonylurea class. for the treatment and/or prevention of 310.518 Drug products containing iron or nocturnal leg muscle cramps. iron salts. 310.547 Drug products containing quinine of- 310.519 Drug products marketed as over-the- fered over-the-counter (OTC) for the counter (OTC) daytime sedatives. treatment and/or prevention of malaria. 310.527 Drug products containing active in- 310.548 Drug products containing colloidal gredients offered over-the-counter (OTC) silver ingredients or silver salts offered for external use as hair growers or for over-the-counter (OTC) for the treatment hair loss prevention. and/or prevention of disease. 310.528 Drug products containing active ingredients offered over-the-counter (OTC) AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, for use as an aphrodisiac. 355, 360b–360f, 360j, 360hh–360ss, 361(a), 371, 374, 310.529 Drug products containing active in- 375, 379e, 379k–l; 42 U.S.C. 216, 241, 242(a), 262. gredients offered over-the-counter (OTC) for oral use as insect repellents. Subpart A—General Provisions 310.530 Topically applied hormone-containing drug products for over-the- § 310.3 Definitions and interpretations. counter (OTC) human use. 310.531 Drug products containing active in- As used in this part: gredients offered over-the-counter (OTC) (a) The term act means the Federal for the treatment of boils. Food, Drug, and Cosmetic Act, as 310.532 Drug products containing active in- amended (secs. 201–902, 52 Stat. 1040 et gredients offered over-the-counter (OTC) seq., as amended; 21 U.S.C. 321–392). to relieve the symptoms of benign prostatic hypertrophy. (b) Department means the Department 310.533 Drug products containing active in- of Health and Human Services. gredients offered over-the-counter (OTC) (c) Secretary means the Secretary of for human use as an anticholinergic in Health and Human Services. cough-cold drug products. (d) Commissioner means the Commis- 310.534 Drug products containing active in- sioner of Food and Drugs. gredients offered over-the-counter (OTC) (e) The term person includes individ- for human use as oral wound healing uals, partnerships, corporations, and agents. 310.536 Drug products containing active in- associations. gredients offered over-the-counter (OTC) (f) The definitions and interpreta- for use as a nailbiting or thumbsucking tions of terms contained in section 201 deterrent. of the act shall be applicable to such

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terms when used in the regulations in manufactured by other manufacturers: this part. and any other drug containing a com- (g) New drug substance means any ponent so related by chemical struc- substance that when used in the manu- ture or known pharmacological prop- facture, processing, or packing of a erties that, in the opinion of experts drug, causes that drug to be a new qualified by scientific training and ex- drug, but does not include intermedi- perience to evaluate the safety and ef- ates used in the synthesis of such sub- fectiveness of drugs, it is prudent to as- stance. sume or ascertain the liability of simi- (h) The newness of a drug may arise lar side effects and contraindications. by reason (among other reasons) of: (l) Special packaging as defined in sec- (1) The newness for drug use of any tion 2(4) of the Poison Prevention substance which composes such drug, Packaging Act of 1970 means packaging in whole or in part, whether it be an that is designed or constructed to be active substance or a menstruum, ex- significantly difficult for children cipient, carrier, coating, or other com- under 5 years of age to open or obtain ponent. a toxic or harmful amount of the sub- (2) The newness for a drug use of a stance contained therein within a rea- combination of two or more sub- sonable time and not difficult for nor- stances, none of which is a new drug. mal adults to use properly, but does (3) The newness for drug use of the not mean packaging which all such proportion of a substance in a combina- children cannot open or obtain a toxic tion, even though such combination or harmful amount within a reasonable containing such substance in other pro- time. portion is not a new drug. (m) [Reserved] (4) The newness of use of such drug in (n) The term radioactive drug means diagnosing, curing, mitigating, treat- any substance defined as a drug in sec- ing, or preventing a disease, or to af- tion 201(g)(1) of the Federal Food, fect a structure or function of the Drug, and Cosmetic Act which exhibits body, even though such drug is not a new drug when used in another disease spontaneous disintegration of unstable or to affect another structure or func- nuclei with the emission of nuclear tion of the body. particles or photons and includes any (5) The newness of a dosage, or meth- nonradioactive reagent kit or nuclide od or duration of administration or ap- generator which is intended to be used plication, or other condition of use pre- in the preparation of any such sub- scribed, recommended, or suggested in stance but does not include drugs such the labeling of such drug, even though as carbon-containing compounds or po- such drug when used in other dosage, tassium-containing salts which contain or other method or duration of admin- trace quantities of naturally occurring istration or application, or different radionuclides. The term ‘‘radioactive condition, is not a new drug. drug’’ includes a ‘‘radioactive biologi- (i) [Reserved] cal product’’ as defined in § 600.3(ee) of (j) The term sponsor means the per- this chapter. son or agency who assumes responsi- [39 FR 11680, Mar. 29, 1974, as amended at 39 bility for an investigation of a new FR 20484, June 11, 1974; 40 FR 31307, July 25, drug, including responsibility for com- 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. pliance with applicable provisions of 22, 1985] the act and regulations. The ‘‘sponsor’’ may be an individual, partnership, cor- § 310.4 Biologics; products subject to poration, or Government agency and license control. may be a manufacturer, scientific in- (a) If a drug has an approved license stitution, or an investigator regularly under section 351 of the Public Health and lawfully engaged in the investiga- Service Act (42 U.S.C. 262 et seq.) or tion of new drugs. under the animal virus, serum, and (k) The phrase related drug(s) includes toxin law of March 4, 1913 (21 U.S.C. 151 other brands, potencies, dosage forms, et seq.), it is not required to have an ap- salts, and esters of the same drug moi- proved application under section 505 of ety, including articles prepared or the act.

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(b) To obtain marketing approval for plicable. Any product not in compli- radioactive biological products for ance with an applicable drug efficacy human use, as defined in § 600.3(ee) of notice is in violation of section 505 this chapter, manufacturers must com- (new drugs) and/or section 502 (mis- ply with the provisions of § 601.2(a) of branding) of the act. this chapter. (b)(1) An identical, related, or similar drug includes other brands, potencies, [64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005] dosage forms, salts, and esters of the same drug moiety as well as of any § 310.6 Applicability of ‘‘new drug’’ or drug moiety related in chemical struc- safety or effectiveness findings in ture or known pharmacological prop- drug efficacy study implementation erties. notices and notices of opportunity (2) Where experts qualified by sci- for hearing to identical, related, entific training and experience to and similar drug products. evaluate the safety and effectiveness of (a) The Food and Drug Administra- drugs would conclude that the findings tion’s conclusions on the effectiveness and conclusions, stated in a drug effi- of drugs are currently being published cacy notice or notice of opportunity for in the FEDERAL REGISTER as Drug Effi- hearing, that a drug product is a ‘‘new cacy Study Implementation (DESI) No- drug’’ or that there is a lack of evi- tices and as Notices of Opportunity for dence to show that a drug product is Hearing. The specific products listed in safe or effective are applicable to an these notices include only those that identical, related, or similar drug prod- were introduced into the market uct, such product is affected by the no- through the new drug procedures from tice. A combination drug product con- 1938–62 and were submitted for review taining a drug that is identical, re- by the National Academy of Sciences- lated, or similar to a drug named in a National Research Council (NAS-NRC), notice may also be subject to the find- Drug Efficacy Study Group. Many ings and conclusions in a notice that a products which are identical to, related drug product is a ‘‘new drug’’ or that to, or similar to the products listed in there is a lack of evidence to show that these notices have been marketed a drug product is safe or effective. under different names or by different (3) Any person may request an opin- firms during this same period or since ion on the applicability of such a no- 1962 without going through the new tice to a specific product by writing to drug procedures or the Academy re- the Food and Drug Administration at view. Even though these products are the address shown in paragraph (e) of not listed in the notices, they are cov- this section. ered by the new drug applications re- (c) Manufacturers and distributors of viewed and thus are subject to these drugs should review their products as notices. All persons with an interest in drug efficacy notices are published and a product that is identical, related, or assure that identical, related, or simi- similar to a drug listed in a drug effi- lar products comply with all applicable cacy notice or a notice of opportunity provisions of the notices. for a hearing will be given the same op- (d) The published notices and sum- portunity as the applicant to submit mary lists of the conclusions are of data and information, to request a particular interest to drug purchasing hearing, and to participate in any hear- agents. These agents should take paring. It is not feasible for the Food and ticular care to assure that the same Drug Administration to list all prod- purchasing policy applies to drug products which are covered by an NDA and ucts that are identical, related, or thus subject to each notice. However, similar to those named in the drug effi- it is essential that the findings and cacy notices. The Food and Drug Ad- conclusions that a drug product is a ministration applies the same regu- ‘‘new drug’’ or that there is a lack of latory policy to all such products. In evidence to show that a drug product is many instances a determination can safe or effective be applied to all iden- readily be made as to the applicability tical, related, and similar drug prod- of a drug efficacy notice by an indi- ucts to which they are reasonably ap- vidual who is knowledgeable about

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drugs and their indications for use. (Public Law 87–781; 76 Stat. 788–89). In Where the relationships are more sub- particular, when approval of a new tle and not readily recognized, the pur- drug application is withdrawn under chasing agent may request an opinion provisions of section 505(e) of the Fed- by writing to the Food and Drug Ad- eral Food, Drug, and Cosmetic Act, a ministration at the address shown in drug generally recognized as safe may paragraph (e) of this section. become a ‘‘new drug’’ within the mean- (e) Interested parties may submit to ing of section 201(p) of said act as the Food and Drug Administration, amended by the Kefauver-Harris Act on Center for Drug Evaluation and Re- October 10, 1962. This is of special im- search, Office of Compliance, 10903 New Hampshire Ave., Silver Spring, MD portance by reason of proposed actions 20993–0002, the names of drug products, to withdraw approval of new drug ap- and of their manufacturers or distribu- plications for lack of substantial evi- tors, that should be the subject of the dence of effectiveness as a result of re- same purchasing and regulatory poli- ports of the National Academy of cies as those reviewed by the Drug Effi- Sciences—National Research Council cacy Study Group. Appropriate action, on its review of drug effectiveness; for including referral to purchasing offi- example, see the notice published in cials of various government agencies, the FEDERAL REGISTER of January 23, will be taken. 1968 (33 FR 818), regarding rutin, quer- (f) This regulation does not apply to cetin, et al. OTC drugs identical, similar, or related (c) Any marketed drug is a ‘‘new to a drug in the Drug Efficacy Study drug’’ if any labeling change made unless there has been or is notification after October 9, 1962, recommends or in the FEDERAL REGISTER that a drug suggests new conditions of use under will not be subject to an OTC panel re- which the drug is not generally recog- view pursuant to §§ 330.10, 330.11, and nized as safe and effective by qualified 330.5 of this chapter. experts. Undisclosed or unreported side [39 FR 11680, Mar. 29, 1974, as amended at 48 effects as well as the emergence of new FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; knowledge presenting questions with 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26, 2009] respect to the safety or effectiveness of a drug may result in its becoming a Subpart B—Specific Administrative ‘‘new drug’’ even though it was previously considered ‘‘not a new drug.’’ Rulings and Decisions Any previously given informal advice § 310.100 New drug status opinions; that an article is ‘‘not a new drug’’ statement of policy. does not apply to such an article if it (a) Over the years since 1938 the Food has been changed in formulation, man- and Drug Administration has given in- ufacture control, or labeling in a way formal advice to inquirers as to the that may significantly affect the safety new drug status of preparations. These of the drug. drugs have sometimes been identified (d) For these reasons, all opinions only by general statements of composi- previously given by the Food and Drug tion. Generally, such informal opinions Administration to the effect that an were incorporated in letters that did article is ‘‘not a new drug’’ or is ‘‘no not explicitly relate all of the nec- longer a new drug’’ are hereby revoked. essary conditions and qualifications This does not mean that all articles such as the quantitative formula for that were the subjects of such prior the drug and the conditions under opinions will be regarded as new drugs. which it was prescribed, recommended, The prior opinions will be replaced by or suggested. This has contributed to opinions of the Food and Drug Admin- misunderstanding and misinterpreta- istration that are qualified and current tion of such opinions. on when an article is ‘‘not a new drug,’’ (b) These informal opinions that an as set forth in this subchapter. article is ‘‘not a new drug’’ or ‘‘no longer a new drug’’ require reexamina- [39 FR 11680, Mar. 29, 1974] tion under the Kefauver-Harris Act

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§ 310.103 New drug substances in- (c) This section does not apply to tended for hypersensitivity testing. drugs or their components that are (a) The Food and Drug Administra- subject to the licensing requirements tion is aware of the need in the prac- of the Public Health Service Act of tice of medicine for the ingredients of 1944, as amended. (See subchapter F— a new drug to be available for tests of Biologics, of this chapter.) hypersensitivity to such ingredients [39 FR 11680, Mar. 29, 1974, as amended at 55 and therefore will not object to the FR 11578, Mar. 29, 1990; 67 FR 4907, Feb. 1, shipment of a new drug substance, as 2002] defined in § 310.3(g), for such purpose if all of the following conditions are met: Subpart C—New Drugs Exempted (1) The shipment is made as a result From Prescription-Dispensing of a specific request made to the manu- Requirements facturer or distributor by a practitioner licensed by law to administer § 310.200 Prescription-exemption pro- such drugs, and the use of such drugs cedure. for patch testing is not promoted by (a) Duration of prescription require- the manufacturer or distributor. ment. Any drug limited to prescription (2) The new drug substance requested use under section 503(b)(1)(B) of the act is an ingredient in a marketed new remains so limited until it is exempted drug and is not one that is an ingre- as provided in paragraph (b) or (e) of dient solely in a new drug that is le- this section. gally available only under the inves- (b) Prescription-exemption procedure for tigational drug provisions of this part. drugs limited by a new drug application. (3) The label bears the following Any drug limited to prescription use prominently placed statements in lieu under section 503(b)(1)(B) of the act of adequate directions for use and in shall be exempted from prescription- addition to complying with the other dispensing requirements when the labeling provisions of the act: Commissioner finds such requirements (i) ‘‘Rx only’’; and are not necessary for the protection of (ii) ‘‘For use only in patch testing’’. the public health by reason of the (4) The quantity shipped is limited to drug’s toxicity or other potentiality an amount reasonable for the purpose for harmful effect, or the method of its of patch testing in the normal course use, or the collateral measures nec- of the practice of medicine and is used essary to its use, and he finds that the solely for such patch testing. drug is safe and effective for use in (5) The new drug substance is manu- self-medication as directed in proposed factured by the same procedures and labeling. A proposal to exempt a drug meets the same specifications as the from the prescription-dispensing re- component used in the finished dosage quirements of section 503(b)(1)(B) of the form. act may be initiated by the Commis- (6) The manufacturer or distributor sioner or by any interested person. Any maintains records of all shipments for interested person may file a petition this purpose for a period of 2 years seeking such exemption, which petition after shipment and will make them may be pursuant to part 10 of this available to the Food and Drug Admin- chapter, or in the form of a supplement istration on request. to an approved new drug application. (b) When the requested new drug sub- (c) New drug status of drugs exempted stance is intended for investigational from the prescription requirement. A drug use in humans or the substance is le- exempted from the prescription re- gally available only under the inves- quirement under the provisions of tigational drug provisions of part 312 of paragraph (b) of this section is a ‘‘new this chapter, the submission of an ‘‘In- drug’’ within the meaning of section vestigational New Drug Application’’ 201(p) of the act until it has been used (IND) is required. The Food and Drug to a material extent and for a material Administration will offer assistance to time under such conditions except as any practitioner wishing to submit an provided in paragraph (e) of this sec- Investigational New Drug Application. tion.

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(d) Prescription legend not allowed on (v) The preparation is labeled with exempted drugs. The use of the prescrip- adequate directions for use in minor tion caution statement quoted in sec- conditions as a simple analgesic. tion 503(b) (4) of the act, in the labeling (vi) The dosages of N-acetyl-p-amino- of a drug exempted under the provi- phenol recommended or suggested in sions of this section, constitutes mis- the labeling do not exceed: For adults, branding. Any other statement or sug- 0.65 gram (10 grains) per dose or 2.6 gestion in the labeling of a drug ex- grams (40 grains) per 24-hour period: for empted under this section, that such children 6 to 12 years of age, one-half of drug is limited to prescription use, the maximum adult dose or dosage; for may constitute misbranding. children 3 to 6 years of age, one-fifth of (e) Prescription-exemption procedure of the maximum adult dose or dosage. OTC drug review. A drug limited to pre- (vii) The labeling bears, in juxtaposi- scription use under section 503(b)(1)(B) tion with the dosage recommendations, of the act may also be exempted from a clear warning statement against ad- prescription-dispensing requirements ministration of the drug to children by the procedure set forth in § 330.13 of under 3 years of age and against use of this chapter. the drug for more than 10 days, unless such uses are directed by a physician. [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, (viii) If the article is offered for use 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, in arthritis or rheumatism, the label- Mar. 30, 2007] ing prominently bears a statement that the beneficial effects claimed are § 310.201 Exemption for certain drugs limited to the temporary relief of limited by new-drug applications to minor aches and pains of arthritis and prescription sale. rheumatism and, in juxtaposition with (a) The prescription-dispensing re- directions for use in such conditions, a quirements of section503(b)(1)(B) of the conspicuous warning statement, such Federal Food, Drug, and Cosmetic Act as ‘‘Caution: If pain persists for more are not necessary for the protection of than 10 days, or redness is present, or the public health with respect to the in conditions affecting children under following drugs subject to new drug ap- 12 years of age, consult a physician implications: mediately’’. (1) N-Acetyl-p-aminophenol (acetami- (2) Sodium gentisate (sodium-2, 5-di- nophen, p-hydroxy-acetanilid) prepara- hydroxybenzoate) preparations meet- tions meeting all the following condi- ing all the following conditions: tions: (i) The sodium gentisate is prepared, (i) The N-acetyl-p-aminophenol is with or without other drugs, in tablet prepared, with or without other drugs, or other dosage form suitable for oral in tablet or other dosage form suitable use in self-medication, and containing for oral use in self-medication, and no drug limited to prescription sale containing no drug limited to prescrip- under the provisions of section 503(b)(1) tion sale under the provisions of sec- of the act. tion 503(b)(1) of the act. (ii) The sodium gentisate and all (ii) The N-acetyl-p-aminophenol and other components of the preparation all other components of the prepara- meet their professed standards of iden- tion meet their professed standards of tity, strength, quality, and purity. identity, strength, quality, and purity. (iii) If the preparation is a new drug, (iii) If the preparation is a new drug, an application pursuant to section an application pursuant to section 505 505(b) of the act is approved for it. (b) of the act is approved for it. (iv) The preparation contains not (iv) The preparation contains not more than 0.5 gram (7.7 grains) of anhy- more than 0.325 gram (5 grains) of N- drous sodium gentisate per dosage acetyl-p-aminophenol per dosage unit, unit. or if it is in liquid form not more than (v) The preparation is labeled with 100 milligrams of N-acetyl-p-amino- adequate directions for use in minor phenol per milliliter. conditions as a simple analgesic.

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(vi) The dosages of sodium gentisate case of rectal bleeding, as this may in- recommended or suggested in the label- dicate serious disease. ing do not exceed: For adults, 0.5 gram (4) Phenyltoloxamine dihydrogen cit- (7.7 grains) per dose of 2.0 grams (31 rate (N,N-dimethyl-(a-phenyl-O-toloxy) grains) per 24-hour period; for children ethylamine dihydrogen citrate), prep- 6 to 12 years of age, one-half of the arations meeting all the following con- maximum adult dose or dosage. ditions: (vii) The labeling bears, in juxtaposi- (i) The phenyltoloxamine dihydrogen tion with the dosage recommendations, citrate is prepared, with or without a clear warning statement against ad- other drugs, in tablet or other dosage ministration of the drug to children form suitable for oral use in self-medi- under 6 years of age and against use of cation, and containing no drug limited the drug for a prolonged period, except to prescription sale under the provi- as such uses may be directed by a phy- sions of section 503(b)(1) of the act. sician. (ii) The phenyltoloxamine dihydro- (3) Isoamylhydrocupreine and zola- gen citrate and all other components of mine hydrochloride (N, N-dimethyl-N′- the preparation meet their professed 2-thiazolyl-N′-p-methoxybenzyl-ethyl- standards of identity, strength, qual- enediamine hydrochloride) prepara- ity, and purity. tions meeting all the following condi- (iii) If the preparation is a new drug, tions: an application pursuant to section (i) The isoamylhydrocupreine and zo- 505(b) of the act is approved for it. lamine hydrochloride are prepared in (iv) The preparation contains not dosage form suitable for self-medica- more than 88 milligrams of phenyl- tion as rectal suppositories or as an toloxamine dihydrogen citrate (equiva- ointment and containing no drug lim- lent to 50 milligrams of phenyltolox- ited to prescription sale under the pro- amine) per dosage unit. visions of section 503(b)(1) of the act. (v) The preparation is labeled with adequate directions for use in the tem- (ii) The isoamylhydrocupreine, zola- porary relief of the symptoms of hay amine hydrochloride, and all other fever and/or the symptoms of other components of the preparation meet minor conditions in which it is indi- their professed standards of identity, cated. strength, quality, and purity. (vi) The dosages recommended or (iii) If the preparation is a new drug, suggested in the labeling do not exceed: an application pursuant to section For adults, 88 milligrams of phenyl- 505(b) of the act is approved for it. toloxamine dihydrogen citrate (equiva- (iv) The preparation contains not lent to 50 milligrams of phenyltolox- more than 0.25 percent of isoamyl- amine) per dose or 264 milligrams of hydrocupreine and 1.0 percent of zola- phenyltoloxamine dihydrogen citrate mine hydrochloride. (equivalent to 150 milligrams of phen- (v) If the preparation is in supposi- yltoloxamine) per 24-hour period; for tory form, it contains not more than children 6 to 12 years of age, one-half of 5.0 milligrams of isoamylhydrocupreine the maximum adult dose or dosage. and not more than 20.0 milligrams of (vii) The labeling bears, in juxtaposi- zolamine hydrochloride per supposi- tion with the dosage recommendations: tory. (a) Clear warning statements against (vi) The preparation is labeled with administration of the drug to children adequate directions for use in the tem- under 6 years of age, except as directed porary relief of local pain and itching by a physician, and against driving a associated with hemorrhoids. car or operating machinery while using (vii) The directions provide for the the drug, since it may cause drowsi- use of not more than two suppositories ness. or two applications of ointment in a 24- (b) If the article is offered for tem- hour period. porary relief of the symptoms of colds, (viii) The labeling bears, in jux- a statement that continued adminis- taposition with the dosage rec- tration for such use should not exceed ommendations, a clear warning state- 3 days, except as directed by a physi- ment against use of the preparation in cian.

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(5)–(7) [Reserved] suitable for self-medication by external (8) Dicyclomine hydrochloride (1- application to the skin as a spray, and cyclohexylhexahydrobenzoic acid. b-di- containing no drug limited to prescrip- ethylaminoethyl ester hydrochloride; tion sale under the provisions of sec- diethylaminocarbethoxy-bicyclohexyl tion 503(b)(1) of the act. hydrochloride) preparations meeting (ii) The hexadenol and all other com- all the following conditions: ponents of the preparation meet their (i) The dicyclomine hydrochloride is professed standards of identity, prepared with suitable antacid and strength, quality, and purity. other components, in tablet or other (iii) If the preparation is a new drug, dosage form for oral use in self-medica- an application pursuant to section tion, and containing no drug limited to 505(b) of the act is approved for it. prescription sale under the provisions (iv) The preparation contains not of section 503(b)(1) of the act. more than 5 percent by weight of (ii) The dicyclomine hydrochloride hexadenol. and all other components of the prepa- (v) The preparation is labeled with ration meet their professed standards adequate directions for use by external of identity, strength, quality, and pu- application in the treatment of minor rity. burns and minor skin irritations. (iii) If the preparation is a new drug, (vi) The labeling bears, in juxtaposi- an application pursuant to section tion with the directions for use, clear 505(b) of the act is approved for it. warning statements against: (iv) The preparation contains not (a) Use on serious burns or skin con- more than 5 milligrams of dicyclomine ditions or prolonged use, except as dihydrochloride per dosage unit, or if it rected by a physician. is in liquid form not more than 0.5 mil- (b) Spraying the preparation in the ligram of dicyclomine hydrochloride vicinity of eyes, mouth, nose, or ears. per milliliter. (12) Sulfur dioxide preparations (v) The preparation is labeled with meeting all the following conditions: adequate directions for use only by adults and children over 12 years of (i) The sulfur dioxide is prepared with age, in the temporary relief of gastric or without other drugs, in an aqueous hyperacidity. solution packaged in a hermetic con- (vi) The dosages recommended or tainer suitable for use in self-medica- suggested in the directions for use do tion by external application to the not exceed 10 milligrams of dicyclo- skin, and containing no drug limited to mine hydrochloride per dose or 30 mil- prescription sale under the provisions ligrams in a 24-hour period. of section 503(b)(1) of the act. (vii) The labeling bears, in juxtaposi- (ii) The sulfur dioxide and all other tion with the dosage recommendations, components of the preparation meet clear warning statements against: their professed standards of identity, (a) Exceeding the recommended dos- strength, quality, and purity. age. (iii) If the preparation is a new drug, (b) Prolonged use, except as directed an application pursuant to section by a physician, since persistent or re- 505(b) of the act is approved for it. curring symptoms may indicate a seri- (iv) The preparation contains not ous disease requiring medical atten- more than 5 grams of sulfur dioxide per tion. 100 milliliters of solution. (c) Administration to children under (v) The preparation is labeled with 12 years of age except as directed by a adequate directions for use by external physician. application to the smooth skin in the (9)–(10) [Reserved] prevention or treatment of minor con- (11) Hexadenol (a mixture of tetra- ditions in which it is indicated. cosanes and their oxidation products) (vi) The directions for use rec- preparations meeting all the following ommend or suggest not more than two conditions: applications a day for not more than 1 (i) The hexadenol is prepared and week, except as directed by a physi- packaged, with or without other drugs, cian. solvents, and propellants, in a form (13)–(15) [Reserved]

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(16) Tuaminoheptane sulfate (2-ami- ester) preparations meeting all the fol- noheptane sulfate) preparations meet- lowing conditions. ing all the following conditions: (i) The vibesate is prepared and pack- (i) The tuaminoheptane sulfate is aged, with or without other drugs, sol- prepared, with or without other drugs, vents, and propellants, in a form suit- in an aqueous vehicle suitable for ad- able for self-medication by external ap- ministration in self-medication as nose plication to the skin as a spray, and drops, and containing no drug limited containing no drug limited to prescrip- to prescription sale under the provi- tion sale under the provisions of sec- sions of section 503(b)(1) of the act. tion 503(b)(1) of the act. (ii) The preparation is packaged with (ii) The vibesate and all other compo- a style of container or assembly suited nents of the preparation meet their to self-medication by the recommended professed standards of identity, route of administration, and delivering strength, quality, and purity. not more than 0.1 milliliter of the prep- (iii) If the preparation is a new drug, aration per drop. an application pursuant to section (iii) The tuaminoheptane sulfate and 505(b) of the act is approved for it. all other components of the prepara- (iv) The preparation contains not tion meet their professed standards of more than 13 percent by weight of vi- identity, strength, quality, and purity. besate. (iv) If the preparation is a new drug, (v) The preparation is labeled with an application pursuant to section adequate directions for use by external 505(b) of the act is approved for it. application as a dressing for minor (v) The tuaminoheptane sulfate con- burns, minor cuts, or other minor skin tent of the preparation does not exceed irritations. 10 milligrams per milliliter. (vi) The labeling bears in juxtaposi- (vi) The preparation is labeled with tion with the directions for use clear adequate directions for use in the tem- warning statements against: porary relief of nasal congestion. (a) Use on serious burns and on in- (vii) The dosages recommended or fected, deep, and puncture wounds un- suggested in the directions for use do less directed by a physician. not exceed the equivalent: For adults, 5 (b) Spraying the preparation near the drops of a 1 percent solution per nostril eyes or other mucous membranes. per dose, and 5 doses in a 24-hour pe- (c) Inhaling the preparation. riod; for children 1 to 6 years of age, 3 (d) Use near open flames. drops of a 1 percent solution per nostril (e) Puncturing the container or per dose, and 5 doses in a 24-hour pe- throwing the container into fire. riod; for infants under 1 year of age, 2 (19) Pramoxine hydrochloride (4-N- drops of a 1 percent solution per nostril butoxyphenyl g-morpholinopropyl per dose, and 5 doses in a 24-hour pe- ether hydrochloride) preparations riod. meeting all the following conditions: (viii) The labeling bears, in jux- (i) The pramoxine hydrochloride is taposition with the dosage rec- prepared, with or without other drugs, ommendations: in a dosage form suitable for use in (a) Clear warning statements against self-medication by external application use of more than 5 doses daily, and to the skin, and containing no drug against use longer than 4 days unless limited to prescription sale under the directed by a physician. provisions of section 503(b)(1) of the (b) A clear warning statement to the act. effect that frequent use may cause (ii) The pramoxine hydrochloride and nervousness or sleeplessness, and that all other components of the prepara- individuals with high blood pressure, tion meet their professed standards of heart disease, diabetes, or thyroid dis- identity, strength, quality, and purity. ease should not use the preparation un- (iii) If the preparation is a new drug, less directed by a physician. an application pursuant to section (17) [Reserved] 505(b) of the act is approved for it. (18) Vibesate (a mixture of copoly- (iv) The preparation contains not mers of hydroxy-vinyl chlorideacetate, more than 1.0 percent of pramoxine hy- sebacic acid, and modified maleic rosin drochloride.

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(v) The preparation is labeled with (i) The diphemanil methylsulfate is adequate directions for use by external prepared, with or without other drugs, application to the skin for the tem- in a dosage form suitable for use in porary relief of pain or itching due to self-medication by external application minor burns and sunburn, nonpoi- to the skin, and containing no drug sonous insect bites, and minor skin ir- limited to prescription sale under the ritations. provisions of section 503(b)(1) of the (vi) The directions for use rec- act. ommend or suggest not more than four (ii) The diphemanil methylsulfate applications of the preparation per day, and all other components of the prepa- unless directed by a physician. ration meet their professed standards (vii) The labeling bears, in juxtaposi- of identity, strength, quality, and pu- tion with the directions for use, clear rity. warning statements against: (iii) If the preparation is a new drug, (a) Prolonged use. an application pursuant to section (b) Application to large areas of the 505(b) of the act is approved for it. body. (iv) The preparation contains not (c) Continued use if redness, irrita- more than 2.0 percent of diphemanil tion, swelling, or pain persists or in- methylsulfate. creases, unless directed by a physician. (v) The preparation is labeled with (d) Use in the eyes or nose. adequate directions for use by external application to the skin for the relief of (20) [Reserved] symptoms of mild poison ivy, oak, and (21) Pamabrom (2-amino-2-methyl- sumac and other minor irritations and propanol-1-8-bromotheophyllinate) itching of the skin. preparations meeting all the following (vi) The directions for use rec- conditions: ommend or suggest not more than four (i) The pamabrom is prepared with applications of the preparation per day, appropriate amounts of a suitable an- unless directed by a physician. algesic and with or without other (vii) The labeling bears, in juxtaposi- drugs, in tablet or other dosage form tion with the directions for use, a clear suitable for oral use in self-medication, warning statement, such as: ‘‘Caution: and containing no drug limited to pre- If redness, irritation, swelling, or pain scription sale under the provisions of persists or increases, discontinue use section 503(b)(1) of the act. and consult physician.’’ (ii) The pamabrom and all other com- (23) Dyclonine hydrochloride (4-but- ponents of the preparation meet their oxy-3-piperidinopropiophenone hydro- professed standards of identity, chloride; 4-n-butoxy-b-piperidono- strength, quality, and purity. propiophenone hydrochloride) prepara- (iii) If the preparation is a new drug, tions meeting all the following condi- an application pursuant to section tions: 505(b) of the act is approved for it. (i) The dyclonine hydrochloride is (iv) The preparation contains not prepared, with or without other drugs, more than 50 milligrams of pamabrom in a dosage form suitable for use as a per dosage unit. cream or ointment in self-medication (v) The preparation is labeled with by external application to the skin, or adequate directions for use in the tem- rectally, and contains no drug limited porary relief of the minor pains and to prescription sale under the provi- discomforts that may occur a few days sions of section 503(b)(1) of the act. before and during the menstrual pe- (ii) The dyclonine hydrochloride and riod. all other components of the prepara- (vi) The dosages recommended or tion meet their professed standards of suggested in the labeling do not exceed identity, strength, quality, and purity. 50 milligrams of pamabrom per dose or (iii) If the preparation is a new drug, 200 milligrams per 24-hour period. an application pursuant to section (22) Diphemanil methylsulfate (4-di- 505(b) of the act is approved for it. phenylmethylene-1,1-dimethyl-piper- (iv) The preparation contains not idinium methylsulfate) preparations more than 1.0 percent of dyclonine hy- meeting all the following conditions: drochloride.

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(v) The preparation is labeled with half of the maximum adult dose or dos- adequate directions for use: age. (a) By external application to the (vii) The labeling bears, in juxtaposi- skin for the temporary relief of pain tion with the dosage recommendations: and itching in sunburn, nonpoisonous (a) Clear warning statements against insect bites, minor burns, cuts, abra- administration of the drug to children sions, and other minor skin irritations. under 6 years of age or exceeding the (b) [Reserved] recommended dosage, unless directed (c) In the prevention or treatment of by a physician, and against driving a other minor conditions in which it is car or operating machinery while using indicated. the drug, since it may cause drowsi- (vi) The labeling bears, in juxtaposi- ness. tion with the directions for use, clear (b) If the article is offered for the warning statements against: temporary relief of symptoms of colds, (a) Continued use if redness, irrita- a statement that continued adminis- tion, swelling, or pain persists or in- tration for such use should not exceed creases, unless directed by a physician. 3 days, unless directed by a physician. (b) Use in case of rectal bleeding, as (25) [Reserved] this may indicate serious disease. (26) Methoxyphenamine hydro- (c) Use in the eyes. chloride (b-(o-methoxyphenyl)-iso- (d) Prolonged use. propyl-methylamine hydrochloride; 1- (e) Application to large areas of the (o-methoxyphenyl)- 2-methylamino- body. propane hydrochloride) preparations (f) Use for deep or puncture wounds meeting all the following conditions: or serious burns. (i) The methoxyphenamine hydro- (24) Chlorothen citrate (chlorometha- chloride is prepared with appropriate pyrilene citrate; N,N-dimethyl-N′-(2- amounts of a suitable antitussive, with pyridyl)-N′-(5-chloro-2-thenyl) ethyl- or without other drugs, in a dosage enediamine citrate) preparations meet- form suitable for oral use in self-medi- ing all the following conditions: cation, and containing no drug limited (i) The chlorothen citrate is pre- to prescription sale under the provi- pared, with or without other drugs, in sions of section 503(b)(1) of the act. tablet or other dosage form suitable for (ii) The methoxyphenamine hydro- oral use in self-medication, and con- chloride and all other components of taining no drug limited to prescription the preparation meet their professed sale under the provisions of section standards of identity, strength, qual- 503(b)(1) of the act. ity, and purity. (ii) The chlorothen citrate and all (iii) If the preparation is a new drug, other components of the preparation an application pursuant to section meet their professed standards of iden- 505(b) of the act is approved for it. tity, strength, quality, and purity. (iv) The preparation contains not (iii) If the preparation is a new drug, more than 3.5 milligrams of methoxy- an application pursuant to section phenamine hydrochloride per milli- 505(b) of the act is approved for it. liter. (iv) The preparation contains not (v) The preparation is labeled with more than 25 milligrams of chlorothen adequate directions for use in the tem- citrate per dosage unit. porary relief of cough due to minor (v) The preparation is labeled with conditions in which it is indicated. adequate directions for use in the tem- (vi) The dosages recommended or porary relief of the symptoms of hay suggested in the labeling do not exceed: fever and/or the symptoms of other For adults, 35 milligrams of methoxy- minor conditions in which it is indi- phenamine hydrochloride per dose or cated. 140 milligrams of methoxyphenamine (vi) The dosages recommended or hydrochloride per 24-hour period; for suggested in the labeling do not exceed: children 6 to 12 years of age, one-half of For adults, 25 milligrams of chlorothen the maximum adult dose or dosage. citrate per dose or 150 milligrams of (vii) The label bears a conspicuous chlorothen citrate per 24-hour period; warning to keep the drug out of the for children 6 to 12 years of age, one- reach of children, and the labeling

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bears, in juxtaposition with the dosage afford adequate protection and be suit- recommendations: able for self-medication with a min- (a) A clear warning statement imum risk of contamination of the so- against administration of the drug to lution during use. Any dispensing unit children under 6 years of age, unless di- is sterile and so packaged as to main- rected by a physician. tain sterility until the package is (b) A clear warning statement to the opened. effect that frequent or prolonged use (iii) The tyloxapol, benzalkonium may cause nervousness, restlessness, or chloride, and other ingredients used to drowsiness, and that individuals with prepare the isotonic aqueous solution high blood pressure, heart disease, dia- meet their professed standards of iden- betes, or thyroid disease should not use tity, strength, quality, and purity. the preparation unless directed by a (iv) An application pursuant to sec- physician. tion 505(b) of the act is approved for (c) A clear warning statement the drug. against use of the drug in the presence (v) The preparation contains 0.25 per- of high fever or if cough persists, since cent of tyloxapol and 0.02 percent of persistent cough as well as high fever benzalkonium chloride. may indicate the presence of a serious (vi) The label bears a conspicuous condition. warning to keep the drug out of the (27) Biphenamine hydrochloride (b-di- reach of children and the labeling ethylaminoethyl-3-phenyl-2-hydroxy- bears, in juxtaposition with the dosage benzoate hydrochloride) preparations recommendations, a clear warning that meeting all the following conditions: if irritation occurs, persists, or in- (i) The biphenamine hydrochloride is creases, use of the drug should be dis- prepared in a form suitable for use as a continued and a physician consulted. shampoo and contains no drug limited The labeling includes a statement that to prescription sale under the provi- the dropper or other dispensing tip sions of section 503(b)(1) of the act. should not touch any surface, since (ii) The biphenamine hydrochloride this may contaminate the solution. meets its professed standards of iden- (29) [Reserved] tity, strength, quality, and purity. (b) [Reserved] (iii) If the preparation is a new drug, an application pursuant to section [39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, 505(b) of the act is approved for it. 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, (iv) The preparation contains not Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR more than 1 percent of biphenamine 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; hydrochloride. 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30, (v) The preparation is labeled with 2007; 72 FR 67640, Nov. 30, 2007] adequate directions for use for the temporary relief of itching and scaling due Subpart D—Records and Reports to dandruff. (vi) The label bears a conspicuous § 310.303 Continuation of long-term warning to keep the drug out of the studies, records, and reports on cer- reach of children. tain drugs for which new drug ap- (28) Tyloxapol (an alkylarylpolyether plications have been approved. alcohol) and benzalkonium chloride (a) A new drug may not be approved ophthalmic preparations meeting all for marketing unless it has been shown the following conditions: to be safe and effective for its intended (i) The tyloxapol and benzalkonium use(s). After approval, the applicant is chloride are prepared, with other ap- required to establish and maintain propriate ingredients which are not records and make reports related to drugs limited to prescription sale clinical experience or other data or in- under the provisions of section 503(b)(1) formation necessary to make or facili- of the act, as a sterile, isotonic aque- tate a determination of whether there ous solution suitable for use in self- are or may be grounds under section medication on eye prostheses. 505(e) of the act for suspending or with- (ii) The preparation is so packaged as drawing approval of the application. to volume and type of container as to Some drugs, because of the nature of

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the condition for which they are in- the reporting requirements of para- tended, must be used for long periods of graph (c) of this section must also de- time—even a lifetime. To acquire nec- velop written procedures for the sur- essary data for determining the safety veillance, receipt, evaluation, and re- and effectiveness of long-term use of porting of postmarketing adverse drug such drugs, extensive animal and clin- experiences to FDA. ical tests are required as a condition of (b) Definitions. The following defini- approval. Nonetheless, the therapeutic tions of terms apply to this section: or prophylactic usefulness of such Adverse drug experience. Any adverse drugs may make it inadvisable in the event associated with the use of a drug public interest to delay the avail- in humans, whether or not considered ability of the drugs for widespread clin- drug related, including the following: ical use pending completion of such An adverse event occurring in the long-term studies. In such cases, the course of the use of a drug product in Food and Drug Administration may ap- professional practice; an adverse event prove the new drug application on con- occurring from drug overdose whether dition that the necessary long-term accidental or intentional; an adverse studies will be conducted and the re- event occurring from drug abuse; an sults recorded and reported in an orga- adverse event occurring from drug nized fashion. The procedures required withdrawal; and any failure of expected by paragraph (b) of this section will be pharmacological action. followed in order to list such a drug in Disability. A substantial disruption of § 310.304. a person’s ability to conduct normal (b) A proposal to require additional life functions. or continued studies with a drug for Individual case safety report (ICSR). A which a new drug application has been description of an adverse drug experi- approved may be made by the Commis- ence related to an individual patient or sioner on his own initiative or on the subject. petition of any interested person, pur- ICSR attachments. Documents related suant to part 10 of this chapter. Prior to the adverse drug experience de- to issuance of such a proposal, the ap- scribed in an ICSR, such as medical plicant will be provided an opportunity records, hospital discharge summaries, for a conference with representatives of or other documentation. the Food and Drug Administration. Life-threatening adverse drug experi- When appropriate, investigators or ence. Any adverse drug experience that other individuals may be invited to places the patient, in the view of the participate in the conference. All re- initial reporter, at immediate risk of quirements for special studies, records, death from the adverse drug experience and reports will be published in as it occurred, i.e., it does not include § 310.304. an adverse drug experience that, had it occurred in a more severe form, might [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, have caused death. 1977] Serious adverse drug experience. Any adverse drug experience occurring at § 310.305 Records and reports con- any dose that results in any of the fol- cerning adverse drug experiences lowing outcomes: Death, a life-threat- on marketed prescription drugs for ening adverse drug experience, inpa- human use without approved new tient hospitalization or prolongation of drug applications. existing hospitalization, a persistent or (a) Scope. FDA is requiring manufac- significant disability/incapacity, or a turers, packers, and distributors of congenital anomaly/birth defect. Im- marketed prescription drug products portant medical events that may not that are not the subject of an approved result in death, be life-threatening, or new drug or abbreviated new drug ap- require hospitalization may be consid- plication to establish and maintain ered a serious adverse drug experience records and make reports to FDA of all when, based upon appropriate medical serious, unexpected adverse drug expe- judgment, they may jeopardize the pa- riences associated with the use of their tient or subject and may require med- drug products. Any person subject to ical or surgical intervention to prevent

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one of the outcomes listed in this defi- must be accompanied by the current nition. Examples of such medical content of labeling in electronic for- events include allergic bronchospasm mat as an ICSR attachment unless it is requiring intensive treatment in an already on file at FDA. emergency room or at home, blood (ii) A person identified in paragraph dyscrasias or convulsions that do not (c)(1)(i) of this section is not required result in inpatient hospitalization, or to submit a 15-day ‘‘Alert report’’ for the development of drug dependency or an adverse drug experience obtained drug abuse. from a postmarketing study (whether Unexpected adverse drug experience. or not conducted under an investiga- Any adverse drug experience that is tional new drug application) unless the not listed in the current labeling for applicant concludes that there is a rea- the drug product. This includes events sonable possibility that the drug that may be symptomatically and caused the adverse experience. pathophysiologically related to an (2) Postmarketing 15-day ‘‘Alert re- event listed in the labeling, but differ ports’’—followup. Each person identified from the event because of greater se- in paragraph (c)(1)(i) of this section verity or specificity. For example, must promptly investigate all serious, under this definition, hepatic necrosis unexpected adverse drug experiences would be unexpected (by virtue of that are the subject of these post- greater severity) if the labeling only marketing 15-day Alert reports and referred to elevated hepatic enzymes or must submit followup reports within 15 hepatitis. Similarly, cerebral thrombo- calendar days of receipt of new infor- embolism and cerebral vasculitis would mation or as requested by FDA. If addi- be unexpected (by virtue of greater tional information is not obtainable, specificity) if the labeling only listed records should be maintained of the un- cerebral vascular accidents. ‘‘Unex- successful steps taken to seek addi- pected,’’ as used in this definition, re- tional information. fers to an adverse drug experience that (3) Submission of reports. To avoid un- has not been previously observed (i.e., necessary duplication in the submis- included in the labeling) rather than sion of, and followup to, reports re- from the perspective of such experience quired in this section, a packer’s or dis- not being anticipated from the pharma- tributor’s obligations may be met by cological properties of the pharma- submission of all reports of serious ad- ceutical product. verse drug experiences to the manufac- (c) Reporting requirements. Each per- turer of the drug product. If a packer son identified in paragraph (c)(1)(i) of or distributor elects to submit these this section must submit to FDA ad- adverse drug experience reports to the verse drug experience information as manufacturer rather than to FDA, it described in this section. Except as must submit, by any appropriate provided in paragraph (e)(2) of this sec- means, each report to the manufac- tion, 15-day ‘‘Alert reports’’ and fol- turer within 5 calendar days of its re- lowup reports, including ICSRs and any ceipt by the packer or distributor, and ICSR attachments, must be submitted the manufacturer must then comply to the Agency in electronic format as with the requirements of this section described in paragraph (e)(1) of this even if its name does not appear on the section. label of the drug product. Under this (1) Postmarketing 15-day ‘‘Alert re- circumstance, the packer or distributor ports’’. (i) Any person whose name ap- must maintain a record of this action pears on the label of a marketed pre- which must include: scription drug product as its manufac- (i) A copy of each adverse drug expe- turer, packer, or distributor must re- rience report; port to FDA each adverse drug experi- (ii) The date the report was received ence received or otherwise obtained by the packer or distributor; that is both serious and unexpected as (iii) The date the report was sub- soon as possible, but no later than 15 mitted to the manufacturer; and calendar days from initial receipt of (iv) The name and address of the the information by the person whose manufacturer. name appears on the label. Each report (4) [Reserved]

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(5) A person identified in paragraph (5) Manufacturer, packer, or distributor (c)(1)(i) of this section is not required information. to resubmit to FDA adverse drug expe- (i) Manufacturer, packer, or dis- rience reports forwarded to that person tributor name and contact office ad- by FDA; however, the person must sub- dress; mit all followup information on such (ii) Telephone number; reports to FDA. (iii) Report source, such as sponta- (d) Information reported on ICSRs. neous, literature, or study; ICSRs include the following informa- (iv) Date the report was received by tion: manufacturer, packer, or distributor; (1) Patient information. (v) Whether the ICSR is a 15-day (i) Patient identification code; ‘‘Alert report’’; (ii) Patient age at the time of adverse (vi) Whether the ICSR is an initial drug experience, or date of birth; report or followup report; and (iii) Patient gender; and (vii) Unique case identification num- (iv) Patient weight. ber, which must be the same in the ini- (2) Adverse drug experience. tial report and any subsequent fol- (i) Outcome attributed to adverse lowup report(s). drug experience; (e) Electronic format for submissions. (1) (ii) Date of adverse drug experience; Each report required to be submitted (iii) Date of ICSR submission; to FDA under this section, including (iv) Description of adverse drug expe- the ICSR and any ICSR attachments, rience (including a concise medical must be submitted in an electronic for- narrative); mat that FDA can process, review, and (v) Adverse drug experience term(s); archive. FDA will issue guidance on (vi) Description of relevant tests, in- how to provide the electronic submis- cluding dates and laboratory data; and sion (e.g., method of transmission, (vii) Other relevant patient history, media, file formats, preparation and including preexisting medical condi- organization of files). tions. (2) Each person identified in para- (3) Suspect medical product(s). graph (c)(1)(i) of this section may re- (i) Name; quest, in writing, a temporary waiver (ii) Dose, frequency, and route of ad- of the requirements in paragraph (e)(1) ministration used; (iii) Therapy dates; of this section. These waivers will be (iv) Diagnosis for use (indication); granted on a limited basis for good (v) Whether the product is a com- cause shown. FDA will issue guidance bination product as defined in § 3.2(e) of on requesting a waiver of the require- this chapter; ments in paragraph (e)(1) of this sec- (vi) Whether the product is a pre- tion. scription or nonprescription product; (f) Patient privacy. Manufacturers, (vii) Whether adverse drug experience packers, and distributors should not in- abated after drug use stopped or dose clude in reports under this section the reduced; names and addresses of individual pa- (viii) Whether adverse drug experi- tients; instead, the manufacturer, ence reappeared after reintroduction of packer, and distributor should assign a drug; unique code for identification of the (ix) Lot number; patient. The manufacturer, packer, and (x) Expiration date; distributor should include the name of (xi) National Drug Code (NDC) num- the reporter from whom the informa- ber; and tion was received as part of the initial (xii) Concomitant medical products reporter information, even when the and therapy dates. reporter is the patient. The names of (4) Initial reporter information. patients, individual reporters, health (i) Name, address, and telephone care professionals, hospitals, and geo- number; graphical identifiers in adverse drug (ii) Whether the initial reporter is a experience reports are not releasable to health care professional; and the public under FDA’s public informa- (iii) Occupation, if a health care pro- tion regulations in part 20 of this chap- fessional. ter.

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(g) Recordkeeping. (1) Each manufac- make the notifications required under turer, packer, and distributor must § 314.81(b)(3)(iii) of this chapter and oth- maintain for a period of 10 years erwise comply with § 314.81(b)(3)(iii) of records of all adverse drug experiences this chapter. If the manufacturer of a required under this section to be re- product subject to this section fails to ported, including raw data and any cor- provide notification as required under respondence relating to the adverse § 314.81(b)(3)(iii), FDA will send a letter drug experiences, and the records re- to the manufacturer and otherwise fol- quired to be maintained under para- low the procedures set forth under graph (c)(3) of this section. § 314.81(b)(3)(iii)(e). (2) Manufacturers and packers may (c) Drug shortages list. FDA will in- retain the records required in para- clude on the drug shortages list re- graph (f)(1) of this section as part of its quired by § 314.81(b)(3)(iii)(d) drug prod- complaint files maintained under ucts that are subject to this section § 211.198 of this chapter. that it determines to be in shortage. (3) Manufacturers, packers, and dis- For such drug products, FDA will pro- tributors must permit any authorized vide the names of each manufacturer FDA employee, at all reasonable times, rather than the names of each appli- to have access to and copy and verify cant. With respect to information col- the records established and maintained lected under this paragraph, FDA will under this section. observe the confidentiality and disclo- (h) Disclaimer. A report or informa- sure provisions set forth in tion submitted by a manufacturer, § 314.81(b)(3)(iii)(d)(2). packer, or distributor under this section (and any release by FDA of that [80 FR 38938, July 8, 2015] report or information) does not necessarily reflect a conclusion by the Subpart E—Requirements for manufacturer, packer, or distributor, Specific New Drugs or Devices or by FDA, that the report or information constitutes an admission that the § 310.501 Patient package inserts for drug caused or contributed to an ad- oral contraceptives. verse effect. The manufacturer, packer, (a) Requirement for a patient package or distributor need not admit, and may insert. The safe and effective use of oral deny, that the report or information contraceptive drug products requires submitted under this section con- that patients be fully informed of the stitutes an admission that the drug benefits and the risks involved in their caused or contributed to an adverse ef- use. An oral contraceptive drug prod- fect. uct that does not comply with the re- [51 FR 24479, July 3, 1986, as amended at 52 quirements of this section is mis- FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, branded under section 502 of the Fed- 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, eral Food, Drug, and Cosmetic Act. June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR Each dispenser of an oral contraceptive 9585, Mar. 4, 2002; 74 FR 13113, Mar. 26, 2009; 79 drug product shall provide a patient FR 33087, June 10, 2014] package insert to each patient (or to § 310.306 Notification of a permanent an agent of the patient) to whom the discontinuance or an interruption product is dispensed, except that the in manufacturing of marketed pre- dispenser may provide the insert to the scription drugs for human use with- parent or legal guardian of a legally in- out approved new drug applica- competent patient (or to the agent of tions. either). The patient package insert is (a) Applicability. Marketed prescrip- required to be placed in or accompany tion drug products that are not the each package dispensed to the patient. subject of an approved new drug or ab- (b) Distribution requirements. (1) For breviated new drug application are sub- oral contraceptive drug products, the ject to this section. manufacturer and distributor shall pro- (b) Notification of a permanent dis- vide a patient package insert in or with continuance or an interruption in manu- each package of the drug product that facturing. The manufacturer of each the manufacturer or distributor in- product subject to this section must tends to be dispensed to a patient.

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(2) Patient package inserts for oral (ii) A statement concerning excretion contraceptives dispensed in acute-care of the drug in human milk and associ- hospitals or long-term care facilities ated risks to the nursing infant; will be considered to have been pro- (iii) A statement about laboratory vided in accordance with this section if tests which may be affected by oral provided to the patient before adminis- contraceptives; and tration of the first oral contraceptive (iv) A statement that identifies ac- and every 30 days thereafter, as long as tivities and drugs, foods, or other sub- the therapy continues. stances the patient should avoid be- (c) Contents of patient package insert. cause of their interactions with oral A patient package insert for an oral contraceptives. contraceptive drug product is required (11) Information about how to take to contain the following: oral contraceptives properly, including (1) The name of the drug. information about what to do if the pa- (2) A summary including a statement tient forgets to take the product, infor- concerning the effectiveness of oral mation about becoming pregnant after contraceptives in preventing preg- discontinuing use of the drug, a state- nancy, the contraindications to the ment that the drug product has been drug’s use, and a statement of the risks prescribed for the use of the patient and benefits associated with the drug’s and should not be used for other condi- use. tions or given to others, and a state- (3) A statement comparing the effec- ment that the patient’s pharmacist or tiveness of oral contraceptives to other practitioner has a more technical leaf- methods of contraception. let about the drug product that the pa- (4) A boxed warning concerning the tient may ask to review. increased risks associated with ciga- (12) A statement of the possible bene- rette smoking and oral contraceptive use. fits associated with oral contraceptive use. (5) A discussion of the contraindications to use, including information (13) The following information about that the patient should provide to the the drug product and the patient pack- prescriber before taking the drug. age insert: (6) A statement of medical conditions (i) The name and place of business of that are not contraindications to use the manufacturer, packer, or dis- but deserve special consideration in tributor, or the name and place of busi- connection with oral contraceptive use ness of the dispenser of the product. and about which the patient should in- (ii) The date, identified as such, of form the prescriber. the most recent revision of the patient (7) A warning regarding the most se- package insert placed prominently im- rious side effects of oral contracep- mediately after the last section of the tives. labeling. (8) A statement of other serious ad- (d) Other indications. The patient verse reactions and potential safety package insert may identify indica- hazards that may result from the use tions in addition to contraception that of oral contraceptives. are identified in the professional label- (9) A statement concerning common, ing for the drug product. but less serious side effects which may (e) Labeling guidance texts. The Food help the patient evaluate the benefits and Drug Administration issues infor- and risks from the use of oral contra- mal labeling guidance texts under ceptives. § 10.90(b)(9) of this chapter to provide (10) Information on precautions the assistance in meeting the requirements patients should observe while taking of this section. A request for a copy of oral contraceptives, including the fol- the guidance texts should be directed lowing: to the Center for Drug Evaluation and (i) A statement of risks to the moth- Research, Division of Reproductive and er and unborn child from the use of Urologic Products, Food and Drug Ad- oral contraceptives before or during ministration, 10903 New Hampshire early pregnancy; Ave., Silver Spring, MD 20993–0002.

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(f) Requirement to supplement approved (14) Timed release dosage forms. application. Holders of approved appli- (15) Vinyl chloride as an ingredient, cations for oral contraceptive drug including propellant, in aerosol drug products that are subject to the re- products. quirements of this section are required (b) [Reserved] to submit supplements under § 314.70(c) [62 FR 12084, Mar. 14, 1997, as amended at 64 of this chapter to provide for the label- FR 401, Jan. 5, 1999] ing required by this section. Such labeling may be put into use without ad- § 310.503 Requirements regarding cer- vance approval by the Food and Drug tain radioactive drugs. Administration. (a) On January 8, 1963 (28 FR 183), the [54 FR 22587, May 25, 1989, as amended at 74 Commissioner of Food and Drugs ex- FR 13113, Mar. 26, 2009] empted investigational radioactive new drugs from part 312 of this chapter pro- § 310.502 Certain drugs accorded new vided they were shipped in complete drug status through rulemaking conformity with the regulations issued procedures. by the Nuclear Regulatory Commis- (a) The drugs listed in this paragraph sion. This exemption also applied to in- have been determined by rulemaking vestigational radioactive biologics. procedures to be new drugs within the (b) It is the opinion of the Nuclear meaning of section 201(p) of the act. An Regulatory Commission, and the Food approved new drug application under and Drug Administration that this ex- section 505 of the act and part 314 of emption should not apply for certain this chapter is required for marketing specific drugs and that these drugs the following drugs: should be appropriately labeled for uses (1) Aerosol drug products for human for which safety and effectiveness can use containing 1,1,1-trichloroethane. be demonstrated by new drug applica- (2) Aerosol drug products containing tions or through licensing under the zirconium. Public Health Service Act (42 U.S.C. 262 (3) Amphetamines (amphetamine, et seq.) in the case of biologics. Contin- dextroamphetamine, and their salts, ued distribution under the investiga- and levamfetamine and its salts) for tional exemption when the drugs are human use. intended for established uses will not (4) Camphorated oil drug products. be permitted. (5) Certain halogenated salicyl- (c) Based on its experience in regu- anilides (tribromsalan (TBS, 3,4′,5-tri- lating investigational radioactive bromosalicylanilide), dibromsalan pharmaceuticals, the Nuclear Regu- (DBS, 4′, 5-dibromosalicylanilide), latory Commission has compiled a list metabromsalan (MBS, 3, 5-dibromo- of reactor-produced isotopes for which salicylanilide), and 3,3′, 4,5′-tetra- it considers that applicants may rea- chlorosalicylanilide (TC-SA)) as an in- sonably be expected to submit ade- gredient in drug products. quate evidence of safety and effective- (6) Chloroform used as an ingredient ness for use as recommended in appro- (active or inactive) in drug products. priate labeling. Such use may include, (7) Cobalt preparations intended for among others, the uses in this tabula- use by man. tion: (8) Intrauterine devices for human use for the purpose of contraception Isotope Chemical form Use that incorporate heavy metals, drugs, Chromium 51 ... Chromate ...... Spleen scans. or other active substances. Do ...... do ...... Placenta localization. (9) Oral prenatal drugs containing Do ...... do ...... Red blood cell label- fluorides intended for human use. ing and survival (10) Parenteral drug products in plas- studies. tic containers. Do ...... Labeled human Gastrointestinal pro- serum albumin. tein loss studies. (11) Sterilization of drugs by irradia- Do ...... do ...... Placenta localization. tion. (12) Sweet spirits of nitre drug prod- Do ...... Labeled red blood Do. cells. ucts. Cobalt 58 or Labeled cyano- Intestinal absorption (13) Thorium dioxide for drug use. Cobalt 60. cobalamin. studies.

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Isotope Chemical form Use Isotope Chemical form Use

Gold 198 ...... Colloidal ...... Liver scans. Do ...... do ...... Brain scans. Do ...... do ...... Intracavitary treat- Mercury 203 1 ...... do ...... Kidney scans. ment of pleural ef- Do ...... do ...... Brain scans. fusions and/or as- Phosphorus 32 Soluble phosphate .. Treatment of poly- cites. cythemia vera. Do ...... do ...... Interstitial treatment Do ...... do ...... Treatment of leu- of cancer. kemia and bone Iodine 131 ...... Iodide ...... Diagnosis of thyroid metastasis. functions. Do ...... Colloidal chromic Intracavitary treat- Do ...... do ...... Thyroid scans. phosphate. ment of pleural ef- Do ...... do ...... Treatment of hyper- fusions and/or as- thyroidism and/or cites. cardiac dysfunc- Do ...... do ...... Interstitial treatment tion. of cancer. Do ...... do ...... Treatment of thyroid Potassium 42 .. Chloride ...... Potassium space carcinoma. studies. Do ...... Iodinated human Blood volume deter- Selenium 75 .... Labeled methionine Pancreas scans. serum albumin. minations. Strontium 85 .... Nitrate or chloride ... Bone scans on pa- Do ...... do ...... Cisternography. tients with diag- Do ...... do ...... Brain tumor localiza- nosed cancer. tion. Technetium Pertechnetate ...... Brain scans. Do ...... do ...... Placenta localiza- 99m. tion. Do ...... do ...... Thyroid scans. Do ...... do ...... Cardiac scans for Do ...... Sulfur colloid ...... Liver and spleen determination of scans. pericardial effu- Do ...... Pertechnetate ...... Placenta localiza- sions. tion. Do ...... Rose Bengal ...... Liver function stud- Do ...... do ...... Blood pool scans. ies. Do ...... do ...... Salivary gland Do ...... do ...... Liver scans. scans. Do ...... Iodopyracet, sodium Kidney function Do ...... Diethylenetri-amine Kidney scans. iodohippurate, so- studies and kid- pentaacetic acid dium diatrizoate, ney scans. (DTPA). diatrizoate methyl- Xenon 133 ...... Gas ...... Diagnosis of cardia glucamine, so- abnormalities. dium diprotrizoate, Cerebral blood- sodium acetri- flow studies. Pul- zoate, or sodium monary function iothalamate. studies. Muscle Do ...... Labeled fats and/or Fat absorption stud- bloodflow studies. fatty acids. ies. Do ...... Cholografin ...... Cardiac scans for 1 This item has been removed from the AEC list for kidney determination of scans but is included as the requirements of this order are pericardial effu- applicable. sions. Do ...... Macroaggregated io- Lung scans. (d)(1) In view of the extent of experi- dinated human ence with the isotopes listed in para- serum albumin. graph (c) of this section, the Nuclear Do ...... Colloidal micro- Liver scans. Regulatory Commission and the Food aggregated human serum al- and Drug Administration conclude that bumin. such isotopes should not be distributed Iodine 125 ...... Iodide ...... Diagnosis of thyroid under investigational-use labeling function. Do ...... Iodinated human Blood volume deter- when they are actually intended for serum albumin. minations. use in medical practice. Do ...... Rose Bengal ...... Liver function stud- (2) The exemption referred to in para- ies. graph (a) of this section, as applied to Do ...... Iodopyracet, sodium Kidney function iodohippurate, so- studies. any drug or biologic containing any of dium diatrizoate, the isotopes listed in paragraph (c) of diatrizoate methyl- this section, in the ‘‘chemical form’’ glucamine, sodium diprotrizoate, and intended for the uses stated, is ter- sodium acetri- minated on March 3, 1972, except as zoate, or sodium provided in paragraph (d)(3) of this sec- iothalamate. tion. Do ...... Labeled fats and/or Fat absorption stud- fatty acids. ies. (3) The exemption referred to in para- Iron 59 ...... Chloride, citrate Iron turnover stud- graph (a) of this section, as applied to and/or sulfate. ies. any drug or biologic containing any of Krypton 85 ...... Gas ...... Diagnosis of cardiac abnormalities. the isotopes listed in paragraph (c) of Mercury 197 .... Chlormerodrin ...... Kidney scans. this section, in the ‘‘chemical form’’

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and intended for the uses stated, for investigational-use labeling when they which drug a new drug application or a are actually intended for use in med- ‘‘Investigational New Drug Applica- ical practice. tion’’ was submitted prior to March 3, (3) Any manufacturer or distributor 1972, or for which biologic an applica- interested in continuing to ship in tion for product license or ‘‘Investiga- interstate commerce drugs containing tional New Drug Application’’ was sub- the isotopes listed in paragraph (f)(1) of mitted prior to March 3, 1972, is termi- this section for any of the indications nated on August 20, 1976, unless an ap- listed, shall submit, on or before Au- provable notice was issued on or before gust 25, 1975 to the Center for Drug August 20, 1976, in which case the ex- Evaluation and Research, Food and emption is terminated either upon the Drug Administration, 5600 Fishers subsequent issuance of a nonapprovable Lane, Rockville, MD 20857, a new drug notice for the new drug application or application or a ‘‘Investigational New on November 20, 1976, whichever occurs Drug Application’’ for each such drug first. for which the manufacturer or dis- (e) No exemption from section 505 of tributor does not have an approved new the act or from part 312 of this chapter drug application pursuant to section is in effect or has been in effect for ra- 505(b) of the act. If the drug is a bio- dioactive drugs prepared from accel- logic, a ‘‘Investigational New Drug Ap- erator-produced radioisotopes, natu- plication’’ or an application for a li- rally occurring isotopes, or nonradio- cense under section 351 of the Public active substances used in conjunction Health Service Act shall be submitted with isotopes. to the Food and Drug Administration, (f)(1) Based on its experience in regu- Center for Biologics Evaluation and lating investigational radioactive Research, Document Control Center, pharmaceuticals, the Nuclear Regu- 10903 New Hampshire Ave., Bldg. 71, latory Commission has compiled a list Rm. G112, Silver Spring, MD 20993–0002, of reactor-produced isotopes for which it considers that applicants may rea- in lieu of any submission to the Center sonably be expected to submit ade- for Drug Evaluation and Research. quate evidence of safety and effective- (4) The exemption referred to in para- ness for use as recommended in appro- graph (a) of this section, as applied to priate labeling; such use may include, any drug or biologic containing any of among others, the uses in this tabula- the isotopes listed in paragraph (f)(1) of tion: this section, in the ‘‘chemical form’’ and intended for the uses stated, is ter- Isotope Chemical form Use minated on August 26, 1975 except as Fluorine 18 ...... Fluoride ...... Bone imaging. provided in paragraph (f)(5) of this sec- Indium-113m ... Diethylenetriamine Brain imaging; kid- tion. pentaacetic acid ney imaging. (5)(i) Except as provided in paragraph (DTPA). Do ...... Chloride ...... Placenta imaging; (f)(5)(ii) of this section, the exemption blood pool imag- referred to in paragraph (a) of this sec- ing. tion, as applied to any drug containing Technetium Human serum albu- Lung imaging. 99m. min microspheres. any of the isotopes listed in paragraph Do ...... Diethylenetriamine Kidney imaging; kid- (f)(1) of this section, in the ‘‘chemical pentaacetic acid ney function stud- form’’ and intended for the uses stated, (Sn). ies. Do ...... do ...... Brain imaging. for which drug a new drug application Do ...... Polyphosphates ...... Bone imaging. or ‘‘Investigational New Drug Applica- Do ...... Technetated aggre- Lung imaging. tion’’ was submitted to the Center for gated albumin Drug Evaluation and Research on or (human). Do ...... Disodium etidronate Bone imaging. before August 25, 1975 is terminated on August 20, 1976, unless an approvable (2) In view of the extent of experience notice was issued on or before August with the isotopes listed in paragraph 20, 1976, in which case the exemption is (f)(1) of this section, the Nuclear Regu- terminated either upon the subsequent latory Commission and the Food and issuance of a nonapprovable notice for Drug Administration conclude that the new drug application or on Novem- they should not be distributed under ber 20, 1976, whichever occurs first.

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(ii) The exemption referred to in graphs (d), (f), and (g) of this section, is paragraph (a) of this section, as applied terminated on August 26, 1975. to any biologic containing any of the [39 FR 11680, Mar. 29, 1974, as amended at 40 isotopes listed in paragraph (f)(1) of FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, this section in the ‘‘chemical form’’ 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, and intended for the uses stated, for Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR which biologic an application for prod- 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999; uct license or ‘‘Investigational New 80 FR 18091, Apr. 3, 2015] Drug Application’’ was submitted to the Center for Biologics Evaluation § 310.509 Parenteral drug products in and Research on or before August 25, plastic containers. 1975 is terminated on October 20, 1976, (a) Any parenteral drug product unless an approvable notice was issued packaged in a plastic immediate con- on or before October 20, 1976, in which tainer is not generally recognized as case the exemption is terminated ei- safe and effective, is a new drug within ther upon the subsequent issuance of a the meaning of section 201(p) of the nonapprovable notice for the new drug act, and requires an approved new drug application or on January 20, 1977, application as a condition for mar- whichever occurs first. keting. An ‘‘Investigational New Drug (g) The exemption referred to in Application’’ set forth in part 312 of paragraph (a) of this section, as applied this chapter is required for clinical in- to any drug intended solely for inves- vestigations designed to obtain evi- tigational use as part of a research dence of safety and effectiveness. project, which use had been approved (b) As used in this section, the term on or before July 25, 1975 in accordance ‘‘large volume parenteral drug prod- with 10 CFR 35.11 (or equivalent regula- uct’’ means a terminally sterilized tion of an Agreement State) is termi- aqueous drug product packaged in a nated on February 20, 1976 if the manu- single-dose container with a capacity facturer of such drug or the sponsor of of 100 milliliters or more and intended the investigation of such drug submits to be administered or used intra- on or before August 25, 1975 to the Food venously in a human. and Drug Administration, Bureau of (c) Until the results of compatibility Drugs, HFD–150, 5600 Fishers Lane, studies are evaluated, a large volume Rockville, MD 20857, the following in- parenteral drug product for intra- formation: venous use in humans that is packaged (1) The research project title; in a plastic immediate container on or (2) A brief description of the purpose after April 16, 1979, is misbranded un- of the project; less its labeling contains a warning (3) The name of the investigator re- that includes the following informa- sponsible; tion: (4) The name and license number of (1) A statement that additives may the institution holding the specific li- be incompatible. cense under 10 CFR 35.11 (or equivalent (2) A statement that, if additive regulation of an Agreement State); drugs are introduced into the paren- (5) The name and maximum amount teral system, aseptic techniques should per subject of the radionuclide used; be used and the solution should be (6) The number of subjects involved; thoroughly mixed. and (3) A statement that a solution con- (7) The date on which the administra- taining an additive drug should not be tion of the radioactive drugs is ex- stored. pected to be completed. (d) This section does not apply to a (h) The exemption referred to in biological product licensed under the paragraph (a) of this section, as applied Public Health Service Act of July 1, to any drug not referred to in para- 1944 (42 U.S.C. 201). [62 FR 12084, Mar. 14, 1997]

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§ 310.515 Patient package inserts for drug product is required to contain the estrogens. following information: (a) Requirement for a patient package (1) The name of the drug. insert. FDA concludes that the safe and (2) The name and place of business of effective use of drug products con- the manufacturer, packer, or dis- taining estrogens requires that pa- tributor. tients be fully informed of the benefits (3) A statement regarding the bene- and risks involved in the use of these fits and proper uses of estrogens. drugs. Accordingly, except as provided (4) The contraindications to use, i.e., in paragraph (e) of this section, each when estrogens should not be used. estrogen drug product restricted to (5) A description of the most serious prescription distribution, including risks associated with the use of estro- products containing estrogens in fixed gens. combinations with other drugs, shall (6) A brief summary of other side ef- be dispensed to patients with a patient fects of estrogens. package insert containing information (7) Instructions on how a patient may concerning the drug’s benefits and reduce the risks of estrogen use. risks. An estrogen drug product that (8) The date, identified as such, of the does not comply with the requirements most recent revision of the patient of this section is misbranded under sec- package insert. tion 502(a) of the Federal Food, Drug, (d) Guidance language. The Food and and Cosmetic Act. Drug Administration issues informal (b) Distribution requirements. (1) For labeling guidance texts under estrogen drug products, the manufac- § 10.90(b)(9) of this chapter to provide turer and distributor shall provide a assistance in meeting the requirements patient package insert in or with each of paragraph (c) of this section. Re- package of the drug product that the quests for a copy of the guidance text manufacturer or distributor intends to should be directed to the Center for be dispensed to a patient. Drug Evaluation and Research, Divi- (2) In the case of estrogen drug prod- sion of Reproductive and Urologic ucts in bulk packages intended for Products, Food and Drug Administra- multiple dispensing, and in the case of tion, 10903 New Hampshire Ave., Silver injectables in multiple-dose vials, a Spring, MD 20993–0002. sufficient number of patient labeling (e) Exemptions. This section does not pieces shall be included in or with each apply to estrogen-progestogen oral con- package to assure that one piece can be traceptives. Labeling requirements for included with each package or dose dis- these products are set forth in § 310.501. pensed or administered to every pa- (f) Requirement to supplement approved tient. Each bulk package shall be la- application. Holders of approved appli- beled with instructions to the cations for estrogen drug products that dispensor to include one patient label- are subject to the requirements of this ing piece with each package dispensed section must submit supplements or, in the case of injectables, with each under § 314.70(c) of this chapter to pro- dose administered to the patient. This vide for the labeling required by para- section does not preclude the manufac- graph (a) of this section. Such labeling turer or labeler from distributing addi- may be put into use without advance tional patient labeling pieces to the approval by the Food and Drug Admin- dispensor. istration. (3) Patient package inserts for estro- [55 FR 18723, May 4, 1990, as amended at 74 gens dispensed in acute-care hospitals FR 13113, Mar. 26, 2009] or long-term care facilities will be considered to have been provided in ac- § 310.517 Labeling for oral hypo- cordance with this section if provided glycemic drugs of the sulfonylurea to the patient before administration of class. the first estrogen and every 30 days (a) The University Group Diabetes thereafter, as long as the therapy con- Program clinical trial has reported an tinues. association between the administration (c) Patient package insert contents. A of tolbutamide and increased cardio- patient package insert for an estrogen vascular mortality. The Food and Drug

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Administration has concluded that this class, in view of their close similarities in reported association provides adequate mode of action and chemical structure. basis for a warning in the labeling. In [49 FR 14331, Apr. 11, 1984] view of the similarities in chemical structure and mode of action, the Food § 310.518 Drug products containing and Drug Administration also believes iron or iron salts. it is prudent from a safety standpoint Drug products containing elemental to consider that the possible increased iron or iron salts as an active ingre- risk of cardiovascular mortality from dient in solid oral dosage form, e.g., tolbutamide applies to all other sulfo- tablets or capsules shall meet the fol- nylurea drugs as well. Therefore, the lowing requirements: labeling for oral hypoglycemic drugs of (a) Labeling. (1) The label of any drug the sulfonylurea class shall include a in solid oral dosage form (e.g., tablets warning concerning the possible in- or capsules) that contains iron or iron creased risk of cardiovascular mor- salts for use as an iron source shall tality associated with such use, as set bear the following statement: forth in paragraph (b) of this section. (b) Labeling for oral hypoglycemic WARNING: Accidental overdose or iron- drugs of the sulfonylurea class shall in- containing products is a leading cause of clude in boldface type at the beginning fatal poisoning in children under 6. Keep this product out of reach of children. In case of of the ‘‘Warnings’’ section of the label- accidental overdose, call a doctor or poison ing the following statement: control center immediately. (2)(i) The warning statement required SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY by paragraph (a)(1) of this section shall appear prominently and conspicuously The administration of oral hypoglycemic on the information panel of the imme- drugs has been reported to be associated diate container label. with increased cardiovascular mortality as compared to treatment with diet alone or (ii) If a drug product is packaged in diet plus insulin. This warning is based on unit-dose packaging, and if the imme- the study conducted by the University Group diate container bears labeling but not a Diabetes Program (UGDP), a long-term pro- label, the warning statement required spective clinical trial designed to evaluate by paragraph (a)(1) of this section shall the effectiveness of glucose-lowering drugs appear prominently and conspicuously in preventing or delaying vascular complica- on the immediate container labeling in tions in patients with non-insulin-dependent a way that maximizes the likelihood diabetes. The study involved 823 patients who were randomly assigned to one of four that the warning is intact until all of treatment groups (Diabetes, 19 (supp. 2): 747– the dosage units to which it applies are 830, 1970). used. UGDP reported that patients treated for 5 (3) Where the immediate container is to 8 years with diet plus a fixed dose of tol- not the retail package, the warning butamide (1.5 grams per day) had a rate of statement required by paragraph (a)(1) cardiovascular mortality approximately 21⁄2 of this section shall also appear promi- times that of patients treated with diet nently and conspicuously on the infor- alone. A significant increase in total mortality was not observed, but the use of tol- mation panel of the retail package butamide was discontinued based on the in- label. crease in cardiovascular mortality, thus lim- (4) The warning statement shall ap- iting the opportunity for the study to show pear on any labeling that contains an increase in overall mortality. Despite warnings. controversy regarding the interpretation of (5) The warning statement required these results, the findings of the UGDP study by paragraph (a)(1) of this section shall provide an adequate basis for this warning. The patient should be informed of the poten- be set off in a box by use of hairlines. tial risks and advantages of (name of drug) (b) The iron-containing inert tablets and of alternative modes of therapy. supplied in monthly packages of oral Although only one drug in the sulfonylurea contraceptives are categorically ex- class (tolbutamide) was included in this empt from the requirements of para- study, it is prudent from a safety standpoint graph (a) of this section. to consider that this warning may also apply to other oral hypoglycemic drugs in this [68 FR 59715, Oct. 17, 2003]

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§ 310.519 Drug products marketed as § 310.527 Drug products containing ac- over-the-counter (OTC) daytime tive ingredients offered over-the- sedatives. counter (OTC) for external use as hair growers or for hair loss pre- (a) Antihistamines, bromides, and vention. scopolamine compounds, either singly (a) Amino acids, aminobenzoic acid, or in combinations, have been mar- ascorbic acid, benzoic acid, biotin and keted as ingredients in over-the- all other B-vitamins, dexpanthenol, es- counter (OTC) drug products for use as tradiol and other topical hormones, daytime sedatives. The following jojoba oil, lanolin, nucleic acids, poly- claims have been made for daytime sorbate 20, polysorbate 60, sulfa- sedative products: ‘‘occasional simple nilamide, sulfur 1 percent on carbon in nervous tension,’’ ‘‘nervous irrita- a fraction of paraffinic hydrocarbons, bility,’’ ‘‘nervous tension headache,’’ tetracaine hydrochloride, urea, and ‘‘simple nervousness due to common wheat germ oil have been marketed as every day overwork and fatigue,’’ ‘‘a ingredients in OTC drug products for relaxed feeling,’’ ‘‘calming down and external use as hair growers or for hair relaxing,’’ ‘‘gently soothe away the loss prevention. There is a lack of ade- tension,’’ ‘‘calmative,’’ ‘‘resolving that quate data to establish general rec- irritability that ruins your day,’’ ognition of the safety and effectiveness ‘‘helps you relax,’’ ‘‘restlessness,’’ of these or any other ingredients in- ‘‘when you’re under occasional stress . tended for OTC external use as a hair . . helps you work relaxed.’’ Based on grower or for hair loss prevention. evidence presently available, there are Based on evidence currently available, no ingredients that can be generally all labeling claims for OTC hair grower recognized as safe and effective for use and hair loss prevention drug products as OTC daytime sedatives. for external use are either false, misleading, or unsupported by scientific (b) Any OTC drug product that is la- data. Therefore, any OTC drug product beled, represented, or promoted as an for external use containing an ingre- OTC daytime sedative (or any similar dient offered for use as a hair grower or or related indication) is regarded as a for hair loss prevention cannot be con- new drug within the meaning of section sidered generally recognized as safe 201(p) of the Federal Food, Drug, and and effective for its intended use. Cosmetic Act for which an approved (b) Any OTC drug product that is la- new drug application under section 505 beled, represented, or promoted for ex- of the act and part 314 of this chapter ternal use as a hair grower or for hair is required for marketing. loss prevention is regarded as a new (c) Clinical investigations designed drug within the meaning of section to obtain evidence that any drug prod- 201(p) of the Federal Food, Drug, and uct labeled, represented, or promoted Cosmetic Act (the act), for which an as an OTC daytime sedative (or any approved new drug application under similar or related indication) is safe section 505 of the act and part 314 of and effective for the purpose intended this chapter is required for marketing. must comply with the requirements In the absence of an approved new drug and procedures governing the use of in- application, such product is also mis- vestigational new drugs set forth in branded under section 502 of the act. part 312 of this chapter. (c) Clinical investigations designed (d) Any OTC daytime sedative drug to obtain evidence that any drug product labeled, represented, or promoted product introduced into interstate for OTC external use as a hair grower commerce after December 24, 1979, that or for hair loss prevention is safe and is not in compliance with this section effective for the purpose intended must is subject to regulatory action. comply with the requirements and pro- [44 FR 36380, June 22, 1979; 45 FR 47422, July cedures governing the use of investiga- 15, 1980, as amended at 55 FR 11579, Mar. 29, tional new drugs set forth in part 312 of 1990] this chapter. (d) After January 8, 1990, any such OTC drug product initially introduced

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or initially delivered for introduction In the absence of an approved new drug into interstate commerce that is not in application, such product is also mis- compliance with this section is subject branded under section 502 of the act. to regulatory action. (c) Clinical investigations designed to obtain evidence that any drug prod- [54 FR 28777, July 7, 1989] uct labeled, represented, or promoted § 310.528 Drug products containing ac- for OTC use as an aphrodisiac is safe tive ingredients offered over-the- and effective for the purpose intended counter (OTC) for use as an aphro- must comply with the requirements disiac. and procedures governing the use of in- (a) Any product that bears labeling vestigational new drugs set forth in claims that it will arouse or increase part 312 of this chapter. sexual desire, or that it will improve (d) After January 8, 1990, any such sexual performance, is an aphrodisiac OTC drug product initially introduced drug product. Anise, cantharides, don or initially delivered for introduction qual, estrogens, fennel, ginseng, golden into interstate commerce that is not in seal, gotu kola, Korean ginseng, lico- compliance with this section is subject rice, mandrake, methyltestosterone, to regulatory action. minerals, nux vomica, Pega Palo, sar- [54 FR 28786, July 7, 1989] saparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine hydro- § 310.529 Drug products containing ac- chloride, and yohimbinum have been tive ingredients offered over-the- present as ingredients in such drug counter (OTC) for oral use as insect products. Androgens (e.g., testosterone repellents. and methyltestosterone) and estrogens (a) Thiamine hydrochloride (vitamin are powerful hormones when adminis- B–1) has been marketed as an ingre- tered internally and are not safe for dient in over-the-counter (OTC) drug use except under the supervision of a products for oral use as an insect repel- physician. There is a lack of adequate lent (an orally administered drug prod- data to establish general recognition of uct intended to keep insects away). the safety and effectiveness of any of There is a lack of adequate data to es- these ingredients, or any other ingre- tablish the effectiveness of this, or any dient, for OTC use as an aphrodisiac. other ingredient for OTC oral use as an Labeling claims for aphrodisiacs for insect repellent. Labeling claims for OTC use are either false, misleading, or OTC orally administered insect repel- unsupported by scientific data. The fol- lent drug products are either false, lowing claims are examples of some misleading, or unsupported by sci- that have been made for aphrodisiac entific data. The following claims are drug products for OTC use: ‘‘acts as an examples of some that have been made aphrodisiac;’’ ‘‘arouses or increases for orally administered OTC insect re- sexual desire and improves sexual per- pellent drug products: ‘‘Oral mosquito formance;’’ ‘‘helps restore sexual vigor, repellent,’’ ‘‘mosquitos avoid you,’’ potency, and performance;’’ ‘‘improves ‘‘bugs stay away,’’ ‘‘keep mosquitos performance, staying power, and sexual away for 12 to 24 hours,’’ and ‘‘the new- potency;’’ and ‘‘builds virility and sex- est way to fight mosquitos.’’ Therefore, ual potency.’’ Based on evidence cur- any drug product containing ingredi- rently available, any OTC drug product ents offered for oral use as an insect re- containing ingredients for use as an pellent cannot be generally recognized aphrodisiac cannot be generally recog- as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for oral beled, represented, or prompted for use use as an insect repellent is regarded as as an aphrodisiac is regarded as a new a new drug within the meaning of sec- drug within the meaning of section tion 201(p) of the Federal Food, Drug 201(p) of the Federal Food, Drug, and and Cosmetic Act for which an ap- Cosmetic Act, (the act), for which an proved new drug application under sec- approved new drug application under tion 505 of the act and part 314 of this section 505 of the act and part 314 of chapter is required for marketing. In this chapter is required for marketing. the absence of an approved new drug

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application, such product is also mis- the labeling indicating that ‘‘hor- branded under section 502 of the act. mones’’ are present in the product, or (c) Clinical investigations designed any statement that features or empha- to obtain evidence that any drug prod- sizes the presence of a hormone ingre- uct labeled, represented, or promoted dient in the product, will be considered OTC for oral use as an insect repellent to be a therapeutic claim for the prod- is safe and effective for the purpose in- uct, or a claim that the product will af- tended must comply with the require- fect the structure or function of the ments and procedures governing the body, and will consequently cause the use of investigational new drugs set product to be a drug. forth in part 312 of this chapter. (b) Any OTC drug product that is la- (d) Any such drug product in inter- beled, represented, or promoted as a state commerce after December 17, topically applied hormone-containing 1985, that is not in compliance with product for drug use, with the excep- this section is subject to regulatory action of those hormones identified in tion. paragraph (e) of this section, is re- [40 FR 25171, June 17, 1985, as amended at 55 garded as a new drug within the mean- FR 11579, Mar. 29, 1990] ing of section 201(p) of the act, for which an approved application or ab- § 310.530 Topically applied hormone- breviated application under section 505 containing drug products for over- of the act and part 314 of this chapter the-counter (OTC) human use. is required for marketing. In the ab- (a) The term ‘‘hormone’’ is used sence of an approved new drug applica- broadly to describe a chemical sub- tion or abbreviated new drug applica- stance formed in some organ of the tion, such product is also misbranded body, such as the adrenal glands or the under section 502 of the act. pituitary, and carried to another organ (c) Clinical investigations designed or tissue, where it has a specific effect. to obtain evidence that any drug prod- Hormones include, for example, estro- uct labeled, represented, or promoted gens, progestins, androgens, anabolic for OTC use as a topically applied hor- steroids, and adrenal corticosteroids, mone-containing drug product is safe and synthetic analogs. Estrogens, pro- and effective for the purpose intended gesterone, pregnenolone, and pregneno- must comply with the requirements lone acetate have been present as in- and procedures governing the use of ingredients in OTC drug products mar- vestigational new drugs set forth in keted for topical use as hormone part 312 of this chapter. creams. However, there is a lack of (d) After March 9, 1994, any such OTC adequate data to establish effective- drug product initially introduced or ness for any OTC drug use of these in- initially delivered for introduction into gredients. Therefore, with the excep- interstate commerce that is not in tion of those hormones identified in compliance with this section is subject paragraph (e) of this section, any OTC to regulatory action. drug product containing an ingredient (e) This section does not apply to hy- offered for use as a topically applied drocortisone and hydrocortisone ace- hormone cannot be considered gen- tate labeled, represented, or promoted erally recognized as safe and effective for OTC topical use in accordance with for its intended use. The intended use part 348 of this chapter. of the product may be inferred from [58 FR 47610, Sept. 9, 1993] the product’s labeling, promotional material, advertising, and any other § 310.531 Drug products containing ac- relevant factor. The use of the word tive ingredients offered over-the- ‘‘hormone’’ in the text of the labeling counter (OTC) for the treatment of or in the ingredient statement is an boils. implied drug claim. The claim implied (a) Aminacrine hydrochloride, benzo- by the use of this term is that the prod- caine, bismuth subnitrate, calomel, uct will have a therapeutic or some camphor, cholesterol, ergot fluid ex- other physiological effect on the body. tract, hexachlorophene, ichthammol, Therefore, reference to a product as a isobutamben, juniper tar (oil of cade), ‘‘hormone cream’’ or any statement in lanolin, magnesium sulfate, menthol,

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methyl salicylate, oxyguinoline sul- ichthammol, sulfur, or triclosan ini- fate, petrolatum, phenol, pine tar, tially introduced or initially delivered rosin, rosin cerate, sassafras oil, sulfur, for introduction into interstate com- thymol, triclosan, and zinc oxide have merce that is not in compliance with been present in OTC boil treatment this section is subject to regulatory ac- drug products. There is a lack of ade- tion. quate data to establish general rec- (f) This section does not apply to ognition of the safety and effectiveness drug products that contain benzocaine of these or any other ingredient for labeled, represented, or promoted for OTC use for the treatment of boils. OTC topical use in accordance with Treatment is defined as reducing the part 348 of this chapter. size of a boil or reducing an infection [58 FR 60336, Nov. 15, 1993] related to a boil. Treatment has involved the use of ‘‘drawing salves’’ for § 310.532 Drug products containing ac- these purposes. These ‘‘drawing salves’’ tive ingredients offered over-the- contained various ingredients. Based counter (OTC) to relieve the symp- on evidence currently available, any toms of benign prostatic hyper- OTC drug product offered for the treat- trophy. ment of boils cannot be considered gen- (a) The amino acids glycine, alanine, erally recognized as safe and effective. and glutamic acid (alone or in com- (b) Any OTC drug product that is la- bination) and the ingredient sabal have beled, represented, or promoted for the been present in over-the-counter (OTC) treatment of boils is regarded as a new drug products to relieve the symptoms drug within the meaning of section of benign prostatic hypertrophy, e.g., 201(p) of the Federal Food, Drug, and urinary urgency and frequency, exces- Cosmetic Act (the act), for which an sive urinating at night, and delayed approved application or abbreviated urination. There is a lack of adequate application under section 505 of the act data to establish general recognition of and part 314 of this chapter is required the safety and effectiveness of these or for marketing. In the absence of an ap- any other ingredients for OTC use in proved new drug application or abbre- relieving the symptoms of benign pros- viated new drug application, such prod- tatic hypertrophy. In addition, there is uct is also misbranded under section no definitive evidence that any drug 502 of the act. product offered for the relief of the (c) Clinical investigations designed symptoms of benign prostatic hyper- to obtain evidence that any OTC boil trophy would alter the obstructive or treatment drug product is safe and ef- inflammatory signs and symptoms of fective for the purpose intended must this condition. Therefore, self-medica- comply with the requirements and pro- tion with OTC drug products might un- cedures governing the use of investiga- necessarily delay diagnosis and treat- tional new drugs set forth in part 312 of ment of progressive obstruction and this chapter. secondary infections. Based on evi- (d) After May 7, 1991, any such OTC dence currently available, any OTC drug product that contains aminacrine drug product containing ingredients of- hydrochloride, bismuth subnitrate, cal- fered for use in relieving the symptoms omel, camphor, cholesterol, ergot fluid of benign prostatic hypertrophy cannot extract, hexachlorophene, isobu- be generally recognized as safe and ef- tamben, juniper tar (oil of cade), lan- fective. olin, magnesium sulfate, menthol, (b) Any OTC drug product that is la- methyl salicylate, oxyguinoline sul- beled, represented, or promoted to re- fate, petrolatum, phenol, pine tar, lieve the symptoms of benign prostatic rosin, rosin cerate, sassafras oil, thy- hypertrophy is regarded as a new drug mol, or zinc oxide initially introduced within the meaning of section 201(p) of or initially delivered for introduction the Federal Food, Drug, and Cosmetic into interstate commerce that is not in Act (the act), for which an approved compliance with this section is subject application under section 505 of the act to regulatory action. and part 314 of this chapter is required (e) After May 16, 1994, any such OTC for marketing. In the absence of an ap- drug product that contains benzocaine, proved application, such product is also

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misbranded under section 502 of the to establish general recognition of the act. safety and/or effectiveness or any of (c) Clinical investigations designed these ingredients, or any other ingre- to obtain evidence that any drug prod- dient, for OTC use as an anticho- uct labeled, represented, or promoted linergic in cough-cold drug products. for OTC use to relieve the symptoms of (b) Any OTC cough-cold drug product benign prostatic hypertrophy is safe that is labeled, represented, or pro- and effective for the purpose intended moted for use as an anticholinergic is must comply with the requirements regarded as a new drug within the and procedures governing the use of in- meaning of section 201(p) of the Fed- vestigational new drugs set forth in eral Food, Drug, and Cosmetic Act, for part 312 of this chapter. which an approved new drug applica- (d) After August 27, 1990, any such tion under section 505 of the act and OTC drug product initially introduced part 314 of this chapter is required for or initially delivered for introduction marketing. In the absence of an ap- into interstate commerce that is not in proved new drug application, such compliance with this section is subject product is also misbranded under sec- to regulatory action. tion 502 of the act. (c) Clinical investigations designed [55 FR 6930, Feb. 27, 1990] to obtain evidence that any cough-cold § 310.533 Drug products containing ac- drug product labeled, represented, or tive ingredients offered over-the- promoted for OTC use as an anticho- counter (OTC) for human use as an linergic is safe and effective for the anticholinergic in cough-cold drug purpose intended must comply with the products. requirements and procedures governing (a) Atropine sulfate, belladonna alka- the use of investigational new drugs loids, and belladonna alkaloids as con- set forth in part 312 of this chapter. tained in Atropa belladonna and Datu- (d) After the effective date of the ra stramonium have been present as in- final regulation, any such OTC cough- gredients in cough-cold drug products cold drug product that is labeled, rep- for use as an anticholinergic. Anticho- resented, or promoted for use as an linergic drugs have been marketed OTC anticholinergic may not be initially in- in cough-cold drug products to relieve troduced or initially delivered for in- excessive secretions of the nose and troduction into interstate commerce eyes, symptoms that are commonly as- unless it is the subject of an approved sociated with hay fever, allergy, rhi- new drug application. nitis, and the common cold. Atropine [50 FR 46587, Nov. 8, 1985, as amended at 55 sulfate for oral use as an anticho- FR 11579, Mar. 29, 1990] linergic is probably safe at dosages that have been used in marketed § 310.534 Drug products containing ac- cough-cold products (0.2 to 0.3 milli- tive ingredients offered over-the- gram); however, there are inadequate counter (OTC) for human use as data to establish general recognition of oral wound healing agents. the effectiveness of this ingredient. (a) Allantoin, carbamide peroxide in The belladonna alkaloids, which con- anhydrous glycerin, water soluble tain atropine (d, dl hyoscyamine) and chlorophyllins, and hydrogen peroxide scopolamine (l- hyoscine), are probably in aqueous solution have been present safe for oral use at dosages that have in oral mucosal injury drug products been used in marketed cough-cold for use as oral wound healing agents. products (0.2 milligram) but there are Oral wound healing agents have been inadequate data to establish general marketed as aids in the healing of recognition of the effectiveness of minor oral wounds by means other these ingredients as an anticholinergic than cleansing and irrigating, or by for cough-cold use. Belladonna alka- serving as a protectant. Allantoin, car- loids for inhalation use, as contained in bamide peroxide in anhydrous glycerin, Atropa belladonna and Datura stramo- water soluble chlorophyllins, and hy- nium, are neither safe nor effective as drogen peroxide in aqueous solution an OTC anticholinergic. There are in- are safe for use as oral wound healing adequate safety and effectiveness data agents, but there are inadequate data

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to establish general recognition of the is regarded as a new drug within the effectiveness of these ingredients as meaning of section 201(p) of the Fed- oral wound healing agents. eral Food, Drug, and Cosmetic Act (the (b) Any OTC drug product that is la- act) for which an approved application beled, represented, or promoted for use or abbreviated application under sec- as an oral wound healing agent is re- tion 505 of the act and part 314 of this garded as a new drug within the mean- chapter is required for marketing. In ing of section 201(p) of the Federal the absence of an approved new drug Food, Drug, and Cosmetic Act, for application or abbreviated new drug which an approved new drug applica- application, such product is also mis- tion under section 505 of the act and branded under section 502 of the act. part 314 of this chapter is required for (c) Clinical investigations designed marketing. In the absence of an ap- to obtain evidence that any drug prod- proved new drug application, such uct labeled, represented, or promoted product is also misbranded under sec- for OTC use as a nailbiting or thumb- tion 502 of the act. sucking deterrent is safe and effective (c) Clinical investigations designed for the purpose intended must comply to obtain evidence that any drug prod- with the requirements and procedures uct labeled, represented, or promoted governing the use of investigational for OTC use as an oral wound healing new drugs set forth in part 312 of this agent is safe and effective for the pur- chapter. pose intended must comply with the re- (d) After March 2, 1994, any such OTC quirements and procedures governing drug product initially introduced or the use of investigational new drugs initially delivered for introduction into set forth in part 312 of this chapter. interstate commerce that is not in (d) After the effective date of the compliance with this section is subject final regulation, any OTC drug product to regulatory action. that is labeled, represented, or pro- [58 FR 46754, Sept. 2, 1993] moted for use as an oral wound healing agent may not be initially introduced § 310.537 Drug products containing ac- or initially delivered for introduction tive ingredients offered over-the- into interstate commerce unless it is counter (OTC) for oral administra- the subject of an approved new drug ap- tion for the treatment of fever blis- plication. ters and cold sores. [51 FR 26114, July 18, 1986, as amended at 55 (a) L-lysine (lysine, lysine hydro- FR 11579, Mar. 29, 1990] chloride), Lactobacillus acidophilus, and Lactobacillus bulgaricus have been § 310.536 Drug products containing ac- present in orally administered OTC tive ingredients offered over-the- drug products to treat fever blisters counter (OTC) for use as a nail- and cold sores. There is a lack of ade- biting or thumbsucking deterrent. quate data to establish general rec- (a) Denatonium benzoate and sucrose ognition of the safety and effectiveness octaacetate have been present in OTC of these or any other orally adminis- nailbiting and thumbsucking deterrent tered ingredients for OTC use to treat drug products. There is a lack of ade- or relieve the symptoms or discomfort quate data to establish general rec- of fever blisters and cold sores. Based ognition of the safety and effectiveness on evidence currently available, any of these and any other ingredients OTC drug product for oral administra- (e.g., cayenne pepper) for OTC use as a tion containing ingredients offered for nailbiting or thumbsucking deterrent. use in treating or relieving the symp- Based on evidence currently available, toms or discomfort of fever blisters and any OTC drug product containing in- cold sores cannot be generally recog- gredients offered for use as a nailbiting nized as safe and effective. or thumbsucking deterrent cannot be (b) Any OTC drug product for oral ad- generally recognized as safe and effec- ministration that is labeled, rep- tive. resented, or promoted to treat or re- (b) Any OTC drug product that is la- lieve the symptoms or discomfort of beled, represented, and promoted as a fever blisters and cold sores is regarded nailbiting or thumbsucking deterrent as a new drug within the meaning of

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section 201(p) of the Federal Food, for marketing. In the absence of an ap- Drug, and Cosmetic Act (the act), for proved new drug application or abbre- which an approved application under viated new drug application, such prod- section 505 of the act and part 314 of uct is also misbranded under section this chapter is required for marketing. 502 of the act. In the absence of an approved applica- (c) Clinical investigations designed tion, such product is also misbranded to obtain evidence that any drug prod- under section 502 of the act. uct labeled, represented, or promoted (c) Clinical investigations designed for OTC use for ingrown toenail relief to obtain evidence that any drug prod- is safe and effective for the purpose in- uct for oral administration labeled, represented, or promoted for OTC use tended must comply with the require- to treat or relieve the symptoms or dis- ments and procedures governing the comfort of fever blisters and cold sores use of investigational new drugs set is safe and effective for the purpose in- forth in part 312 of this chapter. tended must comply with the require- (d) After March 9, 1994, any such OTC ments and procedures governing the drug product initially introduced or use of investigational new drugs set initially delivered for introduction into forth in part 312 of this chapter. interstate commerce that is not in (d) After December 30, 1992, any such compliance with this section is subject OTC drug product initially introduced to regulatory action. or initially delivered for introduction (e) This section does not apply to so- into interstate commerce that is not in dium sulfide labeled, represented, or compliance with this section is subject promoted for OTC topical use for in- to regulatory action. grown toenail relief in accordance with [57 FR 29173, June 30, 1992] part 358, subpart D of this chapter, after June 6, 2003. § 310.538 Drug products containing active ingredients offered over-the- [58 FR 47605, Sept. 9, 1993, as amended at 68 counter (OTC) for use for ingrown FR 24348, May 7, 2003] toenail relief. (a) Any product that bears labeling § 310.540 Drug products containing active ingredients offered over-the- claims such as for ‘‘temporary relief of counter (OTC) for use as stomach discomfort from ingrown toenails,’’ or acidifiers. ‘‘ingrown toenail relief product,’’ or ‘‘ingrown toenail reliever,’’ or similar (a) Betaine hydrochloride, glutamic claims is considered an ingrown toenail acid hydrochloride, diluted hydro- relief drug product. Benzocaine, chloro- chloric acid, and pepsin have been butanol, chloroxylenol, dibucaine, tan- present as ingredients in over-the- nic acid, and urea have been present as counter (OTC) drug products for use as ingredients in such products. There is stomach acidifiers. Because of the lack lack of adequate data to establish gen- of adequate data to establish the effec- eral recognition of the safety and effectiveness of these or any other ingredi- tiveness of these or any other ingredients for use in treating achlorhydria ents for OTC use for ingrown toenail and hypochlorhydria, and because such relief. Based on evidence currently conditions are asymptomatic, any OTC available, any OTC drug product con- drug product containing ingredients of- taining ingredients offered for use for fered for use as a stomach acidifier ingrown toenail relief cannot be gen- cannot be considered generally recog- erally recognized as safe and effective. nized as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or promoted for ingrown toenail relief is regarded as a beled, represented, or promoted for use new drug within the meaning of section as a stomach acidifier is regarded as a 201(p) of the Federal Food, Drug, and new drug within the meaning of section Cosmetic Act (the act), for which an 201(p) of the Federal Food, Drug, and approved application or abbreviated Cosmetic Act, for which an approved application under section 505 of the act new drug application under section 505 and part 314 of this chapter is required of the act and part 314 of this chapter

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is required for marketing. In the ab- drugs set forth in part 312 of his chap- sence of an approved new drug applica- ter. tion, such product is also misbranded (d) After November 12, 1990, any such under section 502 of the act. OTC drug product initially introduced (c) Clinical investigations designed or initially delivered for introduction to obtain evidence that any drug prod- into interstate commerce that is not in uct labeled, represented, or promoted compliance with this section is subject as a stomach acidifier for OTC use is to regulatory action. safe and effective for the purpose intended must comply with the require- [55 FR 19858, May 11, 1990] ments and procedures governing the use of investigational new drugs set § 310.542 Over-the-counter (OTC) drug products containing active ingredi- forth in part 312 of this chapter. ents offered for use in the treat- (d) After the effective date of the ment of hyperphosphatemia. final regulation, any such OTC drug product initially introduced or ini- (a) Hyperphosphatemia is a condition tially delivered for introduction into in which an abnormally high plasma interstate commerce that is not in level of phosphate occurs in the blood. compliance with this section is subject This condition in not amenable to self- to regulatory action. diagnosis or self-treatment. Treatment of this condition should be restricted [53 FR 31271, Aug. 17, 1988] to the supervision of a physician. For this reason, any drug product con- § 310.541 Over-the-counter (OTC) drug products containing active ingredi- taining ingredients offered for OTC use ents offered for use in the treat- in the treatment of hyperphosphatemia ment of hypophosphatemia. cannot be considered generally recog- (a) Hypophosphatemia is a condition nized as safe and effective. in which an abnormally low plasma (b) Any drug product that is labeled, level of phosphate occurs in the blood. represented, or promoted for OTC use This condition is not amenable to self- in the treatment of hyperphosphatemia diagnosis or self-treatment. Treatment is regarded as a new drug within the of this condition should be restricted meaning of section 201(p) of the Fed- to the supervision of a physician. For eral Food, Drug, and Cosmetic Act (the this reason, any drug product con- act), for which an approved application taining ingredients offered for OTC use under section 505 of the act and part 314 in the treatment of hypophosphatemia of this chapter is required for mar- cannot be considered generally recog- keting. In the absence of an approved nized as safe and effective. application, such product is also mis- (b) Any drug product that is labeled, branded under section 502 of the act. represented, or promoted for OTC use (c) Clinical investigations designed in the treatment of hypophosphatemia to obtain evidence that any drug prod- is regarded as a new drug within the uct labeled, represented, or promoted meaning of section 201(p) of the Fed- for use in the treatment of hyper- eral Food, Drug, and Cosmetic Act (the phosphatemia is safe and effective for act), for which an approved application the purpose intended must comply with under section 505 of the act and part 314 the requirements and procedures gov- of this chapter is required for mar- erning use of investigational new drugs keting. In the absence of an approved application, such product is also mis- set forth in part 312 of this chapter. branded under section 502 of the act. (d) After November 12, 1990, any such (c) Clinical investigations designed OTC drug product initially introduced to obtain evidence that any drug prod- or initially delivered for introduction uct labeled, represented, or promoted into interstate commerce that is not in for OTC use in the treatment of hypo- compliance with this section is subject phosphatemia is safe and effective for to regulatory action. the purpose intended must comply with [55 FR 19858, May 11, 1990] the requirements and procedures governing the use of investigational new

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§ 310.543 Drug products containing ac- and procedures governing the use of in- tive ingredients offered over-the- vestigational new drugs set forth in counter (OTC) for human use in part 312 of this chapter. exocrine pancreatic insufficiency. (d) After May 7, 1991, any such OTC (a) Hemicellulase, pancreatin, and drug product that contains hemi- pancrelipase have been present as in- cellulase initially introduced or ini- gredients in exocrine pancreatic insuf- tially delivered for introduction into ficiency drug products. Pancreatin and interstate commerce that is not in pancrelipase are composed of enzymes: compliance with this section is subject amylase, trypsin (protease), and lipase. to regulatory action. Significant differences have been (e) After October 24, 1995, any such shown in the bioavailability of mar- OTC drug product that contains pan- keted exocrine pancreatic insufficiency creatin or pancrelipase initially intro- drug products produced by different duced or initially delivered for intro- manufacturers. These differences raise duction into interstate commerce that a potential for serious risk to patients using these drug products. The bio- is not in compliance with this section availability of pancreatic enzymes is is subject to regulatory action. dependent on the process used to man- [60 FR 20165, Apr. 24, 1995] ufacture the drug products. Informa- tion on this process is not included in § 310.544 Drug products containing ac- an OTC drug monograph. Therefore, tive ingredients offered over-the- the safe and effective use of these en- counter (OTC) for use as a smoking zymes for treating exocrine pancreatic deterrent. insufficiency cannot be regulated ade- (a) Any product that bears labeling quately by an OTC drug monograph. claims that it ‘‘helps stop or reduce the Information on the product’s formula- cigarette urge,’’ ‘‘helps break the ciga- tion, manufacture, quality control pro- rette habit,’’ ‘‘helps stop or reduce cedures, and final formulation effec- smoking,’’ or similar claims is a smok- tiveness testing are necessary in an ap- ing deterrent drug product. Cloves, co- proved application to ensure that a riander, eucalyptus oil, ginger (Ja- company has the ability to manufac- maica), lemon oil (terpeneless), licorice ture a proper bioactive formulation. In root extract, lobeline (in the form of addition, continuous physician moni- lobeline sulfate or natural lobelia alka- toring of patients who take these drug loids or Lobelia inflata herb), menthol, products is a collateral measure nec- methyl salicylate, povidone-silver ni- essary to the safe and effective use of trate, quinine ascorbate, silver acetate, these enzymes, causing such products silver nitrate, and thymol have been to be available by prescription only. present as ingredients in such drug (b) Any drug product that is labeled, products. There is a lack of adequate represented, or promoted for OTC use data to establish general recognition of in the treatment of exocrine pancreatic the safety and effectiveness of these or insufficiency is regarded as a new drug within the meaning of section 201(p) of any other ingredients for OTC use as a the Federal Food, Drug, and Cosmetic smoking deterrent. Based on evidence Act (the act), for which an approved currently available, any OTC drug application under section 505 of the act product containing ingredients offered and part 314 of this chapter is required for use as a smoking deterrent cannot for marketing. In the absence of an ap- be generally recognized as safe and ef- proved application, such product is also fective. misbranded under section 502 of the (b) Any OTC drug product that is la- act. beled, represented, or promoted as a (c) Clinical investigations designed smoking deterrent is regarded as a new to obtain evidence that any drug prod- drug within the meaning of section uct labeled, represented, or promoted 201(p) of the Federal Food, Drug, and for OTC use in the treatment of exo- Cosmetic Act (the act), for which an crine pancreatic insufficiency is safe approved application or abbreviated and effective for the purpose intended application under section 505 of the act must comply with the requirements and part 314 of this chapter is required

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for marketing. In the absence of an ap- Chloroxylenol proved new drug application or abbre- Cloxyquin viated new drug application, such prod- Coal tar uct is also misbranded under section Dibenzothiophene Estrone 502 of the act. Magnesium aluminum silicate (c) Clinical investigations designed Magnesium sulfate to obtain evidence that any drug prod- Phenol uct labeled, represented, or promoted Phenolate sodium for OTC use as a smoking deterrent is Phenyl salicylate safe and effective for the purpose in- Povidone-iodine tended must comply with the require- Pyrilamine maleate ments and procedures governing the Resorcinol (as single ingredient) use of investigational new drugs set Resorcinol monoacetate (as single ingredient) forth in part 312 of this chapter. Salicylic acid (over 2 up to 5 percent) (d) After May 7, 1991, any such OTC Sodium borate drug product containing cloves, cori- Sodium thiosulfate ander, eucalyptus oil, ginger (Ja- Tetracaine hydrochloride maica), lemon oil (terpeneless), licorice Thymol root extract, menthol, methyl salicy- Vitamin E late, quinine ascorbate, silver nitrate, Zinc oxide and/or thymol initially introduced or Zinc stearate initially delivered for introduction into Zinc sulfide interstate commerce that is not in (2) Anticaries drug products—(i) Ap- compliance with this section is subject proved as of May 7, 1991. to regulatory action. After December 1, 1993, any such OTC drug product con- Hydrogen fluoride Sodium carbonate taining lobeline (in the form of lobeline Sodium monofluorophosphate (6 percent sulfate or natural lobelia alkaloids or rinse) Lobelia inflata herb), povidone-silver ni- Sodium phosphate trate, silver acetate, or any other ingredients initially introduced or ini- (ii) Approved as of October 7, 1996. tially delivered for introduction into Calcium sucrose phosphate interstate commerce that is not in Dicalcium phosphate dihydrate compliance with this section is subject Disodium hydrogen phosphate 1 to regulatory action. Phosphoric acid 1 Sodium dihydrogen phosphate [58 FR 31241, June 1, 1993] Sodium dihydrogen phosphate monohydrate Sodium phosphate, dibasic anhydrous rea- § 310.545 Drug products containing gent 1 certain active ingredients offered over-the-counter (OTC) for certain (3) Antidiarrheal drug products—(i) Ap- uses. proved as of May 7, 1991. (a) A number of active ingredients Aluminum hydroxide have been present in OTC drug prod- Atropine sulfate ucts for various uses, as described Calcium carbonate below. However, based on evidence cur- Carboxymethylcellulose sodium rently available, there are inadequate Glycine Homatropine methylbromide data to establish general recognition of Hyoscyamine sulfate the safety and effectiveness of these in- Lactobacillus acidophilus gredients for the specified uses: Lactobacillus bulgaricus (1) Topical acne drug products. Opium, powdered Opium tincture Alcloxa Paregoric Alkyl isoquinolinium bromide Phenyl salicylate Aluminum chlorohydrex Scopolamine hydrobromide Aluminum hydroxide Zinc phenolsulfonate Benzocaine Benzoic acid Boric acid 1 These ingredients are nonmonograph ex- Calcium polysulfide cept when used to prepare acidulated phos- Calcium thiosulfate phate fluoride treatment rinses identified in Camphor § 355.10(a)(3) of this chapter.

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(ii) Approved as of April 19, 2004; April Cedar leaf oil (topical) 18, 2005, for products with annual sales Creosote, beechwood (topical) less than $25,000. Ephedrine (oral) Ephedrine hydrochloride (oral) Attapulgite, activated Ephedrine sulfate (oral) Bismuth subnitrate Racephedrine hydrochloride (oral/topical) Calcium hydroxide Calcium polycarbophil (C) Approved as of April 11, 2007; Oc- Charcoal (activated) tober 11, 2007, for products with annual Pectin sales less than $25,000. Any ingre- Polycarbophil dient(s) labeled with claims or direc- Potassium carbonate tions for use for sinusitis or for relief Rhubarb fluidextract of nasal congestion associated with si- (4) Antiperspirant drug products—(i) nusitis. Ingredients—Approved as of May 7, 1991. (iii) Expectorant drug products. Alum, potassium Ammonium chloride Aluminum bromohydrate Antimony potassium tartrate Aluminum chloride (alcoholic solutions) Beechwood creosote Aluminum chloride (aqueous solution) (aer- Benzoin preparations (compound tincture of osol only) benzoin, tincture of benzoin) Aluminum sulfate Camphor Aluminum sulfate, buffered (aerosol only) Chloroform Sodium aluminum chlorohydroxy lactate Eucalyptol/eucalyptus oil (ii) Approved as of December 9, 2004; Horehound June 9, 2005, for products with annual Iodides (calcium iodide anyhydrous, hydroid- sales less than $25,000. ic acid syrup, iodized lime, potassium iodide) Aluminum sulfate buffered with sodium alu- Ipecac minum lactate Ipecac fluidextract Ipecac syrup (5) [Reserved] Menthol/peppermint oil (6) Cold, cough, allergy, bronchodilator, Pine tar preparations (extract white pine and antiasthmatic drug products—(i) compound, pine tar, syrup of pine tar, com- Antihistamine drug products—(A) Ingre- pound white pine syrup, white pine) dients. Potassium guaiacolsulfonate Sodium citrate Methapyrilene hydrochloride Squill preparations (squill, squill extract) Methapyrilene fumarate Terpin hydrate preparations (terpin hydrate, Thenyldiamine hydrochloride terpin hydrate elixir) (B) Ingredients. Tolu preparations (tolu, tolu balsam, tolu balsam tincture) Phenyltoloxamine dihydrogen citrate Turpentine oil (spirits of turpentine) Methapyrilene hydrochloride Methapyrilene fumarate (iv) Bronchodilator drug products—(A) Thenyldiamine hydrochloride Approved as of October 2, 1987. (ii) Nasal decongestant drug products— Aminophylline (A) Approved as of May 7, 1991. Belladonna alkaloids Euphorbia pilulifera Allyl isothiocyanate Metaproterenol sulfate Camphor (lozenge) Methoxyphenamine hydrochloride Creosote, beechwood (oral) Pseudoephedrine hydrochloride Eucalyptol (lozenge) Pseudoephedrine sulfate Eucalyptol (mouthwash) Theophylline, anhydrous Eucalyptus oil (lozenge) Theophylline calcium salicylate Eucalyptus oil (mouthwash) Menthol (mouthwash) Theophylline sodium glycinate Peppermint oil (mouthwash) (B) Approved as of January 29, 1996. Thenyldiamine hydrochloride Any combination drug product con- Thymol Thymol (lozenge) taining theophylline (e.g., theophylline Thymol (mouthwash) and ephedrine, or theophylline and Turpentine oil ephedrine and phenobarbital). (C) Approved as of June 19, 1996. Any (B) Approved as of August 23, 1995. ingredient(s) in a pressurized metered- Bornyl acetate (topical) dose inhaler container.

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(D) Approved as of October 29, 2001. Alcohol Any oral bronchodilator active ingre- Aluminum hydroxide dient (e.g., ephedrine, ephedrine hydro- Amylase Anise seed chloride, ephedrine sulfate, Aromatic powder racephedrine hydrochloride, or any Asafetida other ephedrine salt) in combination Aspergillus oryza enzymes (except lactase with any analgesic(s) or analgesic-anti- enzyme derived from Aspergillus oryzae) pyretic(s), anticholinergic, antihis- Bacillus acidophilus tamine, oral antitussive, or stimulant Bean active ingredient. Belladonna alkaloids (7) Dandruff/seborrheic dermatitis/psori- Belladonna leaves, powdered extract Betaine hydrochloride asis drug products. Bismuth subcarbonate Alkyl isoquinolinium bromide Bismuth subgallate Allantoin Black radish powder Benzalkonium chloride Blessed thistle (cnicus benedictus) Benzethonium chloride Buckthorn Boric acid Calcium gluconate Calcium undecylenate Capsicum Captan Capsicum, fluid extract of Chloroxylenol Carbon Colloidal oatmeal Cascara sagrada extract Cresol, saponated Catechu, tincture Ethohexadiol Catnip Eucalyptol Chamomile flowers Juniper tar Charcoal, wood Lauryl isoquinolinium bromide Chloroform Menthol Cinnamon oil Mercury oleate Cinnamon tincture Methylbenzethonium chloride Citrus pectin Methyl salicylate Diastase Phenol Diastase malt Phenolate sodium Dog grass Pine tar Elecampane Povidone-iodine Ether Resorcinol Fennel acid Sodium borate Galega Sodium salicylate Ginger Thymol Glycine Undecylenic acid Hydrastis canadensis (golden seal) Hectorite (8) Digestive aid drug products—(i) Ap- Horsetail proved as of May 7, 1991. Huckleberry Hydrastis fluid extract Bismuth sodium tartrate Hydrochloric acid Calcium carbonate Iodine Cellulase Iron ox bile Dehydrocholic acid Johnswort Dihydroxyaluminum sodium carbonate Juniper Duodenal substance Kaolin, colloidal Garlic, dehydrated Knotgrass Glutamic acid hydrochloride Lactic acid Hemicellulase Lactose Homatropine methylbromide Lavender compound, tincture of Magnesium hydroxide Linden Magnesium trisilicate Lipase Ox bile extract Lysine hydrochloride Pancreatin Mannitol Pancrelipase Mycozyme Papain Peppermint oil Myrrh, fluid extract of Pepsin Nettle Sodium bicarbonate Nickel-pectin Sodium citrate Nux vomica extract Sorbitol Orthophosphoric acid Papaya, natural (ii) Approved as of November 10, 1993. Pectin

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Peppermint Methapyrilene hydrochloride Peppermint spirit Methyl nicotinate Phenacetin Methyl salicylate Potassium bicarbonate Pectin Potassium carbonate Salicylamide Protease Strong ammonia solution Prolase Tannic acid Rhubarb fluid extract Thymol Senna Tripelennamine hydrochloride Sodium chloride Trolamine salicylate Sodium salicylate Turpentine oil Stem bromelain Zinc sulfate Strawberry Strychnine (vi) Insect bite and sting drug products. Tannic acid Alcohol Trillium Alcohol, ethoxylated alkyl Woodruff Benzalkonium chloride (iii) Charcoal, activated Calamine (9) [Reserved] Ergot fluidextract (10) External analgesic drug products— Ferric chloride Panthenol (i) Analgesic and anesthetic drug prod- Peppermint oil ucts. Pyrilamine maleate Aspirin Sodium borate Chloral hydrate Trolamine salicylate Chlorobutanol Turpentine oil Cyclomethycaine sulfate Zinc oxide Eugenol Zirconium oxide Hexylresorcinol (vii) Poison ivy, poison oak, and poison Methapyrilene hydrochloride Salicylamide sumac drug products. Thymol Alcohol (ii) Counterirritant drug products. Aspirin Benzethonium chloride Chloral hydrate Benzocaine (0.5 to 1.25 percent) Eucalyptus oil Bithionol Calamine (iii) Male genital desensitizer drug Cetalkonium chloride products. Chloral hydrate Benzyl alcohol Chlorobutanol Camphorated metacresol Chlorpheniramine maleate Ephedrine hydrochloride Creosote, beechwood Cyclomethycaine sulfate (iv) Diaper rash drug products. Any in- Dexpanthenol gredient(s) labeled with claims or di- Diperodon hydrochloride rections for use in the treatment and/ Eucalyptus oil or prevention of diaper rash. Eugenol (v) Fever blister and cold sore treatment Glycerin Glycol salicylate drug products. Hectorite Allyl isothiocyanate Hexylresorcinol Aspirin Hydrogen peroxide Bismuth sodium tartrate Impatiens biflora tincture Camphor (exceeding 3 percent) Iron oxide Capsaicin Isopropyl alcohol Capsicum Lanolin Capsicum oleoresin Lead acetate Chloral hydrate Merbromin Chlorobutanol Mercuric chloride Cyclomethycaine sulfate Methapyrilene hydrochloride Eucalyptus oil Panthenol Eugenol Parethoxycaine hydrochloride Glycol salicylate Phenyltoloxamine dihydrogen citrate Hexylresorcinol Povidone-vinylacetate copolymers Histamine dihydrochloride Pyrilamine maleate Menthol (exceeding 1 percent) Salicylamide

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Salicylic acid (C) Stimulant laxatives—Approved as of Simethicone November 5, 2002. Sulfur Tannic acid Aloe ingredients (aloe, aloe extract, aloe Thymol flower extract) Trolamine salicylate Cascara sagrada ingredients (casanthranol, Turpentine oil cascara fluidextract aromatic, cascara Zirconium oxide sagrada bark, cascara sagrada extract, cascara sagrada fluidextract). Zyloxin (11) [Reserved] (13) [Reserved] (14) Oral health care drug products (12) Laxative drug products—(i)(A) (nonantimicrobial). Bulk laxatives. Antipyrine Agar Camphor Carrageenan (degraded) Cresol Carrageenan (native) Dibucaine Guar gun Dibucaine hydrochloride (i)(B) Bulk laxatives—Approved as of Eucalyptol Lidocaine March 29, 2007. Lidocaine hydrochloride Granular dosage forms containing psyllium Methly salicylate (hemicellulose), psyllium hydrophilic Myrrh tincture mucilloid, psyllium seed, psyllium seed Pyrilamine maleate (blond), psyllium seed husks, plantago Sorbitol husks, or plantago seed including, but not Sugars limited to, any granules that are: Tetracaine (1) Swallowed dry prior to drinking liquid, Tetracaine hydrochloride (2) Dispersed, suspended, or partially dis- Thymol solved in liquid prior to swallowing, (15) Topical otic drug products—(i) For (3) Chewed, partially chewed, or unchewed, the prevention of swimmer’s ear and for and then washed down (or swallowed) with the drying of water-clogged ears, ap- liquid, or (4) Sprinkled over food. proved as of May 7, 1991. (ii) Saline laxative. Acetic acid (ii) For the prevention of swimmer’s ear, Tartaric acid approved as of August 15, 1995. (iii) Stool softener. Glycerin and anhydrous glycerin Poloxamer 188 Isopropyl alcohol (iv)(A) Stimulant laxatives—Approved (16) Poison treatment drug products. as of May 7, 1991. Ipecac fluidextract Aloin Ipecac tincture Bile salts/acids Zinc sulfate Calcium pantothenate (17) Skin bleaching drug products. Calomel Colocynth Mercury, ammoniated Elaterin resin (18) Skin protectant drug products— Frangula (i)(A) Ingredients—Approved as of May 7, Gamboge Ipomea 1991. Jalap Allantoin (wound healing claims only) Ox bile Sulfur Podophyllum resin Tannic acid Prune concentrate dehydrate Zinc acetate (wound healing claims only) Prune powder Rhubarb, Chinese (B) Ingredients—Approved as of June 4, Sodium Oleate 2004; June 6, 2005, for products with annual sales less than $25,000. (iv)(B) Stimulant laxatives—Approved as of January 29, 1999. Beeswax Bismuth subnitrate Danthron Boric acid Phenolphthalein Cetyl alcohol

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Glyceryl stearate (iv) Fever blister and cold sore treat- Isopropyl palmitate ment drug products. Live yeast cell derivative Shark liver oil Bismuth subnitrate Stearyl alcohol Boric acid Pyridoxine hydrochloride (ii) Astringent drug products. Sulfur Acetone Tannic acid Alcohol Topical starch Alum, ammonium Trolamine Alum, potassium Zinc sulfate Aluminum chlorhydroxy complex (v) Insect bite and sting drug products— Aromatics (A) Ingredients—Approved as of November Benzalkonium chloride Benzethonium chloride 10, 1993. Benzocaine Alcohol Benzoic acid Alcohol, ethoxylated alkyl Boric acid Ammonia solution, strong Calcium acetate (except calcium acetate Ammonium hydroxide monohydrate when combined with alu- Benzalkonium chloride minum sulfate tetradecahydrate to provide Camphor an aluminum acetate solution as described Ergot fluid extract in § 347.20(b) of this chapter) Ferric chloride Camphor gum Menthol Clove oil Peppermint oil Colloidal oatmeal Phenol Cresol Pyrilamine maleate Cupric sulfate Sodium borate Eucalyptus oil Trolamine Eugenol Turpentine oil Ferric subsulfate (Monsel’s Solution) Zirconium oxide Honey Isopropyl alcohol (B) Ingredients—Approved as of June 4, Menthol 2004; June 6, 2005, for products with an- Methyl salicylate nual sales less than $25,000. Oxyquinoline sulfate P-t-butyl-m-cresol Beeswax Peppermint oil Bismuth subnitrate Phenol Boric acid Polyoxeythylene laurate Cetyl alcohol Potassium ferrocyanide Glyceryl stearate Sage oil Isopropyl palmitate Silver nitrate Live yeast cell derivative Sodium borate Shark liver oil Sodium diacetate Stearyl alcohol Talc (vi) Poison ivy, poison oak, and poison Tannic acid glycerite sumac drug products—(A) Ingredients— Thymol Topical starch Approved as of November 10, 1993. Zinc chloride Alcohol Zinc oxide Anion and cation exchange resins buffered Zinc phenolsulfonate Benzethonium chloride Zinc stearate Benzocaine Zinc sulfate Benzyl alcohol (iii) Diaper rash drug products. Bismuth subnitrate Bithionol Aluminum hydroxide Boric acid Cocoa butter Camphor Cysteine hydrochloride Cetalkonium chloride Glycerin Chloral hydrate Protein hydrolysate Chlorpheniramine maleate Racemethionine Creosote Sulfur Diperodon hydrochloride Tannic acid Diphenhydramine hydrochloride Zinc acetate Eucalyptus oil Zinc carbonate Ferric chloride

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Glycerin Copper Hectorite Copper gluconate Hydrogen peroxide Corn oil Impatiens biflora tincture Corn syrup Iron oxide Corn silk, potassium extract Isopropyl alcohol Cupric sulfate Lanolin Cyanocobalamin (vitamin B12) Lead acetate Cystine Lidocaine Dextrose Menthol Docusate sodium Merbromin Ergocalciferol Mercuric chloride Ferric ammonium citrate Panthenol Ferric pyrophosphate Parethoxycaine hydrochloride Ferrous fumarate Phenol Ferrous gluconate Phenyltoloxamine dihydrogen citrate Ferrous sulfate (iron) Povidone-vinylacetate copolymers Flax seed Salicylic acid Folic acid Simethicone Fructose Tannic acid Guar gum Topical starch Histidine Trolamine Hydrastis canadensis Turpentine oil Inositol Zirconium oxide Iodine Zyloxin Isoleucine Juniper, potassium extract (B) Ingredients—Approved as of June 4, Karaya gum 2004; June 6, 2005, for products with an- Kelp nual sales less than $25,000. Lactose Lecithin Beeswax Leucine Bismuth subnitrate Liver concentrate Boric acid Lysine Cetyl alcohol Lysine hydrochloride Glyceryl stearate Magnesium Isopropyl palmitate Magnesium oxide Live yeast cell derivative Malt Shark liver oil Maltodextrin Stearyl alcohol Manganese citrate (19) [Reserved] Mannitol (20) Weight control drug products. Methionine Methylcellulose Alcohol Mono- and di-glycerides Alfalfa Niacinamide Alginic acid Organic vegetables Anise oil Pancreatin Arginine Pantothenic acid Ascorbic acid Papain Bearberry Papaya enzymes Biotin Pepsin Bone marrow, red Phenacetin Buchu Phenylalanine Buchu, potassium extract Phosphorus Caffeine Phytolacca Caffeine citrate Pineapple enzymes Calcium Plantago seed Calcium carbonate Potassium citrate Calcium caseinate Pyridoxine hydrochloride (vitamin B6) Calcium lactate Riboflavin Calcium pantothenate Rice polishings Carboxymethylcellulose sodium Saccharin Carrageenan Sea minerals Cholecalcierol Sesame seed Choline Sodium Chondrus Sodium bicarbonate Citric acid Sodium caseinate Cnicus benedictus Sodium chloride (salt)

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Soybean protein Dichlorophen Soy meal Menthol Sucrose Methylparaben Thiamine hydrochloride (vitamin B1) Oxyquinoline Thiamine mononitrate (vitamin B1 mono- Oxyquinoline sulfate nitrate) Phenol Threonine Phenolate sodium Tricalcium phosphate Phenyl salicylate Tryptophan Propionic acid Tyrosine Propylparaben Uva ursi, potassium extract Resorcinol Valine Salicylic acid Vegetable Sodium borate Vitamin A Sodium caprylate Vitamin A acetate Sodium propionate Vitamin A palmitate Sulfur Vitamin E Tannic acid Wheat germ Thymol Xanthan gum Tolindate Yeast Triacetin Zinc caprylate (21) Ophthalmic drug products. (i) Oph- Zinc propionate thalmic anesthetic drug products. (iii) Any ingredient(s) labeled with Antipyrine claims or directions for use on the Piperocaine hydrochloride scalp or on the nails. (ii) Ophthalmic anti-infective drug (iv) Ingredients. products. Camphorated metacresol Boric acid Chloroxylenol Mild silver protein m-cresol Yellow mercuric oxide Nystatin (iii) Ophthalmic astringent drug prod- (23) Internal analgesic drug products— ucts. (i) Approved as of November 10, 1993. Infusion of rose petals Aminobenzoic acid Antipyrine (iv) Ophthalmic demulcent drug prod- Aspirin, aluminum ucts. Calcium salicylate Codeine Polyethylene glycol 6000 Codeine phosphate (v) Ophthalmic vasoconstrictor drug Codeine sulfate products. Iodoantipyrine Lysine aspirin Phenylephrine hydrochloride (less than 0.08 Methapyrilene fumarate percent) Phenacetin (22) Topical antifungal drug products. Pheniramine maleate Pyrilamine maleate (i) Diaper rash drug products. Any ingre- Quinine dient(s) labeled with claims or direc- Salsalate tions for use in the treatment and/or Sodium aminobenzoate prevention of diaper rash. (ii) Approved as of February 22, 1999. (ii) Ingredients. Any atropine ingredient Alcloxa Any ephedrine ingredient Alum, potassium Aluminum sulfate (24) Orally administered menstrual drug Amyltricresols, secondary products—(i) Approved as of November 10, Basic fuchsin 1993. Benzethonium chloride Benzoic acid Alcohol Benzoxiquine Alfalfa leaves Boric acid Aloes Camphor Asclepias tuberosa Candicidin Asparagus Chlorothymol Barosma Coal tar Bearberry (extract of uva ursi)

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Bearberry fluidextract (extract of bearberry) Benzyl alcohol Blessed thistle (cnicus benedictus) Benzyl benzoate Buchu powdered extract (extract of buchu) Chlorophenothane (dichlorodiphenyl tri- Calcium lactate chloroethane) Calcium pantothenate Coconut oil soap, aqueous Capsicum oleoresin Copper oleate Cascara fluidextract, aromatic (extract of Docusate sodium cascara) Formic acid Chlorprophenpyridamine maleate Isobornyl thiocyanoacetate Cimicifuga racemosa Picrotoxin Codeine Propylene glycol Collinsonia (extract stone root) Sabadilla alkaloids Corn silk Sulfur, sublimed Couch grass Thiocyanoacetate Dog grass extract Ethyl nitrite (ii) Approved as of June 14, 1994. The Ferric chloride combination of pyrethrum extract (for- Ferrous sulfate merly named pyrethrins) and piperonyl Gentiana lutea (gentian) butoxide in an aerosol dosage formula- Glycyrrhiza (licorice) tion. Homatropine methylbromide (26) Anorectal drug products—(i) Anti- Hydrangea, powdered extract (extract of hy- cholinergic drug products. drangea) Hydrastis canadensis (golden seal) Atropine Hyoscyamine sulfate Belladonna extract Juniper oil (oil of juniper) Magnesium sulfate (ii) Antiseptic drug products. Methapyrilene hydrochloride Boric acid Methenamine Boroglycerin Methylene blue Hydrastis Natural estrogenic hormone Phenol Niacinamide Resorcinol Nutmeg oil (oil of nutmeg) Sodium salicylic acid phenolate Oil of erigeron Parsley (iii) Astringent drug products. Peppermint spirit Tannic acid Pepsin, essence Phenacetin (iv) Counterirritant drug products. Phenindamine tartrate Phenyl salicylate Camphor (greater than 3 to 11 percent) Piscidia erythrina Hydrastis Pipsissewa Menthol (1.25 to 16 percent) Potassium acetate Turpentine oil (rectified) (6 to 50 percent) Potassium nitrate (v) Keratolytic drug products. Riboflavin Saw palmetto Precipitated sulfur Senecio aureus Sublimed sulfur Sodium benzoate (vi) Local anesthetic drug products. Sodium nitrate Sucrose Diperodon Sulferated oils of turpentine Phenacaine hydrochloride Taraxacum officinale Theobromine sodium salicylate (vii) Other drug products. Theophylline Collinsonia extract Thiamine hydrochloride Escherichia coli vaccines Triticum Lappa extract Turpentine, venice (venice turpertine) Leptandra extract Urea Live yeast cell derivative (ii) Approved as of February 22, 1999. Mullein Any atropine ingredient (viii) Protectant drug products. Any ephedrine ingredient Bismuth oxide (25) Pediculicide drug products—(i) Ap- Bismuth subcarbonate proved as of November 10, 1993. Bismuth subgallate Bismuth subnitrate Benzocaine Lanolin alcohols

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(ix) Vasoconstrictor drug products. Tribromsalan Triclocarban Epinephrine undecylenate Triclosan (x) Wound healinq drug products. Triple Dye Undecoylium chloride iodine complex Cholecalciferol Cod liver oil (iv) Consumer antiseptic body wash Live yeast cell derivative drug products. Approved as of Sep- Peruvian balsam tember 6, 2017. Shark liver oil Cloflucarban Vitamin A Fluorosalan (xi) Combination drug products. Any Hexachlorophene combination drug product containing Hexylresorcinol hydrocortisone and pramoxine hydro- Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) chloride. Iodine tincture (27) Topical antimicrobial drug prod- Methylbenzethonium chloride ucts—(i) First aid antiseptic drug prod- Nonylphenoxypoly (ethyleneoxy) ucts. ethanoliodine Phenol (greater than 1.5 percent) Ammoniated mercury Phenol (less than 1.5 percent) Calomel (mercurous chloride) Poloxamer iodine complex Merbromin (mercurochrome) Povidone-iodine (5 to 10 percent) Mercufenol chloride (ortho- Secondary amyltricresols chloromercuriphenol, ortho- Sodium oxychlorosene hydroxyphenylmercuric chloride) Tribromsalan Mercuric chloride (bichloride of mercury, Triclocarban mercury chloride) Triclosan Mercuric oxide, yellow Triple Dye Mercuric salicylate Undecoylium chloride iodine complex Mercuric sulfide, red Mercury (28) Vaginal contraceptive drug prod- Mercury oleate ucts—(i) Approved as of October 22, 1998. Mercury sulfide Dodecaethylene glycol monolaurate (poly- Nitromersol ethylene glycol 600 monolaurate) Para-chloromercuriphenol Laureth 10S Phenylmercuric nitrate Methoxypolyoxyethyleneglycol 550 laurate Thimerosal Phenylmercuric acetate Vitromersol Phenylmercuric nitrate Zyloxin Any other ingredient containing mercury (ii) Diaper rash drug products. (ii) Approved as of November 5, 2002. Para-chloromercuriphenol Octoxynol 9 Any other ingredient containing mercury (29) Sunscreen drug products. (i) Ingre- (iii) Consumer antiseptic hand wash dients. drug products. Approved as of Sep- Diethanolamine methoxycinnamate tember 6, 2017. Digalloyl trioleate Cloflucarban Ethyl 4-[bis(hydroxypropyl)] aminobenzoate Fluorosalan Glyceryl aminobenzoate Hexachlorophene Lawsone with dihydroxyacetone Hexylresorcinol Red petrolatum Iodine complex (ammonium ether sulfate (ii) Any ingredients labeled with any and polyoxyethylene sorbitan of the following or similar claims. In- monolaurate) stant protection or protection imme- Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol) diately upon application. Methylbenzethonium chloride Claims for ‘‘all-day’’ protection or Nonylphenoxypoly (ethyleneoxy) extended wear claims citing a specific ethanoliodine number of hours of protection that is Phenol (greater than 1.5 percent) inconsistent with the directions for ap- Phenol (less than 1.5 percent) plication in 21 CFR 201.327. Poloxamer iodine complex Povidone-iodine (5 to 10 percent) (30) [Reserved] Secondary amyltricresols (b) Any OTC drug product that is la- Sodium oxychlorosene beled, represented, or promoted for the

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uses specified and containing any ac- section, except those that contain ipe- tive ingredient(s) as specified in para- cac. graph (a) of this section is regarded as (5) September 14, 1993, for products a new drug within the meaning of sec- subject to paragraph (a)(6)(iii) of this tion 210(p) of the Federal Food, Drug, section that contain ipecac. and Cosmetic Act (the Act), for which (6) December 9, 1993, for products sub- an approved new drug application ject to paragraph (a)(6)(i)(B) of this under section 505 of the Act and part section. 314 of this chapter is required for mar- (7) March 6, 1989, for products subject keting. In the absence of an approved to paragraph (a)(21) of this section, ex- new drug application, such product is cept those that contain ophthalmic also misbranded under section 502 of anti-infective ingredients listed in the Act. paragraph (a)(21)(ii). (c) Clinical investigations designed (8) June 18, 1993, for products subject to obtain evidence that any drug prod- to paragraph (a)(21) of this section that uct labeled, represented, or promoted contain ophthalmic anti-infective infor the OTC uses and containing any gredients. active ingredient(s) as specified in (9) June 18, 1993, for products subject paragraph (a) of this section is safe and to paragraph (a)(10)(iv) of this section. effective for the purpose intended must (10) June 18, 1993, for products subject comply with the requirements and pro- to paragraph (a)(22)(i) of this section. cedures governing the use of investiga- (11) November 10, 1993, for products tional new drugs set forth in part 312 of subject to paragraphs (a)(8)(ii), this chapter. (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (d) Any OTC drug product that is not (except products that contain ferric in compliance with this section is sub- subsulfate as covered by paragraph ject to regulatory action if initially in- (d)(22) of this section and except prod- troduced or initially delivered for in- ucts that contain calcium acetate troduction into interstate commerce monohydrate as covered by paragraph after the dates specified in paragraphs (d)(39) of this section) through (d)(1) through (d)(41) of this section. (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), (1) May 7, 1991, for products subject (a)(23)(i), (a)(24)(i), and (a)(25) of this to paragraphs (a)(1) through (a)(2)(i), section. (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (12) March 2, 1994, for products sub- (a)(6)(ii)(A), (a)(7) (except as covered by ject to paragraph (a)(22)(iii) of this sec- paragraph (d)(3) of this section), tion. (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (13) August 5, 1991, for products sub- (a)(12)(i)(A), (a)(12)(ii) through ject to paragraph (a)(26) of this section, (a)(12)(iv)(A), (a)(14) through (a)(15)(i), except for those that contain live yeast (a)(16) through (a)(18)(i)(A), (a)(18)(ii) cell derivative and a combination of (except as covered by paragraph (d)(22) hydrocortisone and pramoxine hydro- of this section), (a)(18)(iii), (a)(18)(iv), chloride. (a)(18)(v)(A), and (a)(18)(vi)(A) of this (14) September 2, 1994, for products section. subject to paragraph (a)(26)(vii) and (2) February 10, 1992, for products (a)(26)(x) of this section that contain subject to paragraph (a)(20) of this sec- live yeast cell derivative. tion. (15) September 23, 1994, for products (3) December 4, 1992, for products sub- subject to paragraph (a)(22)(iv) of this ject to paragraph (a)(7) of this section section. that contain menthol as an anti- (16) June 14, 1994, for products subject pruritic in combination with the anti- to paragraph (a)(25)(ii) of this section. dandruff ingredient coal tar identified (17) April 19, 2004, for products sub- in § 358.710(a)(1) of this chapter. This ject to paragraph (a)(3)(ii) of this sec- section does not apply to products al- tion. April 18, 2005, for products with lowed by § 358.720(b) of this chapter annual sales less than $25,000. after April 5, 2007. (18) August 15, 1995, for products sub- (4) February 28, 1990, for products ject to paragraph (a)(15)(ii) of this sec- subject to paragraph (a)(6)(iii) of this tion.

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(19) October 2, 1987, for products sub- (39) September 6, 2010, for products ject to paragraph (a)(6)(iv)(A) of this subject to paragraph (a)(18)(ii) of this section. section that contain calcium acetate (20) January 29, 1996, for products monohydrate, except as provided in subject to paragraph (a)(6)(iv)(B) of § 347.20(b) of this chapter. this section. (40) December 17, 2012, for products (21) April 21, 1994, for products sub- subject to paragraph (a)(29)(ii) of this ject to paragraph (a)(8)(iii) of this sec- section. December 17, 2013, for products tion. with annual sales less than $25,000. (22) April 21, 1993, for products sub- (41) September 6, 2017, for products ject to paragraph (a)(18)(ii) of this sec- subject to paragraph (a)(27)(iii) or (iv) tion that contain ferric subsulfate. of this section. (23) August 23, 1995, for products sub- [55 FR 46919, Nov. 7, 1990] ject to paragraph (a)(6)(ii)(B) of this section. EDITORIAL NOTE: For FEDERAL REGISTER citations affecting § 310.545, see the List of CFR (24) October 7, 1996, for products sub- Sections Affected, which appears in the ject to paragraph (a)(2)(ii) of this sec- Finding Aids section of the printed volume tion. and at www.fdsys.gov. (25) June 19, 1996, for products subject EFFECTIVE DATE NOTES: 1. At 61 FR 9571, to paragraph (a)(6)(iv)(C) of this sec- Mar. 8, 1996, in § 310.545 in paragraph tion. (a)(6)(ii)(B), the entry for ‘‘l-desoxyephedrine (26) February 22, 1999, for products (topical)’’ was stayed until further notice. subject to paragraphs (a)(23)(ii) and 2. At 82 FR 60502, Dec. 20, 2017, § 310.545 was (a)(24)(ii) of this section. amended by adding reserved paragraphs (27) [Reserved] (a)(27)(v), (vii), and (ix); adding paragraphs (28) October 22, 1998, for products sub- (a)(27)(vi), (viii), (x), (d)(42); and in paragraph (d) introductory text, removing ‘‘(d)(41)’’ and ject to paragraphs (a)(27) and (a)(28)(i) in its place adding ‘‘(42)’’;, effective Dec. 20, of this section. 2018. For the convenience of the user, the (29) January 29, 1999, for products added text is set forth as follows: subject to paragraph (a)(12)(iv)(B) of this section. § 310.545 Drug products containing certain active ingredients offered over-the- (30) November 5, 2002, for products counter (OTC) for certain uses. subject to paragraph (a)(12)(iv)(C) of (a) * * * this section. (27) * * * (31) December 31, 2002, for products (v) [Reserved] subject to paragraph (a)(29)(i) of this (vi) Health care personnel hand wash drug section. products. Approved as of December 20, 2018. (32) June 4, 2004, for products subject Cloflucarban to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), Fluorosalan and (a)(18)(vi)(B) of this section. June Hexachlorophene 6, 2005, for products with annual sales Hexylresorcinol less than $25,000. Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan (33) October 29, 2001, for products sub- monolaurate) ject to paragraph (a)(6)(iv)(D) of this Iodine complex (phosphate ester of section. alkylaryloxy polyethylene glycol) (34) December 9, 2004, for products Methylbenzethonium chloride subject to paragraph (a)(4)(ii) of this Nonylphenoxypoly (ethyleneoxy) section. June 9, 2005, for products with ethanoliodine annual sales less than $25,000. Phenol Poloxamer-iodine complex (35) [Reserved] Secondary amyltricresols (36) November 5, 2002, for products Sodium oxychlorosene subject to paragraph (a)(28)(ii) of this Tribromsalan section. Triclocarban (37) September 25, 2003, for products Triclosan subject to paragraph (a)(26)(xi) of this Undecoylium chloride iodine complex section. (vii) [Reserved] (38) October 1, 2007, for products sub- (viii) Surgical hand scrub drug products. Ap- ject to paragraph (a)(12)(i)(B) of this proved as of December 20, 2018. section. Cloflucarban

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Fluorosalan vention of nocturnal leg muscle Hexachlorophene cramps, i.e., a condition of localized Hexylresorcinol pain in the lower extremities usually Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan occurring in middle life and beyond monolaurate) with no regular pattern concerning Iodine complex (phosphate ester of time or severity. There is a lack of ade- alkylaryloxy polyethylene glycol) quate data to establish general rec- Methylbenzethonium chloride ognition of the safety and effectiveness Nonylphenoxypoly (ethyleneoxy) of quinine sulfate, vitamin E, or any ethanoliodine Phenol other ingredients for OTC use in the Poloxamer-iodine complex treatment and/or prevention of noc- Secondary amyltricresols turnal leg muscle cramps. In the doses Sodium oxychlorosene used to treat or prevent this condition, Tribromsalan quinine sulfate has caused adverse Triclocarban events such as transient visual and au- Triclosan Undecoylium chloride iodine complex ditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. Qui- (ix) [Reserved] nine sulfate may cause unpredictable (x) Patient antiseptic skin preparation drug serious and life-threatening hyper- products. Approved as of December 20, 2018. sensitivity reactions requiring medical Cloflucarban intervention and hospitalization; fa- Fluorosalan talities have been reported. The risk Hexachlorophene Hexylresorcinol associated with use of quinine sulfate, Iodine complex (phosphate ester of in the absence of evidence of its effec- alkylaryloxy polyethylene glycol) tiveness, outweighs any potential ben- Iodine tincture (USP) efit in treating and/or preventing this Iodine topical solution (USP) benign, self-limiting condition. Based Mercufenol chloride upon the adverse benefit-to-risk ratio, Methylbenzethonium chloride any drug product containing quinine or Nonylphenoxypoly (ethyleneoxy) ethanoliodine quinine sulfate cannot be considered Phenol generally recognized as safe for the Poloxamer-iodine complex treatment and/or prevention of noc- Secondary amyltricresols turnal leg muscle cramps. Sodium oxychlorosene (b) Any OTC drug product that is la- Tribromsalan beled, represented, or promoted for the Triclocarban Triclosan treatment and/or prevention of noc- Triple dye turnal leg muscle cramps is regarded as Undecoylium chloride iodine complex a new drug within the meaning of sec- Combination of calomel, oxyquinoline ben- tion 201(p) of the Federal Food, Drug, zoate, triethanolamine, and phenol deriva- and Cosmetic Act (the act), for which tive an approved application or abbreviated Combination of mercufenol chloride and secondary amyltricresols in 50 percent alcohol application under section 505 of the act and part 314 of this chapter is required for marketing. In the absence of an ap- * * * * * proved new drug application or abbre- (d) * * * viated new drug application, such prod- (42) December 20, 2018, for products subject uct is also misbranded under section to paragraphs (a)(27)(vi) through (x) of this 502 of the act. section. (c) Clinical investigations designed § 310.546 Drug products containing ac- to obtain evidence that any drug prod- tive ingredients offered over-the- uct labeled, represented, or promoted counter (OTC) for the treatment for OTC use for the treatment and/or and/or prevention of nocturnal leg prevention of nocturnal leg muscle muscle cramps. cramps is safe and effective for the pur- (a) Quinine sulfate alone or in com- pose intended must comply with the re- bination with vitamin E has been quirements and procedures governing present in over-the-counter (OTC) drug the use of investigational new drugs products for the treatment and/or pre- set forth in part 312 of this chapter.

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(d) After February 22, 1995, any such initially delivered for introduction into OTC drug product initially introduced interstate commerce that is not in or initially delivered for introduction compliance with this section is subject into interstate commerce that is not in to regulatory action. compliance with this section is subject [63 FR 13528, Mar. 20, 1998] to regulatory action. [59 FR 43252, Aug. 22, 1994] § 310.548 Drug products containing colloidal silver ingredients or silver § 310.547 Drug products containing salts offered over-the-counter (OTC) quinine offered over-the-counter for the treatment and/or prevention (OTC) for the treatment and/or pre- of disease. vention of malaria. (a) Colloidal silver ingredients and (a) Quinine and quinine salts have silver salts have been marketed in been used OTC for the treatment and/or over-the-counter (OTC) drug products prevention of malaria, a serious and for the treatment and prevention of nu- potentially life-threatening disease. merous disease conditions. There are Quinine is no longer the drug of choice serious and complicating aspects to for the treatment and/or prevention of many of the diseases these silver ingre- most types of malaria. In addition, dients purport to treat or prevent. Fur- there are serious and complicating as- ther, there is a lack of adequate data pects of the disease itself and some po- to establish general recognition of the tentially serious and life-threatening safety and effectiveness of colloidal sil- risks associated with the use of quinine ver ingredients or silver salts for OTC at doses employed for the treatment of use in the treatment or prevention of malaria. There is a lack of adequate any disease. These ingredients and data to establish general recognition of salts include, but are not limited to, the safety of quinine drug products for silver proteins, mild silver protein, OTC use in the treatment and/or pre- strong silver protein, silver, silver ion, vention of malaria. Therefore, quinine silver chloride, silver cyanide, silver or quinine salts cannot be safely and iodide, silver oxide, and silver phos- effectively used for the treatment and/ phate. or prevention of malaria except under (b) Any OTC drug product containing the care and supervision of a doctor. colloidal silver ingredients or silver (b) Any OTC drug product containing salts that is labeled, represented, or quinine or quinine salts that is labeled, promoted for the treatment and/or pre- represented, or promoted for the treat- vention of any disease is regarded as a ment and/or prevention of malaria is new drug within the meaning of section regarded as a new drug within the 201(p) of the Federal Food, Drug, and meaning of section 201(p) of the act, for Cosmetic Act (the act) for which an ap- which an approved application or ab- proved application or abbreviated ap- breviated application under section 505 plication under section 505 of the act of the act and part 314 of this chapter and part 314 of this chapter is required is required for marketing. In the ab- for marketing. In the absence of an ap- sence of an approved new drug applica- proved new drug application or abbre- tion or abbreviated new drug applica- viated new drug application, such prod- tion, such product is also misbranded uct is also misbranded under section under section 502 of the act. 502 of the act. (c) Clinical investigations designed (c) Clinical investigations designed to obtain evidence that any drug prod- to obtain evidence that any drug product labeled, represented, or promoted uct containing colloidal silver or silver for OTC use for the treatment and/or salts labeled, represented, or promoted prevention of malaria is safe and effec- for any OTC drug use is safe and effective for the purpose intended must tive for the purpose intended must comply with the requirements and pro- comply with the requirements and procedures governing the use of investiga- cedures governing the use of investigational new drugs set forth in part 312 of tional new drugs as set forth in part 312 this chapter. of this chapter. (d) After April 20, 1998, any such OTC (d) After September 16, 1999, any such drug product initially introduced or OTC drug product containing colloidal

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silver or silver salts initially intro- 312.60 General responsibilities of investiga- duced or initially delivered for intro- tors. duction into interstate commerce that 312.61 Control of the investigational drug. is not in compliance with this section 312.62 Investigator recordkeeping and is subject to regulatory action. record retention. 312.64 Investigator reports. [64 FR 44658, Aug. 17, 1999] 312.66 Assurance of IRB review. 312.68 Inspection of investigator’s records PART 312—INVESTIGATIONAL NEW and reports. 312.69 Handling of controlled substances. DRUG APPLICATION 312.70 Disqualification of a clinical investigator. Subpart A—General Provisions Subpart E—Drugs Intended to Treat Life- Sec. 312.1 Scope. threatening and Severely-debilitating 312.2 Applicability. Illnesses 312.3 Definitions and interpretations. 312.6 Labeling of an investigational new 312.80 Purpose. drug. 312.81 Scope. 312.7 Promotion of investigational drugs. 312.82 Early consultation. 312.8 Charging for investigational drugs 312.83 Treatment protocols. under an IND. 312.84 Risk-benefit analysis in review of 312.10 Waivers. marketing applications for drugs to treat life-threatening and severely-debilitating Subpart B—Investigational New Drug illnesses. Application (IND) 312.85 Phase 4 studies. 312.86 Focused FDA regulatory research. 312.20 Requirement for an IND. 312.87 Active monitoring of conduct and 312.21 Phases of an investigation. evaluation of clinical trials. 312.22 General principles of the IND submis- 312.88 Safeguards for patient safety. sion. 312.23 IND content and format. Subpart F—Miscellaneous 312.30 Protocol amendments. 312.31 Information amendments. 312.110 Import and export requirements. 312.32 IND safety reporting. 312.120 Foreign clinical studies not con- 312.33 Annual reports. ducted under an IND. 312.38 Withdrawal of an IND. 312.130 Availability for public disclosure of data and information in an IND. Subpart C—Administrative Actions 312.140 Address for correspondence. 312.40 General requirements for use of an in- 312.145 Guidance documents. vestigational new drug in a clinical investigation. Subpart G—Drugs for Investigational Use in 312.41 Comment and advice on an IND. Laboratory Research Animals or in 312.42 Clinical holds and requests for modi- Vitro Tests fication. 312.44 Termination. 312.160 Drugs for investigational use in lab- 312.45 Inactive status. oratory research animals or in vitro 312.47 Meetings. tests. 312.48 Dispute resolution. Subpart H [Reserved] Subpart D—Responsibilities of Sponsors and Investigators Subpart I—Expanded Access to Investigational Drugs for Treatment Use 312.50 General responsibilities of sponsors. 312.52 Transfer of obligations to a contract 312.300 General. research organization. 312.305 Requirements for all expanded ac- 312.53 Selecting investigators and monitors. cess uses. 312.54 Emergency research under § 50.24 of 312.310 Individual patients, including for this chapter. emergency use. 312.55 Informing investigators. 312.315 Intermediate-size patient popu- 312.56 Review of ongoing investigations. lations. 312.57 Recordkeeping and record retention. 312.320 Treatment IND or treatment pro- 312.58 Inspection of sponsor’s records and tocol. reports. 312.59 Disposition of unused supply of inves- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, tigational drug. 355, 360bbb, 371; 42 U.S.C. 262.

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SOURCE: 52 FR 8831, Mar. 19, 1987, unless ceptability of the risks) associated otherwise noted. with the use of the drug product; EDITORIAL NOTE: Nomenclature changes to (iv) The investigation is conducted in part 312 appear at 69 FR 13717, Mar. 24, 2004. compliance with the requirements for institutional review set forth in part 56 Subpart A—General Provisions and with the requirements for informed consent set forth in part 50; and § 312.1 Scope. (v) The investigation is conducted in (a) This part contains procedures and compliance with the requirements of requirements governing the use of in- § 312.7. vestigational new drugs, including pro- (2)(i) A clinical investigation involv- cedures and requirements for the sub- ing an in vitro diagnostic biological mission to, and review by, the Food product listed in paragraph (b)(2)(ii) of and Drug Administration of investiga- this section is exempt from the re- tional new drug applications (IND’s). quirements of this part if (a) it is in- An investigational new drug for which tended to be used in a diagnostic proce- an IND is in effect in accordance with dure that confirms the diagnosis made this part is exempt from the premar- by another, medically established, di- keting approval requirements that are agnostic product or procedure and (b) it otherwise applicable and may be is shipped in compliance with § 312.160. shipped lawfully for the purpose of con- (ii) In accordance with paragraph ducting clinical investigations of that (b)(2)(i) of this section, the following drug. products are exempt from the require- (b) References in this part to regula- ments of this part: (a) blood grouping tions in the Code of Federal Regula- serum; (b) reagent red blood cells; and tions are to chapter I of title 21, unless (c) anti-human globulin. otherwise noted. (3) A drug intended solely for tests in vitro or in laboratory research animals § 312.2 Applicability. is exempt from the requirements of (a) Applicability. Except as provided this part if shipped in accordance with in this section, this part applies to all § 312.160. clinical investigations of products that (4) FDA will not accept an applica- are subject to section 505 of the Federal tion for an investigation that is ex- Food, Drug, and Cosmetic Act or to the empt under the provisions of paragraph licensing provisions of the Public (b)(1) of this section. Health Service Act (58 Stat. 632, as (5) A clinical investigation involving amended (42 U.S.C. 201 et seq.)). use of a placebo is exempt from the re- (b) Exemptions. (1) The clinical inves- quirements of this part if the investigation of a drug product that is law- tigation does not otherwise require fully marketed in the United States is submission of an IND. exempt from the requirements of this (6) A clinical investigation involving part if all the following apply: an exception from informed consent (i) The investigation is not intended under § 50.24 of this chapter is not ex- to be reported to FDA as a well-con- empt from the requirements of this trolled study in support of a new indi- part. cation for use nor intended to be used (c) Bioavailability studies. The applica- to support any other significant change bility of this part to in vivo bio- in the labeling for the drug; availability studies in humans is sub- (ii) If the drug that is undergoing in- ject to the provisions of § 320.31. vestigation is lawfully marketed as a (d) Unlabeled indication. This part prescription drug product, the inves- does not apply to the use in the prac- tigation is not intended to support a tice of medicine for an unlabeled indi- significant change in the advertising cation of a new drug product approved for the product; under part 314 or of a licensed biologi- (iii) The investigation does not in- cal product. volve a route of administration or dos- (e) Guidance. FDA may, on its own age level or use in a patient population initiative, issue guidance on the appli- or other factor that significantly in- cability of this part to particular increases the risks (or decreases the ac- vestigational uses of drugs. On request,

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FDA will advise on the applicability of ‘‘investigational new drug’’ are deemed this part to a planned clinical inves- to be synonymous for purposes of this tigation. part. Investigator means an individual who [52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999] actually conducts a clinical investigation (i.e., under whose immediate direc- § 312.3 Definitions and interpretations. tion the drug is administered or dis- (a) The definitions and interpreta- pensed to a subject). In the event an in- tions of terms contained in section 201 vestigation is conducted by a team of of the Act apply to those terms when individuals, the investigator is the re- used in this part: sponsible leader of the team. ‘‘Sub- (b) The following definitions of terms investigator’’ includes any other indi- also apply to this part: vidual member of that team. Act means the Federal Food, Drug, Marketing application means an appli- and Cosmetic Act (secs. 201–902, 52 cation for a new drug submitted under Stat. 1040 et seq., as amended (21 U.S.C. section 505(b) of the act or a biologics 301–392)). license application for a biological Clinical investigation means any ex- product submitted under the Public periment in which a drug is adminis- Health Service Act. tered or dispensed to, or used involv- Sponsor means a person who takes re- ing, one or more human subjects. For sponsibility for and initiates a clinical the purposes of this part, an experi- investigation. The sponsor may be an ment is any use of a drug except for the individual or pharmaceutical company, use of a marketed drug in the course of governmental agency, academic insti- medical practice. tution, private organization, or other Contract research organization means a organization. The sponsor does not ac- person that assumes, as an independent tually conduct the investigation unless contractor with the sponsor, one or the sponsor is a sponsor-investigator. A more of the obligations of a sponsor, person other than an individual that e.g., design of a protocol, selection or uses one or more of its own employees monitoring of investigations, evalua- to conduct an investigation that it has tion of reports, and preparation of ma- initiated is a sponsor, not a sponsor-in- terials to be submitted to the Food and vestigator, and the employees are in- Drug Administration. vestigators. FDA means the Food and Drug Ad- Sponsor-Investigator means an indi- ministration. vidual who both initiates and conducts IND means an investigational new an investigation, and under whose im- drug application. For purposes of this mediate direction the investigational part, ‘‘IND’’ is synonymous with ‘‘No- drug is administered or dispensed. The tice of Claimed Investigational Exemp- term does not include any person other tion for a New Drug.’’ than an individual. The requirements Independent ethics committee (IEC) applicable to a sponsor-investigator means a review panel that is respon- under this part include both those ap- sible for ensuring the protection of the plicable to an investigator and a spon- rights, safety, and well-being of human sor. subjects involved in a clinical inves- Subject means a human who partici- tigation and is adequately constituted pates in an investigation, either as a to provide assurance of that protec- recipient of the investigational new tion. An institutional review board drug or as a control. A subject may be (IRB), as defined in § 56.102(g) of this a healthy human or a patient with a chapter and subject to the require- disease. ments of part 56 of this chapter, is one [52 FR 8831, Mar. 19, 1987, as amended at 64 type of IEC. FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; Investigational new drug means a new 73 FR 22815, Apr. 28, 2008] drug or biological drug that is used in a clinical investigation. The term also § 312.6 Labeling of an investigational includes a biological product that is new drug. used in vitro for diagnostic purposes. (a) The immediate package of an in- The terms ‘‘investigational drug’’ and vestigational new drug intended for

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human use shall bear a label with the tablish sufficient data to support a statement ‘‘Caution: New Drug—Lim- marketing application. ited by Federal (or United States) law [52 FR 8831, Mar. 19, 1987, as amended at 52 to investigational use.’’ FR 19476, May 22, 1987; 67 FR 9585, Mar. 4, (b) The label or labeling of an inves- 2002; 74 FR 40899, Aug. 13, 2009] tigational new drug shall not bear any statement that is false or misleading in § 312.8 Charging for investigational drugs under an IND. any particular and shall not represent that the investigational new drug is (a) General criteria for charging. (1) A safe or effective for the purposes for sponsor must meet the applicable re- which it is being investigated. quirements in paragraph (b) of this sec- (c) The appropriate FDA Center Di- tion for charging in a clinical trial or paragraph (c) of this section for charg- rector, according to the procedures set ing for expanded access to an investiga- forth in §§ 201.26 or 610.68 of this chap- tional drug for treatment use under ter, may grant an exception or alter- subpart I of this part, except that spon- native to the provision in paragraph (a) sors need not fulfill the requirements of this section, to the extent that this in this section to charge for an ap- provision is not explicitly required by proved drug obtained from another en- statute, for specified lots, batches, or tity not affiliated with the sponsor for other units of a human drug product use as part of the clinical trial evalua- that is or will be included in the Stra- tion (e.g., in a clinical trial of a new tegic National Stockpile. use of the approved drug, for use of the [52 FR 8831, Mar. 19, 1987, as amended at 72 approved drug as an active control). FR 73599, Dec. 28, 2007] (2) A sponsor must justify the amount to be charged in accordance § 312.7 Promotion of investigational with paragraph (d) of this section. drugs. (3) A sponsor must obtain prior written authorization from FDA to charge (a) Promotion of an investigational new for an investigational drug. drug. A sponsor or investigator, or any (4) FDA will withdraw authorization person acting on behalf of a sponsor or to charge if it determines that charg- investigator, shall not represent in a ing is interfering with the development promotional context that an investiga- of a drug for marketing approval or tional new drug is safe or effective for that the criteria for the authorization the purposes for which it is under in- are no longer being met. vestigation or otherwise promote the (b) Charging in a clinical trial—(1) drug. This provision is not intended to Charging for a sponsor’s drug. A sponsor restrict the full exchange of scientific who wishes to charge for its investiga- information concerning the drug, in- tional drug, including investigational cluding dissemination of scientific use of its approved drug, must: findings in scientific or lay media. (i) Provide evidence that the drug has Rather, its intent is to restrict pro- a potential clinical benefit that, if motional claims of safety or effective- demonstrated in the clinical investiga- ness of the drug for a use for which it tions, would provide a significant ad- is under investigation and to preclude vantage over available products in the commercialization of the drug before it diagnosis, treatment, mitigation, or prevention of a disease or condition; is approved for commercial distribu- (ii) Demonstrate that the data to be tion. obtained from the clinical trial would (b) Commercial distribution of an inves- be essential to establishing that the tigational new drug. A sponsor or inves- drug is effective or safe for the purpose tigator shall not commercially dis- of obtaining initial approval of a drug, tribute or test market an investiga- or would support a significant change tional new drug. in the labeling of an approved drug (c) Prolonging an investigation. A (e.g., new indication, inclusion of com- sponsor shall not unduly prolong an in- parative safety information); and vestigation after finding that the re- (iii) Demonstrate that the clinical sults of the investigation appear to es- trial could not be conducted without

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charging because the cost of the drug is drug for the investigational use for extraordinary to the sponsor. The cost which FDA has authorized cost recov- may be extraordinary due to manufac- ery. Direct costs include costs per unit turing complexity, scarcity of a nat- to manufacture the drug (e.g., raw ma- ural resource, the large quantity of terials, labor, and nonreusable supplies drug needed (e.g., due to the size or du- and equipment used to manufacture ration of the trial), or some combina- the quantity of drug needed for the use tion of these or other extraordinary for which charging is authorized) or circumstances (e.g., resources available costs to acquire the drug from another to a sponsor). manufacturing source, and direct costs (2) Duration of charging in a clinical to ship and handle (e.g., store) the trial. Unless FDA specifies a shorter pe- drug. riod, charging may continue for the (ii) Indirect costs include costs in- length of the clinical trial. curred primarily to produce the drug (c) Charging for expanded access to infor commercial sale (e.g., costs for fa- vestigational drug for treatment use. (1) A cilities and equipment used to manu- sponsor who wishes to charge for ex- facture the supply of investigational panded access to an investigational drug, but that are primarily intended drug for treatment use under subpart I to produce large quantities of drug for of this part must provide reasonable eventual commercial sale) and research assurance that charging will not inter- and development, administrative, fere with developing the drug for mar- labor, or other costs that would be in- keting approval. curred even if the clinical trial or (2) For expanded access under § 312.320 (treatment IND or treatment protocol), treatment use for which charging is au- such assurance must include: thorized did not occur. (i) Evidence of sufficient enrollment (2) For expanded access to an inves- in any ongoing clinical trial(s) needed tigational drug for treatment use for marketing approval to reasonably under §§ 312.315 (intermediate-size pa- assure FDA that the trial(s) will be tient populations) and 312.320 (treat- successfully completed as planned; ment IND or treatment protocol), in (ii) Evidence of adequate progress in addition to the direct costs described the development of the drug for mar- in paragraph (d)(1)(i) of this section, a keting approval; and sponsor may recover the costs of moni- (iii) Information submitted under the toring the expanded access IND or pro- general investigational plan tocol, complying with IND reporting (§ 312.23(a)(3)(iv)) specifying the drug requirements, and other administrative development milestones the sponsor costs directly associated with the ex- plans to meet in the next year. panded access IND. (3) The authorization to charge is (3) To support its calculation for cost limited to the number of patients au- recovery, a sponsor must provide sup- thorized to receive the drug under the porting documentation to show that treatment use, if there is a limitation. the calculation is consistent with the (4) Unless FDA specifies a shorter pe- requirements of paragraphs (d)(1) and, riod, charging for expanded access to if applicable, (d)(2) of this section. The an investigational drug for treatment documentation must be accompanied use under subpart I of this part may by a statement that an independent continue for 1 year from the time of certified public accountant has re- FDA authorization. A sponsor may reviewed and approved the calculations. quest that FDA reauthorize charging for additional periods. [74 FR 40899, Aug. 13, 2009] (d) Costs recoverable when charging for an investigational drug. (1) A sponsor § 312.10 Waivers. may recover only the direct costs of (a) A sponsor may request FDA to making its investigational drug avail- waive applicable requirement under able. this part. A waiver request may be sub- (i) Direct costs are costs incurred by mitted either in an IND or in an infor- a sponsor that can be specifically and mation amendment to an IND. In an exclusively attributed to providing the emergency, a request may be made by

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telephone or other rapid communica- § 312.21 Phases of an investigation. tion means. A waiver request is re- An IND may be submitted for one or quired to contain at least one of the more phases of an investigation. The following: clinical investigation of a previously (1) An explanation why the sponsor’s untested drug is generally divided into compliance with the requirement is un- three phases. Although in general the necessary or cannot be achieved; phases are conducted sequentially, (2) A description of an alternative they may overlap. These three phases submission or course of action that of an investigation are a follows: satisfies the purpose of the require- (a) Phase 1. (1) Phase 1 includes the ment; or initial introduction of an investiga- (3) Other information justifying a tional new drug into humans. Phase 1 waiver. studies are typically closely monitored (b) FDA may grant a waiver if it and may be conducted in patients or finds that the sponsor’s noncompliance normal volunteer subjects. These stud- would not pose a significant and unrea- ies are designed to determine the me- sonable risk to human subjects of the tabolism and pharmacologic actions of investigation and that one of the fol- the drug in humans, the side effects as- lowing is met: sociated with increasing doses, and, if (1) The sponsor’s compliance with the possible, to gain early evidence on ef- requirement is unnecessary for the fectiveness. During Phase 1, sufficient agency to evaluate the application, or information about the drug’s phar- compliance cannot be achieved; macokinetics and pharmacological ef- (2) The sponsor’s proposed alter- fects should be obtained to permit the native satisfies the requirement; or design of well-controlled, scientifically (3) The applicant’s submission other- valid, Phase 2 studies. The total num- wise justifies a waiver. ber of subjects and patients included in Phase 1 studies varies with the drug, [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9585, Mar. 4, but is generally in the range of 20 to 80. 2002] (2) Phase 1 studies also include studies of drug metabolism, structure-activity relationships, and mechanism of Subpart B—Investigational New action in humans, as well as studies in Drug Application (IND) which investigational drugs are used as research tools to explore biological § 312.20 Requirement for an IND. phenomena or disease processes. (a) A sponsor shall submit an IND to (b) Phase 2. Phase 2 includes the con- FDA if the sponsor intends to conduct trolled clinical studies conducted to a clinical investigation with an inves- evaluate the effectiveness of the drug tigational new drug that is subject to for a particular indication or indica- § 312.2(a). tions in patients with the disease or (b) A sponsor shall not begin a clin- condition under study and to deter- ical investigation subject to § 312.2(a) mine the common short-term side ef- until the investigation is subject to an fects and risks associated with the IND which is in effect in accordance drug. Phase 2 studies are typically well with § 312.40. controlled, closely monitored, and con- (c) A sponsor shall submit a separate ducted in a relatively small number of IND for any clinical investigation in- patients, usually involving no more volving an exception from informed than several hundred subjects. consent under § 50.24 of this chapter. (c) Phase 3. Phase 3 studies are ex- Such a clinical investigation is not panded controlled and uncontrolled permitted to proceed without the prior trials. They are performed after pre- written authorization from FDA. FDA liminary evidence suggesting effective- shall provide a written determination ness of the drug has been obtained, and 30 days after FDA receives the IND or are intended to gather the additional earlier. information about effectiveness and [52 FR 8831, Mar. 19, 1987, as amended at 61 safety that is needed to evaluate the FR 51529, Oct. 2, 1996; 62 FR 32479, June 16, overall benefit-risk relationship of the 1997] drug and to provide an adequate basis

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for physician labeling. Phase 3 studies the available information. Section usually include from several hundred 312.23 outlines the information needed to several thousand subjects. for a commercially sponsored IND for a new molecular entity. A sponsor-inves- § 312.22 General principles of the IND tigator who uses, as a research tool, an submission. investigational new drug that is al- (a) FDA’s primary objectives in re- ready subject to a manufacturer’s IND viewing an IND are, in all phases of the or marketing application should follow investigation, to assure the safety and the same general format, but ordi- rights of subjects, and, in Phase 2 and narily may, if authorized by the manu- 3, to help assure that the quality of the facturer, refer to the manufacturer’s scientific evaluation of drugs is ade- IND or marketing application in pro- quate to permit an evaluation of the viding the technical information sup- drug’s effectiveness and safety. There- porting the proposed clinical investiga- fore, although FDA’s review of Phase 1 tion. A sponsor-investigator who uses submissions will focus on assessing the an investigational drug not subject to safety of Phase 1 investigations, FDA’s a manufacturer’s IND or marketing ap- review of Phases 2 and 3 submissions plication is ordinarily required to sub- will also include an assessment of the mit all technical information sup- scientific quality of the clinical inves- porting the IND, unless such informa- tigations and the likelihood that the tion may be referenced from the sci- investigations will yield data capable entific literature. of meeting statutory standards for marketing approval. § 312.23 IND content and format. (b) The amount of information on a (a) A sponsor who intends to conduct particular drug that must be submitted a clinical investigation subject to this in an IND to assure the accomplish- part shall submit an ‘‘Investigational ment of the objectives described in New Drug Application’’ (IND) includ- paragraph (a) of this section depends ing, in the following order: upon such factors as the novelty of the (1) Cover sheet (Form FDA–1571). A drug, the extent to which it has been cover sheet for the application con- studied previously, the known or sustaining the following: pected risks, and the developmental (i) The name, address, and telephone phase of the drug. number of the sponsor, the date of the (c) The central focus of the initial application, and the name of the inves- IND submission should be on the gen- tigational new drug. eral investigational plan and the proto- (ii) Identification of the phase or cols for specific human studies. Subse- phases of the clinical investigation to quent amendments to the IND that be conducted. contain new or revised protocols should (iii) A commitment not to begin clin- build logically on previous submissions ical investigations until an IND cov- and should be supported by additional ering the investigations is in effect. information, including the results of (iv) A commitment that an Institu- animal toxicology studies or other tional Review Board (IRB) that com- human studies as appropriate. Annual plies with the requirements set forth in reports to the IND should serve as the part 56 will be responsible for the ini- focus for reporting the status of studies tial and continuing review and ap- being conducted under the IND and proval of each of the studies in the pro- should update the general investiga- posed clinical investigation and that tional plan for the coming year. the investigator will report to the IRB (d) The IND format set forth in proposed changes in the research activ- § 312.23 should be followed routinely by ity in accordance with the require- sponsors in the interest of fostering an ments of part 56. efficient review of applications. Spon- (v) A commitment to conduct the in- sors are expected to exercise consider- vestigation in accordance with all able discretion, however, regarding the other applicable regulatory require- content of information submitted in ments. each section, depending upon the kind (vi) The name and title of the person of drug being studied and the nature of responsible for monitoring the conduct

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and progress of the clinical investiga- include the following: (a) The rationale tions. for the drug or the research study; (b) (vii) The name(s) and title(s) of the the indication(s) to be studied; (c) the person(s) responsible under § 312.32 for general approach to be followed in review and evaluation of information evaluating the drug; (d) the kinds of relevant to the safety of the drug. clinical trials to be conducted in the (viii) If a sponsor has transferred any first year following the submission (if obligations for the conduct of any clin- plans are not developed for the entire ical study to a contract research orga- year, the sponsor should so indicate); nization, a statement containing the (e) the estimated number of patients to name and address of the contract re- be given the drug in those studies; and search organization, identification of (f) any risks of particular severity or the clinical study, and a listing of the seriousness anticipated on the basis of obligations transferred. If all obliga- the toxicological data in animals or tions governing the conduct of the prior studies in humans with the drug study have been transferred, a general or related drugs. statement of this transfer—in lieu of a (4) [Reserved] listing of the specific obligations trans- (5) Investigator’s brochure. If required ferred—may be submitted. under § 312.55, a copy of the investiga- (ix) The signature of the sponsor or tor’s brochure, containing the fol- the sponsor’s authorized representa- lowing information: tive. If the person signing the applica- (i) A brief description of the drug tion does not reside or have a place of substance and the formulation, includ- business within the United States, the ing the structural formula, if known. IND is required to contain the name (ii) A summary of the pharma- and address of, and be countersigned cological and toxicological effects of by, an attorney, agent, or other au- the drug in animals and, to the extent thorized official who resides or main- known, in humans. tains a place of business within the (iii) A summary of the pharmaco- United States. kinetics and biological disposition of (2) A table of contents. the drug in animals and, if known, in (3) Introductory statement and general humans. investigational plan. (i) A brief introduc- (iv) A summary of information relat- tory statement giving the name of the ing to safety and effectiveness in hu- drug and all active ingredients, the mans obtained from prior clinical stud- drug’s pharmacological class, the ies. (Reprints of published articles on structural formula of the drug (if such studies may be appended when known), the formulation of the dosage useful.) form(s) to be used, the route of admin- (v) A description of possible risks and istration, and the broad objectives and side effects to be anticipated on the planned duration of the proposed clin- basis of prior experience with the drug ical investigation(s). under investigation or with related (ii) A brief summary of previous drugs, and of precautions or special human experience with the drug, with monitoring to be done as part of the in- reference to other IND’s if pertinent, vestigational use of the drug. and to investigational or marketing ex- (6) Protocols. (i) A protocol for each perience in other countries that may planned study. (Protocols for studies be relevant to the safety of the pro- not submitted initially in the IND posed clinical investigation(s). should be submitted in accordance with (iii) If the drug has been withdrawn § 312.30(a).) In general, protocols for from investigation or marketing in any Phase 1 studies may be less detailed country for any reason related to safe- and more flexible than protocols for ty or effectiveness, identification of Phase 2 and 3 studies. Phase 1 protocols the country(ies) where the drug was should be directed primarily at pro- withdrawn and the reasons for the viding an outline of the investigation— withdrawal. an estimate of the number of patients (iv) A brief description of the overall to be involved, a description of safety plan for investigating the drug product exclusions, and a description of the for the following year. The plan should dosing plan including duration, dose, or

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method to be used in determining (f) A description of the observations dose—and should specify in detail only and measurements to be made to fulfill those elements of the study that are the objectives of the study. critical to safety, such as necessary (g) A description of clinical proce- monitoring of vital signs and blood dures, laboratory tests, or other meas- chemistries. Modifications of the ex- ures to be taken to monitor the effects perimental design of Phase 1 studies of the drug in human subjects and to that do not affect critical safety as- minimize risk. sessments are required to be reported (7) Chemistry, manufacturing, and con- to FDA only in the annual report. trol information. (i) As appropriate for (ii) In Phases 2 and 3, detailed proto- the particular investigations covered cols describing all aspects of the study by the IND, a section describing the should be submitted. A protocol for a composition, manufacture, and control Phase 2 or 3 investigation should be de- of the drug substance and the drug signed in such a way that, if the spon- product. Although in each phase of the sor anticipates that some deviation investigation sufficient information is from the study design may become nec- required to be submitted to assure the essary as the investigation progresses, proper identification, quality, purity, alternatives or contingencies to pro- and strength of the investigational vide for such deviation are built into drug, the amount of information need- the protocols at the outset. For exam- ed to make that assurance will vary ple, a protocol for a controlled short- with the phase of the investigation, the term study might include a plan for an proposed duration of the investigation, early crossover of nonresponders to an the dosage form, and the amount of in- alternative therapy. formation otherwise available. FDA (iii) A protocol is required to contain recognizes that modifications to the the following, with the specific ele- method of preparation of the new drug ments and detail of the protocol re- substance and dosage form and changes flecting the above distinctions depending on the phase of study: in the dosage form itself are likely as the investigation progresses. There- (a) A statement of the objectives and fore, the emphasis in an initial Phase 1 purpose of the study. submission should generally be placed (b) The name and address and a state- on the identification and control of the ment of the qualifications (curriculum raw materials and the new drug sub- vitae or other statement of qualifica- stance. Final specifications for the tions) of each investigator, and the name of each subinvestigator (e.g., re- drug substance and drug product are search fellow, resident) working under not expected until the end of the inves- the supervision of the investigator; the tigational process. name and address of the research fa- (ii) It should be emphasized that the cilities to be used; and the name and amount of information to be submitted address of each reviewing Institutional depends upon the scope of the proposed Review Board. clinical investigation. For example, al- (c) The criteria for patient selection though stability data are required in and for exclusion of patients and an es- all phases of the IND to demonstrate timate of the number of patients to be that the new drug substance and drug studied. product are within acceptable chemical (d) A description of the design of the and physical limits for the planned du- study, including the kind of control ration of the proposed clinical inves- group to be used, if any, and a descrip- tigation, if very short-term tests are tion of methods to be used to minimize proposed, the supporting stability data bias on the part of subjects, investiga- can be correspondingly limited. tors, and analysts. (iii) As drug development proceeds (e) The method for determining the and as the scale or production is dose(s) to be administered, the planned changed from the pilot-scale produc- maximum dosage, and the duration of tion appropriate for the limited initial individual patient exposure to the clinical investigations to the larger- drug. scale production needed for expanded

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clinical trials, the sponsor should sub- of any placebo used in a controlled mit information amendments to sup- clinical trial. plement the initial information sub- (d) Labeling. A copy of all labels and mitted on the chemistry, manufac- labeling to be provided to each investi- turing, and control processes with in- gator. formation appropriate to the expanded (e) Environmental analysis require- scope of the investigation. ments. A claim for categorical exclu- (iv) Reflecting the distinctions de- sion under § 25.30 or 25.31 or an environ- scribed in this paragraph (a)(7), and mental assessment under § 25.40. based on the phase(s) to be studied, the (8) Pharmacology and toxicology infor- submission is required to contain the mation. Adequate information about following: pharmacological and toxicological (a) Drug substance. A description of studies of the drug involving labora- the drug substance, including its phys- tory animals or in vitro, on the basis of ical, chemical, or biological character- which the sponsor has concluded that istics; the name and address of its man- it is reasonably safe to conduct the ufacturer; the general method of prepa- proposed clinical investigations. The ration of the drug substance; the ac- kind, duration, and scope of animal and ceptable limits and analytical methods other tests required varies with the du- used to assure the identity, strength, ration and nature of the proposed clin- quality, and purity of the drug sub- ical investigations. Guidance docu- stance; and information sufficient to ments are available from FDA that de- support stability of the drug substance scribe ways in which these require- during the toxicological studies and ments may be met. Such information is the planned clinical studies. Reference required to include the identification to the current edition of the United and qualifications of the individuals States Pharmacopeia—National For- who evaluated the results of such stud- mulary may satisfy relevant require- ies and concluded that it is reasonably ments in this paragraph. safe to begin the proposed investiga- (b) Drug product. A list of all compo- tions and a statement of where the in- nents, which may include reasonable vestigations were conducted and where alternatives for inactive compounds, the records are available for inspec- used in the manufacture of the inves- tion. As drug development proceeds, tigational drug product, including both the sponsor is required to submit infor- those components intended to appear mational amendments, as appropriate, in the drug product and those which with additional information pertinent may not appear but which are used in to safety. the manufacturing process, and, where (i) Pharmacology and drug disposition. applicable, the quantitative composi- A section describing the pharma- tion of the investigational drug prod- cological effects and mechanism(s) of uct, including any reasonable vari- action of the drug in animals, and in- ations that may be expected during the formation on the absorption, distribu- investigational stage; the name and ad- tion, metabolism, and excretion of the dress of the drug product manufac- drug, if known. turer; a brief general description of the (ii) Toxicology. (a) An integrated sum- manufacturing and packaging proce- mary of the toxicological effects of the dure as appropriate for the product; the drug in animals and in vitro. Depend- acceptable limits and analytical meth- ing on the nature of the drug and the ods used to assure the identity, phase of the investigation, the descrip- strength, quality, and purity of the tion is to include the results of acute, drug product; and information suffi- subacute, and chronic toxicity tests; cient to assure the product’s stability tests of the drug’s effects on reproduc- during the planned clinical studies. tion and the developing fetus; any spe- Reference to the current edition of the cial toxicity test related to the drug’s United States Pharmacopeia—National particular mode of administration or Formulary may satisfy certain require- conditions of use (e.g., inhalation, der- ments in this paragraph. mal, or ocular toxicology); and any in (c) A brief general description of the vitro studies intended to evaluate drug composition, manufacture, and control toxicity.

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(b) For each toxicology study that is countries in which the drug has been intended primarily to support the safe- marketed and a list of the countries in ty of the proposed clinical investiga- which the drug has been withdrawn tion, a full tabulation of data suitable from marketing for reasons potentially for detailed review. related to safety or effectiveness. (iii) For each nonclinical laboratory (10) Additional information. In certain study subject to the good laboratory applications, as described below, infor- practice regulations under part 58, a mation on special topics may be need- statement that the study was con- ed. Such information shall be sub- ducted in compliance with the good mitted in this section as follows: laboratory practice regulations in part (i) Drug dependence and abuse poten- 58, or, if the study was not conducted tial. If the drug is a psychotropic sub- in compliance with those regulations, a stance or otherwise has abuse poten- brief statement of the reason for the tial, a section describing relevant clin- noncompliance. ical studies and experience and studies (9) Previous human experience with the in test animals. investigational drug. A summary of pre- (ii) Radioactive drugs. If the drug is a vious human experience known to the radioactive drug, sufficient data from applicant, if any, with the investiga- animal or human studies to allow a tional drug. The information is re- reasonable calculation of radiation-ab- quired to include the following: sorbed dose to the whole body and crit- (i) If the investigational drug has ical organs upon administration to a been investigated or marketed pre- human subject. Phase 1 studies of ra- viously, either in the United States or dioactive drugs must include studies other countries, detailed information which will obtain sufficient data for about such experience that is relevant dosimetry calculations. to the safety of the proposed investiga- (iii) Pediatric studies. Plans for assess- tion or to the investigation’s rationale. ing pediatric safety and effectiveness. If the drug has been the subject of con- (iv) Other information. A brief state- trolled trials, detailed information on ment of any other information that such trials that is relevant to an as- would aid evaluation of the proposed sessment of the drug’s effectiveness for clinical investigations with respect to the proposed investigational use(s) their safety or their design and poten- should also be provided. Any published tial as controlled clinical trials to sup- material that is relevant to the safety port marketing of the drug. of the proposed investigation or to an (11) Relevant information. If requested assessment of the drug’s effectiveness by FDA, any other relevant informa- for its proposed investigational use tion needed for review of the applica- should be provided in full. Published tion. material that is less directly relevant (b) Information previously submitted. may be supplied by a bibliography. The sponsor ordinarily is not required (ii) If the drug is a combination of to resubmit information previously drugs previously investigated or mar- submitted, but may incorporate the in- keted, the information required under formation by reference. A reference to paragraph (a)(9)(i) of this section information submitted previously must should be provided for each active drug identify the file by name, reference component. However, if any component number, volume, and page number in such combination is subject to an where the information can be found. A approved marketing application or is reference to information submitted to otherwise lawfully marketed in the the agency by a person other than the United States, the sponsor is not re- sponsor is required to contain a writ- quired to submit published material ten statement that authorizes the ref- concerning that active drug component erence and that is signed by the person unless such material relates directly to who submitted the information. the proposed investigational use (in- (c) Material in a foreign language. The cluding publications relevant to com- sponsor shall submit an accurate and ponent-component interaction). complete English translation of each (iii) If the drug has been marketed part of the IND that is not in English. outside the United States, a list of the The sponsor shall also submit a copy of

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each original literature publication for view and approval of the study in ac- which an English translation is sub- cordance with the requirements of part mitted. 56. The sponsor may comply with these (d) Number of copies. The sponsor two conditions in either order. shall submit an original and two copies (b) Changes in a protocol. (1) A sponsor of all submissions to the IND file, in- shall submit a protocol amendment de- cluding the original submission and all scribing any change in a Phase 1 pro- amendments and reports. tocol that significantly affects the (e) Numbering of IND submissions. safety of subjects or any change in a Each submission relating to an IND is Phase 2 or 3 protocol that significantly required to be numbered serially using affects the safety of subjects, the scope a single, three-digit serial number. The of the investigation, or the scientific initial IND is required to be numbered quality of the study. Examples of 000; each subsequent submission (e.g., changes requiring an amendment under amendment, report, or correspondence) this paragraph include: is required to be numbered chrono- (i) Any increase in drug dosage or du- logically in sequence. ration of exposure of individual sub- (f) Identification of exception from in- jects to the drug beyond that in the formed consent. If the investigation in- current protocol, or any significant involves an exception from informed con- crease in the number of subjects under sent under § 50.24 of this chapter, the study. sponsor shall prominently identify on (ii) Any significant change in the de- the cover sheet that the investigation sign of a protocol (such as the addition is subject to the requirements in § 50.24 or dropping of a control group). of this chapter. (iii) The addition of a new test or [52 FR 8831, Mar. 19, 1987, as amended at 52 procedure that is intended to improve FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, monitoring for, or reduce the risk of, a 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599, side effect or adverse event; or the July 29, 1997; 63 FR 66669, Dec. 2, 1998; 65 FR dropping of a test intended to monitor 56479, Sept. 19, 2000; 67 FR 9585, Mar. 4, 2002] safety. (2)(i) A protocol change under para- § 312.30 Protocol amendments. graph (b)(1) of this section may be Once an IND is in effect, a sponsor made provided two conditions are met: shall amend it as needed to ensure that (a) The sponsor has submitted the the clinical investigations are con- change to FDA for its review; and ducted according to protocols included (b) The change has been approved by in the application. This section sets the IRB with responsibility for review forth the provisions under which new and approval of the study. The sponsor protocols may be submitted and may comply with these two conditions changes in previously submitted proto- in either order. cols may be made. Whenever a sponsor (ii) Notwithstanding paragraph intends to conduct a clinical investiga- (b)(2)(i) of this section, a protocol tion with an exception from informed change intended to eliminate an appar- consent for emergency research as set ent immediate hazard to subjects may forth in § 50.24 of this chapter, the spon- be implemented immediately provided sor shall submit a separate IND for FDA is subsequently notified by pro- such investigation. tocol amendment and the reviewing (a) New protocol. Whenever a sponsor IRB is notified in accordance with intends to conduct a study that is not § 56.104(c). covered by a protocol already con- (c) New investigator. A sponsor shall tained in the IND, the sponsor shall submit a protocol amendment when a submit to FDA a protocol amendment new investigator is added to carry out containing the protocol for the study. a previously submitted protocol, except Such study may begin provided two that a protocol amendment is not re- conditions are met: (1) The sponsor has quired when a licensed practitioner is submitted the protocol to FDA for its added in the case of a treatment pro- review; and (2) the protocol has been tocol under § 312.315 or § 312.320. Once approved by the Institutional Review the investigator is added to the study, Board (IRB) with responsibility for re- the investigational drug may be

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shipped to the investigator and the in- sible, to include these all in a single vestigator may begin participating in submission. the study. The sponsor shall notify [52 FR 8831, Mar. 19, 1987, as amended at 52 FDA of the new investigator within 30 FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, days of the investigator being added. 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. (d) Content and format. A protocol 4, 2002; 74 FR 40942, Aug. 13, 2009] amendment is required to be prominently identified as such (i.e., ‘‘Pro- § 312.31 Information amendments. tocol Amendment: New Protocol’’, (a) Requirement for information amend- ‘‘Protocol Amendment: Change in Pro- ment. A sponsor shall report in an in- tocol’’, or ‘‘Protocol Amendment: New formation amendment essential infor- Investigator’’), and to contain the fol- mation on the IND that is not within lowing: the scope of a protocol amendment, (1)(i) In the case of a new protocol, a IND safety reports, or annual report. copy of the new protocol and a brief de- Examples of information requiring an scription of the most clinically signifi- information amendment include: cant differences between it and pre- (1) New toxicology, chemistry, or vious protocols. other technical information; or (2) A report regarding the discontinu- (ii) In the case of a change in pro- ance of a clinical investigation. tocol, a brief description of the change (b) Content and format of an informa- and reference (date and number) to the tion amendment. An information amend- submission that contained the pro- ment is required to bear prominent tocol. identification of its contents (e.g., ‘‘In- (iii) In the case of a new investigator, formation Amendment: Chemistry, the investigator’s name, the qualifica- Manufacturing, and Control’’, ‘‘Infor- tions to conduct the investigation, ref- mation Amendment: Pharmacology- erence to the previously submitted pro- Toxicology’’, ‘‘Information Amend- tocol, and all additional information ment: Clinical’’), and to contain the about the investigator’s study as is re- following: quired under § 312.23(a)(6)(iii)(b). (1) A statement of the nature and (2) Reference, if necessary, to specific purpose of the amendment. technical information in the IND or in (2) An organized submission of the a concurrently submitted information data in a format appropriate for sci- amendment to the IND that the spon- entific review. sor relies on to support any clinically (3) If the sponsor desires FDA to com- significant change in the new or ment on an information amendment, a amended protocol. If the reference is request for such comment. made to supporting information al- (c) When submitted. Information ready in the IND, the sponsor shall amendments to the IND should be sub- identify by name, reference number, mitted as necessary but, to the extent volume, and page number the location feasible, not more than every 30 days. of the information. [52 FR 8831, Mar. 19, 1987, as amended at 52 (3) If the sponsor desires FDA to com- FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, ment on the submission, a request for 1988; 67 FR 9585, Mar. 4, 2002] such comment and the specific questions FDA’s response should address. § 312.32 IND safety reporting. (e) When submitted. A sponsor shall (a) Definitions. The following defini- submit a protocol amendment for a tions of terms apply to this section: new protocol or a change in protocol Adverse event means any untoward before its implementation. Protocol medical occurrence associated with the amendments to add a new investigator use of a drug in humans, whether or or to provide additional information not considered drug related. about investigators may be grouped Life-threatening adverse event or life- and submitted at 30-day intervals. threatening suspected adverse reaction. When several submissions of new proto- An adverse event or suspected adverse cols or protocol changes are antici- reaction is considered ‘‘life-threat- pated during a short period, the spon- ening’’ if, in the view of either the in- sor is encouraged, to the extent fea- vestigator or sponsor, its occurrence

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places the patient or subject at imme- in the current application, as amended. diate risk of death. It does not include For example, under this definition, he- an adverse event or suspected adverse patic necrosis would be unexpected (by reaction that, had it occurred in a virtue of greater severity) if the inves- more severe form, might have caused tigator brochure referred only to ele- death. vated hepatic enzymes or hepatitis. Serious adverse event or serious sus- Similarly, cerebral thromboembolism pected adverse reaction. An adverse and cerebral vasculitis would be unex- event or suspected adverse reaction is pected (by virtue of greater specificity) considered ‘‘serious’’ if, in the view of if the investigator brochure listed only either the investigator or sponsor, it cerebral vascular accidents. ‘‘Unex- results in any of the following out- pected,’’ as used in this definition, also comes: Death, a life-threatening ad- refers to adverse events or suspected verse event, inpatient hospitalization adverse reactions that are mentioned or prolongation of existing hospitaliza- in the investigator brochure as occur- tion, a persistent or significant inca- ring with a class of drugs or as antici- pacity or substantial disruption of the pated from the pharmacological prop- ability to conduct normal life func- erties of the drug, but are not specifi- tions, or a congenital anomaly/birth cally mentioned as occurring with the defect. Important medical events that particular drug under investigation. may not result in death, be life-threat- (b) Review of safety information. The ening, or require hospitalization may sponsor must promptly review all in- be considered serious when, based upon formation relevant to the safety of the appropriate medical judgment, they drug obtained or otherwise received by may jeopardize the patient or subject the sponsor from foreign or domestic and may require medical or surgical sources, including information derived intervention to prevent one of the out- from any clinical or epidemiological comes listed in this definition. Exam- investigations, animal or in vitro stud- ples of such medical events include al- ies, reports in the scientific literature, lergic bronchospasm requiring inten- and unpublished scientific papers, as sive treatment in an emergency room well as reports from foreign regulatory or at home, blood dyscrasias or convul- authorities and reports of foreign com- sions that do not result in inpatient mercial marketing experience for drugs hospitalization, or the development of that are not marketed in the United drug dependency or drug abuse. States. Suspected adverse reaction means any (c)(1) IND safety reports. The sponsor adverse event for which there is a rea- must notify FDA and all participating sonable possibility that the drug investigators (i.e., all investigators to caused the adverse event. For the pur- whom the sponsor is providing drug poses of IND safety reporting, ‘‘reason- under its INDs or under any investiga- able possibility’’ means there is evi- tor’s IND) in an IND safety report of dence to suggest a causal relationship potential serious risks, from clinical between the drug and the adverse trials or any other source, as soon as event. Suspected adverse reaction impossible, but in no case later than 15 plies a lesser degree of certainty about calendar days after the sponsor deter- causality than adverse reaction, which mines that the information qualifies means any adverse event caused by a for reporting under paragraph (c)(1)(i), drug. (c)(1)(ii), (c)(1)(iii), or (c)(1)(iv) of this Unexpected adverse event or unexpected section. In each IND safety report, the suspected adverse reaction. An adverse sponsor must identify all IND safety event or suspected adverse reaction is reports previously submitted to FDA considered ‘‘unexpected’’ if it is not concerning a similar suspected adverse listed in the investigator brochure or is reaction, and must analyze the signifi- not listed at the specificity or severity cance of the suspected adverse reaction that has been observed; or, if an inves- in light of previous, similar reports or tigator brochure is not required or any other relevant information. available, is not consistent with the (i) Serious and unexpected suspected risk information described in the gen- adverse reaction. The sponsor must re- eral investigational plan or elsewhere port any suspected adverse reaction

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that is both serious and unexpected. pects of the overall conduct of the clin- The sponsor must report an adverse ical investigation. event as a suspected adverse reaction (iv) Increased rate of occurrence of seri- only if there is evidence to suggest a ous suspected adverse reactions. The causal relationship between the drug sponsor must report any clinically im- and the adverse event, such as: portant increase in the rate of a seri- (A) A single occurrence of an event ous suspected adverse reaction over that is uncommon and known to be that listed in the protocol or investi- strongly associated with drug exposure gator brochure. (e.g., angioedema, hepatic injury, Ste- (v) Submission of IND safety reports. vens-Johnson Syndrome); The sponsor must submit each IND (B) One or more occurrences of an safety report in a narrative format or event that is not commonly associated on FDA Form 3500A or in an electronic with drug exposure, but is otherwise format that FDA can process, review, uncommon in the population exposed and archive. FDA will periodically to the drug (e.g., tendon rupture); issue guidance on how to provide the (C) An aggregate analysis of specific electronic submission (e.g., method of events observed in a clinical trial (such transmission, media, file formats, prep- as known consequences of the under- aration and organization of files). The lying disease or condition under inves- sponsor may submit foreign suspected tigation or other events that com- adverse reactions on a Council for monly occur in the study population International Organizations of Medical independent of drug therapy) that indi- Sciences (CIOMS) I Form instead of a cates those events occur more fre- FDA Form 3500A. Reports of overall quently in the drug treatment group findings or pooled analyses from pub- than in a concurrent or historical con- lished and unpublished in vitro, ani- trol group. mal, epidemiological, or clinical stud- (ii) Findings from other studies. The ies must be submitted in a narrative sponsor must report any findings from format. Each notification to FDA must epidemiological studies, pooled anal- bear prominent identification of its ysis of multiple studies, or clinical contents, i.e., ‘‘IND Safety Report,’’ studies (other than those reported and must be transmitted to the review under paragraph (c)(1)(i) of this sec- division in the Center for Drug Evalua- tion), whether or not conducted under tion and Research or in the Center for an IND, and whether or not conducted Biologics Evaluation and Research by the sponsor, that suggest a signifi- that has responsibility for review of cant risk in humans exposed to the the IND. Upon request from FDA, the drug. Ordinarily, such a finding would sponsor must submit to FDA any addi- result in a safety-related change in the tional data or information that the protocol, informed consent, investi- agency deems necessary, as soon as gator brochure (excluding routine up- possible, but in no case later than 15 dates of these documents), or other as- calendar days after receiving the re- pects of the overall conduct of the clin- quest. ical investigation. (2) Unexpected fatal or life-threatening (iii) Findings from animal or in vitro suspected adverse reaction reports. The testing. The sponsor must report any sponsor must also notify FDA of any findings from animal or in vitro test- unexpected fatal or life-threatening ing, whether or not conducted by the suspected adverse reaction as soon as sponsor, that suggest a significant risk possible but in no case later than 7 cal- in humans exposed to the drug, such as endar days after the sponsor’s initial reports of mutagenicity, receipt of the information. teratogenicity, or carcinogenicity, or (3) Reporting format or frequency. FDA reports of significant organ toxicity at may require a sponsor to submit IND or near the expected human exposure. safety reports in a format or at a fre- Ordinarily, any such findings would re- quency different than that required sult in a safety-related change in the under this paragraph. The sponsor may protocol, informed consent, investi- also propose and adopt a different re- gator brochure (excluding routine up- porting format or frequency if the dates of these documents), or other as- change is agreed to in advance by the

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director of the FDA review division tributed to an adverse event. A sponsor that has responsibility for review of need not admit, and may deny, that the IND. the report or information submitted by (4) Investigations of marketed drugs. A the sponsor constitutes an admission sponsor of a clinical study of a drug that the drug caused or contributed to marketed or approved in the United an adverse event. States that is conducted under an IND [75 FR 59961, Sept. 29, 2010] is required to submit IND safety reports for suspected adverse reactions § 312.33 Annual reports. that are observed in the clinical study, A sponsor shall within 60 days of the at domestic or foreign study sites. The anniversary date that the IND went sponsor must also submit safety infor- into effect, submit a brief report of the mation from the clinical study as pre- progress of the investigation that in- scribed by the postmarketing safety re- cludes: porting requirements (e.g., §§ 310.305, (a) Individual study information. A 314.80, and 600.80 of this chapter). brief summary of the status of each (5) Reporting study endpoints. Study study in progress and each study com- endpoints (e.g., mortality or major pleted during the previous year. The morbidity) must be reported to FDA by summary is required to include the fol- the sponsor as described in the protocol lowing information for each study: and ordinarily would not be reported (1) The title of the study (with any under paragraph (c) of this section. appropriate study identifiers such as However, if a serious and unexpected protocol number), its purpose, a brief adverse event occurs for which there is statement identifying the patient pop- evidence suggesting a causal relation- ulation, and a statement as to whether ship between the drug and the event the study is completed. (e.g., death from anaphylaxis), the (2) The total number of subjects ini- event must be reported under tially planned for inclusion in the § 312.32(c)(1)(i) as a serious and unex- study; the number entered into the pected suspected adverse reaction even study to date, tabulated by age group, if it is a component of the study end- gender, and race; the number whose point (e.g., all-cause mortality). participation in the study was com- (d) Followup. (1) The sponsor must pleted as planned; and the number who promptly investigate all safety infor- dropped out of the study for any rea- mation it receives. son. (2) Relevant followup information to (3) If the study has been completed, an IND safety report must be sub- or if interim results are known, a brief mitted as soon as the information is description of any available study re- available and must be identified as sults. such, i.e., ‘‘Followup IND Safety Re- (b) Summary information. Information port.’’ obtained during the previous year’s (3) If the results of a sponsor’s inves- clinical and nonclinical investigations, tigation show that an adverse event including: not initially determined to be report- (1) A narrative or tabular summary able under paragraph (c) of this section showing the most frequent and most is so reportable, the sponsor must re- serious adverse experiences by body port such suspected adverse reaction in system. an IND safety report as soon as pos- (2) A summary of all IND safety re- sible, but in no case later than 15 cal- ports submitted during the past year. endar days after the determination is (3) A list of subjects who died during made. participation in the investigation, with (e) Disclaimer. A safety report or the cause of death for each subject. other information submitted by a spon- (4) A list of subjects who dropped out sor under this part (and any release by during the course of the investigation FDA of that report or information) in association with any adverse experi- does not necessarily reflect a conclu- ence, whether or not thought to be sion by the sponsor or FDA that the re- drug related. port or information constitutes an ad- (5) A brief description of what, if any- mission that the drug caused or con- thing, was obtained that is pertinent to

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an understanding of the drug’s actions, Institutional Review Boards, together including, for example, information with the reasons for such withdrawal. about dose response, information from [52 FR 8831, Mar. 19, 1987, as amended at 52 controlled trials, and information FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, about bioavailability. 2002] (6) A list of the preclinical studies (including animal studies) completed Subpart C—Administrative Actions or in progress during the past year and a summary of the major preclinical § 312.40 General requirements for use findings. of an investigational new drug in a (7) A summary of any significant clinical investigation. manufacturing or microbiological (a) An investigational new drug may changes made during the past year. be used in a clinical investigation if (c) A description of the general inves- the following conditions are met: tigational plan for the coming year to (1) The sponsor of the investigation replace that submitted 1 year earlier. submits an IND for the drug to FDA; The general investigational plan shall the IND is in effect under paragraph (b) contain the information required under of this section; and the sponsor com- § 312.23(a)(3)(iv). plies with all applicable requirements (d) If the investigator brochure has in this part and parts 50 and 56 with re- been revised, a description of the revi- spect to the conduct of the clinical in- sion and a copy of the new brochure. vestigations; and (e) A description of any significant (2) Each participating investigator Phase 1 protocol modifications made conducts his or her investigation in during the previous year and not pre- compliance with the requirements of viously reported to the IND in a pro- this part and parts 50 and 56. tocol amendment. (b) An IND goes into effect: (f) A brief summary of significant (1) Thirty days after FDA receives foreign marketing developments with the IND, unless FDA notifies the spon- the drug during the past year, such as sor that the investigations described in approval of marketing in any country the IND are subject to a clinical hold or withdrawal or suspension from mar- under § 312.42; or keting in any country. (2) On earlier notification by FDA (g) If desired by the sponsor, a log of that the clinical investigations in the any outstanding business with respect IND may begin. FDA will notify the to the IND for which the sponsor re- sponsor in writing of the date it requests or expects a reply, comment, or ceives the IND. meeting. (c) A sponsor may ship an investiga- [52 FR 8831, Mar. 19, 1987, as amended at 52 tional new drug to investigators named FR 23031, June 17, 1987; 63 FR 6862, Feb. 11, in the IND: 1998; 67 FR 9585, Mar. 4, 2002] (1) Thirty days after FDA receives the IND; or § 312.38 Withdrawal of an IND. (2) On earlier FDA authorization to (a) At any time a sponsor may with- ship the drug. draw an effective IND without preju- (d) An investigator may not admin- dice. ister an investigational new drug to (b) If an IND is withdrawn, FDA shall human subjects until the IND goes into be so notified, all clinical investiga- effect under paragraph (b) of this sections conducted under the IND shall be tion. ended, all current investigators notified, and all stocks of the drug re- § 312.41 Comment and advice on an turned to the sponsor or otherwise dis- IND. posed of at the request of the sponsor (a) FDA may at any time during the in accordance with § 312.59. course of the investigation commu- (c) If an IND is withdrawn because of nicate with the sponsor orally or in a safety reason, the sponsor shall writing about deficiencies in the IND promptly so inform FDA, all partici- or about FDA’s need for more data or pating investigators, and all reviewing information.

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(b) On the sponsor’s request, FDA (iv) The IND does not contain suffi- will provide advice on specific matters cient information required under relating to an IND. Examples of such § 312.23 to assess the risks to subjects of advice may include advice on the ade- the proposed studies. quacy of technical data to support an (v) The IND is for the study of an in- investigational plan, on the design of a vestigational drug intended to treat a clinical trial, and on whether proposed life-threatening disease or condition investigations are likely to produce the that affects both genders, and men or data and information that is needed to women with reproductive potential meet requirements for a marketing ap- who have the disease or condition plication. being studied are excluded from eligi- (c) Unless the communication is ac- bility because of a risk or potential companied by a clinical hold order risk from use of the investigational under § 312.42, FDA communications drug of reproductive toxicity (i.e., af- with a sponsor under this section are fecting reproductive organs) or devel- solely advisory and do not require any opmental toxicity (i.e., affecting poten- modification in the planned or ongoing tial offspring). The phrase ‘‘women clinical investigations or response to with reproductive potential’’ does not the agency. include pregnant women. For purposes [52 FR 8831, Mar. 19, 1987, as amended at 52 of this paragraph, ‘‘life-threatening ill- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, nesses or diseases’’ are defined as ‘‘dis- 2002] eases or conditions where the likelihood of death is high unless the course § 312.42 Clinical holds and requests for of the disease is interrupted.’’ The clin- modification. ical hold would not apply under this (a) General. A clinical hold is an order paragraph to clinical studies con- issued by FDA to the sponsor to delay ducted: a proposed clinical investigation or to (A) Under special circumstances, suspend an ongoing investigation. The such as studies pertinent only to one clinical hold order may apply to one or gender (e.g., studies evaluating the ex- more of the investigations covered by cretion of a drug in semen or the ef- an IND. When a proposed study is fects on menstrual function); placed on clinical hold, subjects may (B) Only in men or women, as long as not be given the investigational drug. a study that does not exclude members When an ongoing study is placed on of the other gender with reproductive clinical hold, no new subjects may be potential is being conducted concur- recruited to the study and placed on rently, has been conducted, or will the investigational drug; patients al- take place within a reasonable time ready in the study should be taken off agreed upon by the agency; or therapy involving the investigational (C) Only in subjects who do not suffer drug unless specifically permitted by from the disease or condition for which FDA in the interest of patient safety. the drug is being studied. (b) Grounds for imposition of clinical (2) Clinical hold of a Phase 2 or 3 study hold—(1) Clinical hold of a Phase 1 study under an IND. FDA may place a pro- under an IND. FDA may place a proposed or ongoing Phase 2 or 3 inves- posed or ongoing Phase 1 investigation tigation on clinical hold if it finds on clinical hold if it finds that: that: (i) Human subjects are or would be (i) Any of the conditions in para- exposed to an unreasonable and signifi- graphs (b)(1)(i) through (b)(1)(v) of this cant risk of illness or injury; section apply; or (ii) The clinical investigators named (ii) The plan or protocol for the in- in the IND are not qualified by reason vestigation is clearly deficient in de- of their scientific training and experi- sign to meet its stated objectives. ence to conduct the investigation de- (3) Clinical hold of an expanded access scribed in the IND; IND or expanded access protocol. FDA (iii) The investigator brochure is may place an expanded access IND or misleading, erroneous, or materially expanded access protocol on clinical incomplete; or hold under the following conditions:

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(i) Final use. FDA may place a pro- controlled investigation is not actively posed expanded access IND or treat- pursuing marketing approval of the in- ment use protocol on clinical hold if it vestigational drug with due diligence; is determined that: or (A) The pertinent criteria in subpart (viii) The Commissioner determines I of this part for permitting the ex- that it would not be in the public inter- panded access use to begin are not sat- est for the study to be conducted or isfied; or continued. FDA ordinarily intends that (B) The expanded access IND or ex- clinical holds under paragraphs panded access protocol does not comply (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this with the requirements for expanded ac- section would only apply to additional cess submissions in subpart I of this enrollment in nonconcurrently con- part. trolled trials rather than eliminating (ii) Ongoing use. FDA may place an continued access to individuals already ongoing expanded access IND or ex- receiving the investigational drug. panded access protocol on clinical hold (5) Clinical hold of any investigation in- if it is determined that the pertinent volving an exception from informed con- criteria in subpart I of this part for sent under § 50.24 of this chapter. FDA permitting the expanded access are no may place a proposed or ongoing inves- longer satisfied. tigation involving an exception from (4) Clinical hold of any study that is informed consent under § 50.24 of this not designed to be adequate and well-con- chapter on clinical hold if it is deter- trolled. FDA may place a proposed or mined that: ongoing investigation that is not de- (i) Any of the conditions in para- signed to be adequate and well-con- graphs (b)(1) or (b)(2) of this section trolled on clinical hold if it finds that: apply; or (i) Any of the conditions in para- (ii) The pertinent criteria in § 50.24 of graph (b)(1) or (b)(2) of this section this chapter for such an investigation apply; or to begin or continue are not submitted (ii) There is reasonable evidence the or not satisfied. investigation that is not designed to be (6) Clinical hold of any investigation adequate and well-controlled is imped- involving an exception from informed ing enrollment in, or otherwise inter- consent under § 50.23(d) of this chapter. fering with the conduct or completion FDA may place a proposed or ongoing of, a study that is designed to be an investigation involving an exception adequate and well-controlled investiga- from informed consent under § 50.23(d) tion of the same or another investiga- of this chapter on clinical hold if it is tional drug; or determined that: (iii) Insufficient quantities of the in- (i) Any of the conditions in para- vestigational drug exist to adequately graphs (b)(1) or (b)(2) of this section conduct both the investigation that is apply; or not designed to be adequate and well- (ii) A determination by the President controlled and the investigations that to waive the prior consent requirement are designed to be adequate and well- for the administration of an investiga- controlled; or tional new drug has not been made. (iv) The drug has been studied in one (c) Discussion of deficiency. Whenever or more adequate and well-controlled FDA concludes that a deficiency exists investigations that strongly suggest in a clinical investigation that may be lack of effectiveness; or grounds for the imposition of clinical (v) Another drug under investigation hold FDA will, unless patients are ex- or approved for the same indication posed to immediate and serious risk, and available to the same patient popu- attempt to discuss and satisfactorily lation has demonstrated a better po- resolve the matter with the sponsor be- tential benefit/risk balance; or fore issuing the clinical hold order. (vi) The drug has received marketing (d) Imposition of clinical hold. The approval for the same indication in the clinical hold order may be made by same patient population; or telephone or other means of rapid com- (vii) The sponsor of the study that is munication or in writing. The clinical designed to be an adequate and well- hold order will identify the studies

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under the IND to which the hold ap- be placed on inactive status by FDA plies, and will briefly explain the basis under § 312.45. for the action. The clinical hold order [52 FR 8831, Mar. 19, 1987, as amended at 52 will be made by or on behalf of the Di- FR 19477, May 22, 1987; 57 FR 13249, Apr. 15, vision Director with responsibility for 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, review of the IND. As soon as possible, Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR and no more than 30 days after imposi- 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009] tion of the clinical hold, the Division § 312.44 Termination. Director will provide the sponsor a written explanation of the basis for the (a) General. This section describes the hold. procedures under which FDA may terminate an IND. If an IND is termi- (e) Resumption of clinical investiga- nated, the sponsor shall end all clinical tions. An investigation may only re- investigations conducted under the sume after FDA (usually the Division IND and recall or otherwise provide for Director, or the Director’s designee, the disposition of all unused supplies of with responsibility for review of the the drug. A termination action may be IND) has notified the sponsor that the based on deficiencies in the IND or in investigation may proceed. Resump- the conduct of an investigation under tion of the affected investigation(s) an IND. Except as provided in para- will be authorized when the sponsor graph (d) of this section, a termination corrects the deficiency(ies) previously shall be preceded by a proposal to ter- cited or otherwise satisfies the agency minate by FDA and an opportunity for that the investigation(s) can proceed. the sponsor to respond. FDA will, in FDA may notify a sponsor of its deter- general, only initiate an action under mination regarding the clinical hold by this section after first attempting to telephone or other means of rapid com- resolve differences informally or, when munication. If a sponsor of an IND that appropriate, through the clinical hold has been placed on clinical hold re- procedures described in § 312.42. quests in writing that the clinical hold (b) Grounds for termination—(1) Phase be removed and submits a complete re- 1. FDA may propose to terminate an sponse to the issue(s) identified in the IND during Phase 1 if it finds that: clinical hold order, FDA shall respond (i) Human subjects would be exposed in writing to the sponsor within 30-cal- to an unreasonable and significant risk of illness or injury. endar days of receipt of the request and (ii) The IND does not contain suffi- the complete response. FDA’s response cient information required under will either remove or maintain the § 312.23 to assess the safety to subjects clinical hold, and will state the reasons of the clinical investigations. for such determination. Notwith- (iii) The methods, facilities, and con- standing the 30-calendar day response trols used for the manufacturing, proc- time, a sponsor may not proceed with a essing, and packing of the investiga- clinical trial on which a clinical hold tional drug are inadequate to establish has been imposed until the sponsor has and maintain appropriate standards of been notified by FDA that the hold has identity, strength, quality, and purity been lifted. as needed for subject safety. (f) Appeal. If the sponsor disagrees (iv) The clinical investigations are with the reasons cited for the clinical being conducted in a manner substan- hold, the sponsor may request recon- tially different than that described in sideration of the decision in accord- the protocols submitted in the IND. ance with § 312.48. (v) The drug is being promoted or dis- (g) Conversion of IND on clinical hold tributed for commercial purposes not to inactive status. If all investigations justified by the requirements of the in- covered by an IND remain on clinical vestigation or permitted by § 312.7. hold for 1 year or more, the IND may (vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

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(vii) The sponsor fails promptly to in- the nonacceptance and provide the vestigate and inform the Food and sponsor with an opportunity for a regu- Drug Administration and all investiga- latory hearing before FDA under part tors of serious and unexpected adverse 16 on the question of whether the IND experiences in accordance with § 312.32 should be terminated. The sponsor’s re- or fails to make any other report request for a regulatory hearing must be quired under this part. made within 10 days of the sponsor’s (viii) The sponsor fails to submit an receipt of FDA’s notification of non- accurate annual report of the inves- acceptance. tigations in accordance with § 312.33. (d) Immediate termination of IND. Not- (ix) The sponsor fails to comply with withstanding paragraphs (a) through any other applicable requirement of (c) of this section, if at any time FDA this part, part 50, or part 56. concludes that continuation of the in- (x) The IND has remained on inactive vestigation presents an immediate and status for 5 years or more. substantial danger to the health of in- (xi) The sponsor fails to delay a proposed investigation under the IND or dividuals, the agency shall imme- to suspend an ongoing investigation diately, by written notice to the spon- that has been placed on clinical hold sor from the Director of the Center for under § 312.42(b)(4). Drug Evaluation and Research or the (2) Phase 2 or 3. FDA may propose to Director of the Center for Biologics terminate an IND during Phase 2 or Evaluation and Research, terminate Phase 3 if FDA finds that: the IND. An IND so terminated is sub- (i) Any of the conditions in para- ject to reinstatement by the Director graphs (b)(1)(i) through (b)(1)(xi) of this on the basis of additional submissions section apply; or that eliminate such danger. If an IND (ii) The investigational plan or pro- is terminated under this paragraph, the tocol(s) is not reasonable as a bona fide agency will afford the sponsor an op- scientific plan to determine whether or portunity for a regulatory hearing not the drug is safe and effective for under part 16 on the question of wheth- use; or er the IND should be reinstated. (iii) There is convincing evidence [52 FR 8831, Mar. 19, 1987, as amended at 52 that the drug is not effective for the FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, purpose for which it is being inves- 1990; 57 FR 13249, Apr. 15, 1992; 67 FR 9586, tigated. Mar. 4, 2002] (3) FDA may propose to terminate a treatment IND if it finds that: § 312.45 Inactive status. (i) Any of the conditions in para- (a) If no subjects are entered into graphs (b)(1)(i) through (x) of this sec- clinical studies for a period of 2 years tion apply; or or more under an IND, or if all inves- (ii) Any of the conditions in tigations under an IND remain on clin- § 312.42(b)(3) apply. (c) Opportunity for sponsor response. ical hold for 1 year or more, the IND (1) If FDA proposes to terminate an may be placed by FDA on inactive sta- IND, FDA will notify the sponsor in tus. This action may be taken by FDA writing, and invite correction or expla- either on request of the sponsor or on nation within a period of 30 days. FDA’s own initiative. If FDA seeks to (2) On such notification, the sponsor act on its own initiative under this sec- may provide a written explanation or tion, it shall first notify the sponsor in correction or may request a conference writing of the proposed inactive status. with FDA to provide the requested ex- Upon receipt of such notification, the planation or correction. If the sponsor sponsor shall have 30 days to respond does not respond to the notification as to why the IND should continue to within the allocated time, the IND remain active. shall be terminated. (b) If an IND is placed on inactive (3) If the sponsor responds but FDA status, all investigators shall be so no- does not accept the explanation or cor- tified and all stocks of the drug shall rection submitted, FDA shall inform be returned or otherwise disposed of in the sponsor in writing of the reason for accordance with § 312.59.

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(c) A sponsor is not required to sub- during the drug investigation process, mit annual reports to an IND on inac- meetings between FDA and a sponsor tive status. An inactive IND is, how- can be especially helpful in minimizing ever, still in effect for purposes of the wasteful expenditures of time and public disclosure of data and informa- money and thus in speeding the drug tion under § 312.130. development and evaluation process. In (d) A sponsor who intends to resume particular, FDA has found that meet- clinical investigation under an IND ings at the end of Phase 2 of an inves- placed on inactive status shall submit tigation (end-of-Phase 2 meetings) are a protocol amendment under § 312.30 of considerable assistance in planning containing the proposed general inves- later studies and that meetings held tigational plan for the coming year and near completion of Phase 3 and before appropriate protocols. If the protocol submission of a marketing application amendment relies on information pre- (‘‘pre-NDA’’ meetings) are helpful in viously submitted, the plan shall ref- developing methods of presentation erence such information. Additional in- and submission of data in the mar- formation supporting the proposed in- keting application that facilitate re- vestigation, if any, shall be submitted view and allow timely FDA response. in an information amendment. Not- (1) —(i) withstanding the provisions of § 312.30, End-of-Phase 2 meetings Pur- clinical investigations under an IND on pose. The purpose of an end-of-phase 2 inactive status may only resume (1) 30 meeting is to determine the safety of days after FDA receives the protocol proceeding to Phase 3, to evaluate the amendment, unless FDA notifies the Phase 3 plan and protocols and the ade- sponsor that the investigations de- quacy of current studies and plans to scribed in the amendment are subject assess pediatric safety and effective- to a clinical hold under § 312.42, or (2) ness, and to identify any additional in- on earlier notification by FDA that the formation necessary to support a mar- clinical investigations described in the keting application for the uses under protocol amendment may begin. investigation. (e) An IND that remains on inactive (ii) Eligibility for meeting. While the status for 5 years or more may be ter- end-of-Phase 2 meeting is designed pri- minated under § 312.44. marily for IND’s involving new molecular entities or major new uses of mar- [52 FR 8831, Mar. 19, 1987, as amended at 52 keted drugs, a sponsor of any IND may FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, 2002] request and obtain an end-of-Phase 2 meeting. § 312.47 Meetings. (iii) Timing. To be most useful to the (a) General. Meetings between a spon- sponsor, end-of-Phase 2 meetings sor and the agency are frequently use- should be held before major commit- ful in resolving questions and issues ments of effort and resources to spe- raised during the course of a clinical cific Phase 3 tests are made. The sched- investigation. FDA encourages such uling of an end-of-Phase 2 meeting is meetings to the extent that they aid in not, however, intended to delay the the evaluation of the drug and in the transition of an investigation from solution of scientific problems con- Phase 2 to Phase 3. cerning the drug, to the extent that (iv) Advance information. At least 1 FDA’s resources permit. The general month in advance of an end-of-Phase 2 principle underlying the conduct of meeting, the sponsor should submit such meetings is that there should be background information on the spon- free, full, and open communication sor’s plan for Phase 3, including sum- about any scientific or medical ques- maries of the Phase 1 and 2 investigation that may arise during the clinical tions, the specific protocols for Phase 3 investigation. These meetings shall be clinical studies, plans for any addi- conducted and documented in accord- tional nonclinical studies, plans for pe- ance with part 10. diatric studies, including a time line (b) ‘‘End-of-Phase 2’’ meetings and for protocol finalization, enrollment, meetings held before submission of a mar- completion, and data analysis, or infor- keting application. At specific times mation to support any planned request

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for waiver or deferral of pediatric stud- status of ongoing or needed studies ies, and, if available, tentative labeling adequate to assess pediatric safety and for the drug. The recommended con- effectiveness, to acquaint FDA review- tents of such a submission are de- ers with the general information to be scribed more fully in FDA Staff Man- submitted in the marketing applica- ual Guide 4850.7 that is publicly avail- tion (including technical information), able under FDA’s public information to discuss appropriate methods for sta- regulations in part 20. tistical analysis of the data, and to dis- (v) Conduct of meeting. Arrangements cuss the best approach to the presen- for an end-of-Phase 2 meeting are to be tation and formatting of data in the made with the division in FDA’s Center marketing application. Arrangements for Drug Evaluation and Research or for such a meeting are to be initiated the Center for Biologics Evaluation by the sponsor with the division re- and Research which is responsible for sponsible for review of the IND. To per- review of the IND. The meeting will be mit FDA to provide the sponsor with scheduled by FDA at a time convenient the most useful advice on preparing a to both FDA and the sponsor. Both the marketing application, the sponsor sponsor and FDA may bring consult- should submit to FDA’s reviewing divi- ants to the meeting. The meeting sion at least 1 month in advance of the should be directed primarily at estab- meeting the following information: lishing agreement between FDA and (i) A brief summary of the clinical the sponsor of the overall plan for studies to be submitted in the applica- Phase 3 and the objectives and design tion. of particular studies. The adequacy of (ii) A proposed format for organizing the technical information to support the submission, including methods for Phase 3 studies and/or a marketing ap- presenting the data. plication may also be discussed. FDA (iii) Information on the status of will also provide its best judgment, at needed or ongoing pediatric studies. that time, of the pediatric studies that (iv) Any other information for discus- will be required for the drug product sion at the meeting. and whether their submission will be [52 FR 8831, Mar. 19, 1987, as amended at 52 deferred until after approval. Agree- FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, ments reached at the meeting on these 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. matters will be recorded in minutes of 4, 2002] the conference that will be taken by FDA in accordance with § 10.65 and pro- § 312.48 Dispute resolution. vided to the sponsor. The minutes (a) General. The Food and Drug Ad- along with any other written material ministration is committed to resolving provided to the sponsor will serve as a differences between sponsors and FDA permanent record of any agreements reviewing divisions with respect to re- reached. Barring a significant sci- quirements for IND’s as quickly and entific development that requires oth- amicably as possible through the coop- erwise, studies conducted in accord- erative exchange of information and ance with the agreement shall be pre- views. sumed to be sufficient in objective and (b) Administrative and procedural design for the purpose of obtaining issues. When administrative or proce- marketing approval for the drug. dural disputes arise, the sponsor should (2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet- first attempt to resolve the matter ings. FDA has found that delays associ- with the division in FDA’s Center for ated with the initial review of a mar- Drug Evaluation and Research or Cen- keting application may be reduced by ter for Biologics Evaluation and Re- exchanges of information about a pro- search which is responsible for review posed marketing application. The pri- of the IND, beginning with the con- mary purpose of this kind of exchange sumer safety officer assigned to the ap- is to uncover any major unresolved plication. If the dispute is not resolved, problems, to identify those studies that the sponsor may raise the matter with the sponsor is relying on as adequate the person designated as ombudsman, and well-controlled to establish the whose function shall be to investigate drug’s effectiveness, to identify the what has happened and to facilitate a

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timely and equitable resolution. Appro- Subpart D—Responsibilities of priate issues to raise with the ombuds- Sponsors and Investigators man include resolving difficulties in scheduling meetings and obtaining § 312.50 General responsibilities of timely replies to inquiries. Further de- sponsors. tails on this procedure are contained in Sponsors are responsible for selecting FDA Staff Manual Guide 4820.7 that is qualified investigators, providing them publicly available under FDA’s public with the information they need to con- information regulations in part 20. duct an investigation properly, ensur- (c) Scientific and medical disputes. (1) ing proper monitoring of the investiga- When scientific or medical disputes tion(s), ensuring that the investiga- arise during the drug investigation tion(s) is conducted in accordance with process, sponsors should discuss the the general investigational plan and matter directly with the responsible protocols contained in the IND, main- reviewing officials. If necessary, spon- taining an effective IND with respect sors may request a meeting with the to the investigations, and ensuring appropriate reviewing officials and that FDA and all participating inves- management representatives in order tigators are promptly informed of sig- to seek a resolution. Requests for such nificant new adverse effects or risks meetings shall be directed to the direc- with respect to the drug. Additional tor of the division in FDA’s Center for specific responsibilities of sponsors are Drug Evaluation and Research or Cen- described elsewhere in this part. ter for Biologics Evaluation and Re- § 312.52 Transfer of obligations to a search which is responsible for review contract research organization. of the IND. FDA will make every attempt to grant requests for meetings (a) A sponsor may transfer responsibility for any or all of the obligations that involve important issues and that set forth in this part to a contract re- can be scheduled at mutually conven- search organization. Any such transfer ient times. shall be described in writing. If not all (2) The ‘‘end-of-Phase 2’’ and ‘‘pre- obligations are transferred, the writing NDA’’ meetings described in § 312.47(b) is required to describe each of the obli- will also provide a timely forum for gations being assumed by the contract discussing and resolving scientific and research organization. If all obligations medical issues on which the sponsor are transferred, a general statement disagrees with the agency. that all obligations have been trans- (3) In requesting a meeting designed ferred is acceptable. Any obligation not to resolve a scientific or medical discovered by the written description pute, applicants may suggest that FDA shall be deemed not to have been trans- seek the advice of outside experts, in ferred. which case FDA may, in its discretion, (b) A contract research organization invite to the meeting one or more of its that assumes any obligation of a spon- advisory committee members or other sor shall comply with the specific regu- consultants, as designated by the agen- lations in this chapter applicable to cy. Applicants may rely on, and may this obligation and shall be subject to bring to any meeting, their own con- the same regulatory action as a spon- sultants. For major scientific and med- sor for failure to comply with any obli- ical policy issues not resolved by infor- gation assumed under these regula- mal meetings, FDA may refer the mat- tions. Thus, all references to ‘‘sponsor’’ ter to one of its standing advisory com- in this part apply to a contract research organization to the extent that mittees for its consideration and rec- it assumes one or more obligations of ommendations. the sponsor. [52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990] § 312.53 Selecting investigators and monitors. (a) Selecting investigators. A sponsor shall select only investigators qualified

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by training and experience as appro- chure, including the potential risks priate experts to investigate the drug. and side effects of the drug; and (b) Control of drug. A sponsor shall (g) Will ensure that all associates, ship investigational new drugs only to colleagues, and employees assisting in investigators participating in the in- the conduct of the study(ies) are investigation. formed about their obligations in (c) Obtaining information from the in- meeting the above commitments. vestigator. Before permitting an investi- (vii) A commitment by the investigator to begin participation in an in- gator that, for an investigation subject vestigation, the sponsor shall obtain to an institutional review requirement the following: under part 56, an IRB that complies (1) A signed investigator statement with the requirements of that part will (Form FDA–1572) containing: be responsible for the initial and con- (i) The name and address of the in- tinuing review and approval of the clin- vestigator; ical investigation and that the investi- (ii) The name and code number, if gator will promptly report to the IRB any, of the protocol(s) in the IND iden- all changes in the research activity and tifying the study(ies) to be conducted all unanticipated problems involving by the investigator; risks to human subjects or others, and (iii) The name and address of any will not make any changes in the re- medical school, hospital, or other research without IRB approval, except search facility where the clinical inves- where necessary to eliminate apparent tigation(s) will be conducted; immediate hazards to the human subjects. (iv) The name and address of any (viii) A list of the names of the sub- clinical laboratory facilities to be used investigators (e.g., research fellows, in the study; residents) who will be assisting the in- (v) The name and address of the IRB vestigator in the conduct of the inves- that is responsible for review and ap- tigation(s). proval of the study(ies); (2) Curriculum vitae. A curriculum (vi) A commitment by the investi- vitae or other statement of qualifica- gator that he or she: tions of the investigator showing the (a) Will conduct the study(ies) in ac- education, training, and experience cordance with the relevant, current that qualifies the investigator as an ex- protocol(s) and will only make changes pert in the clinical investigation of the in a protocol after notifying the spon- drug for the use under investigation. sor, except when necessary to protect (3) Clinical protocol. (i) For Phase 1 in- the safety, the rights, or welfare of vestigations, a general outline of the subjects; planned investigation including the es- (b) Will comply with all requirements timated duration of the study and the regarding the obligations of clinical in- maximum number of subjects that will vestigators and all other pertinent re- be involved. quirements in this part; (ii) For Phase 2 or 3 investigations, (c) Will personally conduct or super- an outline of the study protocol includ- vise the described investigation(s); ing an approximation of the number of (d) Will inform any potential subjects subjects to be treated with the drug that the drugs are being used for inves- and the number to be employed as con- tigational purposes and will ensure trols, if any; the clinical uses to be in- that the requirements relating to ob- vestigated; characteristics of subjects taining informed consent (21 CFR part by age, sex, and condition; the kind of 50) and institutional review board re- clinical observations and laboratory view and approval (21 CFR part 56) are tests to be conducted; the estimated met; duration of the study; and copies or a (e) Will report to the sponsor adverse description of case report forms to be experiences that occur in the course of used. the investigation(s) in accordance with (4) Financial disclosure information. § 312.64; Sufficient accurate financial informa- (f) Has read and understands the in- tion to allow the sponsor to submit formation in the investigator’s bro- complete and accurate certification or

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disclosure statements required under (b) The sponsor shall, as the overall part 54 of this chapter. The sponsor investigation proceeds, keep each par- shall obtain a commitment from the ticipating investigator informed of new clinical investigator to promptly up- observations discovered by or reported date this information if any relevant to the sponsor on the drug, particu- changes occur during the course of the larly with respect to adverse effects investigation and for 1 year following and safe use. Such information may be the completion of the study. distributed to investigators by means (d) Selecting monitors. A sponsor shall of periodically revised investigator select a monitor qualified by training brochures, reprints or published stud- and experience to monitor the progress ies, reports or letters to clinical inves- of the investigation. tigators, or other appropriate means. [52 FR 8831, Mar. 19, 1987, as amended at 52 Important safety information is re- FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, quired to be relayed to investigators in 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. accordance with § 312.32. 4, 2002] [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, § 312.54 Emergency research under 2002] § 50.24 of this chapter. (a) The sponsor shall monitor the § 312.56 Review of ongoing investiga- progress of all investigations involving tions. an exception from informed consent (a) The sponsor shall monitor the under § 50.24 of this chapter. When the progress of all clinical investigations sponsor receives from the IRB informa- being conducted under its IND. tion concerning the public disclosures (b) A sponsor who discovers that an required by § 50.24(a)(7)(ii) and (a)(7)(iii) investigator is not complying with the of this chapter, the sponsor promptly signed agreement (Form FDA–1572), the shall submit to the IND file and to general investigational plan, or the re- Docket Number 95S–0158 in the Divi- quirements of this part or other appli- sion of Dockets Management (HFA– cable parts shall promptly either se- 305), Food and Drug Administration, cure compliance or discontinue ship- 5630 Fishers Lane, rm. 1061, Rockville, ments of the investigational new drug MD 20852, copies of the information to the investigator and end the inves- that was disclosed, identified by the tigator’s participation in the investiga- IND number. tion. If the investigator’s participation (b) The sponsor also shall monitor in the investigation is ended, the spon- such investigations to identify when an sor shall require that the investigator IRB determines that it cannot approve dispose of or return the investigational the research because it does not meet drug in accordance with the require- the criteria in the exception in ments of § 312.59 and shall notify FDA. § 50.24(a) of this chapter or because of (c) The sponsor shall review and other relevant ethical concerns. The evaluate the evidence relating to the sponsor promptly shall provide this in- safety and effectiveness of the drug as formation in writing to FDA, inves- it is obtained from the investigator. tigators who are asked to participate The sponsors shall make such reports in this or a substantially equivalent to FDA regarding information relevant clinical investigation, and other IRB’s to the safety of the drug as are re- that are asked to review this or a sub- quired under § 312.32. The sponsor shall stantially equivalent investigation. make annual reports on the progress of [61 FR 51530, Oct. 2, 1996, as amended at 68 FR the investigation in accordance with 24879, May 9, 2003] § 312.33. (d) A sponsor who determines that its § 312.55 Informing investigators. investigational drug presents an unrea- (a) Before the investigation begins, a sonable and significant risk to subjects sponsor (other than a sponsor-investi- shall discontinue those investigations gator) shall give each participating that present the risk, notify FDA, all clinical investigator an investigator institutional review boards, and all in- brochure containing the information vestigators who have at any time par- described in § 312.23(a)(5). ticipated in the investigation of the

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discontinuance, assure the disposition § 312.58 Inspection of sponsor’s of all stocks of the drug outstanding as records and reports. required by § 312.59, and furnish FDA (a) FDA inspection. A sponsor shall with a full report of the sponsor’s ac- upon request from any properly au- tions. The sponsor shall discontinue thorized officer or employee of the the investigation as soon as possible, Food and Drug Administration, at rea- and in no event later than 5 working days after making the determination sonable times, permit such officer or that the investigation should be dis- employee to have access to and copy continued. Upon request, FDA will con- and verify any records and reports refer with a sponsor on the need to dis- lating to a clinical investigation con- continue an investigation. ducted under this part. Upon written request by FDA, the sponsor shall sub- [52 FR 8831, Mar. 19, 1987, as amended at 52 mit the records or reports (or copies of FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, them) to FDA. The sponsor shall dis- 2002] continue shipments of the drug to any § 312.57 Recordkeeping and record re- investigator who has failed to maintain tention. or make available records or reports of (a) A sponsor shall maintain ade- the investigation as required by this quate records showing the receipt, part. shipment, or other disposition of the (b) Controlled substances. If an inves- investigational drug. These records are tigational new drug is a substance list- required to include, as appropriate, the ed in any schedule of the Controlled name of the investigator to whom the Substances Act (21 U.S.C. 801; 21 CFR drug is shipped, and the date, quantity, part 1308), records concerning ship- and batch or code mark of each such ment, delivery, receipt, and disposition shipment. of the drug, which are required to be (b) A sponsor shall maintain com- kept under this part or other applica- plete and accurate records showing any ble parts of this chapter shall, upon the financial interest in § 54.4(a)(3)(i), request of a properly authorized em- (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this ployee of the Drug Enforcement Ad- chapter paid to clinical investigators ministration of the U.S. Department of by the sponsor of the covered study. A Justice, be made available by the in- sponsor shall also maintain complete vestigator or sponsor to whom the re- and accurate records concerning all quest is made, for inspection and copy- other financial interests of investiga- ing. In addition, the sponsor shall as- tors subject to part 54 of this chapter. sure that adequate precautions are (c) A sponsor shall retain the records taken, including storage of the inves- and reports required by this part for 2 tigational drug in a securely locked, years after a marketing application is substantially constructed cabinet, or approved for the drug; or, if an applica- other securely locked, substantially tion is not approved for the drug, until constructed enclosure, access to which 2 years after shipment and delivery of is limited, to prevent theft or diversion the drug for investigational use is dis- of the substance into illegal channels continued and FDA has been so noti- of distribution. fied. (d) A sponsor shall retain reserve § 312.59 Disposition of unused supply samples of any test article and ref- of investigational drug. erence standard identified in, and used The sponsor shall assure the return in any of the bioequivalence or bio- of all unused supplies of the investiga- availability studies described in, tional drug from each individual inves- § 320.38 or § 320.63 of this chapter, and tigator whose participation in the in- release the reserve samples to FDA vestigation is discontinued or termi- upon request, in accordance with, and nated. The sponsor may authorize al- for the period specified in § 320.38. ternative disposition of unused supplies [52 FR 8831, Mar. 19, 1987, as amended at 52 of the investigational drug provided FR 23031, June 17, 1987; 58 FR 25926, Apr. 28, this alternative disposition does not 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. expose humans to risks from the drug. 4, 2002] The sponsor shall maintain written

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records of any disposition of the drug tional drug or employed as a control in in accordance with § 312.57. the investigation. Case histories in- [52 FR 8831, Mar. 19, 1987, as amended at 52 clude the case report forms and sup- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, porting data including, for example, 2002] signed and dated consent forms and medical records including, for example, § 312.60 General responsibilities of in- progress notes of the physician, the investigators. dividual’s hospital chart(s), and the An investigator is responsible for en- nurses’ notes. The case history for each suring that an investigation is con- individual shall document that in- ducted according to the signed investi- formed consent was obtained prior to gator statement, the investigational participation in the study. plan, and applicable regulations; for (c) Record retention. An investigator protecting the rights, safety, and wel- shall retain records required to be fare of subjects under the investiga- maintained under this part for a period tor’s care; and for the control of drugs of 2 years following the date a mar- under investigation. An investigator keting application is approved for the shall, in accordance with the provi- drug for the indication for which it is sions of part 50 of this chapter, obtain being investigated; or, if no application the informed consent of each human is to be filed or if the application is not subject to whom the drug is adminis- approved for such indication, until 2 tered, except as provided in §§ 50.23 or years after the investigation is discon- 50.24 of this chapter. Additional spe- tinued and FDA is notified. cific responsibilities of clinical investigators are set forth in this part and [52 FR 8831, Mar. 19, 1987, as amended at 52 in parts 50 and 56 of this chapter. FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, 1996; 67 FR 9586, Mar. 4, 2002] [52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51530, Oct. 2, 1996] § 312.64 Investigator reports. § 312.61 Control of the investigational (a) Progress reports. The investigator drug. shall furnish all reports to the sponsor An investigator shall administer the of the drug who is responsible for col- drug only to subjects under the inves- lecting and evaluating the results ob- tigator’s personal supervision or under tained. The sponsor is required under the supervision of a subinvestigator re- § 312.33 to submit annual reports to sponsible to the investigator. The in- FDA on the progress of the clinical investigator shall not supply the inves- vestigations. tigational drug to any person not au- (b) Safety reports. An investigator thorized under this part to receive it. must immediately report to the sponsor any serious adverse event, whether § 312.62 Investigator recordkeeping or not considered drug related, includ- and record retention. ing those listed in the protocol or in- (a) Disposition of drug. An investi- vestigator brochure and must include gator is required to maintain adequate an assessment of whether there is a records of the disposition of the drug, reasonable possibility that the drug including dates, quantity, and use by caused the event. Study endpoints that subjects. If the investigation is termi- are serious adverse events (e.g., all- nated, suspended, discontinued, or cause mortality) must be reported in completed, the investigator shall re- accordance with the protocol unless turn the unused supplies of the drug to there is evidence suggesting a causal the sponsor, or otherwise provide for relationship between the drug and the disposition of the unused supplies of event (e.g., death from anaphylaxis). In the drug under § 312.59. that case, the investigator must imme- (b) Case histories. An investigator is diately report the event to the sponsor. required to prepare and maintain ade- The investigator must record non- quate and accurate case histories that serious adverse events and report them record all observations and other data to the sponsor according to the time- pertinent to the investigation on each table for reporting specified in the pro- individual administered the investiga- tocol.

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(c) Final report. An investigator shall § 312.69 Handling of controlled sub- provide the sponsor with an adequate stances. report shortly after completion of the If the investigational drug is subject investigator’s participation in the in- to the Controlled Substances Act, the vestigation. investigator shall take adequate pre- (d) Financial disclosure reports. The cautions, including storage of the in- clinical investigator shall provide the vestigational drug in a securely locked, sponsor with sufficient accurate finan- substantially constructed cabinet, or cial information to allow an applicant other securely locked, substantially to submit complete and accurate cer- constructed enclosure, access to which tification or disclosure statements as is limited, to prevent theft or diversion required under part 54 of this chapter. of the substance into illegal channels The clinical investigator shall prompt- of distribution. ly update this information if any relevant changes occur during the course § 312.70 Disqualification of a clinical of the investigation and for 1 year fol- investigator. lowing the completion of the study. (a) If FDA has information indicating that an investigator (including a spon- [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63 FR 5252, Feb. 2, sor-investigator) has repeatedly or de- 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963, liberately failed to comply with the re- Sept. 29, 2010] quirements of this part, part 50 or part 56 of this chapter, or has repeatedly or § 312.66 Assurance of IRB review. deliberately submitted to FDA or to the sponsor false information in any An investigator shall assure that an required report, the Center for Drug IRB that complies with the require- Evaluation and Research or the Center ments set forth in part 56 will be re- for Biologics Evaluation and Research sponsible for the initial and continuing will furnish the investigator written review and approval of the proposed notice of the matter complained of and clinical study. The investigator shall offer the investigator an opportunity also assure that he or she will prompt- to explain the matter in writing, or, at ly report to the IRB all changes in the the option of the investigator, in an in- research activity and all unanticipated formal conference. If an explanation is problems involving risk to human sub- offered and accepted by the applicable jects or others, and that he or she will Center, the Center will discontinue the not make any changes in the research disqualification proceeding. If an ex- without IRB approval, except where planation is offered but not accepted necessary to eliminate apparent imme- by the applicable Center, the investi- diate hazards to human subjects. gator will be given an opportunity for [52 FR 8831, Mar. 19, 1987, as amended at 52 a regulatory hearing under part 16 of FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, this chapter on the question of whether 2002] the investigator is eligible to receive test articles under this part and eligi- § 312.68 Inspection of investigator’s ble to conduct any clinical investiga- records and reports. tion that supports an application for a An investigator shall upon request research or marketing permit for prod- from any properly authorized officer or ucts regulated by FDA. employee of FDA, at reasonable times, (b) After evaluating all available in- permit such officer or employee to formation, including any explanation have access to, and copy and verify any presented by the investigator, if the records or reports made by the investi- Commissioner determines that the in- gator pursuant to § 312.62. The investi- vestigator has repeatedly or delib- gator is not required to divulge subject erately failed to comply with the re- names unless the records of particular quirements of this part, part 50 or part individuals require a more detailed 56 of this chapter, or has repeatedly or study of the cases, or unless there is deliberately submitted to FDA or to reason to believe that the records do the sponsor false information in any not represent actual case studies, or do required report, the Commissioner will not represent actual results obtained. notify the investigator, the sponsor of

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any investigation in which the investi- of any obligation under any other ap- gator has been named as a participant, plicable regulation to submit to FDA and the reviewing institutional review the results of the investigation. boards (IRBs) that the investigator is (e) If the Commissioner determines, not eligible to receive test articles after the unreliable data submitted by under this part. The notification to the the investigator are eliminated from investigator, sponsor, and IRBs will consideration, that the continued ap- provide a statement of the basis for proval of the product for which the such determination. The notification data were submitted cannot be justi- also will explain that an investigator fied, the Commissioner will proceed to determined to be ineligible to receive withdraw approval of the product in ac- test articles under this part will be in- cordance with the applicable provisions eligible to conduct any clinical inves- of the relevant statutes. tigation that supports an application (f) An investigator who has been de- for a research or marketing permit for termined to be ineligible under para- products regulated by FDA, including graph (b) of this section may be rein- drugs, biologics, devices, new animal stated as eligible when the Commis- drugs, foods, including dietary supple- sioner determines that the investigator ments, that bear a nutrient content has presented adequate assurances that claim or a health claim, infant for- the investigator will employ all test mulas, food and color additives, and to- articles, and will conduct any clinical bacco products. investigation that supports an applica- (c) Each application or submission to tion for a research or marketing per- FDA under the provisions of this chap- mit for products regulated by FDA, ter containing data reported by an in- solely in compliance with the applica- vestigator who has been determined to ble provisions of this chapter. be ineligible to receive FDA-regulated [77 FR 25359, Apr. 30, 2012] test articles is subject to examination to determine whether the investigator Subpart E—Drugs Intended to has submitted unreliable data that are essential to the continuation of an in- Treat Life-threatening and Se- vestigation or essential to the approval verely-debilitating Illnesses of a marketing application, or essential to the continued marketing of an AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371; FDA-regulated product. 42 U.S.C. 262. (d) If the Commissioner determines, SOURCE: 53 FR 41523, Oct. 21, 1988, unless after the unreliable data submitted by otherwise noted. the investigator are eliminated from consideration, that the data remaining § 312.80 Purpose. are inadequate to support a conclusion The purpose of this section is to es- that it is reasonably safe to continue tablish procedures designed to expedite the investigation, the Commissioner the development, evaluation, and mar- will notify the sponsor, who shall have keting of new therapies intended to an opportunity for a regulatory hear- treat persons with life-threatening and ing under part 16 of this chapter. If a severely-debilitating illnesses, espe- danger to the public health exists, how- cially where no satisfactory alter- ever, the Commissioner shall termi- native therapy exists. As stated nate the IND immediately and notify § 314.105(c) of this chapter, while the the sponsor and the reviewing IRBs of statutory standards of safety and effec- the termination. In such case, the tiveness apply to all drugs, the many sponsor shall have an opportunity for a kinds of drugs that are subject to regulatory hearing before FDA under them, and the wide range of uses for part 16 on the question of whether the those drugs, demand flexibility in ap- IND should be reinstated. The deter- plying the standards. The Food and mination that an investigation may Drug Administration (FDA) has deter- not be considered in support of a re- mined that it is appropriate to exercise search or marketing application or a the broadest flexibility in applying the notification or petition submission statutory standards, while preserving does not, however, relieve the sponsor appropriate guarantees for safety and

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effectiveness. These procedures reflect meeting with FDA-reviewing officials. the recognition that physicians and pa- The primary purpose of this meeting is tients are generally willing to accept to review and reach agreement on the greater risks or side effects from prod- design of animal studies needed to ini- ucts that treat life-threatening and se- tiate human testing. The meeting may verely-debilitating illnesses, than they also provide an opportunity for dis- would accept from products that treat cussing the scope and design of phase 1 less serious illnesses. These procedures testing, plans for studying the drug also reflect the recognition that the product in pediatric populations, and benefits of the drug need to be evalu- the best approach for presentation and ated in light of the severity of the disease being treated. The procedure out- formatting of data in the IND. lined in this section should be inter- (b) End-of-phase 1 meetings. When data preted consistent with that purpose. from phase 1 clinical testing are available, the sponsor may again request a § 312.81 Scope. meeting with FDA-reviewing officials. This section applies to new drug and The primary purpose of this meeting is biological products that are being stud- to review and reach agreement on the ied for their safety and effectiveness in design of phase 2 controlled clinical treating life-threatening or severely- trials, with the goal that such testing debilitating diseases. will be adequate to provide sufficient (a) For purposes of this section, the data on the drug’s safety and effective- term ‘‘life-threatening’’ means: ness to support a decision on its ap- (1) Diseases or conditions where the provability for marketing, and to dis- likelihood of death is high unless the cuss the need for, as well as the design course of the disease is interrupted; and timing of, studies of the drug in pe- and diatric patients. For drugs for life- (2) Diseases or conditions with poten- threatening diseases, FDA will provide tially fatal outcomes, where the end its best judgment, at that time, wheth- point of clinical trial analysis is sur- er pediatric studies will be required vival. and whether their submission will be (b) For purposes of this section, the deferred until after approval. The pro- term ‘‘severely debilitating’’ means cedures outlined in § 312.47(b)(1) with diseases or conditions that cause major irreversible morbidity. respect to end-of-phase 2 conferences, (c) Sponsors are encouraged to con- including documentation of agree- sult with FDA on the applicability of ments reached, would also be used for these procedures to specific products. end-of-phase 1 meetings. [53 FR 41523, Oct. 21, 1988, as amended at 64 [53 FR 41523, Oct. 21, 1988, as amended at 63 FR 401, Jan. 5, 1999] FR 66669, Dec. 2, 1998]

§ 312.82 Early consultation. § 312.83 Treatment protocols. For products intended to treat life- If the preliminary analysis of phase 2 threatening or severely-debilitating ill- test results appears promising, FDA nesses, sponsors may request to meet may ask the sponsor to submit a treat- with FDA-reviewing officials early in ment protocol to be reviewed under the the drug development process to review procedures and criteria listed in and reach agreement on the design of §§ 312.305 and 312.320. Such a treatment necessary preclinical and clinical stud- protocol, if requested and granted, ies. Where appropriate, FDA will invite would normally remain in effect while to such meetings one or more outside the complete data necessary for a mar- expert scientific consultants or advi- keting application are being assembled sory committee members. To the ex- by the sponsor and reviewed by FDA tent FDA resources permit, agency re- (unless grounds exist for clinical hold viewing officials will honor requests of ongoing protocols, as provided in for such meetings § 312.42(b)(3)(ii)). (a) Pre-investigational new drug (IND) meetings. Prior to the submission of the [53 FR 41523, Oct. 21, 1988, as amended at 76 initial IND, the sponsor may request a FR 13880, Mar. 15, 2011]

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§ 312.84 Risk-benefit analysis in review sponsor to conduct certain post- of marketing applications for drugs marketing (phase 4) studies to delin- to treat life-threatening and se- eate additional information about the verely-debilitating illnesses. drug’s risks, benefits, and optimal use. (a) FDA’s application of the statu- These studies could include, but would tory standards for marketing approval not be limited to, studying different shall recognize the need for a medical doses or schedules of administration risk-benefit judgment in making the than were used in phase 2 studies, use final decision on approvability. As part of the drug in other patient popu- of this evaluation, consistent with the lations or other stages of the disease, statement of purpose in § 312.80, FDA or use of the drug over a longer period will consider whether the benefits of of time. the drug outweigh the known and potential risks of the drug and the need § 312.86 Focused FDA regulatory re- to answer remaining questions about search. risks and benefits of the drug, taking At the discretion of the agency, FDA into consideration the severity of the may undertake focused regulatory re- disease and the absence of satisfactory search on critical rate-limiting aspects alternative therapy. of the preclinical, chemical/manufac- (b) In making decisions on whether turing, and clinical phases of drug de- to grant marketing approval for prod- velopment and evaluation. When initi- ucts that have been the subject of an ated, FDA will undertake such re- end-of-phase 1 meeting under § 312.82, FDA will usually seek the advice of search efforts as a means for meeting a outside expert scientific consultants or public health need in facilitating the advisory committees. Upon the filing development of therapies to treat life- of such a marketing application under threatening or severely debilitating ill- § 314.101 or part 601 of this chapter, FDA nesses. will notify the members of the relevant standing advisory committee of the ap- § 312.87 Active monitoring of conduct and evaluation of clinical trials. plication’s filing and its availability for review. For drugs covered under this section, (c) If FDA concludes that the data the Commissioner and other agency of- presented are not sufficient for mar- ficials will monitor the progress of the keting approval, FDA will issue a com- conduct and evaluation of clinical plete response letter under § 314.110 of trials and be involved in facilitating this chapter or the biological product their appropriate progress. licensing procedures. Such letter, in describing the deficiencies in the appli- § 312.88 Safeguards for patient safety. cation, will address why the results of All of the safeguards incorporated the research design agreed to under within parts 50, 56, 312, 314, and 600 of § 312.82, or in subsequent meetings, this chapter designed to ensure the have not provided sufficient evidence safety of clinical testing and the safety for marketing approval. Such letter of products following marketing ap- will also describe any recommenda- proval apply to drugs covered by this tions made by the advisory committee section. This includes the requirements regarding the application. for informed consent (part 50 of this (d) Marketing applications submitted chapter) and institutional review under the procedures contained in this boards (part 56 of this chapter). These section will be subject to the require- safeguards further include the review ments and procedures contained in part of animal studies prior to initial 314 or part 600 of this chapter, as well human testing (§ 312.23), and the moni- as those in this subpart. toring of adverse drug experiences [53 FR 41523, Oct. 21, 1988, as amended at 73 through the requirements of IND safe- FR 39607, July 10, 2008] ty reports (§ 312.32), safety update reports during agency review of a mar- § 312.85 Phase 4 studies. keting application (§ 314.50 of this chap- Concurrent with marketing approval, ter), and postmarketing adverse reac- FDA may seek agreement from the tion reporting (§ 314.80 of this chapter).

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Subpart F—Miscellaneous Programs (HFG–1), Food and Drug Ad- ministration, 5600 Fishers Lane, Rock- § 312.110 Import and export require- ville, MD 20857, at the time the drug is ments. first exported and maintains records (a) Imports. An investigational new documenting compliance with this drug offered for import into the United paragraph. The certification shall de- States complies with the requirements scribe the drug that is to be exported of this part if it is subject to an IND (i.e., trade name (if any), generic name, that is in effect for it under § 312.40 and: and dosage form), identify the country (1) The consignee in the United States or countries to which the drug is to be is the sponsor of the IND; (2) the con- exported, and affirm that: signee is a qualified investigator (i) The drug is intended for export; named in the IND; or (3) the consignee (ii) The drug is intended for inves- is the domestic agent of a foreign spon- tigational use in a foreign country; sor, is responsible for the control and (iii) The drug meets the foreign pur- distribution of the investigational chaser’s or consignee’s specifications; drug, and the IND identifies the con- (iv) The drug is not in conflict with signee and describes what, if any, ac- the importing country’s laws; tions the consignee will take with re- (v) The outer shipping package is la- spect to the investigational drug. beled to show that the package is in- (b) Exports. An investigational new tended for export from the United drug may be exported from the United States; States for use in a clinical investiga- (vi) The drug is not sold or offered for tion under any of the following condi- sale in the United States; tions: (vii) The clinical investigation will (1) An IND is in effect for the drug be conducted in accordance with under § 312.40, the drug complies with § 312.120; the laws of the country to which it is (viii) The drug is manufactured, proc- being exported, and each person who essed, packaged, and held in substan- receives the drug is an investigator in tial conformity with current good man- a study submitted to and allowed to ufacturing practices; proceed under the IND; or (ix) The drug is not adulterated with- (2) The drug has valid marketing au- in the meaning of section 501(a)(1), thorization in Australia, Canada, (a)(2)(A), (a)(3), (c), or (d) of the act; Israel, Japan, New Zealand, Switzer- (x) The drug does not present an im- land, South Africa, or in any country minent hazard to public health, either in the European Union or the European in the United States, if the drug were Economic Area, and complies with the to be reimported, or in the foreign laws of the country to which it is being country; and exported, section 802(b)(1)(A), (f), and (xi) The drug is labeled in accordance (g) of the act, and § 1.101 of this chap- with the foreign country’s laws. ter; or (5) In the event of a national emer- (3) The drug is being exported to Aus- gency in a foreign country, where the tralia, Canada, Israel, Japan, New Zea- national emergency necessitates expor- land, Switzerland, South Africa, or to tation of an investigational new drug, any country in the European Union or the requirements in paragraph (b)(4) of the European Economic Area, and com- this section apply as follows: plies with the laws of the country to (i) Situations where the investigational which it is being exported, the applica- new drug is to be stockpiled in anticipa- ble provisions of section 802(c), (f), and tion of a national emergency. There may (g) of the act, and § 1.101 of this chap- be instances where exportation of an ter. Drugs exported under this para- investigational new drug is needed so graph that are not the subject of an that the drug may be stockpiled and IND are exempt from the label require- made available for use by the import- ment in § 312.6(a); or ing country if and when a national (4) Except as provided in paragraph emergency arises. In such cases: (b)(5) of this section, the person export- (A) A person may export an inves- ing the drug sends a written certifi- tigational new drug under paragraph cation to the Office of International (b)(4) of this section without making

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an affirmation with respect to any one (A) A person may export an inves- or more of paragraphs (b)(4)(i), tigational new drug under paragraph (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), (b)(4) of this section without making (b)(4)(viii), and/or (b)(4)(ix) of this sec- an affirmation with respect to any one tion, provided that he or she: or more of paragraphs (b)(4)(i), (1) Provides a written statement ex- (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii), plaining why compliance with each (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), such paragraph is not feasible or is provided that he or she: contrary to the best interests of the in- (1) Provides a written statement ex- dividuals who may receive the inves- plaining why compliance with each tigational new drug; such paragraph is not feasible or is (2) Provides a written statement contrary to the best interests of the in- from an authorized official of the im- dividuals who are expected to receive porting country’s government. The the investigational new drug and statement must attest that the official agrees with the exporter’s statement (2) Provides sufficient information made under paragraph (b)(5)(i)(A)(1) of from an authorized official of the im- this section; explain that the drug is to porting country’s government to en- be stockpiled solely for use of the im- able the Secretary, or his or her des- porting country in a national emer- ignee, to decide whether a national gency; and describe the potential na- emergency has developed or is devel- tional emergency that warrants expor- oping in the importing country, wheth- tation of the investigational new drug er the investigational new drug will be under this provision; and used solely for that national emer- (3) Provides a written statement gency, and whether prompt exportation showing that the Secretary of Health of the investigational new drug is nec- and Human Services (the Secretary), or essary. Persons who wish to obtain a his or her designee, agrees with the determination from the Secretary findings of the authorized official of should direct their requests to Sec- the importing country’s government. retary’s Operations Center, Office of Persons who wish to obtain a written Emergency Operations and Security statement from the Secretary should Programs, Office of Public Health direct their requests to Secretary’s Op- Emergency Preparedness, Office of the erations Center, Office of Emergency Secretary, Department of Health and Operations and Security Programs, Of- Human Services, 200 Independence Ave. fice of Public Health Emergency Pre- SW., Washington, DC 20201. Requests paredness, Office of the Secretary, De- may be also be sent by FAX: 202–619– partment of Health and Human Serv- 7870 or by e-mail: [email protected]. ices, 200 Independence Ave. SW., Wash- (B) Exportation may proceed without ington, DC 20201. Requests may be also prior FDA authorization. be sent by FAX: 202–619–7870 or by e- (c) Limitations. Exportation under mail: [email protected]. paragraph (b) of this section may not (B) Exportation may not proceed occur if: until FDA has authorized exportation (1) For drugs exported under para- of the investigational new drug. FDA graph (b)(1) of this section, the IND may deny authorization if the state- pertaining to the clinical investigation ments provided under paragraphs is no longer in effect; (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this section are inadequate or if expor- (2) For drugs exported under para- tation is contrary to public health. graph (b)(2) of this section, the require- (ii) Situations where the investigational ments in section 802(b)(1), (f), or (g) of new drug is to be used for a sudden and the act are no longer met; immediate national emergency. There (3) For drugs exported under para- may be instances where exportation of graph (b)(3) of this section, the require- an investigational new drug is needed ments in section 802(c), (f), or (g) of the so that the drug may be used in a sud- act are no longer met; den and immediate national emergency (4) For drugs exported under para- that has developed or is developing. In graph (b)(4) of this section, the condi- such cases: tions underlying the certification or

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the statements submitted under para- § 50.24(a) of this chapter, or that the graph (b)(5) of this section are no measures described in the study pro- longer met; or tocol or elsewhere will protect the (5) For any investigational new drugs rights, safety, and well-being of sub- under this section, the drug no longer jects; and complies with the laws of the import- (ii) FDA is able to validate the data ing country. from the study through an onsite in- (d) Insulin and antibiotics. New insulin spection if the agency deems it nec- and antibiotic drug products may be essary. exported for investigational use in ac- (2) Although FDA will not accept as cordance with section 801(e)(1) of the support for an IND or application for act without complying with this sec- marketing approval a study that does tion. not meet the conditions of paragraph [52 FR 8831, Mar. 19, 1987, as amended at 52 (a)(1) of this section, FDA will examine FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999; data from such a study. 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23, (3) Marketing approval of a new drug 2005] based solely on foreign clinical data is governed by § 314.106 of this chapter. § 312.120 Foreign clinical studies not (b) Supporting information. A sponsor conducted under an IND. or applicant who submits data from a (a) Acceptance of studies. (1) FDA will foreign clinical study not conducted accept as support for an IND or appli- under an IND as support for an IND or cation for marketing approval (an ap- application for marketing approval plication under section 505 of the act or must submit to FDA, in addition to in- section 351 of the Public Health Service formation required elsewhere in parts Act (the PHS Act) (42 U.S.C. 262)) a 312, 314, or 601 of this chapter, a de- well-designed and well-conducted for- scription of the actions the sponsor or eign clinical study not conducted under applicant took to ensure that the re- an IND, if the following conditions are search conformed to GCP as described met: in paragraph (a)(1)(i) of this section. (i) The study was conducted in ac- The description is not required to du- cordance with good clinical practice plicate information already submitted (GCP). For the purposes of this section, in the IND or application for mar- GCP is defined as a standard for the de- keting approval. Instead, the descrip- sign, conduct, performance, moni- tion must provide either the following toring, auditing, recording, analysis, information or a cross-reference to an- and reporting of clinical trials in a way other section of the submission where that provides assurance that the data the information is located: and reported results are credible and (1) The investigator’s qualifications; accurate and that the rights, safety, (2) A description of the research fa- and well-being of trial subjects are pro- cilities; tected. GCP includes review and ap- (3) A detailed summary of the pro- proval (or provision of a favorable tocol and results of the study and, opinion) by an independent ethics com- should FDA request, case records main- mittee (IEC) before initiating a study, tained by the investigator or addi- continuing review of an ongoing study tional background data such as hos- by an IEC, and obtaining and docu- pital or other institutional records; menting the freely given informed con- (4) A description of the drug sub- sent of the subject (or a subject’s le- stance and drug product used in the gally authorized representative, if the study, including a description of the subject is unable to provide informed components, formulation, specifica- consent) before initiating a study. GCP tions, and, if available, bioavailability does not require informed consent in of the specific drug product used in the life-threatening situations when the clinical study; IEC reviewing the study finds, before (5) If the study is intended to support initiation of the study, that informed the effectiveness of a drug product, in- consent is not feasible and either that formation showing that the study is the conditions present are consistent adequate and well controlled under with those described in § 50.23 or § 314.126 of this chapter;

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(6) The name and address of the IEC (2) FDA may grant a waiver if it finds that reviewed the study and a state- that doing so would be in the interest ment that the IEC meets the definition of the public health. in § 312.3 of this chapter. The sponsor or (d) Records. A sponsor or applicant applicant must maintain records sup- must retain the records required by porting such statement, including this section for a foreign clinical study records of the names and qualifications not conducted under an IND as follows: of IEC members, and make these (1) If the study is submitted in sup- records available for agency review port of an application for marketing upon request; approval, for 2 years after an agency (7) A summary of the IEC’s decision decision on that application; to approve or modify and approve the (2) If the study is submitted in sup- study, or to provide a favorable opin- port of an IND but not an application ion; for marketing approval, for 2 years (8) A description of how informed after the submission of the IND. consent was obtained; (9) A description of what incentives, [73 FR 22815, Apr. 28, 2008] if any, were provided to subjects to § 312.130 Availability for public disclo- participate in the study; sure of data and information in an (10) A description of how the spon- IND. sor(s) monitored the study and ensured (a) The existence of an investiga- that the study was carried out consist- ently with the study protocol; and tional new drug application will not be disclosed by FDA unless it has pre- (11) A description of how investiga- viously been publicly disclosed or ac- tors were trained to comply with GCP (as described in paragraph (a)(1)(i) of knowledged. this section) and to conduct the study (b) The availability for public disclo- in accordance with the study protocol, sure of all data and information in an and a statement on whether written investigational new drug application commitments by investigators to com- for a new drug will be handled in ac- ply with GCP and the protocol were ob- cordance with the provisions estab- tained. Any signed written commit- lished in § 314.430 for the confidentiality ments by investigators must be main- of data and information in applications tained by the sponsor or applicant and submitted in part 314. The availability made available for agency review upon for public disclosure of all data and in- request. formation in an investigational new (c) Waivers. (1) A sponsor or applicant drug application for a biological prod- may ask FDA to waive any applicable uct will be governed by the provisions requirements under paragraphs (a)(1) of §§ 601.50 and 601.51. and (b) of this section. A waiver re- (c) Notwithstanding the provisions of quest may be submitted in an IND or in § 314.430, FDA shall disclose upon re- an information amendment to an IND, quest to an individual to whom an in- or in an application or in an amend- vestigational new drug has been given ment or supplement to an application a copy of any IND safety report relat- submitted under part 314 or 601 of this ing to the use in the individual. chapter. A waiver request is required (d) The availability of information to contain at least one of the following: required to be publicly disclosed for in- (i) An explanation why the sponsor’s vestigations involving an exception or applicant’s compliance with the re- from informed consent under § 50.24 of quirement is unnecessary or cannot be this chapter will be handled as follows: achieved; Persons wishing to request the publicly (ii) A description of an alternative disclosable information in the IND that submission or course of action that was required to be filed in Docket satisfies the purpose of the require- Number 95S–0158 in the Division of ment; or Dockets Management (HFA–305), Food (iii) Other information justifying a and Drug Administration, 5630 Fishers waiver. Lane, rm. 1061, Rockville, MD 20852,

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shall submit a request under the Free- (c) All correspondence relating to ex- dom of Information Act. port of an investigational drug under [52 FR 8831, Mar. 19, 1987. Redesignated at 53 § 312.110(b)(2) shall be submitted to the FR 41523, Oct. 21, 1988, as amended at 61 FR International Affairs Staff (HFY–50), 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 Office of Health Affairs, Food and Drug FR 24879, May 9, 2003] Administration, 5600 Fishers Lane, Rockville, MD 20857. § 312.140 Address for correspondence. [70 FR 14981, Mar. 24, 2005, as amended at 74 (a) A sponsor must send an initial FR 13113, Mar. 26, 2009; 74 FR 55771, Oct. 29, IND submission to the Center for Drug 2009; 75 FR 37295, June 29, 2010; 80 FR 18091, Evaluation and Research (CDER) or to Apr. 3, 2015; 81 FR 17066, Mar. 28, 2016] the Center for Biologics Evaluation and Research (CBER), depending on the § 312.145 Guidance documents. Center responsible for regulating the (a) FDA has made available guidance product as follows: documents under § 10.115 of this chapter (1) For drug products regulated by to help you to comply with certain re- CDER. Send the IND submission to the Central Document Room, Center for quirements of this part. Drug Evaluation and Research, Food (b) The Center for Drug Evaluation and Drug Administration, 5901–B and Research (CDER) and the Center Ammendale Rd., Beltsville, MD 20705– for Biologics Evaluation and Research 1266; except send an IND submission for (CBER) maintain lists of guidance doc- an in vivo bioavailability or bioequiva- uments that apply to the centers’ regu- lence study in humans to support an lations. The lists are maintained on abbreviated new drug application to the Internet and are published annu- the Office of Generic Drugs (HFD–600), ally in the FEDERAL REGISTER. A re- Center for Drug Evaluation and Re- quest for a copy of the CDER list search, Food and Drug Administration, should be directed to the Office of Metro Park North VII, 7620 Standish Training and Communications, Divi- Pl., Rockville, MD 20855. sion of Drug Information, Center for (2) For biological products regulated by Drug Evaluation and Research, Food CDER. Send the IND submission to the and Drug Administration, 10903 New Central Document Room, Center for Hampshire Ave., Silver Spring, MD Drug Evaluation and Research, Food 20993–0002. A request for a copy of the and Drug Administration, 5901–B CBER list should be directed to the Ammendale Rd., Beltsville, MD 20705– Food and Drug Administration, Center 1266. for Biologics Evaluation and Research, (3) For biological products regulated by Office of Communication, Outreach and CBER. Send the IND submission to the Development, 10903 New Hampshire Food and Drug Administration, Center Ave., Bldg. 71, Rm. 3103, Silver Spring, for Biologics Evaluation and Research, MD 20993–0002. Document Control Center, 10903 New [65 FR 56479, Sept. 19, 2000, as amended at 74 Hampshire Ave., Bldg. 71, Rm. G112, FR 13113, Mar. 26, 2009; 80 FR 18091, Apr. 3, Silver Spring, MD 20993–0002. 2015] (b) On receiving the IND, the responsible Center will inform the sponsor which one of the divisions in CDER or Subpart G—Drugs for Investiga- CBER is responsible for the IND. tional Use in Laboratory Re- Amendments, reports, and other cor- search Animals or In Vitro respondence relating to matters cov- Tests ered by the IND should be sent to the appropriate center at the address indi- § 312.160 Drugs for investigational use cated in this section and marked to the in laboratory research animals or attention of the responsible division. in vitro tests. The outside wrapper of each submis- (a) Authorization to ship. (1)(i) A per- sion shall state what is contained in son may ship a drug intended solely for the submission, for example, ‘‘IND Ap- tests in vitro or in animals used only plication’’, ‘‘Protocol Amendment’’, for laboratory research purposes if it is etc. labeled as follows:

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CAUTION: Contains a new drug for inves- for a regulatory hearing before FDA tigational use only in laboratory research pursuant to part 16. animals, or for tests in vitro. Not for use in (c) Disposition of unused drug. The humans. person who ships the drug under para- (ii) A person may ship a biological graph (a) of this section shall assure product for investigational in vitro di- the return of all unused supplies of the agnostic use that is listed in drug from individual investigators § 312.2(b)(2)(ii) if it is labeled as follows: whenever the investigation discon- tinues or the investigation is termi- CAUTION: Contains a biological product nated. The person who ships the drug for investigational in vitro diagnostic tests only. may authorize in writing alternative disposition of unused supplies of the (2) A person shipping a drug under drug provided this alternative disposi- paragraph (a) of this section shall use tion does not expose humans to risks due diligence to assure that the con- from the drug, either directly or indi- signee is regularly engaged in con- rectly (e.g., through food-producing ducting such tests and that the ship- animals). The shipper shall maintain ment of the new drug will actually be records of any alternative disposition. used for tests in vitro or in animals used only for laboratory research. [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987. Redesignated at 53 (3) A person who ships a drug under FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, paragraph (a) of this section shall 2002] maintain adequate records showing the name and post office address of the ex- Subpart H Reserved pert to whom the drug is shipped and [ ] the date, quantity, and batch or code mark of each shipment and delivery. Subpart I—Expanded Access to Records of shipments under paragraph Investigational Drugs for Treat- (a)(1)(i) of this section are to be main- ment Use tained for a period of 2 years after the shipment. Records and reports of data SOURCE: 74 FR 40942, Aug. 13, 2009, unless and shipments under paragraph otherwise noted. (a)(1)(ii) of this section are to be maintained in accordance with § 312.57(b). § 312.300 General. The person who ships the drug shall (a) Scope. This subpart contains the upon request from any properly au- requirements for the use of investiga- thorized officer or employee of the tional new drugs and approved drugs Food and Drug Administration, at rea- where availability is limited by a risk sonable times, permit such officer or evaluation and mitigation strategy employee to have access to and copy (REMS) when the primary purpose is to and verify records required to be main- diagnose, monitor, or treat a patient’s tained under this section. disease or condition. The aim of this (b) Termination of authorization to subpart is to facilitate the availability ship. FDA may terminate authoriza- of such drugs to patients with serious tion to ship a drug under this section if diseases or conditions when there is no it finds that: comparable or satisfactory alternative (1) The sponsor of the investigation therapy to diagnose, monitor, or treat has failed to comply with any of the the patient’s disease or condition. conditions for shipment established (b) Definitions. The following defini- under this section; or tions of terms apply to this subpart: (2) The continuance of the investiga- Immediately life-threatening disease or tion is unsafe or otherwise contrary to condition means a stage of disease in the public interest or the drug is used which there is reasonable likelihood for purposes other than bona fide sci- that death will occur within a matter entific investigation. FDA will notify of months or in which premature death the person shipping the drug of its find- is likely without early treatment. ing and invite immediate correction. If Serious disease or condition means a correction is not immediately made, disease or condition associated with the person shall have an opportunity morbidity that has substantial impact

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on day-to-day functioning. Short-lived (i) A cover sheet (Form FDA 1571) and self-limiting morbidity will usu- meeting the requirements of § 312.23(a); ally not be sufficient, but the mor- (ii) The rationale for the intended use bidity need not be irreversible, proof the drug, including a list of available vided it is persistent or recurrent. therapeutic options that would ordi- Whether a disease or condition is seri- narily be tried before resorting to the ous is a matter of clinical judgment, investigational drug or an explanation based on its impact on such factors as of why the use of the investigational survival, day-to-day functioning, or the drug is preferable to the use of avail- likelihood that the disease, if left unable therapeutic options; treated, will progress from a less severe (iii) The criteria for patient selection condition to a more serious one. or, for an individual patient, a description of the patient’s disease or condi- § 312.305 Requirements for all expanded access uses. tion, including recent medical history and previous treatments of the disease The criteria, submission require- or condition; ments, safeguards, and beginning treat- (iv) The method of administration of ment information set out in this sec- the drug, dose, and duration of ther- tion apply to all expanded access uses apy; described in this subpart. Additional (v) A description of the facility where criteria, submission requirements, and the drug will be manufactured; safeguards that apply to specific types of expanded access are described in (vi) Chemistry, manufacturing, and §§ 312.310 through 312.320. controls information adequate to ensure the proper identification, quality, (a) Criteria. FDA must determine that: purity, and strength of the investiga- (1) The patient or patients to be tional drug; treated have a serious or immediately (vii) Pharmacology and toxicology life-threatening disease or condition, information adequate to conclude that and there is no comparable or satisfac- the drug is reasonably safe at the dose tory alternative therapy to diagnose, and duration proposed for expanded ac- monitor, or treat the disease or condi- cess use (ordinarily, information that tion; would be adequate to permit clinical (2) The potential patient benefit jus- testing of the drug in a population of tifies the potential risks of the treat- the size expected to be treated); and ment use and those potential risks are (viii) A description of clinical proce- not unreasonable in the context of the dures, laboratory tests, or other moni- disease or condition to be treated; and toring necessary to evaluate the effects (3) Providing the investigational drug of the drug and minimize its risks. for the requested use will not interfere (3) The expanded access submission with the initiation, conduct, or com- and its mailing cover must be plainly pletion of clinical investigations that marked ‘‘EXPANDED ACCESS SUB- could support marketing approval of MISSION.’’ If the expanded access sub- the expanded access use or otherwise mission is for a treatment IND or compromise the potential development treatment protocol, the applicable box of the expanded access use. on Form FDA 1571 must be checked. (b) Submission. (1) An expanded access (c) Safeguards. The responsibilities of submission is required for each type of sponsors and investigators set forth in expanded access described in this sub- subpart D of this part are applicable to part. The submission may be a new expanded access use under this subpart IND or a protocol amendment to an ex- as described in this paragraph. isting IND. Information required for a (1) A licensed physician under whose submission may be supplied by refer- immediate direction an investigational ring to pertinent information con- drug is administered or dispensed for tained in an existing IND if the sponsor an expanded access use under this sub- of the existing IND grants a right of part is considered an investigator, for reference to the IND. purposes of this part, and must comply (2) The expanded access submission with the responsibilities for investiga- must include: tors set forth in subpart D of this part

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to the extent they are applicable to the panded access, other sponsor respon- expanded access use. sibilities under subpart D may also (2) An individual or entity that sub- apply. mits an expanded access IND or pro- (d) Beginning treatment—(1) INDs. An tocol under this subpart is considered a expanded access IND goes into effect 30 sponsor, for purposes of this part, and days after FDA receives the IND or on must comply with the responsibilities earlier notification by FDA that the for sponsors set forth in subpart D of expanded access use may begin. this part to the extent they are appli- (2) Protocols. With the following ex- cable to the expanded access use. ceptions, expanded access use under a (3) A licensed physician under whose protocol submitted under an existing immediate direction an investigational IND may begin as described in drug is administered or dispensed, and § 312.30(a). who submits an IND for expanded ac- (i) Expanded access use under the cess use under this subpart is consid- emergency procedures described in ered a sponsor-investigator, for purposes § 312.310(d) may begin when the use is of this part, and must comply with the authorized by the FDA reviewing offi- responsibilities for sponsors and inves- cial. tigators set forth in subpart D of this (ii) Expanded access use under part to the extent they are applicable § 312.320 may begin 30 days after FDA to the expanded access use. receives the protocol or upon earlier (4) Investigators. In all cases of ex- notification by FDA that use may panded access, investigators are re- begin. sponsible for reporting adverse drug (3) Clinical holds. FDA may place any events to the sponsor, ensuring that expanded access IND or protocol on the informed consent requirements of clinical hold as described in § 312.42. part 50 of this chapter are met, ensuring that IRB review of the expanded ac- § 312.310 Individual patients, includ- cess use is obtained in a manner con- ing for emergency use. sistent with the requirements of part Under this section, FDA may permit 56 of this chapter, and maintaining ac- an investigational drug to be used for curate case histories and drug disposi- the treatment of an individual patient tion records and retaining records in a by a licensed physician. manner consistent with the require- (a) Criteria. The criteria in § 312.305(a) ments of § 312.62. Depending on the type must be met; and the following deter- of expanded access, other investigator minations must be made: responsibilities under subpart D may (1) The physician must determine also apply. that the probable risk to the person (5) Sponsors. In all cases of expanded from the investigational drug is not access, sponsors are responsible for greater than the probable risk from the submitting IND safety reports and an- disease or condition; and nual reports (when the IND or protocol (2) FDA must determine that the pa- continues for 1 year or longer) to FDA tient cannot obtain the drug under an- as required by §§ 312.32 and 312.33, en- other IND or protocol. suring that licensed physicians are (b) Submission. The expanded access qualified to administer the investiga- submission must include information tional drug for the expanded access adequate to demonstrate that the cri- use, providing licensed physicians with teria in § 312.305(a) and paragraph (a) of the information needed to minimize this section have been met. The ex- the risk and maximize the potential panded access submission must meet benefits of the investigational drug the requirements of § 312.305(b). (the investigator’s brochure must be (1) If the drug is the subject of an ex- provided if one exists for the drug), isting IND, the expanded access sub- maintaining an effective IND for the mission may be made by the sponsor or expanded access use, and maintaining by a licensed physician. adequate drug disposition records and (2) A sponsor may satisfy the submis- retaining records in a manner con- sion requirements by amending its ex- sistent with the requirements of isting IND to include a protocol for in- § 312.57. Depending on the type of ex- dividual patient expanded access.

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(3) A licensed physician may satisfy ter, 866–300–4374, e-mail: emer- the submission requirements by ob- [email protected]. taining from the sponsor permission (2) The licensed physician or sponsor for FDA to refer to any information in must explain how the expanded access the IND that would be needed to sup- use will meet the requirements of port the expanded access request (right §§ 312.305 and 312.310 and must agree to of reference) and by providing any submit an expanded access submission other required information not con- within 15 working days of FDA’s au- tained in the IND (usually only the in- thorization of the use. formation specific to the individual pa- [74 FR 40942, Aug. 13, 2009, as amended at 75 tient). FR 32659, June 9, 2010; 80 FR 18091, Apr. 3, (c) Safeguards. (1) Treatment is gen- 2015] erally limited to a single course of therapy for a specified duration unless § 312.315 Intermediate-size patient FDA expressly authorizes multiple populations. courses or chronic therapy. Under this section, FDA may permit (2) At the conclusion of treatment, an investigational drug to be used for the licensed physician or sponsor must the treatment of a patient population provide FDA with a written summary smaller than that typical of a treat- of the results of the expanded access ment IND or treatment protocol. FDA use, including adverse effects. may ask a sponsor to consolidate ex- (3) FDA may require sponsors to panded access under this section when monitor an individual patient ex- the agency has received a significant panded access use if the use is for an number of requests for individual pa- extended duration. tient expanded access to an investiga- (4) When a significant number of tional drug for the same use. similar individual patient expanded ac- (a) Need for expanded access. Expanded cess requests have been submitted, access under this section may be need- FDA may ask the sponsor to submit an ed in the following situations: IND or protocol for the use under (1) Drug not being developed. The drug § 312.315 or § 312.320. is not being developed, for example, be- (d) Emergency procedures. If there is cause the disease or condition is so an emergency that requires the patient rare that the sponsor is unable to re- to be treated before a written submis- cruit patients for a clinical trial. sion can be made, FDA may authorize (2) Drug being developed. The drug is the expanded access use to begin with- being studied in a clinical trial, but pa- out a written submission. The FDA re- tients requesting the drug for expanded viewing official may authorize the access use are unable to participate in emergency use by telephone. the trial. For example, patients may (1) Emergency expanded access use not be able to participate in the trial may be requested by telephone, fac- because they have a different disease or simile, or other means of electronic stage of disease than the one being communications. For investigational studied or otherwise do not meet the biological drug products regulated by enrollment criteria, because enroll- the Center for Biologics Evaluation ment in the trial is closed, or because and Research, the request should be di- the trial site is not geographically ac- rected to the Office of Communication, cessible. Outreach and Development, Center for (3) Approved or related drug. (i) The Biologics Evaluation and Research, 240- drug is an approved drug product that 402-8010 or 1–800–835–4709, e-mail: is no longer marketed for safety rea- [email protected]. For all other inves- sons or is unavailable through mar- tigational drugs, the request for au- keting due to failure to meet the con- thorization should be directed to the ditions of the approved application, or Division of Drug Information, Center (ii) The drug contains the same ac- for Drug Evaluation and Research, 301– tive moiety as an approved drug prod- 796–3400, e-mail: [email protected]. uct that is unavailable through mar- After normal working hours (8 a.m. to keting due to failure to meet the con- 4:30 p.m.), the request should be di- ditions of the approved application or a rected to the FDA Emergency Call Cen- drug shortage.

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(b) Criteria. The criteria in § 312.305(a) (iii) As the number of patients en- must be met; and FDA must determine rolled increases, FDA may ask the that: sponsor to submit an IND or protocol (1) There is enough evidence that the for the use under § 312.320. drug is safe at the dose and duration (2) The sponsor is responsible for proposed for expanded access use to monitoring the expanded access pro- justify a clinical trial of the drug in tocol to ensure that licensed physi- the approximate number of patients ex- cians comply with the protocol and the pected to receive the drug under ex- regulations applicable to investigators. panded access; and (2) There is at least preliminary clin- § 312.320 Treatment IND or treatment ical evidence of effectiveness of the protocol. drug, or of a plausible pharmacologic Under this section, FDA may permit effect of the drug to make expanded ac- an investigational drug to be used for cess use a reasonable therapeutic op- widespread treatment use. tion in the anticipated patient popu- (a) Criteria. The criteria in § 312.305(a) lation. must be met, and FDA must determine (c) Submission. The expanded access that: submission must include information (1) Trial status. (i) The drug is being adequate to satisfy FDA that the cri- investigated in a controlled clinical teria in § 312.305(a) and paragraph (b) of trial under an IND designed to support this section have been met. The ex- a marketing application for the expanded access submission must meet panded access use, or the requirements of § 312.305(b). In addi- (ii) All clinical trials of the drug tion: have been completed; and (1) The expanded access submission (2) Marketing status. The sponsor is must state whether the drug is being actively pursuing marketing approval developed or is not being developed and of the drug for the expanded access use describe the patient population to be with due diligence; and treated. (3) Evidence. (i) When the expanded (2) If the drug is not being actively access use is for a serious disease or developed, the sponsor must explain condition, there is sufficient clinical why the drug cannot currently be de- evidence of safety and effectiveness to veloped for the expanded access use and support the expanded access use. Such under what circumstances the drug evidence would ordinarily consist of could be developed. data from phase 3 trials, but could con- (3) If the drug is being studied in a sist of compelling data from completed clinical trial, the sponsor must explain phase 2 trials; or why the patients to be treated cannot (ii) When the expanded access use is be enrolled in the clinical trial and for an immediately life-threatening under what circumstances the sponsor disease or condition, the available sci- would conduct a clinical trial in these entific evidence, taken as a whole, pro- patients. vides a reasonable basis to conclude (d) Safeguards. (1) Upon review of the that the investigational drug may be IND annual report, FDA will determine effective for the expanded access use whether it is appropriate for the ex- and would not expose patients to an panded access to continue under this unreasonable and significant risk of ill- section. ness or injury. This evidence would or- (i) If the drug is not being actively dinarily consist of clinical data from developed or if the expanded access use phase 3 or phase 2 trials, but could be is not being developed (but another use based on more preliminary clinical evi- is being developed), FDA will consider dence. whether it is possible to conduct a clin- (b) Submission. The expanded access ical study of the expanded access use. submission must include information (ii) If the drug is being actively de- adequate to satisfy FDA that the cri- veloped, FDA will consider whether teria in § 312.305(a) and paragraph (a) of providing the investigational drug for this section have been met. The ex- expanded access use is interfering with panded access submission must meet the clinical development of the drug. the requirements of § 312.305(b).

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(c) Safeguard. The sponsor is respon- Subpart D—FDA Action on Applications sible for monitoring the treatment pro- and Abbreviated Applications tocol to ensure that licensed physi- 314.100 Timeframes for reviewing applica- cians comply with the protocol and the tions and abbreviated applications. regulations applicable to investigators. 314.101 Filing an NDA and receiving an ANDA. PART 314—APPLICATIONS FOR FDA 314.102 Communications between FDA and applicants. APPROVAL TO MARKET A NEW 314.103 Dispute resolution. DRUG 314.104 Drugs with potential for abuse. 314.105 Approval of an NDA and an ANDA. Subpart A—General Provisions 314.106 Foreign data. 314.107 Date of approval of a 505(b)(2) appli- Sec. cation or ANDA. 314.1 Scope of this part. 314.108 New drug product exclusivity. 314.2 Purpose. 314.110 Complete response letter to the ap- 314.3 Definitions. plicant. 314.120 [Reserved] Subpart B—Applications 314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) petition that re- 314.50 Content and format of an NDA. lies on, a listed drug that is no longer 314.52 Notice of certification of invalidity, marketed. unenforceability, or noninfringement of 314.125 Refusal to approve an NDA. a patent. 314.126 Adequate and well-controlled stud- 314.53 Submission of patent information. ies. 314.127 Refusal to approve an ANDA. 314.54 Procedure for submission of a 314.150 Withdrawal of approval of an appli- 505(b)(2) application requiring investiga- cation or abbreviated application. tions for approval of a new indication 314.151 Withdrawal of approval of an abbre- for, or other change from, a listed drug. viated new drug application under sec- 314.55 Pediatric use information. tion 505(j)(5) of the act. 314.60 Amendments to an unapproved appli- 314.152 Notice of withdrawal of approval of cation, supplement, or resubmission. an application or abbreviated application 314.65 Withdrawal by the applicant of an un- for a new drug. approved application. 314.153 Suspension of approval of an abbre- 314.70 Supplements and other changes to an viated new drug application. approved NDA. 314.160 Approval of an application or abbre- 314.71 Procedures for submission of a sup- viated application for which approval plement to an approved application. was previously refused, suspended, or 314.72 Change in ownership of an applica- withdrawn. tion. 314.161 Determination of reasons for voluntary withdrawal of a listed drug. 314.80 Postmarketing reporting of adverse 314.162 Removal of a drug product from the drug experiences. list. 314.81 Other postmarketing reports. 314.170 Adulteration and misbranding of an 314.90 Waivers. approved drug.

Subpart C—Abbreviated Applications Subpart E—Hearing Procedures for New 314.92 Drug products for which abbreviated Drugs applications may be submitted. 314.200 Notice of opportunity for hearing; 314.93 Petition to request a change from a notice of participation and request for listed drug. hearing; grant or denial of hearing. 314.94 Content and format of an ANDA. 314.201 Procedure for hearings. 314.95 Notice of certification of invalidity, 314.235 Judicial review. unenforceability, or noninfringement of a patent. Subpart F [Reserved] 314.96 Amendments to an unapproved ANDA. Subpart G—Miscellaneous Provisions 314.97 Supplements and other changes to an 314.410 Imports and exports of new drugs. approved ANDA. 314.420 Drug master files. 314.98 Postmarketing reports. 314.430 Availability for public disclosure of 314.99 Other responsibilities of an applicant data and information in an application of an ANDA. or abbreviated application.

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314.440 Addresses for applications and ab- tions are to chapter I of title 21, unless breviated applications. otherwise noted. 314.445 Guidance documents. [50 FR 7493, Feb. 22, 1985, as amended at 57 Subpart H—Accelerated Approval of New FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999] Drugs for Serious or Life-Threatening Ill- § 314.2 Purpose. nesses The purpose of this part is to estab- 314.500 Scope. lish an efficient and thorough drug re- 314.510 Approval based on a surrogate end- view process in order to: (a) Facilitate point or on an effect on a clinical end- the approval of drugs shown to be safe point other than survival or irreversible morbidity. and effective; and (b) ensure the dis- 314.520 Approval with restrictions to assure approval of drugs not shown to be safe safe use. and effective. These regulations are 314.530 Withdrawal procedures. also intended to establish an effective 314.540 Postmarketing safety reporting. system for FDA’s surveillance of mar- 314.550 Promotional materials. keted drugs. These regulations shall be 314.560 Termination of requirements. construed in light of these objectives.

Subpart I—Approval of New Drugs When § 314.3 Definitions. Human Efficacy Studies Are Not Ethical (a) The definitions and interpreta- or Feasible tions contained in section 201 of the 314.600 Scope. Federal Food, Drug, and Cosmetic Act 314.610 Approval based on evidence of effec- apply to those terms when used in this tiveness from studies in animals. part and part 320 of this chapter. 314.620 Withdrawal procedures. (b) The following definitions of terms 314.630 Postmarketing safety reporting. apply to this part and part 320 of this 314.640 Promotional materials. chapter: 314.650 Termination of requirements. 180-day exclusivity period is the 180- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, day period beginning on the date of the 355, 355a, 355f, 356, 356a, 356b, 356c, 356e, 360cc, first commercial marketing of the drug 371, 374, 379e, 379k–1. (including the commercial marketing of the reference listed drug) by any SOURCE: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. first applicant. The 180-day period ends on the day before the date on which an EDITORIAL NOTE: Nomenclature changes to ANDA submitted by an applicant other part 314 appear at 69 FR 13717, Mar. 24, 2004; than a first applicant could be ap- 81 FR 69639, Oct. 6, 2016. proved. 505(b)(2) application is an NDA sub- Subpart A—General Provisions mitted under section 505(b)(1) of the Federal Food, Drug, and Cosmetic Act § 314.1 Scope of this part. for a drug for which at least some of (a) This part sets forth procedures the investigations described in section and requirements for the submission 505(b)(1)(A) of the Federal Food, Drug, to, and the review by, the Food and and Cosmetic Act and relied upon by Drug Administration of applications the applicant for approval of the NDA and abbreviated applications to market were not conducted by or for the appli- a new drug under section 505 of the cant and for which the applicant has Federal Food, Drug, and Cosmetic Act, not obtained a right of reference or use as well as amendments, supplements, from the person by or for whom the in- and postmarketing reports to them. vestigations were conducted. (b) This part does not apply to drug Abbreviated application, abbreviated products subject to licensing by FDA new drug application, or ANDA is the ap- under the Public Health Service Act (58 plication described under § 314.94, in- Stat. 632 as amended (42 U.S.C. 201 et cluding all amendments and supple- seq.)) and subchapter F of chapter I of ments to the application. title 21 of the Code of Federal Regula- Acknowledgment letter is a written, tions. postmarked communication from FDA (c) References in this part to regula- to an applicant stating that the Agen- tions in the Code of Federal Regula- cy has determined that an ANDA is

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sufficiently complete to permit a sub- Authorized generic drug is a listed stantive review. An acknowledgment drug, as defined in this section, that letter indicates that the ANDA is re- has been approved under section 505(c) garded as received. of the Federal Food, Drug, and Cos- Act is the Federal Food, Drug, and metic Act and is marketed, sold, or dis- Cosmetic Act (section 201 et seq. (21 tributed directly or indirectly to the U.S.C. 301 et seq.)). retail class of trade with labeling, Active ingredient is any component packaging (other than repackaging as that is intended to furnish pharma- the listed drug in blister packs, unit cological activity or other direct effect doses, or similar packaging for use in in the diagnosis, cure, mitigation, institutions), product code, labeler treatment, or prevention of disease, or code, trade name, or trademark that to affect the structure or any function differs from that of the listed drug. of the body of man or other animals. Bioavailability is the rate and extent The term includes those components to which the active ingredient or ac- that may undergo chemical change in tive moiety is absorbed from a drug the manufacture of the drug product product and becomes available at the and be present in the drug product in a site of drug action. For drug products modified form intended to furnish the that are not intended to be absorbed specified activity or effect. into the bloodstream, bioavailability Active moiety is the molecule or ion, may be assessed by scientifically valid excluding those appended portions of measurements intended to reflect the the molecule that cause the drug to be rate and extent to which the active in- an ester, salt (including a salt with hy- gredient or active moiety becomes drogen or coordination bonds), or other available at the site of drug action. noncovalent derivative (such as a com- Bioequivalence is the absence of a sig- plex, chelate, or clathrate) of the mol- nificant difference in the rate and ex- ecule, responsible for the physiological tent to which the active ingredient or or pharmacological action of the drug active moiety in pharmaceutical substance. equivalents or pharmaceutical alter- ANDA holder is the applicant that natives becomes available at the site of owns an approved ANDA. drug action when administered at the Applicant is any person who submits same molar dose under similar condi- an NDA (including a 505(b)(2) applications in an appropriately designed tion) or ANDA or an amendment or study. Where there is an intentional supplement to an NDA or ANDA under difference in rate (e.g., in certain ex- this part to obtain FDA approval of a tended-release dosage forms), certain new drug and any person who owns an pharmaceutical equivalents or alter- approved NDA (including a 505(b)(2) ap- natives may be considered bioequiva- plication) or ANDA. lent if there is no significant difference Application, new drug application, or in the extent to which the active ingre- NDA is the application described under dient or moiety from each product be- § 314.50, including all amendments and comes available at the site of drug ac- supplements to the application. An tion. This applies only if the difference NDA refers to ‘‘stand-alone’’ applica- in the rate at which the active ingre- tions submitted under section 505(b)(1) dient or moiety becomes available at of the Federal Food, Drug, and Cos- the site of drug action is intentional metic Act and to 505(b)(2) applications. and is reflected in the proposed label- Approval letter is a written commu- ing, is not essential to the attainment nication to an applicant from FDA ap- of effective body drug concentrations proving an NDA or an ANDA. on chronic use, and is considered medi- Assess the effects of the change is to cally insignificant for the drug. For evaluate the effects of a manufacturing drug products that are not intended to change on the identity, strength, qual- be absorbed into the bloodstream, bio- ity, purity, and potency of a drug prod- equivalence may be assessed by sci- uct as these factors may relate to the entifically valid measurements in- safety or effectiveness of the drug prod- tended to reflect the rate and extent to uct. which the active ingredient or active

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moiety becomes available at the site of the NDA or ANDA is approved, except drug action. that the date of approval for an NDA Bioequivalence requirement is a re- described in section 505(x)(1) of the quirement imposed by FDA for in vitro Federal Food, Drug, and Cosmetic Act and/or in vivo testing of specified drug is determined as described in section products that must be satisfied as a 505(x)(2) of the Federal Food, Drug, and condition of marketing. Cosmetic Act. ‘‘Date of approval’’ re- Class 1 resubmission is the resubmis- fers only to a final approval and not to sion of an NDA or efficacy supplement, a tentative approval. following receipt of a complete re- Dosage form is the physical mani- sponse letter, that contains one or festation containing the active and in- more of the following: Final printed la- active ingredients that delivers a dose beling, draft labeling, certain safety of the drug product. This includes such updates, stability updates to support factors as: provisional or final dating periods, (1) The physical appearance of the commitments to perform post- drug product; marketing studies (including proposals (2) The physical form of the drug for such studies), assay validation product prior to dispensing to the pa- data, final release testing on the last tient; lots used to support approval, minor (3) The way the product is adminis- reanalyses of previously submitted tered; and data, and other comparatively minor (4) The design features that affect information. frequency of dosing. Class 2 resubmission is the resubmis- Drug product is a finished dosage sion of an NDA or efficacy supplement, form, e.g., tablet, capsule, or solution, following receipt of a complete re- that contains a drug substance, gen- sponse letter, that includes any item erally, but not necessarily, in associa- not specified in the definition of ‘‘Class tion with one or more other ingredi- 1 resubmission,’’ including any item ents. that would require presentation to an Drug substance is an active ingredient advisory committee. that is intended to furnish pharma- Commercial marketing is the introduc- cological activity or other direct effect tion or delivery for introduction into in the diagnosis, cure, mitigation, interstate commerce of a drug product treatment, or prevention of disease or described in an ANDA, outside the con- to affect the structure or any function trol of the ANDA applicant, except of the human body, but does not in- that the term does not include transfer clude intermediates used in the syn- of the drug product for investigational thesis of such ingredient. use under part 312 of this chapter or Efficacy supplement is a supplement transfer of the drug product to parties to an approved NDA proposing to make identified in the ANDA for reasons one or more related changes from other than sale. Commercial mar- among the following changes to prod- keting includes the introduction or de- uct labeling: livery for introduction into interstate (1) Add or modify an indication or commerce of the reference listed drug claim; by the ANDA applicant. (2) Revise the dose or dose regimen; Complete response letter is a written (3) Provide for a new route of admin- communication to an applicant from istration; FDA usually describing all of the defi- (4) Make a comparative efficacy ciencies that the Agency has identified claim naming another drug product; in an NDA or ANDA that must be satis- (5) Significantly alter the intended factorily addressed before it can be ap- patient population; proved. (6) Change the marketing status from Component is any ingredient intended prescription to over-the-counter use; for use in the manufacture of a drug (7) Provide for, or provide evidence of product, including those that may not effectiveness necessary for, the tradi- appear in such drug product. tional approval of a product originally Date of approval is the date on the ap- approved under subpart H of this part; proval letter from FDA stating that or

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(8) Incorporate other information Paragraph IV acknowledgment letter is based on at least one adequate and a written, postmarked communication well-controlled clinical study. from FDA to an applicant stating that FDA or Agency is the Food and Drug the Agency has determined that a Administration. 505(b)(2) application or ANDA con- First applicant is an ANDA applicant taining a paragraph IV certification is that, on the first day on which a sub- sufficiently complete to permit a substantially complete application con- stantive review. A paragraph IV ac- taining a paragraph IV certification is knowledgment letter indicates that the submitted for approval of a drug, sub- 505(b)(2) application is regarded as filed mits a substantially complete applica- or the ANDA is regarded as received. tion that contains, and for which the Paragraph IV certification is a patent applicant lawfully maintains, a para- certification of invalidity, unenforce- graph IV certification for the drug. ability, or noninfringement described Inactive ingredient is any component in § 314.50(i)(1)(i)(A)(4) or other than an active ingredient. § 314.94(a)(12)(i)(A)(4). Listed drug is a new drug product that Patent owner is the owner of the pat- has been approved under section 505(c) ent for which information is submitted of the Federal Food, Drug, and Cos- for an NDA. metic Act for safety and effectiveness Pharmaceutical alternatives are drug or under section 505(j) of the Federal products that contain the identical Food, Drug, and Cosmetic Act, which therapeutic moiety, or its precursor, has not been withdrawn or suspended but not necessarily in the same under section 505(e)(1) through (5) or amount or dosage form or as the same section 505(j)(6) of the Federal Food, salt or ester. Each such drug product Drug, and Cosmetic Act, and which has individually meets either the identical not been withdrawn from sale for what or its own respective compendial or FDA has determined are reasons of other applicable standard of identity, safety or effectiveness. Listed drug sta- strength, quality, and purity, including tus is evidenced by the drug product’s potency and, where applicable, content identification in the current edition of uniformity, disintegration times, and/ FDA’s ‘‘Approved Drug Products With or dissolution rates. Therapeutic Equivalence Evaluations’’ Pharmaceutical equivalents are drug (the list) as an approved drug. A drug products in identical dosage forms and product is deemed to be a listed drug route(s) of administration that contain on the date of approval for the NDA or identical amounts of the identical ac- ANDA for that drug product. tive drug ingredient, i.e., the same salt NDA holder is the applicant that owns or ester of the same therapeutic moi- an approved NDA. ety, or, in the case of modified-release Newly acquired information is data, dosage forms that require a reservoir analyses, or other information not pre- or overage or such forms as prefilled viously submitted to the Agency, syringes where residual volume may which may include (but is not limited vary, that deliver identical amounts of to) data derived from new clinical stud- the active drug ingredient over the ies, reports of adverse events, or new identical dosing period; do not nec- analyses of previously submitted data essarily contain the same inactive in- (e.g., meta-analyses) if the studies, gredients; and meet the identical events, or analyses reveal risks of a dif- compendial or other applicable stand- ferent type or greater severity or fre- ard of identity, strength, quality, and quency than previously included in purity, including potency and, where submissions to FDA. applicable, content uniformity, disinte- Original application or original NDA is gration times, and/or dissolution rates. a pending NDA for which FDA has Postmark is an independently never issued a complete response letter verifiable evidentiary record of the or approval letter, or an NDA that was date on which a document is trans- submitted again after FDA had refused mitted, in an unmodifiable format, to to file it or after it was withdrawn another party. For postmarks made by without being approved. the U.S. Postal Service or a designated

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delivery service, the date of trans- of a drug substance or drug product. mission is the date on which the docu- For the purpose of this definition, ac- ment is received by the domestic mail ceptance criteria means numerical lim- service of the U.S. Postal Service or by its, ranges, or other criteria for the a designated delivery service. For post- tests described. marks documenting an electronic Strength is the amount of drug sub- event, the date of transmission is the stance contained in, delivered, or deliv- date (in a particular time zone) that erable from a drug product, which in- FDA sends the electronic transmission cludes: on its host system as evidenced by a (1)(i) The total quantity of drug sub- verifiable record. If the sender and the stance in mass or units of activity in a intended recipient are located in dif- dosage unit or container closure (e.g., ferent time zones, it is the sender’s weight/unit dose, weight/volume or time zone that provides the controlling weight/weight in a container closure, date of electronic transmission. Reference listed drug is the listed drug or units/volume or units/weight in a identified by FDA as the drug product container closure); and/or, as applica- upon which an applicant relies in seek- ble. ing approval of its ANDA. (ii) The concentration of the drug Reference standard is the drug product substance in mass or units of activity selected by FDA that an applicant per unit volume or mass (e.g., weight/ seeking approval of an ANDA must use weight, weight/volume, or units/vol- in conducting an in vivo bioequiva- ume); or lence study required for approval. (2) Such other criteria the Agency es- Resubmission, in the context of a com- tablishes for determining the amount plete response letter, is submission by of drug substance contained in, deliv- the applicant of all materials needed to ered, or deliverable from a drug prod- fully address all deficiencies identified uct if the weights and measures de- in the complete response letter. An scribed in paragraph (i) of this defini- NDA or ANDA for which FDA issued a tion do not apply (e.g., certain drug-de- complete response letter, but which vice combination products for which was withdrawn before approval and the amount of drug substance is emit- later submitted again, is not a resub- ted per use or unit time). mission. Substantially complete application is an Right of reference or use is the author- ANDA that on its face is sufficiently ity to rely upon, and otherwise use, an complete to permit a substantive re- investigation for the purpose of obtain- view. Sufficiently complete means that ing approval of an NDA, including the the ANDA contains all the information ability to make available the under- required under section 505(j)(2)(A) of lying raw data from the investigation the Federal Food, Drug, and Cosmetic for FDA audit, if necessary. Act and does not contain a deficiency Same drug product formulation is the formulation of the drug product sub- described in § 314.101(d) and (e). mitted for approval and any formula- Tentative approval is notification that tions that have minor differences in an NDA or ANDA otherwise meets the composition or method of manufacture requirements for approval under the from the formulation submitted for ap- Federal Food, Drug, and Cosmetic Act, proval, but are similar enough to be but cannot be approved because there relevant to the Agency’s determination is a 7-year period of orphan exclusivity of bioequivalence. for a listed drug under section 527 of Specification is the quality standard the Federal Food, Drug, and Cosmetic (i.e., tests, analytical procedures, and Act and § 316.31 of this chapter, or that acceptance criteria) provided in an ap- a 505(b)(2) application or ANDA other- proved NDA or ANDA to confirm the wise meets the requirements for ap- quality of drug substances, drug prod- proval under the Federal Food, Drug, ucts, intermediates, raw materials, re- and Cosmetic Act, but cannot be ap- agents, components, in-process mate- proved until the conditions in rials, container closure systems, and § 314.107(b)(1)(iii), (b)(3), or (c) are met; other materials used in the production because there is a period of exclusivity

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for the listed drug under § 314.108; be- Act, an amendment, and a supplement. cause there is a period of pediatric ex- The NDA is required to contain reports clusivity for the listed drug under sec- of all investigations of the drug prod- tion 505A of the Federal Food, Drug, uct sponsored by the applicant, and all and Cosmetic Act; because there is a other information about the drug perti- period of exclusivity for the listed drug nent to an evaluation of the NDA that under section 505E of the Federal Food, is received or otherwise obtained by Drug, and Cosmetic Act; or because a the applicant from any source. FDA court order pursuant to 35 U.S.C. will maintain guidance documents on 271(e)(4)(A) orders that the NDA or the format and content of NDAs to as- ANDA may be approved no earlier than sist applicants in their preparation. the date specified. A drug product that (a) Application form. The applicant is granted tentative approval is not an must submit a completed and signed approved drug and will not be approved application form that contains the fol- until FDA issues an approval letter lowing: after any necessary additional review (1) The name and address of the ap- of the NDA or ANDA. plicant; the date of the NDA; the NDA The list is the list of approved drug number if previously issued (for exam- products published in FDA’s current ple, if the NDA is a resubmission or an ‘‘Approved Drug Products With Thera- amendment or supplement); the name peutic Equivalence Evaluations,’’ of the drug product, including its es- available electronically on FDA’s Web tablished, proprietary, code, and chem- site at http://www.fda.gov/cder. ical names; the dosage form and Therapeutic equivalents are approved strength; the route of administration; drug products that are pharmaceutical the identification numbers of all INDs equivalents for which bioequivalence (as defined in § 312.3(b) of this chapter) has been demonstrated, and that can be that are referenced in the NDA; the expected to have the same clinical ef- identification numbers of all drug mas- fect and safety profile when administer files and other applications under tered to patients under the conditions this part that are referenced in the specified in the labeling. NDA; and the drug product’s proposed [81 FR 69636, Oct. 6, 2016] indications for use. (2) A statement whether the submis- Subpart B—Applications sion is an original submission, a 505(b)(2) application, a resubmission, or § 314.50 Content and format of an a supplement to an application under NDA. § 314.70. NDAs and supplements to approved (3) A statement whether the appli- NDAs are required to be submitted in cant proposes to market the drug prod- the form and contain the information, uct as a prescription or an over-the- as appropriate for the particular sub- counter product. mission, required under this section. (4) A check-list identifying what en- Three copies of the NDA are required: closures required under this section the An archival copy, a review copy, and a applicant is submitting. field copy. An NDA for a new chemical (5) The applicant, or the applicant’s entity will generally contain an appli- attorney, agent, or other authorized of- cation form, an index, a summary, five ficial must sign the NDA. If the person or six technical sections, case report signing the NDA does not reside or tabulations of patient data, case report have a place of business within the forms, drug samples, and labeling, in- United States, the NDA is required to cluding, if applicable, any Medication contain the name and address of, and Guide required under part 208 of this be countersigned by, an attorney, chapter. Other NDAs will generally agent, or other authorized official who contain only some of those items, and resides or maintains a place of business information will be limited to that within the United States. needed to support the particular sub- (b) Index. The archival copy of the mission. These include an NDA of the NDA is required to contain a com- type described in section 505(b)(2) of prehensive index by volume number the Federal Food, Drug, and Cosmetic and page number to the summary

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under paragraph (c) of this section, the the drug, its intended use, and the po- technical sections under paragraph (d) tential clinical benefits of the drug of this section, and the supporting in- product. formation under paragraph (f) of this (iii) A brief description of the mar- section. keting history, if any, of the drug out- (c) Summary. (1) An NDA is required side the United States, including a list to contain a summary of the NDA in of the countries in which the drug has enough detail that the reader may gain been marketed, a list of any countries a good general understanding of the in which the drug has been withdrawn data and information in the NDA, in- from marketing for any reason related cluding an understanding of the quan- to safety or effectiveness, and a list of titative aspects of the data. The sum- countries in which applications for mary is not required for supplements marketing are pending. The descrip- under § 314.70. Resubmissions of an NDA tion is required to describe both mar- should contain an updated summary, keting by the applicant and, if known, as appropriate. The summary should the marketing history of other persons. discuss all aspects of the NDA, and (iv) A summary of the chemistry, synthesize the information into a well- manufacturing, and controls section of structured and unified document. The the NDA. summary should be written at approxi- (v) A summary of the nonclinical mately the level of detail required for pharmacology and toxicology section publication in, and meet the editorial of the NDA. standards generally applied by, ref- (vi) A summary of the human phar- ereed scientific and medical journals. macokinetics and bioavailability sec- In addition to the agency personnel re- tion of the NDA. viewing the summary in the context of (vii) A summary of the microbiology their review of the NDA, FDA may fur- section of the NDA (for anti-infective nish the summary to FDA advisory drugs only). committee members and agency offi- (viii) A summary of the clinical data cials whose duties require an under- section of the NDA, including the re- standing of the NDA. To the extent sults of statistical analyses of the clin- possible, data in the summary should ical trials. be presented in tabular and graphic (ix) A concluding discussion that pre- forms. FDA has prepared a guideline sents the benefit and risk consider- under § 10.90(b) that provides informa- ations related to the drug, including a tion about how to prepare a summary. discussion of any proposed additional The summary required under this para- studies or surveillance the applicant graph may be used by FDA or the ap- intends to conduct postmarketing. plicant to prepare the Summary Basis (d) Technical sections. The NDA is re- of Approval document for public disclo- quired to contain the technical sec- sure (under § 314.430(e)(2)(ii)) when the tions described below. Each technical NDA is approved. section is required to contain data and (2) The summary is required to con- information in sufficient detail to pertain the following information: mit the agency to make a knowledge- (i) The proposed text of the labeling, able judgment about whether to ap- including, if applicable, any Medica- prove the NDA or whether grounds tion Guide required under part 208 of exist under section 505(d) of the Fed- this chapter, for the drug, with annota- eral Food, Drug, and Cosmetic Act to tions to the information in the sum- refuse to approve the NDA. The re- mary and technical sections of the quired technical sections are as fol- NDA that support the inclusion of each lows: statement in the labeling, and, if the (1) Chemistry, manufacturing, and con- NDA is for a prescription drug, state- trols section. A section describing the ments describing the reasons for omit- composition, manufacture, and speci- ting a section or subsection of the la- fication of the drug substance and the beling format in § 201.57 of this chapter. drug product, including the following: (ii) A statement identifying the phar- (i) Drug substance. A full description macologic class of the drug and a dis- of the drug substance including its cussion of the scientific rationale for physical and chemical characteristics

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and stability; the name and address of batch production record; the specifica- its manufacturer; the method of syn- tion for each component and for the thesis (or isolation) and purification of drug product; the names and addresses the drug substance; the process con- of the sources of the active and trols used during manufacture and noncompendial inactive components packaging; and the specifications nec- and of the container and closure sys- essary to ensure the identity, strength, tem for the drug product; the name and quality, and purity of the drug sub- address of each contract facility in- stance and the bioavailability of the volved in the manufacture, processing, drug products made from the sub- packaging, or testing of the drug prod- stance, including, for example, tests, uct and identification of the operation analytical procedures, and acceptance performed by each contract facility; criteria relating to stability, sterility, and the results of any test performed particle size, and crystalline form. The on the components used in the manu- NDA may provide additionally for the facture of the drug product as required use of alternatives to meet any of these by § 211.84(d) of this chapter and on the requirements, including alternative drug product as required by § 211.165 of sources, process controls, and analyt- this chapter. ical procedures. Reference to the cur- (c) The proposed or actual master rent edition of the U.S. Pharmacopeia production record, including a descrip- and the National Formulary may sat- tion of the equipment, to be used for isfy relevant requirements in this para- the manufacture of a commercial lot of graph. the drug product or a comparably de- (ii)((a)) Drug product. A list of all tailed description of the production components used in the manufacture of process for a representative batch of the drug product (regardless of whether the drug product. they appear in the drug product) and a (iii) Environmental impact. The NDA is statement of the composition of the required to contain either a claim for drug product; the specifications for categorical exclusion under § 25.30 or each component; the name and address 25.31 of this chapter or an environ- of each manufacturer of the drug prod- mental assessment under § 25.40 of this uct; a description of the manufacturing chapter. and packaging procedures and in-proc- (iv) The applicant may, at its option, ess controls for the drug product; the submit a complete chemistry, manu- specifications necessary to ensure the facturing, and controls section 90 to 120 identity, strength, quality, purity, po- days before the anticipated submission tency, and bioavailability of the drug of the remainder of the NDA. FDA will product, including, for example, tests, review such early submissions as re- analytical procedures, and acceptance sources permit. criteria relating to sterility, dissolu- (v) The applicant must include a tion rate, container closure systems; statement certifying that the field and stability data with proposed expi- copy of the NDA has been provided to ration dating. The NDA may provide the applicant’s home FDA district of- additionally for the use of alternatives fice. to meet any of these requirements, in- (2) Nonclinical pharmacology and toxi- cluding alternative components, manu- cology section. A section describing, facturing and packaging procedures, with the aid of graphs and tables, ani- in-process controls, and analytical pro- mal and in vitro studies with drug, in- cedures. Reference to the current edi- cluding the following: tion of the U.S. Pharmacopeia and the (i) Studies of the pharmacological ac- National Formulary may satisfy rel- tions of the drug in relation to its pro- evant requirements in this paragraph. posed therapeutic indication and stud- (b) Unless provided by paragraph ies that otherwise define the pharma- (d)(1)(ii)(a) of this section, for each cologic properties of the drug or are batch of the drug product used to con- pertinent to possible adverse effects. duct a bioavailability or bioequiva- (ii) Studies of the toxicological ef- lence study described in § 320.38 or fects of the drug as they relate to the § 320.63 of this chapter or used to con- drug’s intended clinical uses, includ- duct a primary stability study: The ing, as appropriate, studies assessing

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the drug’s acute, subacute, and chronic and the bioavailability or bioequiva- toxicity; carcinogenicity; and studies lence, or both, of the drug product. of toxicities related to the drug’s par- (4) Microbiology section. If the drug is ticular mode of administration or con- an anti-infective drug, a section de- ditions of use. scribing the microbiology data, includ- (iii) Studies, as appropriate, of the ef- ing the following: fects of the drug on reproduction and (i) A description of the biochemical on the developing fetus. basis of the drug’s action on microbial (iv) Any studies of the absorption, physiology. distribution, metabolism, and excre- (ii) A description of the anti- tion of the drug in animals. microbial spectra of the drug, includ- (v) For each nonclinical laboratory ing results of in vitro preclinical stud- study subject to the good laboratory ies to demonstrate concentrations of practice regulations under part 58 a the drug required for effective use. statement that it was conducted in (iii) A description of any known compliance with the good laboratory mechanisms of resistance to the drug, practice regulations in part 58, or, if including results of any known epi- the study was not conducted in compli- demiologic studies to demonstrate ance with those regulations, a brief prevalence of resistance factors. statement of the reason for the non- (iv) A description of clinical microbiology laboratory procedures (for exam- compliance. ple, in vitro sensitivity discs) needed (3) Human pharmacokinetics and bio- for effective use of the drug. availability section. A section describing (5) Clinical data section. A section de- the human pharmacokinetic data and scribing the clinical investigations of human bioavailability data, or infor- the drug, including the following: mation supporting a waiver of the sub- (i) A description and analysis of each mission of in vivo bioavailability data clinical pharmacology study of the under subpart B of part 320, including drug, including a brief comparison of the following: the results of the human studies with (i) A description of each of the bio- the animal pharmacology and toxi- availability and pharmacokinetic stud- cology data. ies of the drug in humans performed by (ii) A description and analysis of each or on behalf of the applicant that in- controlled clinical study pertinent to a cludes a description of the analytical proposed use of the drug, including the procedures and statistical methods protocol and a description of the statis- used in each study and a statement tical analyses used to evaluate the with respect to each study that it ei- study. If the study report is an interim ther was conducted in compliance with analysis, this is to be noted and a pro- the institutional review board regula- jected completion date provided. Con- tions in part 56, or was not subject to trolled clinical studies that have not the regulations under § 56.104 or § 56.105, been analyzed in detail for any reason and that it was conducted in compli- (e.g., because they have been discon- ance with the informed consent regula- tinued or are incomplete) are to be in- tions in part 50. cluded in this section, including a copy (ii) If the NDA describes in the chem- of the protocol and a brief description istry, manufacturing, and controls sec- of the results and status of the study. tion tests, analytical procedures, and (iii) A description of each uncon- acceptance criteria needed to assure trolled clinical study, a summary of the bioavailability of the drug product the results, and a brief statement ex- or drug substance, or both, a statement plaining why the study is classified as in this section of the rationale for es- uncontrolled. tablishing the tests, analytical proce- (iv) A description and analysis of any dures, and acceptance criteria, includ- other data or information relevant to ing data and information supporting an evaluation of the safety and effec- the rationale. tiveness of the drug product obtained (iii) A summarizing discussion and or otherwise received by the applicant analysis of the pharmacokinetics and from any source, foreign or domestic, metabolism of the active ingredients including information derived from

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clinical investigations, including con- this chapter. These ‘‘safety update re- trolled and uncontrolled studies of uses ports’’ must include the same kinds of of the drug other than those proposed information (from clinical studies, ani- in the NDA, commercial marketing ex- mal studies, and other sources) and perience, reports in the scientific lit- must be submitted in the same format erature, and unpublished scientific pa- as the integrated summary in para- pers. graph (d)(5)(vi)(a) of this section. In ad- (v) An integrated summary of the dition, the reports must include the data demonstrating substantial evi- case report forms for each patient who dence of effectiveness for the claimed died during a clinical study or who did indications. Evidence is also required not complete the study because of an to support the dosage and administra- adverse event (unless this requirement tion section of the labeling, including is waived). The applicant must submit support for the dosage and dose inter- these reports (1) 4 months after the ini- val recommended. The effectiveness tial submission; (2) in a resubmission data must be presented by gender, age, following receipt of a complete re- and racial subgroups and must identify sponse letter; and (3) at other times as any modifications of dose or dose inter- requested by FDA. Before submitting val needed for specific subgroups. Ef- the first such report, applicants are en- fectiveness data from other subgroups couraged to consult with FDA regard- of the population of patients treated, ing further details on its form and con- when appropriate, such as patients tent. with renal failure or patients with dif- (vii) If the drug has a potential for ferent levels of severity of the disease, abuse, a description and analysis of also must be presented. studies or information related to abuse (vi) A summary and updates of safety of the drug, including a proposal for information, as follows: scheduling under the Controlled Sub- (a) The applicant must submit an instances Act. A description of any stud- tegrated summary of all available in- ies related to overdosage is also re- formation about the safety of the drug quired, including information on dialy- product, including pertinent animal sis, antidotes, or other treatments, if data, demonstrated or potential ad- known. verse effects of the drug, clinically sig- (viii) An integrated summary of the nificant drug/drug interactions, and benefits and risks of the drug, includ- other safety considerations, such as ing a discussion of why the benefits ex- data from epidemiological studies of ceed the risks under the conditions related drugs. The safety data must be stated in the labeling. presented by gender, age, and racial (ix) A statement with respect to each subgroups. When appropriate, safety clinical study involving human sub- data from other subgroups of the popu- jects that it either was conducted in lation of patients treated also must be compliance with the institutional represented, such as for patients with view board regulations in part 56, or renal failure or patients with different was not subject to the regulations levels of severity of the disease. A de- under § 56.104 or § 56.105, and that it was scription of any statistical analyses conducted in compliance with the in- performed in analyzing safety data formed consent regulations in part 50. should also be included, unless already (x) If a sponsor has transferred any included under paragraph (d)(5)(ii) of obligations for the conduct of any clin- this section. ical study to a contract research orga- (b) The applicant must, under section nization, a statement containing the 505(i) of the Federal Food, Drug, and name and address of the contract re- Cosmetic Act, update periodically its search organization, identification of pending NDA with new safety informa- the clinical study, and a listing of the tion learned about the drug that may obligations transferred. If all obliga- reasonably affect the statement of con- tions governing the conduct of the traindications, warnings, precautions, study have been transferred, a general and adverse reactions in the draft la- statement of this transfer—in lieu of a beling and, if applicable, any Medica- listing of the specific obligations trans- tion Guide required under part 208 of ferred—may be submitted.

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(xi) If original subject records were (a) The drug product proposed for audited or reviewed by the sponsor in marketing; the course of monitoring any clinical (b) The drug substance used in the study to verify the accuracy of the case drug product from which the samples reports submitted to the sponsor, a list of the drug product were taken; and identifying each clinical study so au- (c) Reference standards and blanks dited or reviewed. (except that reference standards recog- (6) Statistical section. A section de- nized in an official compendium need scribing the statistical evaluation of not be submitted). clinical data, including the following: (ii) Samples of the finished market (i) A copy of the information sub- package, if requested by FDA. mitted under paragraph (d)(5)(ii) of this (2) The applicant must submit the section concerning the description and following in the archival copy of the analysis of each controlled clinical NDA: study, and the documentation and sup- (i) Three copies of the analytical pro- porting statistical analyses used in cedures and related descriptive infor- evaluating the controlled clinical stud- mation contained in the chemistry, ies. manufacturing, and controls section (ii) A copy of the information sub- under paragraph (d)(1) of this section mitted under paragraph (d)(5)(vi)(a) of for the drug substance and the drug this section concerning a summary of product that are necessary for FDA’s information about the safety of the laboratories to perform all necessary drug product, and the documentation tests on the samples and to validate and supporting statistical analyses the applicant’s analytical procedures. used in evaluating the safety informa- The related descriptive information in- tion. cludes a description of each sample; (7) Pediatric use section. A section de- the proposed regulatory specifications scribing the investigation of the drug for the drug; a detailed description of for use in pediatric populations, includ- the methods of analysis; supporting ing an integrated summary of the in- data for accuracy, specificity, precision formation (the clinical pharmacology and ruggedness; and complete results studies, controlled clinical studies, or of the applicant’s tests on each sample. uncontrolled clinical studies, or other (ii) Copies of the label and all label- data or information) that is relevant to ing for the drug product (including, if the safety and effectiveness and bene- applicable, any Medication Guide re- fits and risks of the drug in pediatric quired under part 208 of this chapter) populations for the claimed indica- for the drug product (4 copies of draft tions, a reference to the full descrip- labeling or 12 copies of final printed lations of such studies provided under beling). paragraphs (d)(3) and (d)(5) of this sec- (f) Case report forms and tabulations. tion, and information required to be The archival copy of the NDA is re- submitted under § 314.55. quired to contain the following case re- (e) Samples and labeling. (1) Upon report tabulations and case report forms: quest from FDA, the applicant must (1) Case report tabulations. The NDA is submit the samples described below to required to contain tabulations of the the places identified in the Agency’s data from each adequate and well-con- request. FDA generally will ask appli- trolled study under § 314.126 (Phase 2 cants to submit samples directly to and Phase 3 studies as described in two or more Agency laboratories that §§ 312.21 (b) and (c) of this chapter), tab- will perform all necessary tests on the ulations of the data from the earliest samples and validate the applicant’s clinical pharmacology studies (Phase 1 analytical procedures. studies as described in § 312.21(a) of this (i) Four representative samples of the chapter), and tabulations of the safety following, each sample in sufficient data from other clinical studies. Rou- quantity to permit FDA to perform tine submission of other patient data three times each test described in the from uncontrolled studies is not re- NDA to determine whether the drug quired. The tabulations are required to substance and the drug product meet include the data on each patient in the specifications given in the NDA: each study, except that the applicant

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may delete those tabulations which the the technical sections under paragraph agency agrees, in advance, are not per- (d) of this section. tinent to a review of the drug’s safety (1) The applicant ordinarily is not re- or effectiveness. Upon request, FDA quired to resubmit information pre- will discuss with the applicant in a viously submitted, but may incor- ‘‘pre-NDA’’ conference those tabula- porate the information by reference. A tions that may be appropriate for such reference to information submitted deletion. Barring unforeseen cir- previously is required to identify the cumstances, tabulations agreed to be file by name, reference number, vol- deleted at such a conference will not be ume, and page number in the agency’s requested during the conduct of FDA’s records where the information can be review of the NDA. If such unforeseen found. A reference to information sub- circumstances do occur, any request mitted to the agency by a person other for deleted tabulations will be made by than the applicant is required to con- the director of the FDA division retain a written statement that author- sponsible for reviewing the NDA, in ac- izes the reference and that is signed by cordance with paragraph (f)(3) of this the person who submitted the informa- section. tion. (2) Case report forms. The NDA is re- (2) The applicant must submit an acquired to contain copies of individual curate and complete English trans- case report forms for each patient who lation of each part of the NDA that is died during a clinical study or who did not in English. The applicant must not complete the study because of an submit a copy of each original lit- adverse event, whether believed to be erature publication for which an drug related or not, including patients English translation is submitted. receiving reference drugs or placebo. (3) If an applicant who submits an This requirement may be waived by NDA under section 505(b) of the Federal FDA for specific studies if the case re- Food, Drug, and Cosmetic Act obtains port forms are unnecessary for a proper a ‘‘right of reference or use,’’ as defined under § 314.3(b), to an investigation de- review of the study. scribed in clause (A) of section 505(b)(1) (3) Additional data. The applicant of the Federal Food, Drug, and Cos- must submit to FDA additional case metic Act, the applicant must include report forms and tabulations needed to in its NDA a written statement signed conduct a proper review of the NDA, as by the owner of the data from each requested by the director of the FDA such investigation that the applicant division responsible for reviewing the may rely on in support of the approval NDA. The applicant’s failure to submit of its NDA, and provide FDA access to, information requested by FDA within the underlying raw data that provide 30 days after receipt of the request may the basis for the report of the inves- result in the agency viewing any even- tigation submitted in its NDA. tual submission as a major amendment (h) Patent information. The NDA is re- under § 314.60 and extending the review quired to contain the patent informa- period as necessary. If desired by the tion described under § 314.53. applicant, the FDA division director (i) Patent certification—(1) Contents. A will verify in writing any request for 505(b)(2) application is required to con- additional data that was made orally. tain the following: (4) Presentation and format. Appli- (i) Patents claiming drug substance, cants are invited to meet with FDA be- drug product, or method of use. (A) An fore submitting an NDA to discuss the appropriate patent certification or presentation and format of supporting statement with respect to each patent information. If the applicant and FDA issued by the U.S. Patent and Trade- agree, the applicant may submit tab- mark Office that, in the opinion of the ulations of patient data and case report applicant and to the best of its knowl- forms in an alternate form. edge, claims the drug substance or drug (g) Other. The following general re- product on which investigations that quirements apply to the submission of are relied upon by the applicant for ap- information within the summary under proval of its 505(b)(2) application were paragraph (c) of this section and within conducted or that claims an approved

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use for such drug and for which infor- spect to each patent that claims the mation is required to be filed under first-approved patented drug or that section 505(b) and (c) of the Federal claims an approved use for such a drug. Food, Drug, and Cosmetic Act and (C) If, before the date of submission § 314.53. For each such patent, the ap- of an original 505(b)(2) application, plicant must provide the patent num- there is a drug product approved in an ber and certify, in its opinion and to NDA that is pharmaceutically equiva- the best of its knowledge, one of the lent to the drug product for which the following circumstances: original 505(b)(2) application is sub- (1) That the patent information has mitted, an appropriate patent certifi- not been submitted to FDA. The application or statement under this section cant must entitle such a certification with respect to each patent that claims ‘‘Paragraph I Certification’’; the drug substance or drug product or (2) That the patent has expired. The that claims an approved use for one applicant must entitle such a certifi- such drug product. cation ‘‘Paragraph II Certification’’; (ii) No relevant patents. If, in the opin- (3) The date on which the patent will ion of the applicant and to the best of expire. The applicant must entitle such its knowledge, there are no patents de- a certification ‘‘Paragraph III Certifi- scribed in paragraph (i)(1)(i) of this sec- cation’’; or tion, a certification in the following (4)(i) That the patent is invalid, un- form: enforceable, or will not be infringed by In the opinion and to the best knowledge of the manufacture, use, or sale of the (name of applicant), there are no patents that drug product for which the 505(b)(2) ap- claim the drug or drugs on which investiga- plication is submitted. The applicant tions that are relied upon in this 505(b)(2) ap- must entitle such a certification plication were conducted or that claim a use ‘‘Paragraph IV Certification’’. This cer- of such drug or drugs. tification must be submitted in the fol- (iii) Method-of-use patent. (A) If infor- lowing form: mation that is submitted under section I, (name of applicant), certify that Patent 505(b) or (c) of the Federal Food, Drug, No. llll (is invalid, unenforceable, or will and Cosmetic Act and § 314.53 is for a not be infringed by the manufacture, use, or method-of-use patent, and the labeling sale of) (name of proposed drug product) for for the drug product for which the ap- which this 505(b)(2) application is submitted. plicant is seeking approval does not in- (ii) The certification must be accom- clude an indication or other condition panied by a statement that the appli- of use that is covered by the method- cant will comply with the require- of-use patent, a statement explaining ments under § 314.52(a) with respect to that the method-of-use patent does not providing a notice to each owner of the claim a proposed indication or other patent or its representative and to the condition of use. NDA holder (or, if the NDA holder does (B) If the labeling of the drug product not reside or maintain a place of busi- for which the applicant is seeking ap- ness within the United States, its at- proval includes an indication or other torney, agent, or other authorized offi- condition of use that, according to the cial) for the drug product that is patent information submitted under claimed by the patent or a use of which section 505(b) or (c) of the Federal is claimed by the patent and with the Food, Drug, and Cosmetic Act and requirements under § 314.52(b) with re- § 314.53 or in the opinion of the appli- spect to sending the notice and under cant, is claimed by a method-of-use § 314.52(c) with respect to the content of patent, the applicant must submit an the notice. applicable certification under para- (B) If the drug on which investiga- graph (i)(1)(i) of this section. tions that are relied upon by the appli- (2) [Reserved] cant were conducted is itself a licensed (3) Licensing agreements. If a 505(b)(2) generic drug of a patented drug first application is submitted for a drug or approved under section 505(b) of the method of using a drug claimed by a Federal Food, Drug, and Cosmetic Act, patent and the applicant has a licens- an appropriate patent certification or ing agreement with the patent owner, statement under this section with re- the applicant must submit a paragraph

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IV certification as to that patent and a formation or whose 505(b)(2) applica- statement that the applicant has been tion was previously filed but did not granted a patent license. If the patent contain an appropriate patent certifi- owner consents to approval of the cation or statement at the time of the 505(b)(2) application (if otherwise eligi- patent submission must submit a cer- ble for approval) as of a specific date, tification under paragraph (i)(1)(i) of the 505(b)(2) application must contain a this section and/or a statement under written statement from the patent paragraph (i)(1)(iii) of this section as to owner that it has a licensing agree- that patent. ment with the applicant and that it (5) Disputed patent information. If an consents to approval of the 505(b)(2) ap- applicant disputes the accuracy or rel- plication as of a specific date. evance of patent information sub- (4) Untimely filing of patent informa- mitted to FDA, the applicant may seek tion. (i) If a patent described in para- a confirmation of the correctness of graph (i)(1)(i)(A) of this section is the patent information in accordance issued and the holder of the approved with the procedures under § 314.53(f). NDA for the patented drug does not file Unless the patent information is with- with FDA the required information on drawn, the applicant must submit an the patent within 30 days of issuance of appropriate certification or statement the patent, an applicant who submitted for each listed patent. a 505(b)(2) application that, before the (6) Amended certifications. A patent submission of the patent information, certification or statement submitted contained an appropriate patent cer- under paragraphs (i)(1)(i) through (iii) tification or statement is not required of this section may be amended at any to submit a patent certification or time before the approval of the 505(b)(2) statement to address the patent or pat- application. An applicant must submit ent information that is late-listed with an amended certification as an amend- respect to the pending 505(b)(2) applica- ment to a pending 505(b)(2) application. tion. Except as provided in § 314.53(f)(1), If an applicant with a pending 505(b)(2) an NDA holder’s amendment to the de- application voluntarily makes a patent scription of the approved method(s) of certification for an untimely filed pat- use claimed by the patent will be con- ent, the applicant may withdraw the sidered untimely filing of patent infor- patent certification for the untimely mation unless: filed patent. Once an amendment is (A) The amendment to the descrip- submitted to change the certification, tion of the approved method(s) of use the 505(b)(2) application will no longer claimed by the patent is submitted be considered to contain the prior cer- within 30 days of patent issuance; tification. (B) The amendment to the descrip- (i) After finding of infringement. An ap- tion of the approved method(s) of use plicant who has submitted a paragraph claimed by the patent is submitted IV certification and is sued for patent within 30 days of approval of a cor- infringement must submit an amend- responding change to product labeling; ment to change its certification if a or court enters a final decision from (C) The amendment to the descrip- which no appeal has been or can be tion of the approved method(s) of use taken, or signs and enters a settlement claimed by the patent is submitted order or consent decree in the action within 30 days of a decision by the U.S. that includes a finding that the patent Patent and Trademark Office or by a is infringed, unless the final decision, Federal district court, the Court of Ap- settlement order, or consent decree peals for the Federal Circuit, or the also finds the patent to be invalid. In U.S. Supreme Court that is specific to its amendment, the applicant must cer- the patent and alters the construction tify under paragraph (i)(1)(i)(A)(3) of of a method-of-use claim(s) of the pat- this section that the patent will expire ent, and the amendment contains a on a specific date or, with respect to a copy of the decision. patent claiming a method of use, the (ii) An applicant whose 505(b)(2) ap- applicant may instead provide a state- plication is submitted after the NDA ment under paragraph (i)(1)(iii) of this holder’s untimely filing of patent in- section if the applicant amends its

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505(b)(2) application such that the ap- (iii) Other amendments. (A) Except as plicant is no longer seeking approval provided in paragraphs (i)(4) and for a method of use claimed by the pat- (i)(6)(iii)(B) of this section: ent. Once an amendment for the (1) An applicant must amend a sub- change has been submitted, the mitted certification or statement if, at 505(b)(2) application will no longer be any time before the approval of the considered to contain a paragraph IV 505(b)(2) application, the applicant certification to the patent. If a final learns that the submitted certification decision finds the patent to be invalid or statement is no longer accurate; and and infringed, an amended certification (2) An applicant must submit an ap- is not required. propriate patent certification or state- (ii) After request to remove a patent or ment under paragraph (i)(1) of this sec- patent information from the list. If the tion if, after submission of the 505(b)(2) list reflects that an NDA holder has re- application, a new patent is issued by quested that a patent or patent infor- the U.S. Patent and Trademark Office mation be removed from the list and no that, in the opinion of the applicant ANDA applicant is eligible for 180-day and to the best of its knowledge, exclusivity based on a paragraph IV claims a listed drug relied upon or that certification to that patent, the patent claims an approved use for such listed or patent information will be removed drug for which information is required and any applicant with a pending to be filed under section 505(b) and (c) 505(b)(2) application (including a ten- of the Federal Food, Drug, and Cos- metic Act and § 314.53. tatively approved 505(b)(2) application) who has made a certification with re- (B) An applicant is not required to spect to such patent must submit an submit a supplement to change a submitted certification when information amendment to withdraw its certifi- on an otherwise applicable patent is cation. In the amendment, the appli- submitted after the approval of the cant must state the reason for with- 505(b)(2) application. drawing the certification or statement (j) Claimed exclusivity. A new drug (that the patent has been removed product, upon approval, may be enti- from the list). If the list reflects that tled to a period of marketing exclu- an NDA holder has requested that a sivity under the provisions of § 314.108. patent or patent information be re- If an applicant believes its drug prod- moved from the list and one or more uct is entitled to a period of exclu- first applicants are eligible for 180-day sivity, it must submit with the NDA exclusivity based on a paragraph IV prior to approval the following infor- certification to that patent, the patent mation: will remain listed until any 180-day ex- (1) A statement that the applicant is clusivity based on that patent has ex- claiming exclusivity. pired or has been extinguished. A (2) A reference to the appropriate 505(b)(2) applicant is not required to paragraph under § 314.108 that supports provide or maintain a certification to a its claim. patent or patent information that re- (3) If the applicant claims exclusivity mains listed only for purposes of a first under § 314.108(b)(2), information to applicant’s 180-day exclusivity for its show that, to the best of its knowledge ANDA. Once an amendment to with- or belief, a drug has not previously draw the certification has been sub- been approved under section 505(b) of mitted, the 505(b)(2) application will no the Federal Food, Drug, and Cosmetic longer be considered to contain a para- Act containing any active moiety in graph IV certification to the patent. If the drug for which the applicant is removal of a patent from the list re- seeking approval. sults in there being no patents listed (4) If the applicant claims exclusivity for the listed drug(s) identified in the under § 314.108(b)(4) or (b)(5), the fol- 505(b)(2) application, the applicant lowing information to show that the must submit an amended certification NDA contains ‘‘new clinical investiga- reflecting that there are no listed pat- tions’’ that are ‘‘essential to approval ents. of the NDA or supplement’’ and were

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‘‘conducted or sponsored by the appli- has purchased all rights to the drug. cant:’’ Purchase of nonexclusive rights to a (i) ‘‘New clinical investigations.’’ A cer- clinical investigation after it is com- tification that to the best of the appli- pleted is not sufficient to satisfy this cant’s knowledge each of the clinical definition. investigations included in the NDA (k) Financial certification or disclosure meets the definition of ‘‘new clinical statement. The NDA must contain a fi- investigation’’ set forth in § 314.108(a). nancial certification or disclosure (ii) ‘‘Essential to approval.’’ A list of statement or both as required by part all published studies or publicly avail- 54 of this chapter. able reports of clinical investigations (l) Format of an original NDA—(1) Ar- known to the applicant through a lit- chival copy. The applicant must submit erature search that are relevant to the a complete archival copy of the NDA conditions for which the applicant is that contains the information required seeking approval, a certification that under paragraphs (a) through (f) of this the applicant has thoroughly searched section. FDA will maintain the archi- the scientific literature and, to the val copy during the review of the NDA best of the applicant’s knowledge, the to permit individual reviewers to refer list is complete and accurate and, in to information that is not contained in the applicant’s opinion, such published their particular technical sections of studies or publicly available reports do the NDA, to give other agency per- not provide a sufficient basis for the sonnel access to the NDA for official approval of the conditions for which business, and to maintain in one place the applicant is seeking approval with- a complete copy of the NDA. Except as out reference to the new clinical inves- required by paragraph (l)(1)(i) of this tigation(s) in the NDA, and an expla- section, applicants may submit the ar- nation as to why the studies or reports chival copy on paper or in electronic are insufficient. format provided that electronic sub- (iii) ‘‘Conducted or sponsored by.’’ If missions are made in accordance with the applicant was the sponsor named in part 11 of this chapter. the Form FDA 1571 for an IND under (i) Labeling. The content of labeling which the new clinical investigation(s) required under § 201.100(d)(3) of this that is essential to the approval of its chapter (commonly referred to as the NDA was conducted, identification of package insert or professional label- the IND by number. If the applicant ing), including all text, tables, and fig- was not the sponsor of the IND under ures, must be submitted to the agency which the clinical investigation(s) was in electronic format as described in conducted, a certification that the ap- paragraph (l)(5) of this section. This re- plicant or its predecessor in interest quirement is in addition to the require- provided substantial support for the ments of paragraph (e)(2)(ii) of this sec- clinical investigation(s) that is essen- tion that copies of the formatted label tial to the approval of its NDA, and in- and all labeling be submitted. Submis- formation supporting the certification. sions under this paragraph must be To demonstrate ‘‘substantial support,’’ made in accordance with part 11 of this an applicant must either provide a cer- chapter, except for the requirements of tified statement from a certified public § 11.10(a), (c) through (h), and (k), and accountant that the applicant provided the corresponding requirements of 50 percent or more of the cost of con- § 11.30. ducting the study or provide an expla- (ii) [Reserved] nation of why FDA should consider the (2) Review copy. The applicant must applicant to have conducted or spon- submit a review copy of the NDA. Each sored the study if the applicant’s finan- of the technical sections, described in cial contribution to the study is less paragraphs (d)(1) through (6) of this than 50 percent or the applicant did not section, in the review copy is required sponsor the investigational new drug. to be separately bound with a copy of A predecessor in interest is an entity, the application form required under e.g., a corporation, that the applicant paragraph (a) of this section and a copy has taken over, merged with, or pur- of the summary required under para- chased, or from which the applicant graph (c) of this section.

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(3) Field copy. The applicant must the patent and for which the applicant submit a field copy of the NDA that is seeking approval, or, if the NDA contains the technical section de- holder does not reside or maintain a scribed in paragraph (d)(1) of this sec- place of business within the United tion, a copy of the application form re- States, the NDA holder’s attorney, quired under paragraph (a) of this sec- agent, or other authorized official. The tion, a copy of the summary required name and address of the NDA holder or under paragraph (c) of this section, and its attorney, agent, or authorized offi- a certification that the field copy is a cial may be obtained by sending a writ- true copy of the technical section de- ten or electronic communication to the scribed in paragraph (d)(1) of this sec- Orange Book Staff, Office of Generic tion contained in the archival and re- Drugs, 7620 Standish Pl., Rockville, MD view copies of the NDA. 20855, or to the Orange Book Staff at (4) Binding folders. The applicant may the email address listed on the Agen- obtain from FDA sufficient folders to cy’s Web site at http://www.fda.gov. bind the archival, the review, and the (3) This paragraph (a) does not apply field copies of the NDA. to a method-of-use patent that does (5) Electronic format submissions. Elec- not claim a use for which the applicant tronic format submissions must be in a is seeking approval. form that FDA can process, review, and (4) An applicant may send notice by archive. FDA will periodically issue an alternative method only if FDA has guidance on how to provide the elec- agreed in advance that the method will tronic submission (e.g., method of produce an acceptable form of docu- transmission, media, file formats, prep- mentation. aration and organization of files). (b) Sending the notice. (1) Except as [50 FR 7493, Feb. 22, 1985] provided under paragraph (d) of this EDITORIAL NOTE: For FEDERAL REGISTER ci- section, the applicant must send the tations affecting § 314.50, see the List of CFR notice required by paragraph (a) of this Sections Affected, which appears in the section on or after the date of filing de- Finding Aids section of the printed volume scribed in § 314.101(a)(2) or (3), as appli- and at www.fdsys.gov. cable, but not later than 20 days after § 314.52 Notice of certification of inva- the date of the postmark on the para- lidity, unenforceability, or non- graph IV acknowledgment letter. The infringement of a patent. 20-day clock described in this para- (a) Notice of certification. For each graph (b) begins on the day after the patent that claims the listed drug or date of the postmark on the paragraph drugs relied upon or that claims a use IV acknowledgment letter. When the for such listed drug or drugs and for 20th day falls on Saturday, Sunday, or which the 505(b)(2) applicant submits a a Federal holiday, the 20th day will be paragraph IV certification, the appli- the next day that is not a Saturday, cant must send notice of such certifi- Sunday, or Federal holiday. cation by registered or certified mail, (2) Any notice required by paragraph return receipt requested, or by a des- (a) of this section is invalid if it is sent ignated delivery service, as defined in before the date of filing described in paragraph (g) of this section, to each of § 314.101(a)(2) or, if FDA notifies the ap- the following persons: plicant that FDA has refused to file the (1) Each owner of the patent that is 505(b)(2) application, before the date the subject of the certification or the described in § 314.101(a)(3) on which the representative designated by the owner 505(b)(2) application is filed. The appli- to receive the notice. The name and ad- cant will not have complied with this dress of the patent owner or its rep- paragraph (b) until it sends valid no- resentative may be obtained from the tice. U.S. Patent and Trademark Office; and (3) The applicant must submit to (2) The holder of the approved NDA FDA an amendment to its 505(b)(2) ap- under section 505(b) of the Federal plication that includes a statement Food, Drug, and Cosmetic Act for each certifying that the notice has been pro- drug product which is claimed by the vided to each person identified under patent or a use of which is claimed by paragraph (a) of this section and that

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the notice met the content require- to accept service of process for the ap- ment under paragraph (c) of this sec- plicant. tion. A copy of the notice itself need (d) Amendment or supplement to a not be submitted to the Agency. 505(b)(2) application. (1) If, after the (c) Content of a notice. In the notice, date of filing described in § 314.101(a)(2) the applicant must cite section or (3), as applicable, an applicant sub- 505(b)(3)(D) of the Federal Food, Drug, mits an amendment or supplement to and Cosmetic Act and the notice must its 505(b)(2) application that includes a include, but is not limited to, the fol- paragraph IV certification, the appli- lowing information: cant must send the notice required by (1) A statement that a 505(b)(2) appli- paragraph (a) of this section at the cation that contains any required bio- same time that the amendment or sup- availability or bioequivalence studies plement to the 505(b)(2) application is has been submitted by the applicant submitted to FDA, regardless of wheth- and filed by FDA. er the applicant has already given no- (2) The NDA number. tice with respect to another such cer- (3) The established name, if any, as tification contained in the 505(b)(2) ap- defined in section 502(e)(3) of the Fed- plication or in an amendment or sup- eral Food, Drug, and Cosmetic Act, of plement to the 505(b)(2) application. the proposed drug product. (2) If, before the date of filing de- (4) The active ingredient, strength, scribed in § 314.101(a)(2) or (3), as appli- and dosage form of the proposed drug cable, an applicant submits a para- product. graph IV certification in an amend- (5) The patent number and expiration ment, the applicant must send the no- date of each patent on the list alleged tice required by paragraph (a) of this to be invalid, unenforceable, or not in- section in accordance with the proce- fringed. dures in paragraph (b) of this section. (6) A detailed statement of the fac- (3) An applicant that submits an tual and legal basis of the applicant’s amendment or supplement to seek ap- opinion that the patent is not valid, proval of a different strength must pro- unenforceable, or will not be infringed. vide notice of any paragraph IV certifi- The applicant must include in the de- cation in accordance with paragraph tailed statement: (d)(1) or (2) of this section, as applica- (i) For each claim of a patent alleged ble. not to be infringed, a full and detailed (e) Documentation of timely sending explanation of why the claim is not in- and receipt of notice. The applicant fringed. must amend its 505(b)(2) application to (ii) For each claim of a patent al- provide documentation of the date of leged to be invalid or unenforceable, a receipt of the notice required under full and detailed explanation of the paragraph (a) of this section by each grounds supporting the allegation. person provided the notice. The amend- (7) If the applicant alleges that the ment must be submitted to FDA within patent will not be infringed and the ap- 30 days after the last date on which no- plicant seeks to preserve the option to tice was received by a person described later file a civil action for declaratory in paragraph (a) of this section. The ap- judgment in accordance with section plicant’s amendment also must include 505(c)(3)(D) of the Federal Food, Drug, documentation that its notice was sent and Cosmetic Act, then the notice on a date that complies with the time- must be accompanied by an offer of frame required by paragraph (b) or (d) confidential access to the 505(b)(2) ap- of this section, as applicable. FDA will plication for the sole and limited pur- accept, as adequate documentation of pose of evaluating possible infringe- the date the notice was sent, a copy of ment of the patent that is the subject the registered mail receipt, certified of the paragraph IV certification. mail receipt, or receipt from a des- (8) If the applicant does not reside or ignated delivery service, as defined in have a place of business in the United paragraph (g) of this section. FDA will States, the name and address of an accept as adequate documentation of agent in the United States authorized the date of receipt a return receipt, a

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signature proof of delivery by a des- (b) Patents for which information must ignated delivery service, or a letter ac- be submitted and patents for which infor- knowledging receipt by the person pro- mation must not be submitted—(1) General vided the notice. An applicant may requirements. An applicant described in rely on another form of documentation paragraph (a) of this section must sub- only if FDA has agreed to such docu- mit to its NDA the required informa- mentation in advance. A copy of the tion, on the required FDA declaration notice itself need not be submitted to form, set forth in paragraph (c) of this the Agency. section for each patent that claims the (f) Forty-five day period after receipt of drug or a method of using the drug that notice. If the requirements of this sec- is the subject of the NDA or amend- tion are met, the Agency will presume ment or supplement to it and with re- the notice to be complete and suffi- spect to which a claim of patent in- cient and will count the day following fringement could reasonably be as- the date of receipt of the notice by the serted if a person not licensed by the patent owner or its representative and owner of the patent engaged in the by the approved NDA holder or its at- manufacture, use, or sale of the drug torney, agent, or other authorized offi- product. For purposes of this part, such cial as the first day of the 45-day period patents consist of drug substance (ac- provided for in section 505(c)(3)(C) of tive ingredient) patents, drug product the Federal Food, Drug, and Cosmetic (formulation and composition) patents, Act. FDA may, if the applicant amends and method-of-use patents. For patents its 505(b)(2) application with a written that claim the drug substance, the ap- statement that a later date should be plicant must submit information only used, count from such later date. on those patents that claim the drug (g) Designated delivery services. (1) For substance that is the subject of the purposes of this section, the term pending or approved NDA or that claim ‘‘designated delivery service’’ is any a drug substance that is the same as delivery service provided by a trade or the active ingredient that is the sub- business that the Agency determines: ject of the approved or pending NDA. (i) Is available to the general public For patents that claim only a poly- throughout the United States; morph that is the same as the active (ii) Records electronically to its ingredient described in the approved or database, kept in the regular course of pending NDA, the applicant must cer- its business, or marks on the cover in tify in the required FDA declaration which any item referred to in this sec- form that the applicant has test data, tion is to be delivered, the date on as set forth in paragraph (b)(2) of this which such item was given to such section, demonstrating that a drug trade or business for delivery; and product containing the polymorph will (iii) Provides overnight or 2-day de- perform the same as the drug product livery service throughout the United described in the NDA. For patents that States. claim a drug product, the applicant (2) FDA may periodically issue guid- must submit information only on those ance regarding designated delivery patents that claim the drug product, as services. is defined in § 314.3, that is described in [81 FR 69641, Oct. 6, 2016] the pending or approved NDA. For patents that claim a method of use, the § 314.53 Submission of patent informa- applicant must submit information tion. only on those patents that claim indi- (a) Who must submit patent informa- cations or other conditions of use for tion. This section applies to any appli- which approval is sought or has been cant who submits to FDA an NDA or granted in the NDA. The applicant an amendment to it under section must separately identify each pending 505(b) of the Federal Food, Drug, and or approved method of use and related Cosmetic Act and § 314.50 or a supple- patent claim(s). For approved NDAs, ment to an approved NDA under the NDA holder’s description of the § 314.70, except as provided in paragraph patented method of use required by (d)(2) of this section. paragraph (c)(2)(ii)(P)(3) of this section

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must describe only the approved meth- (iv) A list of all components used in od(s) of use claimed by the patent for the manufacture of the drug product which a claim of patent infringement containing the polymorphic form and a could reasonably be asserted if a person statement of the composition of the not licensed by the owner of the patent drug product; a statement of the speci- engaged in the manufacture, use, or fications and analytical methods for sale of the drug product. If the meth- each component; a description of the od(s) of use claimed by the patent does manufacturing and packaging proce- not cover an indication or other ap- dures and in-process controls for the proved condition of use in its entirety, drug product; such specifications and the applicant must describe only the analytical methods as are necessary to specific approved method of use assure the identity, strength, quality, claimed by the patent for which a purity, and bioavailability of the drug claim of patent infringement could rea- product, including release and stability sonably be asserted if a person not li- data complying with the approved censed by the owner of the patent en- product specifications to demonstrate gaged in the manufacture, use, or sale pharmaceutical equivalence and com- of the drug product. For approved parable product stability; and NDAs, the NDA holder submitting in- (v) Comparative in vitro dissolution formation on the method-of-use patent testing on 12 dosage units each of the must identify with specificity the sec- executed test batch and the NDA prod- tion(s) and subsection(s) of the ap- uct. proved labeling that describes the (c) Reporting requirements—(1) General method(s) of use claimed by the patent requirements. An applicant described in submitted. Process patents, patents paragraph (a) of this section must sub- claiming packaging, patents claiming mit the required patent information metabolites, and patents claiming described in paragraph (c)(2) of this intermediates are not covered by this section for each patent that meets the section, and information on these pat- requirements described in paragraph ents must not be submitted to FDA. (b) of this section. We will not accept the patent information unless it is sub- (2) Test data for submission of patent mitted on the appropriate form, Form information for patents that claim only a FDA 3542 or 3542a, and contains the in- polymorph. The test data, referenced in formation required in paragraph (c)(2) paragraph (b)(1) of this section, must of this section. These forms may be ob- include the following: tained on the Internet at http:// (i) A full description of the poly- www.fda.gov by searching for ‘‘forms’’. morphic form of the drug substance, in- (2) Drug substance (active ingredient), cluding its physical and chemical char- drug product (formulation or composi- acteristics and stability; the method of tion), and method-of-use patents—(i) synthesis (or isolation) and purifi- Original declaration. For each patent cation of the drug substance; the proc- that claims a drug substance (active ess controls used during manufacture ingredient), drug product (formulation and packaging; and such specifications and composition), or method of use, the and analytical methods as are nec- applicant must submit Form FDA essary to assure the identity, strength, 3542a. The following information and quality, and purity of the polymorphic verification is required, subject to the form of the drug substance; exceptions listed in paragraph (ii) The executed batch record for a (c)(2)(i)(S) of this section: drug product containing the poly- (A) NDA number; morphic form of the drug substance (B) The NDA applicant’s name, full and documentation that the batch was address, phone number and, if avail- manufactured under current good man- able, fax number and email address; ufacturing practice requirements; (C) Trade name (or proposed trade (iii) Demonstration of bioequivalence name) of new drug; between the executed batch of the drug (D) Active ingredient(s) of new drug; product that contains the polymorphic (E) Strength(s) of new drug; form of the drug substance and the (F) Dosage form(s) and route(s) of ad- drug product as described in the NDA; ministration of new drug, and whether

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the applicant proposes to market the (5) Whether the patent claims only new drug for prescription use or over- an intermediate; the-counter use; (N) Information on the drug product (G) U.S. patent number, issue date, (composition/formulation) patent, in- and expiration date of patent sub- cluding the following: mitted; (1) Whether the patent claims the (H) The patent owner’s name, full ad- drug product for which approval is dress, phone number and, if available, being sought, as defined in § 314.3; and fax number and email address; (2) Whether the patent claims only (I) The name, full address, phone an intermediate; number and, if available, fax number (O) Information on each method-of- and email address of an agent or rep- use patent, including the following: resentative who resides or maintains a (1) Whether the patent claims one or place of business within the United more methods of using the drug prod- States authorized to receive notice of uct for which approval is being sought patent certification under section and a description of each pending 505(b)(3) and (j)(2)(B) of the Federal method of use and related patent claim Food, Drug, and Cosmetic Act and of the patent being submitted; §§ 314.52 and 314.95 (if patent owner or (2) Identification of the specific sec- NDA applicant or holder does not re- tion(s) and subsection(s) of the pro- side or have a place of business within posed labeling for the drug product the United States); that describes the method of use (J) Information on whether the pat- claimed by the patent submitted; and ent has been submitted previously for (3) An applicant that submits infor- the NDA or supplement; mation for a patent that claims one or (K) If the patent has been submitted more methods of using the drug prod- previously for listing, identify all uct must also submit information de- change(s) from the previously sub- scribed in either paragraph (c)(2)(i)(M) mitted patent information and specify or (N) of this section, regarding wheth- whether the change is related to the er that patent also claims either the patent or related to an FDA action or drug substance (active ingredient) or procedure; the drug product (composition/formula- (L) Information on whether the pat- tion). ent is a product-by-process patent in (P) Whether there are no relevant which the product claimed is novel; patents that claim the drug substance (M) Information on the drug sub- (active ingredient), drug product (for- stance (active ingredient) patent, in- mulation or composition), or method(s) cluding the following: of use, for which the applicant is seeking approval and with respect to which (1) Whether the patent claims a drug a claim of patent infringement could substance that is an active ingredient reasonably be asserted if a person not in the drug product described in the licensed by the owner of the patent en- NDA or supplement; gaged in the manufacture, use, or sale ( ) Whether the patent claims only a 2 of the drug product; polymorph that is the same active in- (Q) A signed verification that states: gredient that is described in the pending NDA or supplement; The undersigned declares that this is an (3) Whether the applicant has test accurate and complete submission of patent data, described in paragraph (b)(2) of information for the NDA, amendment, or supplement pending under section 505 of the this section, demonstrating that a drug Federal Food, Drug, and Cosmetic Act. This product containing only the polymorph time-sensitive patent information is sub- will perform the same as the drug prod- mitted pursuant to 21 CFR 314.53. I attest uct described in the NDA or supple- that I am familiar with 21 CFR 314.53 and ment, and a description of the poly- this submission complies with the require- morphic form(s) claimed by the patent ments of the regulation. I verify under pen- for which such test data exist; alty of perjury that the foregoing is true and (4) Whether the patent claims only a correct. metabolite of the active ingredient; (R) Information on whether the ap- and plicant, patent owner or attorney,

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agent, representative, or other author- patent. If the applicant submits the re- ized official signed the form; the name quired patent information within the of the person; and the full address, 30 days, but we notify an applicant that phone number and, if available, the fax a declaration form is incomplete or number and email address; and shows that the patent is not eligible (S) Exceptions to required submis- for listing, the applicant must submit sion of patent information: an acceptable declaration form within (1) If an applicant submits the infor- 15 days of FDA notification to be con- mation described in paragraph sidered timely filed. The following in- (c)(2)(i)(M) of this section for a patent formation and verification statement that claims the drug substance (active is required, subject to the exceptions ingredient) and meets the requirements listed in paragraph (c)(2)(ii)(T) of this for listing on that basis, then the appli- section: cant is not required to provide the in- (A) NDA number; formation described in paragraph (B) The NDA holder’s name, full ad- (c)(2)(i)(N) of this section on whether dress, phone number and, if available, that patent also claims the drug prod- fax number and email address; uct (composition/formulation); (C) Trade name of new drug; (2) If an applicant submits the infor- (D) Active ingredient(s) of new drug; mation described in paragraph (E) Strength(s) of new drug; (c)(2)(i)(N) of this section for a patent (F) Dosage form(s) and route(s) of ad- that claims the drug product (composi- ministration of new drug, and whether tion/formulation) and meets the re- the new drug is approved for prescrip- quirements for listing on that basis, tion use or over-the-counter use; then the applicant is not required to (G) Approval date of NDA or supple- provide the information described in ment; paragraph (c)(2)(i)(M) of this section on whether that patent also claims the (H) U.S. patent number, issue date, drug substance (active ingredient); and expiration date of patent sub- (3) If the applicant submits a supple- mitted; ment for a change other than one of (I) The patent owner’s name, full ad- the changes listed under paragraph dress, phone number and, if available, (d)(2)(i) of this section, then the patent fax number and email address; information submission requirements (J) The name, full address, phone of paragraph (d)(2)(ii) of this section number and, if available, fax number apply. and email address of an agent or rep- (ii) Submission of patent information resentative who resides or maintains a upon and after approval. Within 30 days place of business within the United after the date of approval of its NDA or States authorized to receive notice of supplement, the applicant must submit patent certification under section Form FDA 3542 for each patent that 505(b)(3) and (j)(2)(B) of the Federal claims the drug substance (active in- Food, Drug, and Cosmetic Act and gredient), drug product (formulation §§ 314.52 and 314.95 (if patent owner or and composition), or approved method NDA applicant or holder does not re- of use. FDA will not list or publish pat- side or have a place of business within ent information if it is not provided on the United States); this form or if the patent declaration (K) Information on whether the pat- does not contain the required informa- ent has been submitted previously for tion or indicates the patent is not eli- the NDA or supplement; gible for listing. Patent information (L) If the patent has been submitted must also be submitted for patents previously for listing, identify all issued after the date of approval of the change(s) from the previously sub- NDA as required in paragraph (c)(2)(ii) mitted patent information and specify of this section. As described in para- whether the change is related to the graph (d)(3) of this section, to be time- patent or related to an FDA action or ly filed, patent information for patents procedure; issued after the date of approval of the (M) Information on whether the pat- NDA must be submitted to FDA within ent is a product-by-process patent in 30 days of the date of issuance of the which the product claimed is novel;

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(N) Information on the drug sub- method of use claimed by the patent stance (active ingredient) patent, infor which a claim of patent infringe- cluding the following: ment could reasonably be asserted if a (1) Whether the patent claims a drug person not licensed by the owner of the substance that is an active ingredient patent engaged in the manufacture, in the drug product described in the ap- use, or sale of the drug product); and proved NDA; (4) An applicant that submits infor- (2) Whether the patent claims only a mation for a patent that claims one or polymorph that is the same as the ac- more methods of using the drug prod- tive ingredient that is described in the uct must also submit information de- approved NDA; scribed in either paragraph (c)(2)(ii)(N) (3) Whether the applicant has test or (O) of this section, regarding wheth- data, described in paragraph (b)(2) of er that patent also claims either the this section, demonstrating that a drug drug substance (active ingredient) or product containing only the polymorph the drug product (composition/formula- will perform the same as the drug prod- tion). uct described in the approved NDA and (Q) Whether there are no relevant a description of the polymorphic patents that claim the approved drug form(s) claimed by the patent for substance (active ingredient), the ap- which such test data exist; proved drug product (formulation or (4) Whether the patent claims only a composition), or approved method(s) of metabolite of the active ingredient; use and with respect to which a claim and of patent infringement could reason- (5) Whether the patent claims only ably be asserted if a person not li- an intermediate; censed by the owner of the patent en- (O) Information on the drug product gaged in the manufacture, use, or sale (composition/formulation) patent, in- of the drug product; cluding the following: (R) A signed verification that states: (1) Whether the patent claims the approved drug product as defined in The undersigned declares that this is an § 314.3; and accurate and complete submission of patent information for the NDA, amendment, or (2) Whether the patent claims only supplement approved under section 505 of the an intermediate; Federal Food, Drug, and Cosmetic Act. This (P) Information on each method-of- time-sensitive patent information or reuse patent, including the following: sponse to a request under 21 CFR 314.53(f)(1) (1) Whether the patent claims one or is submitted pursuant to 21 CFR 314.53. I at- more approved methods of using the test that I am familiar with 21 CFR 314.53 approved drug product and a descrip- and this submission complies with the re- tion of each approved method of use quirements of the regulation. I verify under penalty of perjury that the foregoing is true and related patent claim of the patent and correct. being submitted; (2) Identification of the specific sec- (S) Information on whether the appli- tion(s) and subsection(s) of the ap- cant, patent owner or attorney, agent, proved labeling for the drug product representative, or other authorized of- that describes the method of use ficial signed the form; the name of the claimed by the patent submitted; person; and the full address, phone (3) The description of the patented number and, if available, the fax num- method of use as required for publica- ber and email address; and tion, which must contain adequate in- (T) Exceptions to required submis- formation to assist 505(b)(2) and ANDA sion of patent information: applicants in determining whether a (1) If an applicant submits the infor- listed method-of-use patent claims a mation described in paragraph use for which the 505(b)(2) or ANDA ap- (c)(2)(ii)(N) of this section for a patent plicant is not seeking approval (for ex- that claims the drug substance (active ample, if the method(s) of use claimed ingredient) and meets the requirements by the patent does not cover an indica- for listing on that basis, then the appli- tion or other approved condition of use cant is not required to provide the in- in its entirety, then the applicant must formation described in paragraph describe only the specific approved (c)(2)(ii)(O) of this section on whether

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that patent also claims the drug prod- (2) Supplements. (i) An applicant must uct (composition/formulation). submit patent information required (2) If an applicant submits the infor- under paragraph (c) of this section for mation described in paragraph a patent that claims the drug sub- (c)(2)(ii)(O) of this section for a patent stance, drug product, or method of use that claims the drug product (composi- for which approval is sought in any of tion/formulation) and meets the re- the following supplements: quirements for listing on that basis, (A) To add or change the dosage form then the applicant is not required to or route of administration; provide the information described in (B) To add or change the strength; or paragraph (c)(2)(ii)(N) of this section (C) To change the drug product from on whether that patent also claims the prescription use to over-the-counter drug substance (active ingredient). use. (3) If the applicant submits a supple- (ii) If the applicant submits a supplement for a change other than one of ment for a change other than one of the changes listed under paragraph the changes listed under paragraph (d)(2)(i) of this section, then the patent (d)(2)(i) of this section (for example, to information submission requirements change the formulation, to add a new of paragraph (d)(2)(ii) of this section indication or other condition of use, or apply. to make any other patented change re- (3) No relevant patents. If the appli- garding the drug substance, drug prod- cant believes that there are no relevant uct, or any method of use), the fol- patents that claim the drug substance lowing patent information submission (active ingredient), drug product (for- requirements apply: mulation or composition), or the meth- (A) If existing patents for which in- od(s) of use for which the applicant has formation required by paragraph (c) of received approval, and with respect to this section has already been sub- which a claim of patent infringement mitted to FDA for the product ap- could reasonably be asserted if a person proved in the original NDA claim the not licensed by the owner of the patent changed product, the applicant is not engaged in the manufacture, use, or required to resubmit this patent infor- sale of the drug product, the applicant mation pursuant to paragraph (c) of will verify this information in the ap- this section unless the published de- propriate form, Form FDA 3542 or scription of the patented method of use 3542a. would change upon approval of the sup- (4) Authorized signature. The declara- plement, and FDA will continue to list tions required by this section must be this patent information for the prod- signed by the applicant or patent uct; owner, or the applicant’s or patent (B) If one or more existing patents owner’s attorney, agent (representa- for which information has already been tive), or other authorized official. submitted to FDA no longer claim the (d) When and where to submit patent changed product, the applicant must information—(1) Original NDA. An appli- submit a request under paragraph cant must submit with its original (f)(2)(iv) of this section to remove that NDA submitted under this part, the in- patent information from the list at the formation described in paragraph (c) of time of approval of the supplement; this section on each drug substance (C) If one or more existing drug sub- (active ingredient), drug product (for- stance (active ingredient), drug prod- mulation and composition), and meth- uct (formulation and composition), or od-of-use patent issued before the NDA method-of-use patents claim the is filed with FDA and for which patent changed product for which approval is information is required to be submitted sought in the supplement and such pat- under this section. If a patent is issued ent information has not been sub- after the NDA is filed with FDA but be- mitted to FDA, the applicant must fore the NDA is approved, the applicant submit the patent information required must, within 30 days of the date of under paragraph (c) of this section. issuance of the patent, submit the re- (3) Newly issued patents. If a patent is quired patent information in an issued for a drug substance, drug prod- amendment to the NDA under § 314.60. uct, or method of use after an NDA is

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approved, the applicant must submit to contents, i.e., ‘‘Patent Information,’’ FDA, as described in paragraph (d)(4) of or, if submitted after approval of an this section, the required patent infor- NDA, ‘‘Time Sensitive Patent Informa- mation within 30 days of the date of tion.’’ issuance of the patent. If the required (e) Public disclosure of patent informa- patent information is not submitted tion. FDA will publish in the list the within 30 days of the issuance of the patent number and expiration date of patent, FDA will list the patent, but each patent that is required to be, and patent certifications or statements is, submitted to FDA by an applicant, will be governed by the provisions re- and for each method-of-use patent, the garding untimely filed patent informa- description of the method of use tion at §§ 314.50(i)(4) and (6) and claimed by the patent as required by 314.94(a)(12)(vi) and (viii). § 314.53(c)(2)(ii)(P)(3). FDA will publish (4) Submission of Forms FDA 3542a and such patent information upon approval 3542—(i) Patent information submitted of the NDA, or, if the patent informa- with the filing of an NDA, amendment, or tion is submitted by the applicant after supplement. The applicant must submit approval of an NDA as provided under patent information required by para- paragraph (d)(2) of this section, as soon graphs (c)(1) and (c)(2)(i) of this section as possible after the submission to the and § 314.50(h) or § 314.70(f) on Form Agency of the patent information. A FDA 3542a to the Central Document request for copies of the submitted pat- Room, Center for Drug Evaluation and ent information must be sent in writ- Research, Food and Drug Administra- ing to the Freedom of Information tion, 5901–B Ammendale Rd., Beltsville, Staff at the address listed on the Agen- MD 20705–1266, or to FDA in an elec- cy’s Web site at . The tronic format submission that complies http://www.fda.gov with § 314.50(l)(5). Form FDA 3542a submitted patent information, and re- should not be submitted to the Orange quests to remove a patent or patent in- Book Staff in the Office of Generic formation from the list, may be subject Drugs. to public disclosure. (ii) Patent information submitted upon (f) Correction of patent information er- and after approval of an NDA or supple- rors—(1) Requests by persons other than ment. The applicant must submit pat- the NDA holder. If any person disputes ent information required by paragraphs the accuracy or relevance of patent in- (c)(1) and (c)(2)(ii) of this section on formation submitted to the Agency Form FDA 3542 to the Central Docu- under this section and published by ment Room, Center for Drug Evalua- FDA in the list, or believes that an tion and Research, Food and Drug Ad- NDA holder has failed to submit re- ministration, 5901–B Ammendale Rd., quired patent information, that person Beltsville, MD 20705–1266, or to FDA in must first notify the Agency in a writ- an electronic format submission that ten or electronic communication titled complies with § 314.50(l)(5). Form FDA ‘‘314.53(f) Patent Listing Dispute.’’ The 3542 should not be submitted to the Or- patent listing dispute communication ange Book Staff in the Office of Ge- must include a statement of dispute neric Drugs. that describes the specific grounds for (5) Submission date. Patent informa- disagreement regarding the accuracy tion will be considered to be submitted or relevance of patent information for to FDA for purposes of paragraph (d)(3) FDA to send to the applicable NDA of this section as of the earlier of the holder. For a dispute regarding the ac- date the information submitted on curacy or relevance of patent informa- Form FDA 3542 is date-stamped by the tion regarding an approved method of Central Document Room, or officially using the drug product, this statement received by FDA in an electronic for- of dispute must be only a narrative de- mat submission that complies with scription (no more than 250 words) of § 314.50(l)(5). the person’s interpretation of the scope (6) Identification. Each submission of of the patent. This statement of dis- patent information, except information pute must only contain information for submitted with an original NDA, must which the person consents to disclosure bear prominent identification as to its because FDA will send the text of the

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statement to the applicable NDA hold- clude the signed verification required er without review or redaction. The by paragraph (c)(2)(ii)(R) of this sec- patent listing dispute communication tion within 30 days of the date on should be directed to the Office of Ge- which the Agency sends the statement neric Drugs, OGD Document Room, At- of dispute. The narrative description tention: Orange Book Staff, 7620 Stand- must only contain information for ish Pl., Rockville, MD 20855, or to the which the NDA holder consents to dis- Orange Book Staff at the email address closure because FDA will send the text listed on the Agency’s Web site at of the statement to the person who http://www.fda.gov. submitted the patent listing dispute (i) Communication with the NDA hold- without review or redaction. er—(A) Drug substance or drug product (1) If the NDA holder confirms the claim. For requests submitted under correctness of the patent information, this paragraph (f)(1) that are directed provides the narrative description re- to the accuracy or relevance of sub- quired by paragraph (f)(1)(i)(B) of this mitted patent information regarding a section, and includes the signed drug substance or drug product claim, verification required by paragraph the Agency will send the statement of (c)(2)(ii)(R) of this section within 30 dispute to the applicable NDA holder. days of the date on which the Agency The NDA holder must confirm the cor- sends the statement of dispute, the rectness of the patent information and Agency will not change the patent in- include the signed verification required formation in the Orange Book. by paragraph (c)(2)(ii)(R) of this sec- (2) If the NDA holder responds to the tion or withdraw or amend the patent patent listing dispute with amended information in accordance with para- patent information in accordance with graph (f)(2) of this section within 30 paragraph (f)(2) of this section, pro- days of the date on which the Agency vides the narrative description re- sends the statement of dispute. Unless quired by paragraph (f)(1)(i)(B) of this the NDA holder withdraws or amends section, and includes the signed its patent information in response to verification required by paragraph the patent listing dispute, the Agency (c)(2)(ii)(R) of this section within 30 will not change the patent information days of the date on which the Agency in the Orange Book. sends the statement of dispute, FDA (B) Method-of-use claim. For requests will update the Orange Book to reflect submitted under this paragraph (f)(1) the amended patent information. that are directed to the accuracy or relevance of submitted patent informa- (ii) Patent certification or statement tion regarding an approved method of during and after patent listing dispute. A using the drug product, FDA will send 505(b)(2) application or ANDA must the statement of dispute to the NDA contain an appropriate certification or holder. The NDA holder must confirm statement for each listed patent, in- the correctness of its description of the cluding the disputed patent, during and approved method of use claimed by the after the patent listing dispute. patent that has been included as the (iii) Information on patent listing dis- ‘‘Use Code’’ in the Orange Book, or putes. FDA will promptly post informa- withdraw or amend the patent information on its Web site regarding whether tion in accordance with paragraph (f)(2) a patent listing dispute has been sub- of this section, provide a narrative de- mitted for a published description of a scription (no more than 250 words) of patented method of use for a drug prod- the NDA holder’s interpretation of the uct and whether the NDA holder has scope of the patent that explains why timely responded to the patent listing the existing or amended ‘‘Use Code’’ dispute. describes only the specific approved (2) Requests by the NDA holder—(i) method of use claimed by the patent Patents or patent claims that no longer for which a claim of patent infringe- meet the statutory requirements for list- ment could reasonably be asserted if a ing. If the NDA holder determines that person not licensed by the owner of the a patent or patent claim no longer patent engaged in the manufacture, meets the requirements for listing in use, or sale of the drug product, and in- section 505(b)(1) or (c)(2) of the Federal

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Food, Drug, and Cosmetic Act (includ- list. Withdrawal of a patent and re- ing if there has been a judicial finding quests to remove a patent from the list of invalidity for a listed patent, from must be submitted to the same ad- which no appeal has been or can be dresses described in paragraph (d)(4)(ii) taken), the NDA holder is required to of this section, except that the with- promptly notify FDA to amend the drawal or request to remove a patent patent information or withdraw the from the list is not required to be sub- patent or patent information and re- mitted on Form FDA 3542 and may be quest that the patent or patent infor- submitted by letter. Withdrawal of a mation be removed from the list. If the patent and a request to remove a pat- NDA holder is required by court order ent from the list must contain the fol- to amend patent information or with- lowing information: draw a patent from the list, it must (A) The NDA number to which the resubmit an amendment to its NDA that quest applies; includes a copy of the order, within 14 (B) Each product(s) approved in the days of the date the order was entered, NDA to which the request applies; and to the Central Document Room, Center (C) The patent number. for Drug Evaluation and Research, [81 FR 69643, Oct. 6, 2016] Food and Drug Administration, 5901–B Ammendale Rd., Beltsville, MD 20705– § 314.54 Procedure for submission of a 1266. The amendment to the NDA must 505(b)(2) application requiring in- bear the identification described in vestigations for approval of a new paragraph (d)(6) of this section. FDA indication for, or other change will remove a patent or patent infor- from, a listed drug. mation from the list if there is no first (a) The Federal Food, Drug, and Cos- applicant eligible for 180-day exclu- metic Act does not permit approval of sivity based on a paragraph IV certifi- an ANDA for a new indication, nor does cation to that patent or after the 180- it permit approval of other changes in day exclusivity period of a first appli- a listed drug if investigations, other cant based on that patent has expired than bioavailability or bioequivalence or has been extinguished. studies, are essential to the approval of (ii) Patent term restoration. If the term the change. Any person seeking ap- of a listed patent is extended pursuant proval of a drug product that rep- to 35 U.S.C. 156(e), the NDA holder resents a modification of a listed drug must submit on Form FDA 3542 a cor- (e.g., a new indication or new dosage rection to the expiration date of the form) and for which investigations, patent. This correction must be sub- other than bioavailability or bio- mitted within 30 days of receipt of a equivalence studies, are essential to certificate of extension as described in the approval of the changes may, ex- 35 U.S.C. 156(e)(1) or documentation of cept as provided in paragraph (b) of an extension of the term of the patent this section, submit a 505(b)(2) applica- as described in 35 U.S.C. 156(e)(2). tion. This 505(b)(2) application need (iii) Submission of corrections or contain only that information needed changes to patent information. Correc- to support the modification(s) of the tions or changes to previously sub- listed drug. mitted patent information, other than (1) The applicant must submit a com- withdrawal of a patent and requests to plete archival copy of the application remove a patent from the list, must be that contains the following: submitted on Form FDA 3542 or 3542a, (i) The information required under as appropriate, in an amendment or § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and supplement to the NDA. The amend- (g), except that § 314.50(d)(1)(ii)(c) must ment or supplement to the NDA must contain the proposed or actual master bear the identification described in production record, including a descrip- paragraph (d)(6) of this section. We will tion of the equipment, to be used for not accept the corrections or changes the manufacture of a commercial lot of unless they are submitted on the ap- the drug product. propriate forms. (ii) The information required under (iv) Submission of patent withdrawals § 314.50 (d)(2), (d)(4) (if an anti-infective and requests to remove a patent from the drug), (d)(5), (d)(6), and (f) as needed to

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support the safety and effectiveness of § 314.50(d)(1)(ii)(c) must contain the pro- the drug product. posed or actual master production (iii) Identification of each listed drug record, including a description of the for which FDA has made a finding of equipment, to be used for the manufac- safety and effectiveness and on which ture of a commercial lot of the drug finding the applicant relies in seeking product, and § 314.50(d)(3), and the tech- approval of its proposed drug product nical sections described in § 314.50(d)(2), by established name, if any, propri- (d)(4) through (6), and (f) when needed etary name, dosage form, strength, to support the modification. Each of route of administration, name of listed the technical sections in the review drug’s application holder, and listed copy is required to be separately bound drug’s approved NDA number. The list- with a copy of the information required ed drug(s) identified as relied upon under § 314.50(a), (b), and (c) and a copy must include a drug product approved of the proposed labeling. in an NDA that: (3) The information required by (A) Is pharmaceutically equivalent to § 314.50 (d)(2), (d)(4) (if an anti-infective the drug product for which the original drug), (d)(5), (d)(6), and (f) for the listed 505(b)(2) application is submitted; and drug on which the applicant relies (B) Was approved before the original must be satisfied by reference to the 505(b)(2) application was submitted. listed drug under paragraph (a)(1)(iii) (iv) If the applicant is seeking ap- of this section. proval only for a new indication and (4) The applicant must submit a field not for the indications approved for the copy of the 505(b)(2) application that listed drug on which the applicant re- contains the technical section de- lies, a certification so stating. scribed in § 314.50(d)(1), a copy of the in- (v) Any patent information required formation required under § 314.50(a) and under section 505(b)(1) of the Federal (c), and certification that the field Food, Drug, and Cosmetic Act with re- copy is a true copy of the technical sec- spect to any patent which claims the tion described in § 314.50(d)(1) contained drug for which approval is sought or a in the archival and review copies of the method of using such drug and to 505(b)(2) application. which a claim of patent infringement (b) A 505(b)(2) application may not be could reasonably be asserted if a person submitted under this section for a drug not licensed by the owner of the patent product whose only difference from a engaged in the manufacture, use, or listed drug is that: sale of the drug product. (1) The extent to which its active in- (vi) Any patent certification or state- gredient(s) is absorbed or otherwise ment required under section 505(b)(2) of made available to the site of action is the Federal Food, Drug, and Cosmetic less than that of the listed drug; or Act with respect to any relevant pat- (2) The rate at which its active ingre- ents that claim the listed drug(s) on dient(s) is absorbed or otherwise made which investigations relied on by the available to the site of action is unin- applicant for approval of the applica- tentionally less than that of the listed tion were conducted, or that claim a drug. use for the listed drug(s). A 505(b)(2) ap- [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. plicant seeking approval of a drug that 28, 1992, as amended at 58 FR 47351, Sept. 8, is pharmaceutically equivalent to a 1993; 59 FR 50364, Oct. 3, 1994; 81 FR 69647, listed drug approved in an NDA implic- Oct. 6, 2016] itly relies upon one such pharmaceutically equivalent listed drug. § 314.55 Pediatric use information. (vii) If the applicant believes the (a) Required assessment. Except as pro- change for which it is seeking approval vided in paragraphs (b), (c), and (d) of is entitled to a period of exclusivity, this section, each application for a new the information required under active ingredient, new indication, new § 314.50(j). dosage form, new dosing regimen, or (2) The applicant must submit a re- new route of administration shall con- view copy that contains the technical tain data that are adequate to assess sections described in § 314.50(d)(1), ex- the safety and effectiveness of the drug cept that the section described in product for the claimed indications in

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all relevant pediatric subpopulations, tion on its own initiative or at the re- and to support dosing and administra- quest of an applicant. A request for a tion for each pediatric subpopulation waiver must provide an adequate jus- for which the drug is safe and effective. tification. Where the course of the disease and the (2) Full waiver. An applicant may re- effects of the drug are sufficiently quest a waiver of the requirements of similar in adults and pediatric pa- paragraph (a) of this section if the ap- tients, FDA may conclude that pedi- plicant certifies that: atric effectiveness can be extrapolated (i) The drug product does not rep- from adequate and well-controlled resent a meaningful therapeutic ben- studies in adults usually supplemented efit over existing treatments for pedi- with other information obtained in pe- atric patients and is not likely to be diatric patients, such as pharmaco- used in a substantial number of pedi- kinetic studies. Studies may not be atric patients; needed in each pediatric age group, if (ii) Necessary studies are impossible data from one age group can be extrap- or highly impractical because, e.g., the olated to another. Assessments of safe- number of such patients is so small or ty and effectiveness required under this geographically dispersed; or section for a drug product that rep- (iii) There is evidence strongly sug- resents a meaningful therapeutic ben- gesting that the drug product would be efit over existing treatments for pedi- ineffective or unsafe in all pediatric atric patients must be carried out age groups. using appropriate formulations for (3) Partial waiver. An applicant may each age group(s) for which the assess- request a waiver of the requirements of ment is required. paragraph (a) of this section with re- (b) Deferred submission. (1) FDA may, spect to a specified pediatric age group, on its own initiative or at the request if the applicant certifies that: of an applicant, defer submission of (i) The drug product does not rep- some or all assessments of safety and resent a meaningful therapeutic ben- effectiveness described in paragraph (a) efit over existing treatments for pedi- of this section until after approval of atric patients in that age group, and is the drug product for use in adults. De- not likely to be used in a substantial ferral may be granted if, among other number of patients in that age group; reasons, the drug is ready for approval (ii) Necessary studies are impossible in adults before studies in pediatric pa- or highly impractical because, e.g., the tients are complete, or pediatric stud- number of patients in that age group is ies should be delayed until additional so small or geographically dispersed; safety or effectiveness data have been (iii) There is evidence strongly sug- collected. If an applicant requests de- gesting that the drug product would be ferred submission, the request must ineffective or unsafe in that age group; provide a certification from the appli- or cant of the grounds for delaying pedi- (iv) The applicant can demonstrate atric studies, a description of the that reasonable attempts to produce a planned or ongoing studies, and evi- pediatric formulation necessary for dence that the studies are being or will that age group have failed. be conducted with due diligence and at (4) FDA action on waiver. FDA shall the earliest possible time. grant a full or partial waiver, as appro- (2) If FDA determines that there is priate, if the agency finds that there is an adequate justification for tempo- a reasonable basis on which to con- rarily delaying the submission of as- clude that one or more of the grounds sessments of pediatric safety and effec- for waiver specified in paragraphs (c)(2) tiveness, the drug product may be ap- or (c)(3) of this section have been met. proved for use in adults subject to the If a waiver is granted on the ground requirement that the applicant submit that it is not possible to develop a pedi- the required assessments within a spec- atric formulation, the waiver will ified time. cover only those pediatric age groups (c) Waivers—(1) General. FDA may requiring that formulation. If a waiver grant a full or partial waiver of the re- is granted because there is evidence quirements of paragraph (a) of this sec- that the product would be ineffective

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or unsafe in pediatric populations, this section 505(c) of the Federal Food, information will be included in the Drug, and Cosmetic Act to extend the product’s labeling. initial review cycle by 3 months. (For (5) Definition of ‘‘meaningful thera- references to a resubmission of an NDA peutic benefit’’. For purposes of this sec- or efficacy supplement in paragraph (b) tion and § 201.23 of this chapter, a drug of this section, the timeframe for re- will be considered to offer a meaningful viewing the resubmission is the ‘‘re- therapeutic benefit over existing thera- view cycle’’ rather than the ‘‘initial re- pies if FDA estimates that: view cycle.’’) FDA may instead defer (i) If approved, the drug would rep- review of the amendment until the sub- resent a significant improvement in sequent review cycle. If the agency ex- the treatment, diagnosis, or prevention tends the initial review cycle for an of a disease, compared to marketed original NDA, efficacy supplement, or products adequately labeled for that resubmission under this paragraph, the use in the relevant pediatric popu- division responsible for reviewing the lation. Examples of how improvement NDA, supplement, or resubmission will might be demonstrated include, for ex- notify the applicant of the extension. ample, evidence of increased effective- The initial review cycle for an original ness in treatment, prevention, or diag- NDA, efficacy supplement, or resubmis- nosis of disease, elimination or sub- sion of an NDA or efficacy supplement stantial reduction of a treatment-limiting drug reaction, documented en- may be extended only once due to sub- hancement of compliance, or evidence mission of a major amendment. FDA of safety and effectiveness in a new may, at its discretion, review any sub- subpopulation; or sequent major amendment during the (ii) The drug is in a class of drugs or initial review cycle (as extended) or for an indication for which there is a defer review until the subsequent re- need for additional therapeutic op- view cycle. tions. (2) Submission of a major amend- (d) Exemption for orphan drugs. This ment to an original NDA, efficacy sup- section does not apply to any drug for plement, or resubmission of an NDA or an indication or indications for which efficacy supplement more than 3 orphan designation has been granted months before the end of the initial re- under part 316, subpart C, of this chap- view cycle will not extend the cycle. ter. FDA may, at its discretion, review such an amendment during the initial [63 FR 66670, Dec. 2, 1998] review cycle or defer review until the § 314.60 Amendments to an unap- subsequent review cycle. proved NDA, supplement, or resub- (3) Submission of an amendment to mission. an original NDA, efficacy supplement, (a) Submission of NDA. FDA generally or resubmission of an NDA or efficacy assumes that when an original NDA, supplement that is not a major amend- supplement to an approved NDA, or re- ment will not extend the initial review submission of an NDA or supplement is cycle. FDA may, at its discretion, re- submitted to the Agency for review, view such an amendment during the the applicant believes that the Agency initial review cycle or defer review can approve the NDA, supplement, or until the subsequent review cycle. resubmission as submitted. However, (4) Submission of a major amend- the applicant may submit an amendment to a manufacturing supplement ment to an NDA, supplement, or resub- within 2 months of the end of the ini- mission that has been filed under tial review cycle constitutes an agree- § 314.101 but is not yet approved. ment by the applicant under section (b) Submission of major amendment. (1) 505(c) of the Federal Food, Drug, and Submission of a major amendment to Cosmetic Act to extend the initial re- an original NDA, efficacy supplement, view cycle by 2 months. FDA may in- or resubmission of an NDA or efficacy stead defer review of the amendment supplement within 3 months of the end until the subsequent review cycle. If of the initial review cycle constitutes the agency extends the initial review an agreement by the applicant under cycle for a manufacturing supplement

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under this paragraph, the division re- (2) The submission of an amendment sponsible for reviewing the supplement described in paragraph (c)(1) of this will notify the applicant of the exten- section will cause the unapproved NDA sion. The initial review cycle for a to be deemed to be withdrawn by the manufacturing supplement may be ex- applicant under § 314.65 on the date of tended only once due to submission of receipt by FDA of the amendment. The a major amendment. FDA may, at its amendment will be considered a resub- discretion, review any subsequent mission of the NDA, which may not be major amendment during the initial accepted except as provided in accord- review cycle (as extended) or defer re- ance with section 505(c)(3)(E)(ii) of the view until the subsequent review cycle. Federal Food, Drug, and Cosmetic Act. (5) Submission of an amendment to a (d) Field copy. The applicant must supplement other than an efficacy or submit a field copy of each amendment manufacturing supplement will not ex- to a section of the NDA described in tend the initial review cycle. FDA § 314.50(d)(1). The applicant must in- may, at its discretion, review such an clude in its submission of each such amendment during the initial review amendment to FDA a statement certi- cycle or defer review until the subse- fying that a field copy of the amend- quent review cycle. ment has been sent to the applicant’s (6) A major amendment may not in- home FDA district office. clude data to support an indication or (e) Different drug. An applicant may claim that was not included in the not amend a 505(b)(2) application to original NDA, supplement, or resub- seek approval of a drug that is a dif- mission, but it may include data to ferent drug from the drug in the origi- support a minor modification of an in- nal submission of the 505(b)(2) applica- dication or claim that was included in tion. For purposes of this paragraph the original NDA, supplement, or re- (e), a drug is a different drug if it has submission. been modified to have a different ac- (7) When FDA defers review of an tive ingredient, different route of ad- amendment until the subsequent re- ministration, different dosage form, or view cycle, the agency will notify the difference in excipients that requires applicant of the deferral in the com- either a separate clinical study to es- plete response letter sent to the appli- tablish safety or effectiveness or, for cant under § 314.110 of this part. topical products, that requires a sepa- (c) Limitation on certain amend- rate in vivo demonstration of bio- ments.(1) An unapproved NDA may not equivalence. However, notwithstanding be amended if all of the following con- the limitation described in this para- ditions apply: graph (e), an applicant may amend the (i) The unapproved NDA is for a drug 505(b)(2) application to seek approval of for which a previous NDA has been ap- a different strength. proved and granted a period of exclu- (f) Patent certification requirements. (1) sivity in accordance with section An amendment to a 505(b)(2) applica- 505(c)(3)(E)(ii) of the Federal Food, tion is required to contain an appro- Drug, and Cosmetic Act that has not priate patent certification or state- expired; ment described in § 314.50(i) or a recer- (ii) The applicant seeks to amend the tification for a previously submitted unapproved NDA to include a published paragraph IV certification if approval report of an investigation that was is sought for any of the following types conducted or sponsored by the appli- of amendments: cant entitled to exclusivity for the (i) To add a new indication or other drug; condition of use; (iii) The applicant has not obtained a (ii) To add a new strength; right of reference or use to the inves- (iii) To make other than minor tigation described in paragraph changes in product formulation; or (c)(1)(ii) of this section; and (iv) To change the physical form or (iv) The report of the investigation crystalline structure of the active in- described in paragraph (c)(1)(ii) of this gredient. section would be essential to the ap- (2) If the amendment to the 505(b)(2) proval of the unapproved NDA. application does not contain a patent

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certification or statement, the appli- as part of the annual report to the NDA cant must verify that the proposed under paragraph (d) of this section. change described in the amendment is (2) The NDA holder must assess the not one of the types of amendments de- effects of the change before distrib- scribed in paragraph (f)(1) of this sec- uting a drug product made with a man- tion. ufacturing change. [50 FR 7493, Feb. 22, 1985, as amended at 57 (3) Notwithstanding the requirements FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, of paragraphs (b) and (c) of this sec- 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. tion, an applicant must make a change 8, 2004; 73 FR 39608, July 10, 2008; 81 FR 69648, provided for in those paragraphs in ac- Oct. 6, 2016] cordance with a regulation or guidance that provides for a less burdensome no- § 314.65 Withdrawal by the applicant tification of the change (for example, of an unapproved application. by submission of a supplement that An applicant may at any time with- does not require approval prior to dis- draw an application that is not yet ap- tribution of the product or in an an- proved by notifying the Food and Drug nual report). Administration in writing. If, by the (4) The applicant must promptly re- time it receives such notice, the agen- vise all promotional labeling and ad- cy has identified any deficiencies in vertising to make it consistent with the application, we will list such defi- any labeling change implemented in ciencies in the letter we send the appli- accordance with paragraphs (b) and (c) cant acknowledging the withdrawal. A of this section. decision to withdraw the application is (5) Except for a supplement providing without prejudice to refiling. The agen- for a change in the labeling, the appli- cy will retain the application and will cant must include in each supplement provide a copy to the applicant on re- and amendment to a supplement pro- quest under the fee schedule in § 20.45 of viding for a change under paragraph (b) FDA’s public information regulations. or (c) of this section a statement certi- [50 FR 7493, Feb. 22, 1985, as amended at 68 fying that a field copy has been pro- FR 25287, May 12, 2003; 73 FR 39609, July 10, vided in accordance with § 314.440(a)(4). 2008] (6) A supplement or annual report must include a list of all changes con- § 314.70 Supplements and other tained in the supplement or annual re- changes to an approved NDA. port. For supplements, this list must (a) Changes to an approved NDA. (1)(i) be provided in the submission. Except as provided in paragraph (b) Changes requiring supplement sub- (a)(1)(ii) of this section, the applicant mission and approval prior to distribution must notify FDA about each change in of the product made using the change each condition established in an ap- (major changes). (1) A supplement must proved NDA beyond the variations al- be submitted for any change in the ready provided for in the NDA. The no- drug substance, drug product, produc- tice is required to describe the change tion process, quality controls, equip- fully. Depending on the type of change, ment, or facilities that has a substan- the applicant must notify FDA about tial potential to have an adverse effect the change in a supplement under para- on the identity, strength, quality, pu- graph (b) or (c) of this section or by in- rity, or potency of the drug product as clusion of the information in the an- these factors may relate to the safety nual report to the NDA under para- or effectiveness of the drug product. graph (d) of this section. (2) These changes include, but are not (ii) The submission and grant of a limited to: written request for an exception or al- (i) Except those described in para- ternative under § 201.26 of this chapter graphs (c) and (d) of this section, satisfies the applicable requirements in changes in the qualitative or quan- paragraphs (a) through (c) of this sec- titative formulation of the drug prod- tion. However, any grant of a request uct, including inactive ingredients, or for an exception or alternative under in the specifications provided in the § 201.26 of this chapter must be reported approved NDA;

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(ii) Changes requiring completion of (B) Changes in the source material or studies in accordance with part 320 of cell line; and this chapter to demonstrate the (C) Establishment of a new master equivalence of the drug product to the cell bank or seed. drug product as manufactured without (viii) Changes to a drug product the change or to the reference listed under an NDA that is subject to a va- drug; lidity assessment because of signifi- (iii) Changes that may affect drug cant questions regarding the integrity substance or drug product sterility as- of the data supporting that NDA. surance, such as changes in drug sub- (3) The applicant must obtain ap- stance, drug product, or component proval of a supplement from FDA prior sterilization method(s) or an addition, to distribution of a drug product made deletion, or substitution of steps in an using a change under paragraph (b) of aseptic processing operation; this section. Except for submissions (iv) Changes in the synthesis or man- under paragraph (e) of this section, the ufacture of the drug substance that following information must be con- may affect the impurity profile and/or tained in the supplement: the physical, chemical, or biological (i) A detailed description of the pro- properties of the drug substance; posed change; (v) The following labeling changes: (ii) The drug product(s) involved; (A) Changes in labeling, except those (iii) The manufacturing site(s) or described in paragraphs (c)(6)(iii), area(s) affected; (d)(2)(ix), or (d)(2)(x) of this section; (iv) A description of the methods used and studies performed to assess (B) If applicable, any change to a the effects of the change; Medication Guide required under part (v) The data derived from such stud- 208 of this chapter, except for changes ies; in the information specified in (vi) For a natural product, a recom- § 208.20(b)(8)(iii) and (b)(8)(iv) of this binant DNA-derived protein/ chapter; and polypeptide, or a complex or conjugate (C) Any change to the information of a drug substance with a monoclonal required by § 201.57(a) of this chapter, antibody, relevant validation protocols with the following exceptions that may and a list of relevant standard oper- be reported in an annual report under ating procedures must be provided in paragraph (d)(2)(x) of this section: addition to the requirements in para- (1) Removal of a listed section(s) graphs (b)(3)(iv) and (b)(3)(v) of this specified in § 201.57(a)(5) of this chapter; section; and and (vii) For sterilization process and (2) Changes to the most recent revi- test methodologies related to steriliza- sion date of the labeling as specified in tion process validation, relevant vali- § 201.57(a)(15) of this chapter. dation protocols and a list of relevant (vi) Changes in a drug product con- standard operating procedures must be tainer closure system that controls the provided in addition to the require- drug product delivered to a patient or ments in paragraphs (b)(3)(iv) and changes in the type (e.g., glass to high (b)(3)(v) of this section. density polyethylene (HDPE), HDPE to (4) An applicant may ask FDA to ex- polyvinyl chloride, vial to syringe) or pedite its review of a supplement for composition (e.g., one HDPE resin to public health reasons or if a delay in another HDPE resin) of a packaging making the change described in it component that may affect the impu- would impose an extraordinary hard- rity profile of the drug product. ship on the applicant. Such a supple- (vii) Changes solely affecting a nat- ment should be plainly marked: ‘‘Prior ural product, a recombinant DNA-de- Approval Supplement-Expedited Re- rived protein/polypeptide, or a complex view Requested.’’ or conjugate of a drug substance with a (c) Changes requiring supplement sub- monoclonal antibody for the following: mission at least 30 days prior to distribu- (A) Changes in the virus or adven- tion of the drug product made using the titious agent removal or inactivation change (moderate changes). (1) A supple- method(s); ment must be submitted for any

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change in the drug substance, drug change if within 30 days following product, production process, quality FDA’s receipt of the supplement, FDA controls, equipment, or facilities that informs the applicant that either: has a moderate potential to have an (i) The change requires approval adverse effect on the identity, prior to distribution of the drug prod- strength, quality, purity, or potency of uct in accordance with paragraph (b) of the drug product as these factors may this section; or relate to the safety or effectiveness of (ii) Any of the information required the drug product. If the supplement under paragraph (c)(4) of this section is provides for a labeling change under missing; the applicant must not dis- paragraph (c)(6)(iii) of this section, 12 tribute the drug product made using copies of the final printed labeling the change until the supplement has must be included. been amended to provide the missing (2) These changes include, but are not information. limited to: (i) A change in the container closure (6) The agency may designate a cat- system that does not affect the quality egory of changes for the purpose of proof the drug product, except those de- viding that, in the case of a change in scribed in paragraphs (b) and (d) of this such category, the holder of an ap- section; and proved NDA may commence distribu- (ii) Changes solely affecting a nat- tion of the drug product involved upon ural protein, a recombinant DNA-de- receipt by the agency of a supplement rived protein/polypeptide or a complex for the change. These changes include, or conjugate of a drug substance with a but are not limited to: monoclonal antibody, including: (i) Addition to a specification or (A) An increase or decrease in pro- changes in the methods or controls to duction scale during finishing steps provide increased assurance that the that involves different equipment; and drug substance or drug product will (B) Replacement of equipment with have the characteristics of identity, that of a different design that does not strength, quality, purity, or potency affect the process methodology or proc- that it purports or is represented to ess operating parameters. possess; (iii) Relaxation of an acceptance cri- (ii) A change in the size and/or shape terion or deletion of a test to comply of a container for a nonsterile drug with an official compendium that is product, except for solid dosage forms, consistent with FDA statutory and reg- without a change in the labeled ulatory requirements. amount of drug product or from one (3) A supplement submitted under container closure system to another; paragraph (c)(1) of this section is re- (iii) Changes in the labeling to reflect quired to give a full explanation of the newly acquired information, except for basis for the change and identify the changes to the information required in date on which the change is to be § 201.57(a) of this chapter (which must made. The supplement must be labeled be made under paragraph (b)(2)(v)(C) of ‘‘Supplement—Changes Being Effected this section), to accomplish any of the in 30 Days’’ or, if applicable under following: paragraph (c)(6) of this section, ‘‘Sup- plement—Changes Being Effected.’’ (A) To add or strengthen a contra- (4) Pending approval of the supple- indication, warning, precaution, or ad- ment by FDA, except as provided in verse reaction for which the evidence paragraph (c)(6) of this section, dis- of a causal association satisfies the tribution of the drug product made standard for inclusion in the labeling using the change may begin not less under § 201.57(c) of this chapter; than 30 days after receipt of the supple- (B) To add or strengthen a statement ment by FDA. The information listed about drug abuse, dependence, psycho- in paragraphs (b)(3)(i) through logical effect, or overdosage; (b)(3)(vii) of this section must be con- (C) To add or strengthen an instruc- tained in the supplement. tion about dosage and administration (5) The applicant must not distribute that is intended to increase the safe the drug product made using the use of the drug product;

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(D) To delete false, misleading, or un- (vii) The addition or revision of an al- supported indications for use or claims ternative analytical procedure that for effectiveness; or provides the same or increased assur- (E) Any labeling change normally re- ance of the identity, strength, quality, quiring a supplement submission and purity, or potency of the material approval prior to distribution of the being tested as the analytical proce- drug product that FDA specifically re- dure described in the approved NDA, or quests be submitted under this provi- deletion of an alternative analytical sion. procedure; (7) If the agency disapproves the sup- (viii) The addition by embossing, de- plemental NDA, it may order the man- bossing, or engraving of a code imprint ufacturer to cease distribution of the to a solid oral dosage form drug prod- drug product(s) made with the manu- uct other than a modified release dos- facturing change. age form, or a minor change in an ex- (d) Changes to be described in an an- isting code imprint; nual report (minor changes). (1) Changes (ix) A change in the labeling con- in the drug substance, drug product, cerning the description of the drug production process, quality controls, product or in the information about equipment, or facilities that have a how the drug product is supplied, that minimal potential to have an adverse does not involve a change in the dosage effect on the identity, strength, qual- strength or dosage form; and ity, purity, or potency of the drug (x) An editorial or similar minor product as these factors may relate to change in labeling, including a change the safety or effectiveness of the drug to the information allowed by para- product must be documented by the ap- graphs (b)(2)(v)(C)(1) and (2) of this sec- plicant in the next annual report in action. cordance with § 314.81(b)(2). (3) For changes under this category, (2) These changes include, but are not the applicant is required to submit in limited to: the annual report: (i) Any change made to comply with a change to an official compendium, (i) A statement by the holder of the except a change described in paragraph approved NDA that the effects of the (c)(2)(iii) of this section, that is con- change have been assessed; sistent with FDA statutory and regu- (ii) A full description of the manufac- latory requirements. turing and controls changes, including (ii) The deletion or reduction of an the manufacturing site(s) or area(s) in- ingredient intended to affect only the volved; color of the drug product; (iii) The date each change was imple- (iii) Replacement of equipment with mented; that of the same design and operating (iv) Data from studies and tests per- principles except those equipment formed to assess the effects of the changes described in paragraph (c) of change; and, this section; (v) For a natural product, recom- (iv) A change in the size and/or shape binant DNA-derived protein/ of a container containing the same polypeptide, complex or conjugate of a number of dosage units for a nonsterile drug substance with a monoclonal anti- solid dosage form drug product, with- body, sterilization process or test out a change from one container clo- methodology related to sterilization sure system to another; process validation, a cross-reference to (v) A change within the container relevant validation protocols and/or closure system for a nonsterile drug standard operating procedures. product, based upon a showing of (e) Protocols. An applicant may sub- equivalency to the approved system mit one or more protocols describing under a protocol approved in the NDA the specific tests and studies and ac- or published in an official compendium; ceptance criteria to be achieved to (vi) An extension of an expiration demonstrate the lack of adverse effect dating period based upon full shelf life for specified types of manufacturing data on production batches obtained changes on the identity, strength, from a protocol approved in the NDA; quality, purity, and potency of the

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drug product as these factors may re- also apply to supplements, except that late to the safety or effectiveness of the information required in the supple- the drug product. Any such protocols, ment is limited to that needed to sup- if not included in the approved NDA, or port the change. A supplement is re- changes to an approved protocol, must quired to contain an archival copy and be submitted as a supplement requiring a review copy that include an applica- approval from FDA prior to distribution form and appropriate technical tion of a drug product produced with sections, samples, and labeling; except the manufacturing change. The supple- that a supplement for a change other ment, if approved, may subsequently than a change in labeling is required justify a reduced reporting category for also to contain a field copy. the particular change because the use (c) All procedures and actions that of the protocol for that type of change apply to applications under this part, reduces the potential risk of an adverse including actions by applicants and the effect. Food and Drug Administration, also (f) Patent information. The applicant apply to supplements except as speci- must comply with the patent informa- fied otherwise in this part. tion requirements under section [50 FR 7493, Feb. 22, 1985, as amended at 50 505(c)(2) of the Federal Food, Drug, and FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, Cosmetic Act and § 314.53. 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, (g) Claimed exclusivity. If an applicant July 10, 2008] claims exclusivity under § 314.108 upon approval of a supplement for change to § 314.72 Change in ownership of an ap- its previously approved drug product, plication. the applicant must include with its (a) An applicant may transfer owner- supplement the information required ship of its application. At the time of under § 314.50(j). transfer the new and former owners are (h) Different drug. An applicant may required to submit information to the not supplement a 505(b)(2) application Food and Drug Administration as fol- to seek approval of a drug that is a dif- lows: ferent drug from the drug in the ap- (1) The former owner shall submit a proved 505(b)(2) application. For pur- letter or other document that states poses of this paragraph (h), a drug is a that all rights to the application have different drug if it has been modified to been transferred to the new owner. have a different active ingredient, dif- (2) The new owner shall submit an ferent route of administration, dif- application form signed by the new ferent dosage form, or difference in owner and a letter or other document excipients that requires either a sepa- containing the following: rate clinical study to establish safety (i) The new owner’s commitment to or effectiveness or, for topical prod- agreements, promises, and conditions ucts, that requires a separate in vivo made by the former owner and con- demonstration of bioequivalence. How- tained in the application; ever, notwithstanding the limitation (ii) The date that the change in own- described in this paragraph (h), an ap- ership is effective; and plicant may supplement the 505(b)(2) (iii) Either a statement that the new application to seek approval of a dif- owner has a complete copy of the ap- ferent strength. proved application, including supplements and records that are required to [69 FR 18764, Apr. 8, 2004, as amended at 71 FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, be kept under § 314.81, or a request for a 2007; 73 FR 49609, Aug. 22, 2008; 81 FR 69648, copy of the application from FDA’s Oct. 6, 2016] files. FDA will provide a copy of the application to the new owner under the § 314.71 Procedures for submission of fee schedule in § 20.45 of FDA’s public a supplement to an approved appli- information regulations. cation. (b) The new owner shall advise FDA (a) Only the applicant may submit a about any change in the conditions in supplement to an application. the approved application under § 314.70, (b) All procedures and actions that except the new owner may advise FDA apply to an application under § 314.50 in the next annual report about a

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change in the drug product’s label or ered a serious adverse drug experience labeling to change the product’s brand when, based upon appropriate medical or the name of its manufacturer, pack- judgment, they may jeopardize the pa- er, or distributor. tient or subject and may require medical or surgical intervention to prevent [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 FR 21238, May 23, 1985; one of the outcomes listed in this defi- 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, nition. Examples of such medical 2003] events include allergic bronchospasm requiring intensive treatment in an § 314.80 Postmarketing reporting of emergency room or at home, blood adverse drug experiences. dyscrasias or convulsions that do not (a) Definitions. The following defini- result in inpatient hospitalization, or tions of terms apply to this section: the development of drug dependency or Adverse drug experience. Any adverse drug abuse. event associated with the use of a drug Unexpected adverse drug experience. in humans, whether or not considered Any adverse drug experience that is drug related, including the following: not listed in the current labeling for An adverse event occurring in the the drug product. This includes events course of the use of a drug product in that may be symptomatically and professional practice; an adverse event pathophysiologically related to an occurring from drug overdose whether event listed in the labeling, but differ accidental or intentional; an adverse from the event because of greater se- event occurring from drug abuse; an verity or specificity. For example, adverse event occurring from drug under this definition, hepatic necrosis withdrawal; and any failure of expected would be unexpected (by virtue of pharmacological action. greater severity) if the labeling only Individual case safety report (ICSR). A referred to elevated hepatic enzymes or description of an adverse drug experi- hepatitis. Similarly, cerebral thrombo- ence related to an individual patient or embolism and cerebral vasculitis would subject. be unexpected (by virtue of greater ICSR attachments. Documents related specificity) if the labeling only listed to the adverse drug experience de- cerebral vascular accidents. ‘‘Unex- scribed in an ICSR, such as medical pected,’’ as used in this definition, re- records, hospital discharge summaries, fers to an adverse drug experience that or other documentation. has not been previously observed (i.e., Disability. A substantial disruption of included in the labeling) rather than a person’s ability to conduct normal from the perspective of such experience life functions. not being anticipated from the pharma- Life-threatening adverse drug experi- cological properties of the pharma- ence. Any adverse drug experience that ceutical product. places the patient, in the view of the (b) Review of adverse drug experiences. initial reporter, at immediate risk of Each applicant having an approved ap- death from the adverse drug experience plication under § 314.50 or, in the case as it occurred, i.e., it does not include of a 505(b)(2) application, an effective an adverse drug experience that, had it approved application, must promptly occurred in a more severe form, might review all adverse drug experience in- have caused death. formation obtained or otherwise re- Serious adverse drug experience. Any ceived by the applicant from any adverse drug experience occurring at source, foreign or domestic, including any dose that results in any of the fol- information derived from commercial lowing outcomes: Death, a life-threat- marketing experience, postmarketing ening adverse drug experience, inpa- clinical investigations, postmarketing tient hospitalization or prolongation of epidemiological/surveillance studies, existing hospitalization, a persistent or reports in the scientific literature, and significant disability/incapacity, or a unpublished scientific papers. Appli- congenital anomaly/birth defect. Im- cants are not required to resubmit to portant medical events that may not FDA adverse drug experience reports result in death, be life-threatening, or forwarded to the applicant by FDA; require hospitalization may be consid- however, applicants must submit all

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followup information on such reports applicant, and the applicant must then to FDA. Any person subject to the re- comply with the requirements of this porting requirements under paragraph section. Under this circumstance, the (c) of this section must also develop nonapplicant must maintain a record written procedures for the surveillance, of this action which must include: receipt, evaluation, and reporting of (A) A copy of each adverse drug expe- postmarketing adverse drug experi- rience report; ences to FDA. (B) The date the report was received (c) Reporting requirements. The appli- by the nonapplicant; cant must submit to FDA adverse drug (C) The date the report was sub- experience information as described in mitted to the applicant; and this section. Except as provided in (D) The name and address of the ap- paragraph (g)(2) of this section, these plicant. reports must be submitted to the Agen- (2) Periodic adverse drug experience re- cy in electronic format as described in ports. (i) The applicant must report paragraph (g)(1) of this section. each adverse drug experience not re- (1)(i) Postmarketing 15-day ‘‘Alert reported under paragraph (c)(1)(i) of this ports’’. The applicant must report each section at quarterly intervals, for 3 adverse drug experience that is both se- years from the date of approval of the rious and unexpected, whether foreign application, and then at annual inter- or domestic, as soon as possible but no vals. The applicant must submit each later than 15 calendar days from initial quarterly report within 30 days of the receipt of the information by the appli- close of the quarter (the first quarter cant. beginning on the date of approval of (ii) Postmarketing 15-day ‘‘Alert re- the application) and each annual report ports’’—followup. The applicant must within 60 days of the anniversary date promptly investigate all adverse drug of approval of the application. Upon experiences that are the subject of written notice, FDA may extend or re- these postmarketing 15-day Alert reestablish the requirement that an ap- ports and must submit followup reports plicant submit quarterly reports, or re- within 15 calendar days of receipt of quire that the applicant submit reports new information or as requested by under this section at different times FDA. If additional information is not than those stated. For example, the obtainable, records should be main- agency may reestablish a quarterly retained of the unsuccessful steps taken porting requirement following the ap- to seek additional information. proval of a major supplement. Fol- (iii) Submission of reports. The re- lowup information to adverse drug ex- quirements of paragraphs (c)(1)(i) and periences submitted in a periodic re- (c)(1)(ii) of this section, concerning the port may be submitted in the next peri- submission of postmarketing 15-day odic report. Alert reports, also apply to any person (ii) Each periodic report is required other than the applicant whose name to contain: appears on the label of an approved (A) Descriptive information. (1) A nar- drug product as a manufacturer, pack- rative summary and analysis of the in- er, or distributor (nonapplicant). To formation in the report; avoid unnecessary duplication in the (2) An analysis of the 15-day Alert resubmission to FDA of reports required ports submitted during the reporting by paragraphs (c)(1)(i) and (c)(1)(ii) of interval (all 15-day Alert reports being this section, obligations of a non- appropriately referenced by the appli- applicant may be met by submission of cant’s patient identification code, ad- all reports of serious adverse drug ex- verse reaction term(s), and date of sub- periences to the applicant. If a non- mission to FDA); applicant elects to submit adverse drug (3) A history of actions taken since experience reports to the applicant the last report because of adverse drug rather than to FDA, the nonapplicant experiences (for example, labeling must submit, by any appropriate changes or studies initiated); and means, each report to the applicant (4) An index consisting of a line list- within 5 calendar days of initial receipt ing of the applicant’s patient identi- of the information by the non- fication code, and adverse reaction

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term(s) for all ICSRs submitted under (iv) Description of adverse drug expe- paragraph (c)(2)(ii)(B) of this section. rience (including a concise medical (B) ICSRs for serious, expected, and narrative); nonserious adverse drug experiences. An (v) Adverse drug experience term(s); ICSR for each adverse drug experience (vi) Description of relevant tests, in- not reported under paragraph (c)(1)(i) cluding dates and laboratory data; and of this section (all serious, expected (vii) Other relevant patient history, and nonserious adverse drug experi- including preexisting medical condi- ences). All such ICSRs must be sub- tions. mitted to FDA (either individually or (3) Suspect medical product(s). in one or more batches) within the (i) Name; timeframe specified in paragraph (ii) Dose, frequency, and route of ad- (c)(2)(i) of this section. ICSRs must ministration used; only be submitted to FDA once. (iii) Therapy dates; (iii) Periodic reporting, except for in- (iv) Diagnosis for use (indication); formation regarding 15-day Alert re- (v) Whether the product is a prescrip- ports, does not apply to adverse drug tion or nonprescription product; experience information obtained from (vi) Whether the product is a com- postmarketing studies (whether or not bination product as defined in § 3.2(e) of conducted under an investigational this chapter; new drug application), from reports in (vii) Whether adverse drug experience the scientific literature, and from for- abated after drug use stopped or dose eign marketing experience. reduced; (d) Scientific literature. A 15-day Alert (viii) Whether adverse drug experi- report based on information in the science reappeared after reintroduction of entific literature must be accompanied drug; by a copy of the published article. The (ix) Lot number; 15-day reporting requirements in para- (x) Expiration date; graph (c)(1)(i) of this section (i.e., seri- (xi) National Drug Code (NDC) num- ous, unexpected adverse drug experi- ber; and ences) apply only to reports found in (xii) Concomitant medical products scientific and medical journals either and therapy dates. as case reports or as the result of a for- (4) Initial reporter information. mal clinical trial. (i) Name, address, and telephone (e) Postmarketing studies. An applicant number; is not required to submit a 15-day Alert (ii) Whether the initial reporter is a report under paragraph (c) of this sec- health care professional; and tion for an adverse drug experience ob- (iii) Occupation, if a health care pro- tained from a postmarketing study fessional. (whether or not conducted under an in- (5) Applicant information. vestigational new drug application) un- (i) Applicant name and contact office less the applicant concludes that there address; is a reasonable possibility that the (ii) Telephone number; drug caused the adverse experience. (iii) Report source, such as sponta- (f) Information reported on ICSRs. neous, literature, or study; ICSRs include the following informa- (iv) Date the report was received by tion: applicant; (v) Application number and type; (1) Patient information. (vi) Whether the ICSR is a 15-day (i) Patient identification code; ‘‘Alert report’’; (ii) Patient age at the time of adverse (vii) Whether the ICSR is an initial drug experience, or date of birth; report or followup report; and (iii) Patient gender; and (viii) Unique case identification num- (iv) Patient weight. ber, which must be the same in the ini- (2) Adverse drug experience. tial report and any subsequent fol- (i) Outcome attributed to adverse lowup report(s). drug experience; (g) Electronic format for submissions. (ii) Date of adverse drug experience; (1) Safety report submissions, includ- (iii) Date of ICSR submission; ing ICSRs, ICSR attachments, and the

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descriptive information in periodic re- approval of the application and, thus, ports, must be in an electronic format prohibit continued marketing of the that FDA can process, review, and ar- drug product that is the subject of the chive. FDA will issue guidance on how application. to provide the electronic submission (l) Disclaimer. A report or information (e.g., method of transmission, media, submitted by an applicant under this file formats, preparation and organiza- section (and any release by FDA of tion of files). that report or information) does not (2) An applicant or nonapplicant may necessarily reflect a conclusion by the request, in writing, a temporary waiver applicant or FDA that the report or in- of the requirements in paragraph (g)(1) formation constitutes an admission of this section. These waivers will be that the drug caused or contributed to granted on a limited basis for good an adverse effect. An applicant need cause shown. FDA will issue guidance not admit, and may deny, that the re- on requesting a waiver of the require- port or information submitted under ments in paragraph (g)(1) of this sec- this section constitutes an admission tion. that the drug caused or contributed to (h) Multiple reports. An applicant an adverse effect. For purposes of this should not include in reports under provision, the term ‘‘applicant’’ also this section any adverse drug experi- includes any person reporting under ences that occurred in clinical trials if paragraph (c)(1)(iii) of this section. they were previously submitted as part of the approved application. If a report [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, applies to a drug for which an appli- 1985, as amended at 50 FR 21238, May 23, 1985; cant holds more than one approved ap- 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, plication, the applicant should submit 1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, the report to the application that was Apr. 28, 1992; 62 FR 34168, June 25, 1997; 62 FR 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 1998; first approved. If a report refers to 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, more than one drug marketed by an ap- 2004; 74 FR 13113, Mar. 26, 2009; 79 FR 33088, plicant, the applicant should submit June 10, 2014] the report to the application for the drug listed first in the report. § 314.81 Other postmarketing reports. (i) Patient privacy. An applicant (a) Applicability. Each applicant shall should not include in reports under make the reports for each of its ap- this section the names and addresses of proved applications and abbreviated individual patients; instead, the appli- applications required under this sec- cant should assign a unique code for tion and section 505(k) of the act. identification of the patient. The applicant should include the name of the re- (b) Reporting requirements. The appli- porter from whom the information was cant shall submit to the Food and Drug received as part of the initial reporter Administration at the specified times information, even when the reporter is two copies of the following reports: the patient. The names of patients, (1) NDA—Field alert report. The appli- health care professionals, hospitals, cant shall submit information of the and geographical identifiers in adverse following kinds about distributed drug drug experience reports are not releas- products and articles to the FDA dis- able to the public under FDA’s public trict office that is responsible for the information regulations in part 20 of facility involved within 3 working days this chapter. of receipt by the applicant. The infor- (j) Recordkeeping. The applicant must mation may be provided by telephone maintain for a period of 10 years or other rapid communication means, records of all adverse drug experiences with prompt written followup. The re- known to the applicant, including raw port and its mailing cover should be data and any correspondence relating plainly marked: ‘‘NDA—Field Alert Re- to adverse drug experiences. port.’’ (k) Withdrawal of approval. If an ap- (i) Information concerning any inci- plicant fails to establish and maintain dent that causes the drug product or records and make reports required its labeling to be mistaken for, or ap- under this section, FDA may withdraw plied to, another article.

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(ii) Information concerning any bac- mestic use and the quantities distrib- teriological contamination, or any sig- uted for foreign use. Disclosure of fi- nificant chemical, physical, or other nancial or pricing data is not required. change or deterioration in the distrib- (b) Authorized generic drugs. If appli- uted drug product, or any failure of one cable, the date each authorized generic or more distributed batches of the drug drug (as defined in § 314.3) entered the product to meet the specification es- market, the date each authorized ge- tablished for it in the application. neric drug ceased being distributed, (2) Annual report. The applicant shall and the corresponding trade or brand submit each year within 60 days of the name. Each dosage form and/or anniversary date of U.S. approval of strength is a different authorized ge- the application, two copies of the re- neric drug and should be listed sepa- port to the FDA division responsible rately. The first annual report sub- for reviewing the application. Each an- mitted on or after January 25, 2010 nual report is required to be accom- must include the information listed in panied by a completed transmittal this paragraph for any authorized ge- Form FDA 2252 (Transmittal of Peri- neric drug that was marketed during odic Reports for Drugs for Human Use), the time period covered by an annual and must include all the information report submitted after January 1, 1999. required under this section that the ap- If information is included in the annual plicant received or otherwise obtained report with respect to any authorized during the annual reporting interval generic drug, a copy of that portion of that ends on the U.S. anniversary date. the annual report must be sent to the The report is required to contain in the Food and Drug Administration, Center order listed: for Drug Evaluation and Research, Of- (i) Summary. A brief summary of sig- fice of New Drug Quality Assessment, nificant new information from the pre- Bldg. 21, rm. 2562, 10903 New Hampshire vious year that might affect the safety, Ave., Silver Spring, MD 20993–0002, and effectiveness, or labeling of the drug marked ‘‘Authorized Generic Submis- product. The report is also required to sion’’ or, by e-mail, to the Authorized contain a brief description of actions Generics electronic mailbox at the applicant has taken or intends to [email protected] with take as a result of this new informa- ‘‘Authorized Generic Submission’’ indi- tion, for example, submit a labeling cated in the subject line. However, at supplement, add a warning to the label- such time that FDA has required that ing, or initiate a new study. The sum- annual reports be submitted in an elec- mary shall briefly state whether label- tronic format, the information re- ing supplements for pediatric use have quired by this paragraph must be sub- been submitted and whether new stud- mitted as part of the annual report, in ies in the pediatric population to sup- the electronic format specified for sub- port appropriate labeling for the pedi- mission of annual reports at that time, atric population have been initiated. and not as a separate submission under Where possible, an estimate of patient the preceding sentence in this para- exposure to the drug product, with spe- graph. cial reference to the pediatric popu- (iii) Labeling. (a) Currently used pro- lation (neonates, infants, children, and fessional labeling, patient brochures or adolescents) shall be provided, includ- package inserts (if any), and a rep- ing dosage form. resentative sample of the package la- (ii)(a) Distribution data. Information bels. about the quantity of the drug product (b) The content of labeling required distributed under the approved applica- under § 201.100(d)(3) of this chapter (i.e., tion, including that distributed to dis- the package insert or professional la- tributors. The information is required beling), including all text, tables, and to include the National Drug Code figures, must be submitted in elec- (NDC) number, the total number of tronic format. Electronic format sub- dosage units of each strength or po- missions must be in a form that FDA tency distributed (e.g., 100,000/5 milli- can process, review, and archive. FDA gram tablets, 50,000/10 milliliter vials), will periodically issue guidance on how and the quantities distributed for do- to provide the electronic submission

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(e.g., method of transmission, media, that do not contain tabulations or file formats, preparation and organiza- summaries of original data should not tion of files). Submissions under this be reported. paragraph must be made in accordance (b) Summaries of completed unpub- with part 11 of this chapter, except for lished clinical trials, or prepublication the requirements of § 11.10(a), (c) manuscripts if available, conducted by, through (h), and (k), and the cor- or otherwise obtained by, the appli- responding requirements of § 11.30. cant. Supporting information should (c) A summary of any changes in la- not be reported. (A study is considered beling that have been made since the completed 1 year after it is concluded.) last report listed by date in the order (c) Analysis of available safety and in which they were implemented, or if efficacy data in the pediatric popu- no changes, a statement of that fact. lation and changes proposed in the la- (iv) Chemistry, manufacturing, and beling based on this information. An controls changes. (a) Reports of experi- assessment of data needed to ensure ences, investigations, studies, or tests appropriate labeling for the pediatric involving chemical or physical prop- population shall be included. erties, or any other properties of the (vii) Status reports of postmarketing drug (such as the drug’s behavior or study commitments. A status report of properties in relation to microorga- each postmarketing study of the drug nisms, including both the effects of the product concerning clinical safety, drug on microorganisms and the effects clinical efficacy, clinical pharma- of microorganisms on the drug). These cology, and nonclinical toxicology that reports are only required for new infor- is required by FDA (e.g., accelerated mation that may affect FDA’s previous approval clinical benefit studies, pedi- conclusions about the safety or effec- atric studies) or that the applicant has tiveness of the drug product. committed, in writing, to conduct ei- (b) A full description of the manufac- ther at the time of approval of an ap- turing and controls changes not requir- plication for the drug product or a sup- ing a supplemental application under plement to an application, or after ap- § 314.70 (b) and (c), listed by date in the proval of the application or a supple- order in which they were implemented. ment. For pediatric studies, the status (v) Nonclinical laboratory studies. Cop- report shall include a statement indi- ies of unpublished reports and sum- cating whether postmarketing clinical maries of published reports of new toxi- studies in pediatric populations were cological findings in animal studies required by FDA under § 201.23 of this and in vitro studies (e.g., mutage- chapter. The status of these post- nicity) conducted by, or otherwise ob- marketing studies shall be reported an- tained by, the applicant concerning the nually until FDA notifies the appli- ingredients in the drug product. The cant, in writing, that the agency con- applicant shall submit a copy of a pub- curs with the applicant’s determina- lished report if requested by FDA. tion that the study commitment has (vi) Clinical data. (a) Published clin- been fulfilled or that the study is ei- ical trials of the drug (or abstracts of ther no longer feasible or would no them), including clinical trials on safe- longer provide useful information. ty and effectiveness; clinical trials on (a) Content of status report. The fol- new uses; biopharmaceutic, pharmaco- lowing information must be provided kinetic, and clinical pharmacology for each postmarketing study reported studies; and reports of clinical experi- under this paragraph: ence pertinent to safety (for example, (1) Applicant’s name. epidemiologic studies or analyses of ex- (2) Product name. Include the ap- perience in a monitored series of pa- proved drug product’s established name tients) conducted by or otherwise ob- and proprietary name, if any. tained by the applicant. Review arti- (3) NDA, ANDA, and supplement num- cles, papers describing the use of the ber. drug product in medical practice, pa- (4) Date of U.S. approval of NDA or pers and abstracts in which the drug is ANDA. used as a research tool, promotional (5) Date of postmarketing study commit- articles, press clippings, and papers ment.

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(6) Description of postmarketing study graph (b)(2)(vii)(a)(8) of this section. If commitment. The description must in- the study has been completed, include clude sufficient information to unique- the date the study was completed and ly describe the study. This information the date the final study report was sub- may include the purpose of the study, mitted to FDA, as applicable. Provide a the type of study, the patient popu- revised schedule, as well as the rea- lation addressed by the study and the son(s) for the revision, if the schedule indication(s) and dosage(s) that are to under paragraph (b)(2)(vii)(a)(7) of this be studied. section has changed since the last re- (7) Schedule for completion and report- port. ing of the postmarketing study commit- (b) Public disclosure of information. Ex- ment. The schedule should include the cept for the information described in actual or projected dates for submis- this paragraph, FDA may publicly dis- sion of the study protocol to FDA, close any information described in completion of patient accrual or initi- paragraph (b)(2)(vii) of this section, ation of an animal study, completion of the study, submission of the final concerning a postmarketing study, if study report to FDA, and any addi- the agency determines that the infor- tional milestones or submissions for mation is necessary to identify the ap- which projected dates were specified as plicant or to establish the status of the part of the commitment. In addition, it study, including the reasons, if any, for should include a revised schedule, as failure to conduct, complete, and re- appropriate. If the schedule has been port the study. Under this section, previously revised, provide both the FDA will not publicly disclose trade se- original schedule and the most recent, crets, as defined in § 20.61 of this chap- previously submitted revision. ter, or information, described in § 20.63 (8) Current status of the postmarketing of this chapter, the disclosure of which study commitment. The status of each would constitute an unwarranted inva- postmarketing study should be cat- sion of personal privacy. egorized using one of the following (viii) Status of other postmarketing terms that describes the study’s status studies. A status report of any post- on the anniversary date of U.S. ap- marketing study not included under proval of the application or other paragraph (b)(2)(vii) of this section agreed upon date: that is being performed by, or on behalf (i) Pending. The study has not been of, the applicant. A status report is to initiated, but does not meet the cri- be included for any chemistry, manu- terion for delayed. facturing, and controls studies that the (ii) Ongoing. The study is proceeding applicant has agreed to perform and for according to or ahead of the original all product stability studies. schedule described under paragraph (ix) Log of outstanding regulatory busi- (b)(2)(vii)(a)(7) of this section. ness. To facilitate communications be- (iii) Delayed. The study is behind the tween FDA and the applicant, the re- original schedule described under para- port may, at the applicant’s discretion, graph (b)(2)(vii)(a)(7) of this section. (iv) Terminated. The study was ended also contain a list of any open regu- before completion but a final study re- latory business with FDA concerning port has not been submitted to FDA. the drug product subject to the appli- (v) Submitted. The study has been cation (e.g., a list of the applicant’s un- completed or terminated and a final answered correspondence with the study report has been submitted to agency, a list of the agency’s unan- FDA. swered correspondence with the appli- (9) Explanation of the study’s status. cant). Provide a brief description of the sta- (3) Other reporting—(i) Advertisements tus of the study, including the patient and promotional labeling. The applicant accrual rate (expressed by providing shall submit specimens of mailing the number of patients or subjects en- pieces and any other labeling or adver- rolled to date, and the total planned tising devised for promotion of the enrollment), and an explanation of the drug product at the time of initial dis- study’s status identified under para- semination of the labeling and at the

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time of initial publication of the adver- (c) Notifications required by para- tisement for a prescription drug prod- graph (b)(3)(iii)(a) of this section must uct. Mailing pieces and labeling that include the following information: are designed to contain samples of a (1) The name of the drug subject to drug product are required to be com- the notification, including the NDC for plete, except the sample of the drug such drug; product may be omitted. Each submis- (2) The name of the applicant; sion is required to be accompanied by a (3) Whether the notification relates completed transmittal Form FDA–2253 to a permanent discontinuance of the (Transmittal of Advertisements and drug or an interruption in manufac- Promotional Labeling for Drugs for turing of the drug; Human Use) and is required to include (4) A description of the reason for the a copy of the product’s current profes- permanent discontinuance or interrup- sional labeling. Form FDA–2253 is tion in manufacturing; and available on the Internet at http:// (5) The estimated duration of the www.fda.gov/opacom/morechoices/ interruption in manufacturing. fdaforms/cder.html. ( )( ) FDA will maintain a publicly (ii) Special reports. Upon written re- d 1 quest the agency may require that the available list of drugs that are deter- applicant submit the reports under this mined by FDA to be in shortage. This section at different times than those drug shortages list will include the fol- stated. lowing information: (iii) Notification of a permanent dis- (i) The names and NDC(s) for such continuance or an interruption in manu- drugs; facturing. (a) An applicant of a pre- (ii) The name of each applicant for scription drug product must notify such drugs; FDA in writing of a permanent dis- (iii) The reason for the shortage, as continuance of manufacture of the determined by FDA from the following drug product or an interruption in categories: Requirements related to manufacturing of the drug product complying with good manufacturing that is likely to lead to a meaningful practices; regulatory delay; shortage of disruption in supply of that drug in the an active ingredient; shortage of an in- United States if: active ingredient component; dis- (1) The drug product is life sup- continuation of the manufacture of the porting, life sustaining, or intended for drug; delay in shipping of the drug; de- use in the prevention or treatment of a mand increase for the drug; or other debilitating disease or condition, in- reason; and cluding any such drug used in emer- (iv) The estimated duration of the gency medical care or during surgery; shortage. and (2) FDA may choose not to make in- (2) The drug product is not a radio- formation collected to implement this pharmaceutical drug product. paragraph available on the drug short- (b) Notifications required by para- ages list or available under section graph (b)(3)(iii)(a) of this section must 506C(c) of the Federal Food, Drug, and be submitted to FDA electronically in Cosmetic Act (21 U.S.C. 356c(c)) if FDA a format that FDA can process, review, determines that disclosure of such in- and archive: formation would adversely affect the (1) At least 6 months prior to the public health (such as by increasing date of the permanent discontinuance the possibility of hoarding or other dis- or interruption in manufacturing; or ruption of the availability of the drug (2) If 6 months’ advance notice is not to patients). FDA will also not provide possible because the permanent dis- information on the public drug short- continuance or interruption in manu- ages list or under section 506C(c) of the facturing was not reasonably antici- Federal Food, Drug, and Cosmetic Act pated 6 months in advance, as soon as that is protected by 18 U.S.C. 1905 or 5 practicable thereafter, but in no case U.S.C. 552(b)(4), including trade secrets later than 5 business days after the and commercial or financial informa- permanent discontinuance or interruption that is considered confidential or tion in manufacturing occurs. privileged under § 20.61 of this chapter.

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(e) If an applicant fails to submit a changes in manufacturing so long as notification as required under para- the manufacturer expects to resume graph (b)(3)(iii)(a) of this section and in operations in a short period of time. accordance with paragraph (b)(3)(iii)(b) (iv) Withdrawal of approved drug prod- of this section, FDA will issue a letter uct from sale. (a) Within 30 calendar to the applicant informing it of such days of the withdrawal of an approved failure. drug from sale, applicants who are (1) Not later than 30 calendar days manufacturers, repackers, or relabelers after the issuance of such a letter, the subject to part 207 of this chapter must applicant must submit to FDA a writ- submit the following information ten response setting forth the basis for about the drug, in accordance with the noncompliance and providing the re- applicable requirements described in quired notification under paragraph §§ 207.61 and 207.65: (b)(3)(iii)(a) of this section and includ- (1) The National Drug Code (NDC); ing the information required under (2) The identity of the drug by estab- paragraph (b)(3)(iii)(c) of this section; lished name and by proprietary name, and if any; (2) Not later than 45 calendar days (3) The new drug application number after the issuance of a letter under or abbreviated application number; paragraph (b)(3)(iii)(e) of this section, (4) The date on which the drug is ex- FDA will make the letter and the ap- pected to be no longer in commercial plicant’s response to the letter public, distribution. FDA requests that the unless, after review of the applicant’s reason for withdrawal of the drug from response, FDA determines that the ap- sale be included with the information. plicant had a reasonable basis for not (b) Within 30 calendar days of the notifying FDA as required under para- withdrawal of an approved drug from graph (b)(3)(iii)(a) of this section. sale, applicants who are not subject to (f) The following definitions of terms part 207 of this chapter must submit apply to paragraph (b)(3)(iii) of this the information listed in paragraphs section: (b)(3)(iv)(a)(1) through (4) of this sec- Drug shortage or shortage means a pe- tion. The information must be sub- riod of time when the demand or pro- mitted either electronically or in writ- jected demand for the drug within the ing to the Drug Registration and List- United States exceeds the supply of the ing Office, Food and Drug Administra- drug. tion, Center for Drug Evaluation and Intended for use in the prevention or Research. treatment of a debilitating disease or con- (c) Reporting under paragraph dition means a drug product intended (b)(3)(iv)(a) of this section constitutes for use in the prevention or treatment compliance with the requirements of of a disease or condition associated § 207.57 of this chapter to update drug with mortality or morbidity that has a listing information with respect to the substantial impact on day-to-day func- withdrawal from sale. tioning. (c) General requirements—(1) Multiple Life supporting or life sustaining means applications. For all reports required by a drug product that is essential to, or this section, the applicant shall submit that yields information that is essen- the information common to more than tial to, the restoration or continuation one application only to the application of a bodily function important to the first approved, and shall not report sep- continuation of human life. arately on each application. The sub- Meaningful disruption means a change mission is required to identify all the in production that is reasonably likely applications to which the report ap- to lead to a reduction in the supply of plies. a drug by a manufacturer that is more (2) Patient identification. Applicants than negligible and affects the ability should not include in reports under of the manufacturer to fill orders or this section the names and addresses of meet expected demand for its product, individual patients; instead, the appli- and does not include interruptions in cant should code the patient names manufacturing due to matters such as whenever possible and retain the code routine maintenance or insignificant in the applicant’s files. The applicant

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shall maintain sufficient patient iden- (1) The applicant’s compliance with tification information to permit FDA, the requirement is unnecessary for the by using that information alone or agency to evaluate the NDA or compli- along with records maintained by the ance cannot be achieved; investigator of a study, to identify the (2) The applicant’s alternative sub- name and address of individual pa- mission satisfies the requirement; or tients; this will ordinarily occur only (3) The applicant’s submission other- when the agency needs to investigate wise justifies a waiver. the reports further or when there is (c) If FDA grants the applicant’s reason to believe that the reports do waiver request with respect to a re- not represent actual results obtained. quirement under §§ 314.50 through (d) Withdrawal of approval. If an ap- 314.81, the waived requirement will not plicant fails to make reports required constitute a basis for refusal to ap- under this section, FDA may withdraw prove an NDA under § 314.125. approval of the application and, thus, [50 FR 7493, Feb. 22, 1985, as amended at 50 prohibit continued marketing of the FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, drug product that is the subject of the 2002; 81 FR 69649, Oct. 6, 2016] application. (Collection of information requirements ap- Subpart C—Abbreviated proved by the Office of Management and Applications Budget under control number 0910–0001)

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, SOURCE: 57 FR 17983, Apr. 28, 1992, unless 1985, as amended at 50 FR 21238, May 23, 1985; otherwise noted. 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. § 314.92 Drug products for which ab- 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815, breviated applications may be sub- Feb. 20, 2001; 68 FR 69019, Dec. 11, 2003; 69 FR mitted. 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; 72 FR 58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, (a) Abbreviated applications are suit- 2009; 74 FR 37167, July 28, 2009; 76 FR 78539, able for the following drug products Dec. 19, 2011; 80 FR 38938, July 8, 2015; 81 FR within the limits set forth under 60221, Aug. 31, 2016] § 314.93: (1) Drug products that are the same § 314.90 Waivers. as a listed drug. A ‘‘listed drug’’ is de- (a) An applicant may ask the Food fined in § 314.3. For determining the and Drug Administration to waive suitability of an abbreviated new drug under this section any requirement application, the term ‘‘same as’’ means that applies to the applicant under identical in active ingredient(s), dosage §§ 314.50 through 314.81. An applicant form, strength, route of administra- may ask FDA to waive under tion, and conditions of use, except that § 314.126(c) any criteria of an adequate conditions of use for which approval and well-controlled study described in cannot be granted because of exclu- § 314.126(b). A waiver request under this sivity or an existing patent may be section is required to be submitted omitted. If a listed drug has been vol- with supporting documentation in an untarily withdrawn from or not offered NDA, or in an amendment or supple- for sale by its manufacturer, a person ment to an NDA. The waiver request is who wishes to submit an abbreviated required to contain one of the fol- new drug application for the drug shall lowing: comply with § 314.122. (1) An explanation why the appli- (2) [Reserved] cant’s compliance with the require- (3) Drug products that have been de- ment is unnecessary or cannot be clared suitable for an abbreviated new achieved; drug application submission by FDA (2) A description of an alternative through the petition procedures set submission that satisfies the purpose of forth under § 10.30 of this chapter and the requirement; or § 314.93. (3) Other information justifying a (b) FDA will publish in the list listed waiver. drugs for which abbreviated applica- (b) FDA may grant a waiver if it tions may be submitted. The list is finds one of the following: available from the Superintendent of

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Documents, U.S. Government Printing (1) The active ingredients of the pro- Office, Washington, DC 20402, 202–783– posed drug product are of the same 3238. pharmacological or therapeutic class as those of the reference listed drug. [57 FR 17983, Apr. 28, 1992, as amended at 64 (2) The drug product can be expected FR 401, Jan. 5, 1999] to have the same therapeutic effect as § 314.93 Petition to request a change the reference listed drug when adminis- from a listed drug. tered to patients for each condition of use in the reference listed drug’s label- (a) The only changes from a listed ing for which the applicant seeks ap- drug for which the agency will accept a proval. petition under this section are those (3) If the proposed drug product is a changes described in paragraph (b) of combination product with one different this section. Petitions to submit active ingredient, including a different ANDAs for other changes from a listed ester or salt, from the reference listed drug will not be approved. drug, that the different active ingre- (b) A person who wants to submit an dient has previously been approved in a ANDA for a drug product which is not listed drug or is a drug that does not identical to a listed drug in route of ad- meet the definition of ‘‘new drug’’ in ministration, dosage form, and section 201(p) of the Federal Food, strength, or in which one active ingre- Drug, and Cosmetic Act. dient is substituted for one of the ac- (e) No later than 90 days after the tive ingredients in a listed combina- date a petition that is permitted under tion drug, must first obtain permission paragraph (a) of this section is sub- from FDA to submit such an ANDA. mitted, FDA will approve or disapprove (c) To obtain permission to submit an the petition. ANDA for a change described in para- (1) FDA will approve a petition prop- graph (b) of this section, a person must erly submited under this section unless submit and obtain approval of a peti- it finds that: tion requesting the change. A person (i) Investigations must be conducted seeking permission to request such a to show the safety and effectiveness of change from a reference listed drug the drug product or of any of its active shall submit a petition in accordance ingredients, its route of administra- with § 10.20 of this chapter and in the tion, dosage form, or strength which format specified in § 10.30 of this chap- differs from the reference listed drug; ter. The petition shall contain the in- or formation specified in § 10.30 of this (ii) For a petition that seeks to chapter and any additional information change an active ingredient, the drug required by this section. If any provi- product that is the subject of the peti- sion of § 10.20 or § 10.30 of this chapter is tion is not a combination drug; or inconsistent with any provision of this (iii) For a combination drug product section, the provisions of this section that is the subject of the petition and apply. has an active ingredient different from (d) The petitioner shall identify a the reference listed drug: listed drug and include a copy of the (A) The drug product may not be ade- proposed labeling for the drug product quately evaluated for approval as safe that is the subject of the petition and and effective on the basis of the infor- a copy of the approved labeling for the mation required to be submitted under listed drug. The petitioner may, under § 314.94; or limited circumstances, identify more (B) The petition does not contain in- than one listed drug, for example, when formation to show that the different the proposed drug product is a com- active ingredient of the drug product is bination product that differs from the of the same pharmacological or thera- combination reference listed drug with peutic class as the ingredient of the regard to an active ingredient, and the reference listed drug that is to be different active ingredient is an active changed and that the drug product can ingredient of a listed drug. The peti- be expected to have the same thera- tioner shall also include information to peutic effect as the reference listed show that: drug when administered to patients for

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each condition of use in the listed the petition and the listed drug identi- drug’s labeling for which the applicant fied in the petition can no longer be seeks approval; or the basis for ANDA submission, irre- (C) The different active ingredient is spective of whether FDA has with- not an active ingredient in a listed drawn approval of the petition. A per- drug or a drug that meets the require- son seeking approval for such drug ments of section 201(p) of the Federal product must submit a new ANDA that Food, Drug, and Cosmetic Act; or identifies the pharmaceutically equiva- (D) The remaining active ingredients lent reference listed drug as the basis are not identical to those of the listed for ANDA submission and comply with combination drug; or applicable regulatory requirements. (iv) Any of the proposed changes from the listed drug would jeopardize [57 FR 17983, Apr. 28, 1992, as amended at 81 FR 69649, Oct. 6, 2016] the safe or effective use of the product so as to necessitate significant labeling § 314.94 Content and format of an changes to address the newly intro- ANDA. duced safety or effectiveness problem; or ANDAs are required to be submitted (v) FDA has determined that the ref- in the form and contain the informa- erence listed drug has been withdrawn tion required under this section. Three from sale for safety or effectiveness copies of the ANDA are required, an ar- reasons under § 314.161, or the reference chival copy, a review copy, and a field listed drug has been voluntarily with- copy. FDA will maintain guidance doc- drawn from sale and the agency has uments on the format and content of not determined whether the with- ANDAs to assist applicants in their drawal is for safety or effectiveness preparation. reasons; or (a) ANDAs. Except as provided in (vi) A drug product is approved in an paragraph (b) of this section, the appli- NDA for the change described in the cant must submit a complete archival petition. copy of the abbreviated new drug appli- (2) For purposes of this paragraph, cation that includes the following: ‘‘investigations must be conducted’’ (1) Application form. The applicant means that information derived from must submit a completed and signed animal or clinical studies is necessary application form that contains the in- to show that the drug product is safe or formation described under § 314.50(a)(1), effective. Such information may be (a)(3), (a)(4), and (a)(5). The applicant contained in published or unpublished must state whether the submission is reports. an ANDA under this section or a sup- (3) If FDA approves a petition sub- plement to an ANDA under § 314.97. mitted under this section, the agency’s (2) Table of contents. The archival response may describe what additional copy of the ANDA is required to con- information, if any, will be required to tain a table of contents that shows the support an ANDA for the drug product. volume number and page number of the FDA may, at any time during the contents of the submission. course of its review of an ANDA, re- (3) Basis for ANDA submission. An quest additional information required ANDA must refer to a listed drug. Ordi- to evaluate the change approved under narily, that listed drug will be the drug the petition. product selected by the Agency as the (f)(1) FDA may withdraw approval of reference standard for conducting bio- a petition if the agency receives any equivalence testing. The ANDA must information demonstrating that the contain: petition no longer satisfies the condi- (i) The name of the reference listed tions under paragraph (e) of this sec- drug, including its dosage form and tion. strength. For an ANDA based on an ap- (2) If, after approval of a petition and proved petition under § 10.30 of this before approval of an ANDA submitted chapter and § 314.93, the reference listed pursuant to the approved petition, a drug must be the same as the listed drug product is approved in an NDA for drug referenced in the approved peti- the change described in the petition, tion.

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(ii) A statement as to whether, ac- dient is an active ingredient of another cording to the information published in listed drug or of a drug that does not the list, the reference listed drug is en- meet the definition of ‘‘new drug’’ in titled to a period of marketing exclu- section 201(p) of the Federal Food, sivity under section 505(j)(5)(F) of the Drug, and Cosmetic Act, and such Federal Food, Drug, and Cosmetic Act. other information about the different (iii) For an ANDA based on an ap- active ingredient that FDA may re- proved petition under § 10.30 of this quire. chapter and § 314.93, a reference to the (B) A reference to the applicant’s an- FDA-assigned docket number for the notated proposed labeling and to the petition and a copy of FDA’s cor- currently approved labeling for the ref- respondence approving the petition. erence listed drug provided under para- (4) Conditions of use. (i) A statement graph (a)(8) of this section. that the conditions of use prescribed, (6) Route of administration, dosage recommended, or suggested in the la- form, and strength. (i) Information to beling proposed for the drug product show that the route of administration, have been previously approved for the dosage form, and strength of the drug reference listed drug. product are the same as those of the (ii) A reference to the applicant’s an- reference listed drug except for any dif- notated proposed labeling and to the ferences that have been the subject of currently approved labeling for the ref- an approved petition, as follows: erence listed drug provided under para- (A) A statement that the route of ad- graph (a)(8) of this section. ministration, dosage form, and (5) Active ingredients. (i) For a single- strength of the proposed drug product active-ingredient drug product, infor- are the same as those of the reference mation to show that the active ingre- listed drug. dient is the same as that of the ref- (B) A reference to the applicant’s an- erence single-active-ingredient listed notated proposed labeling and to the drug, as follows: currently approved labeling for the ref- (A) A statement that the active in- erence listed drug provided under para- gredient of the proposed drug product graph (a)(8) of this section. is the same as that of the reference (ii) If the route of administration, listed drug. dosage form, or strength of the drug (B) A reference to the applicant’s an- product differs from the reference list- notated proposed labeling and to the ed drug and the ANDA is submitted currently approved labeling for the ref- under an approved petition under erence listed drug provided under para- § 314.93, such information about the dif- graph (a)(8) of this section. ferent route of administration, dosage (ii) For a combination drug product, form, or strength that FDA may re- information to show that the active in- quire. gredients are the same as those of the (7) Bioequivalence. (i) Information reference listed drug except for any dif- that shows that the drug product is ferent active ingredient that has been bioequivalent to the reference listed the subject of an approved petition, as drug upon which the applicant relies. A follows: complete study report must be sub- (A) A statement that the active in- mitted for the bioequivalence study gredients of the proposed drug product upon which the applicant relies for ap- are the same as those of the reference proval. For all other bioequivalence listed drug, or if one of the active in- studies conducted on the same drug gredients differs from one of the active product formulation as defined in ingredients of the reference listed drug § 314.3(b), the applicant must submit ei- and the ANDA is submitted under the ther a complete or summary report. If approval of a petition under § 314.93 to a summary report of a bioequivalence vary such active ingredient, informa- study is submitted and FDA deter- tion to show that the other active in- mines that there may be bioequiva- gredients of the drug product are the lence issues or concerns with the prod- same as the other active ingredients of uct, FDA may require that the appli- the reference listed drug, information cant submit a complete report of the to show that the different active ingre- bioequivalence study to FDA; or

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(ii) If the ANDA is submitted pursu- sent regulations in part 50 of this chap- ant to a petition approved under ter. § 314.93, the results of any bio- (8) Labeling—(i) Listed drug labeling. A availability or bioequivalence testing copy of the currently approved labeling required by the Agency, or any other (including, if applicable, any Medica- information required by the Agency to tion Guide required under part 208 of show that the active ingredients of the this chapter) for the listed drug re- proposed drug product are of the same ferred to in the ANDA, if the ANDA re- pharmacological or therapeutic class lies on a reference listed drug. as those in the reference listed drug (ii) Copies of proposed labeling. Copies and that the proposed drug product can of the label and all labeling for the be expected to have the same thera- drug product including, if applicable, peutic effect as the reference listed any Medication Guide required under drug. If the proposed drug product con- part 208 of this chapter (4 copies of tains a different active ingredient than draft labeling or 12 copies of final the reference listed drug, FDA will con- printed labeling). sider the proposed drug product to have (iii) Statement on proposed labeling. A the same therapeutic effect as the ref- statement that the applicant’s pro- erence listed drug if the applicant proposed labeling including, if applicable, vides information demonstrating that: any Medication Guide required under (A) There is an adequate scientific part 208 of this chapter is the same as basis for determining that substitution the labeling of the reference listed drug of the specific proposed dose of the dif- except for differences annotated and ferent active ingredient for the dose of explained under paragraph (a)(8)(iv) of the member of the same pharma- this section. cological or therapeutic class in the (iv) Comparison of approved and pro- reference listed drug will yield a re- posed labeling. A side-by-side compari- sulting drug product whose safety and son of the applicant’s proposed labeling effectiveness have not been adversely including, if applicable, any Medica- affected. tion Guide required under part 208 of (B) The unchanged active ingredients this chapter with the approved labeling in the proposed drug product are bio- for the reference listed drug with all equivalent to those in the reference differences annotated and explained. listed drug. Labeling (including the container (C) The different active ingredient in label, package insert, and, if applica- the proposed drug product is bioequiva- ble, Medication Guide) proposed for the lent to an approved dosage form con- drug product must be the same as the taining that ingredient and approved labeling approved for the reference list- for the same indication as the proposed ed drug, except for changes required be- drug product or is bioequivalent to a cause of differences approved under a drug product offered for that indication petition filed under § 314.93 or because which does not meet the definition of the drug product and the reference list- ‘‘new drug’’ under section 201(p) of the ed drug are produced or distributed by Federal Food, Drug, and Cosmetic Act. different manufacturers. Such dif- (iii) For each in vivo or in vitro bio- ferences between the applicant’s pro- equivalence study contained in the posed labeling and labeling approved ANDA: for the reference listed drug may in- (A) A description of the analytical clude differences in expiration date, and statistical methods used in each formulation, bioavailability, or phar- study; and macokinetics, labeling revisions made (B) With respect to each study in- to comply with current FDA labeling volving human subjects, a statement guidelines or other guidance, or omis- that the study either was conducted in sion of an indication or other aspect of compliance with the institutional re- labeling protected by patent or ac- view board regulations in part 56 of corded exclusivity under section this chapter, or was not subject to the 505(j)(5)(F) of the Federal Food, Drug, regulations under § 56.104 or § 56.105 of and Cosmetic Act. this chapter, and that it was conducted (9) Chemistry, manufacturing, and con- in compliance with the informed controls. (i) The information required

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under § 314.50(d)(1), except that the in- vantage over or difference from the formation required under listed drug, e.g., by using a balanced § 314.50(d)(1)(ii)(c) must contain the pro- salt solution as a diluent as opposed to posed or actual master production an isotonic saline solution, or by mak- record, including a description of the ing a significant change in the pH or equipment, to be used for the manufac- other change that may raise questions ture of a commercial lot of the drug of irritability. product. (v) Inactive ingredient changes per- (ii) Inactive ingredients. Unless other- mitted in drug products intended for top- wise stated in paragraphs (a)(9)(iii) ical use. Generally, a drug product in- through (a)(9)(v) of this section, an ap- tended for topical use, solutions for plicant must identify and characterize aerosolization or nebulization, and the inactive ingredients in the pro- nasal solutions shall contain the same posed drug product and provide infor- inactive ingredients as the reference mation demonstrating that such inac- listed drug identified by the applicant tive ingredients do not affect the safe- under paragraph (a)(3) of this section. ty or efficacy of the proposed drug However, an ANDA may include dif- product. ferent inactive ingredients provided (iii) Inactive ingredient changes per- that the applicant identifies and char- mitted in drug products intended for par- acterizes the differences and provides enteral use. Generally, a drug product information demonstrating that the intended for parenteral use must con- differences do not affect the safety or tain the same inactive ingredients and efficacy of the proposed drug product. in the same concentration as the ref- (10) Samples. The information re- erence listed drug identified by the ap- quired under § 314.50(e)(1) and (e)(2)(i). plicant under paragraph (a)(3) of this Samples need not be submitted until section. However, an applicant may requested by FDA. seek approval of a drug product that (11) Other. The information required differs from the reference listed drug in under § 314.50(g). preservative, buffer, or antioxidant (12) Patent certification—(i) Patents provided that the applicant identifies claiming drug substance, drug product, or and characterizes the differences and method of use. (A) An appropriate pat- provides information demonstrating ent certification or statement with re- that the differences do not affect the spect to each patent issued by the U.S. safety or efficacy of the proposed drug Patent and Trademark Office that, in product. the opinion of the applicant and to the (iv) Inactive ingredient changes per- best of its knowledge, claims the ref- mitted in drug products intended for oph- erence listed drug or that claims a use thalmic or otic use. Generally, a drug of such listed drug for which the appli- product intended for ophthalmic or cant is seeking approval under section otic use must contain the same inac- 505(j) of the Federal Food, Drug, and tive ingredients and in the same con- Cosmetic Act and for which informa- centration as the reference listed drug tion is required to be filed under sec- identified by the applicant under para- tion 505(b) and (c) of the Federal Food, graph (a)(3) of this section. However, Drug, and Cosmetic Act and § 314.53. an applicant may seek approval of a For each such patent, the applicant drug product that differs from the ref- must provide the patent number and erence listed drug in preservative, buff- certify, in its opinion and to the best of er, substance to adjust tonicity, or its knowledge, one of the following cir- thickening agent provided that the ap- cumstances: plicant identifies and characterizes the (1) That the patent information has differences and provides information not been submitted to FDA. The appli- demonstrating that the differences do cant must entitle such a certification not affect the safety or efficacy of the ‘‘Paragraph I Certification’’; proposed drug product, except that, in (2) That the patent has expired. The a product intended for ophthalmic use, applicant must entitle such a certifi- an applicant may not change a buffer cation ‘‘Paragraph II Certification’’; or substance to adjust tonicity for the (3) The date on which the patent will purpose of claiming a therapeutic ad- expire. The applicant must entitle such

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a certification ‘‘Paragraph III Certifi- applicant is seeking approval does not cation’’; or include an indication or other condi- (4)(i) That the patent is invalid, un- tion of use that is covered by the meth- enforceable, or will not be infringed by od-of-use patent, a statement explain- the manufacture, use, or sale of the ing that the method-of-use patent does drug product for which the ANDA is not claim a proposed indication or submitted. The applicant must entitle other condition of use. such a certification ‘‘Paragraph IV Cer- (B) If the labeling of the drug product tification’’. This certification must be for which the applicant is seeking ap- submitted in the following form: proval includes an indication or other I, (name of applicant), certify that Patent condition of use that, according to the No. lllll (is invalid, unenforceable, or will patent information submitted under not be infringed by the manufacture, use, or section 505(b) or (c) of the Federal sale of) (name of proposed drug product) for Food, Drug, and Cosmetic Act and which this ANDA is submitted. § 314.53 or in the opinion of the appli- (ii) The certification must be accom- cant, is claimed by a method-of-use panied by a statement that the appli- patent, an applicable certification cant will comply with the require- under paragraph (a)(12)(i) of this sec- ments under § 314.95(a) with respect to tion. providing a notice to each owner of the (iv) [Reserved] patent or its representative and to the (v) Licensing agreements. If the ANDA NDA holder (or, if the NDA holder does is for a drug or method of using a drug not reside or maintain a place of busi- claimed by a patent and the applicant ness within the United States, its at- has a licensing agreement with the pat- torney, agent, or other authorized offi- ent owner, the applicant must submit a cial) for the listed drug, with the re- paragraph IV certification as to that quirements under § 314.95(b) with re- patent and a statement that the appli- spect to sending the notice, and with cant has been granted a patent license. the requirements under § 314.95(c) with If the patent owner consents to ap- respect to the content of the notice. proval of the ANDA (if otherwise eligi- (B) If the ANDA refers to a listed ble for approval) as of a specific date, drug that is itself a licensed generic the ANDA must contain a written product of a patented drug first ap- statement from the patent owner that proved under section 505(b) of the Fed- it has a licensing agreement with the eral Food, Drug, and Cosmetic Act, an applicant and that it consents to ap- appropriate patent certification or proval of the ANDA as of a specific statement under paragraph (a)(12)(i) date. and/or (iii) of this section with respect (vi) Untimely filing of patent informa- to each patent that claims the first-ap- tion. (A) If a patent on the listed drug proved patented drug or that claims a is issued and the holder of the approved use for such drug. NDA for the listed drug does not file (ii) No relevant patents. If, in the opin- with FDA the required information on ion of the applicant and to the best of the patent within 30 days of issuance of its knowledge, there are no patents de- the patent, an applicant who submitted scribed in paragraph (a)(12)(i) of this an ANDA for that drug that contained section, a certification in the following an appropriate patent certification or form: statement before the submission of the In the opinion and to the best knowledge of patent information is not required to (name of applicant), there are no patents submit a patent certification or state- that claim the listed drug referred to in this ment to address the patent or patent ANDA or that claim a use of the listed drug. information that is late-listed with re- (iii) Method-of-use patent. (A) If pat- spect to the pending ANDA. Except as ent information is submitted under provided in § 314.53(f)(1), an NDA hold- section 505(b) or (c) of the Federal er’s amendment to the description of Food, Drug, and Cosmetic Act and the approved method(s) of use claimed § 314.53 for a patent claiming a method by the patent will be considered un- of using the listed drug, and the label- timely filing of patent information un- ing for the drug product for which the less:

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(1) The amendment to the description certification, the ANDA will no longer of the approved method(s) of use be considered to contain the prior cer- claimed by the patent is submitted tification. within 30 days of patent issuance; (A) After finding of infringement. An (2) The amendment to the description applicant who has submitted a para- of the approved method(s) of use graph IV certification and is sued for claimed by the patent is submitted patent infringement must submit an within 30 days of approval of a cor- amendment to change its certification responding change to product labeling; if a court enters a final decision from or which no appeal has been or can be (3) The amendment to the description taken, or signs and enters a settlement of the approved method(s) of use order or consent decree in the action claimed by the patent is submitted that includes a finding that the patent within 30 days of a decision by the U.S. is infringed, unless the final decision, Patent and Trademark Office or by a settlement order, or consent decree Federal district court, the Court of Ap- also finds the patent to be invalid. In peals for the Federal Circuit, or the its amendment, the applicant must cer- U.S. Supreme Court that is specific to tify under paragraph (a)(12)(i)(A)(3) of the patent and alters the construction this section that the patent will expire of a method-of-use claim(s) of the pat- on a specific date or, with respect to a ent, and the amendment contains a patent claiming a method of use, the copy of the decision. applicant may instead provide a state- (B) An applicant whose ANDA is sub- ment under paragraph (a)(12)(iii) of mitted after the NDA holder’s un- this section if the applicant amends its timely filing of patent information, or ANDA such that the applicant is no whose pending ANDA was previously submitted but did not contain an ap- longer seeking approval for a method propriate patent certification or state- of use claimed by the patent. Once an ment at the time of the patent submis- amendment for the change has been sion, must submit a certification under submitted, the ANDA will no longer be paragraph (a)(12)(i) of this section and/ considered to contain a paragraph IV or a statement under paragraph certification to the patent. If a final (a)(12)(iii) of this section as to that pat- judgment finds the patent to be invalid ent. and infringed, an amended certification (vii) Disputed patent information. If an is not required. applicant disputes the accuracy or rel- (B) After request to remove a patent or evance of patent information sub- patent information from the list. If the mitted to FDA, the applicant may seek list reflects that an NDA holder has re- a confirmation of the correctness of quested that a patent or patent infor- the patent information in accordance mation be removed from the list and no with the procedures under § 314.53(f). ANDA applicant is eligible for 180-day Unless the patent information is with- exclusivity based on a paragraph IV drawn, the applicant must submit an certification to that patent, the patent appropriate certification or statement or patent information will be removed for each listed patent. and any applicant with a pending (viii) Amended certifications. A patent ANDA (including a tentatively ap- certification or statement submitted proved ANDA) who has made a certifi- under paragraphs (a)(12)(i) through (iii) cation with respect to such patent of this section may be amended at any must submit an amendment to with- time before the approval of the ANDA. draw its certification. In the amend- If an applicant with a pending ANDA ment, the applicant must state the rea- voluntarily makes a patent certifi- son for withdrawing the certification cation for an untimely filed patent, the or statement (that the patent has been applicant may withdraw the patent removed from the list). If the list recertification for the untimely filed pat- flects that an NDA holder has re- ent. An applicant must submit an quested that a patent or patent infor- amended certification as an amend- mation be removed from the list and ment to a pending ANDA. Once an one or more first applicants are eligi- amendment is submitted to change a ble for 180-day exclusivity based on a

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paragraph IV certification to that pat- statement as required by part 54 of this ent, the patent will remain listed until chapter. any 180-day exclusivity based on that (b) Drug products subject to the Drug patent has expired or has been extin- Efficacy Study Implementation (DESI) re- guished. After any applicable 180-day view. If the ANDA is for a duplicate of exclusivity has expired or has been ex- a drug product that is subject to FDA’s tinguished, the patent or patent infor- DESI review (a review of drug products mation will be removed and any appli- approved as safe between 1938 and 1962) cant with a pending ANDA (including a or other DESI-like review and the drug tentatively approved ANDA) who has product evaluated in the review is a made a certification with respect to listed drug, the applicant must comply such patent must submit an amend- with the provisions of paragraph (a) of ment to withdraw its certification. this section. Once an amendment to withdraw the (c) [Reserved] certification has been submitted, the (d) Format of an ANDA. (1) The appli- ANDA will no longer be considered to cant must submit a complete archival contain a paragraph IV certification to copy of the ANDA as required under the patent. If removal of a patent from paragraphs (a) and (c) of this section. the list results in there being no pat- FDA will maintain the archival copy ents listed for the listed drug identified during the review of the ANDA to per- in the ANDA, the applicant must submit individual reviewers to refer to in- mit an amended certification reflecting formation that is not contained in that there are no relevant patents. their particular technical sections of (C) Other amendments. (1) Except as the ANDA, to give other Agency per- provided in paragraphs (a)(12)(vi) and sonnel access to the ANDA for official (a)(12)(viii)(C)(2) of this section: business, and to maintain in one place (i) An applicant must amend a sub- a complete copy of the ANDA. mitted certification or statement if, at (i) Format of submission. An applicant any time before the date of approval of may submit portions of the archival the ANDA, the applicant learns that copy of the ANDA in any form that the the submitted certification or state- applicant and FDA agree is acceptable, ment is no longer accurate; and except as provided in paragraph (ii) An applicant must submit an ap- (d)(1)(ii) of this section. propriate patent certification or state- (ii) Labeling. The content of labeling ment under paragraph (a)(12)(i) and/or required under § 201.100(d)(3) of this (iii) of this section if, after submission chapter (commonly referred to as the of the ANDA, a new patent is issued by package insert or professional label- the U.S. Patent and Trademark Office ing), including all text, tables, and fig- that, in the opinion of the applicant ures, must be submitted to the agency and to the best of its knowledge, in electronic format as described in claims the reference listed drug or that paragraph (d)(1)(iii) of this section. claims an approved use for such ref- This requirement applies to the con- erence listed drug and for which infor- tent of labeling for the proposed drug mation is required to be filed under product only and is in addition to the section 505(b) and (c) of the Federal requirements of paragraph (a)(8)(ii) of Food, Drug, and Cosmetic Act and this section that copies of the for- § 314.53. For a paragraph IV certifi- matted label and all proposed labeling cation, the certification must not be be submitted. Submissions under this submitted earlier than the first work- paragraph must be made in accordance ing day after the day the patent is pub- with part 11 of this chapter, except for lished in the list. the requirements of § 11.10(a), (c) (2) An applicant is not required to through (h), and (k), and the cor- submit a supplement to change a sub- responding requirements of § 11.30. mitted certification when information (iii) Electronic format submissions. on a patent on the listed drug is sub- Electronic format submissions must be mitted after the approval of the ANDA. in a form that FDA can process, re- (13) Financial certification or disclosure view, and archive. FDA will periodi- statement. An ANDA must contain a fi- cally issue guidance on how to provide nancial certification or disclosure the electronic submission (e.g., method

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of transmission, media, file formats, designated delivery service, as defined preparation and organization of files). in paragraph (g) of this section to each (2) For ANDAs, the applicant must of the following persons: submit a review copy of the ANDA that (1) Each owner of the patent that is contains two separate sections. One the subject of the certification or the section must contain the information representative designated by the owner described under paragraphs (a)(2) to receive the notice. The name and ad- through (6) and (8) and (9) of this sec- dress of the patent owner or its rep- tion and section 505(j)(2)(A)(vii) of the resentative may be obtained from the Federal Food, Drug, and Cosmetic Act U.S. Patent and Trademark Office; and and a copy of the analytical procedures and descriptive information needed by (2) The holder of the approved NDA FDA’s laboratories to perform tests on under section 505(b) of the Federal samples of the proposed drug product Food, Drug, and Cosmetic Act for the and to validate the applicant’s analyt- listed drug that is claimed by the pat- ical procedures. The other section must ent and for which the applicant is seek- contain the information described ing approval, or, if the NDA holder under paragraphs (a)(3), (7), and (8) of does not reside or maintain a place of this section. Each of the sections in the business within the United States, the review copy is required to contain a NDA holder’s attorney, agent, or other copy of the application form described authorized official. The name and ad- under paragraph (a) of this section. dress of the NDA holder or its attor- (3) [Reserved] ney, agent, or authorized official may (4) The applicant may obtain from be obtained by sending a written or FDA sufficient folders to bind the ar- electronic communication to the Or- chival, the review, and the field copies ange Book Staff, Office of Generic of the ANDA. Drugs, 7620 Standish Pl., Rockville, MD (5) The applicant must submit a field 20855 or to the Orange Book Staff at copy of the ANDA that contains the the email address listed on the Agen- technical section described in para- cy’s Web site at http://www.fda.gov. graph (a)(9) of this section, a copy of (3) This paragraph (a) does not apply the application form required under to a method-of-use patent that does paragraph (a)(1) of this section, and a certification that the field copy is a not claim a use for which the applicant true copy of the technical section de- is seeking approval. scribed in paragraph (a)(9) of this sec- (4) An applicant may send notice by tion contained in the archival and re- an alternative method only if FDA has view copies of the ANDA. agreed in advance that the method will produce an acceptable form of docu- [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July mentation. 1, 1992, as amended at 58 FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. (b) Sending the notice. (1) Except as 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, provided under paragraph (d) of this Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR section, the applicant must send the 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003; notice required by paragraph (a) of this 69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, section on or after the date it receives 2009; 76 FR 13880, Mar. 15, 2011; 81 FR 69649, a paragraph IV acknowledgment letter Oct. 6, 2016] from FDA, but not later than 20 days § 314.95 Notice of certification of inva- after the date of the postmark on the lidity, unenforceability, or non- paragraph IV acknowledgment letter. infringement of a patent. The 20-day clock described in this para- (a) Notice of certification. For each graph (b) begins on the day after the patent that claims the listed drug or date of the postmark on the paragraph that claims a use for such listed drug IV acknowledgment letter. When the for which the applicant is seeking ap- 20th day falls on Saturday, Sunday, or proval and for which the applicant sub- a Federal holiday, the 20th day will be mits a paragraph IV certification, the the next day that is not a Saturday, applicant must send notice of such cer- Sunday, or Federal holiday. tification by registered or certified (2) Any notice required by paragraph mail, return receipt requested, or by a (a) of this section is invalid if it is sent

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before the applicant’s receipt of a para- plicant seeks to preserve the option to graph IV acknowledgment letter, or be- later file a civil action for declaratory fore the first working day after the day judgment in accordance with section the patent is published in the list. The 505(j)(5)(C) of the Federal Food, Drug, applicant will not have complied with and Cosmetic Act, then the notice this paragraph (b) until it sends valid must be accompanied by an offer of notice. confidential access to the ANDA for (3) The applicant must submit to the sole and limited purpose of evalu- FDA an amendment to its ANDA that ating possible infringement of the pat- includes a statement certifying that ent that is the subject of the paragraph the notice has been provided to each IV certification. person identified under paragraph (a) of (9) If the applicant does not reside or this section and that the notice met have a place of business in the United the content requirements under para- States, the name and address of an graph (c) of this section. A copy of the agent in the United States authorized notice itself need not be submitted to to accept service of process for the ap- the Agency. plicant. (c) Contents of a notice. In the notice, (d) Amendment or supplement to an the applicant must cite section ANDA. (1) If, after receipt of a para- 505(j)(2)(B)(iv) of the Federal Food, graph IV acknowledgment letter or ac- Drug, and Cosmetic Act and the notice knowledgment letter, an applicant sub- must include, but is not limited to, the mits an amendment or supplement to following information: its ANDA that includes a paragraph IV (1) A statement that FDA has recertification, the applicant must send ceived an ANDA submitted by the ap- the notice required by paragraph (a) of plicant containing any required bio- this section at the same time that the availability or bioequivalence data or amendment or supplement to the information. ANDA is submitted to FDA, regardless (2) The ANDA number. of whether the applicant has already (3) A statement that the applicant given notice with respect to another has received the paragraph IV acknowl- such certification contained in the edgment letter for the ANDA. (4) The established name, if any, as ANDA or in an amendment or supple- defined in section 502(e)(3) of the Fed- ment to the ANDA. eral Food, Drug, and Cosmetic Act, of (2) If, before receipt of a paragraph IV the proposed drug product. acknowledgment letter, an applicant (5) The active ingredient, strength, submits an amendment to its ANDA and dosage form of the proposed drug that includes a paragraph IV certifi- product. cation, the applicant must send the no- (6) The patent number and expiration tice required by paragraph (a) of this date of each listed patent for the ref- section in accordance with the proce- erence listed drug alleged to be invalid, dures in paragraph (b) of this section. unenforceable, or not infringed. If an ANDA applicant’s notice of its (7) A detailed statement of the fac- paragraph IV certification is timely tual and legal basis of the applicant’s provided in accordance with paragraph opinion that the patent is not valid, (b) of this section and the applicant has unenforceable, or will not be infringed. not submitted a previous paragraph IV The applicant must include in the de- certification, FDA will base its deter- tailed statement: mination of whether the applicant is a (i) For each claim of a patent alleged first applicant on the date of submis- not to be infringed, a full and detailed sion of the amendment containing the explanation of why the claim is not in- paragraph IV certification. fringed. (3) An applicant that submits an (ii) For each claim of a patent al- amendment or supplement to seek ap- leged to be invalid or unenforceable, a proval of a different strength must pro- full and detailed explanation of the vide notice of any paragraph IV certifi- grounds supporting the allegation. cation in accordance with paragraph (8) If the applicant alleges that the (d)(1) or (2) of this section, as applica- patent will not be infringed and the ap- ble.

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(e) Documentation of timely sending trade or business that the Agency de- and receipt of notice. The applicant termines: must amend its ANDA to provide docu- (i) Is available to the general public mentation of the date of receipt of the throughout the United States; notice required under paragraph (a) of (ii) Records electronically to its this section by each person provided database, kept in the regular course of the notice. The amendment must be its business, or marks on the cover in submitted to FDA within 30 days after which any item referred to in this sec- the last date on which notice was re- tion is to be delivered, the date on ceived by a person described in para- which such item was given to such graph (a) of this section. The appli- trade or business for delivery; and cant’s amendment also must include (iii) Provides overnight or 2-day de- documentation that its notice was sent livery service throughout the United on a date that complies with the time- States. frame required by paragraph (b) or (d) (2) FDA may periodically issue guid- of this section, as applicable, and a ance regarding designated delivery dated printout of the entry for the ref- services. erence listed drug in FDA’s ‘‘Approved [81 FR 69651, Oct. 6, 2016] Drug Products With Therapeutic Equivalence Evaluations’’ (the list) § 314.96 Amendments to an unap- that includes the patent that is the proved ANDA. subject of the paragraph IV certifi- (a) ANDA. (1) An applicant may cation. FDA will accept, as adequate amend an ANDA that is submitted documentation of the date the notice under § 314.94, but not yet approved, to was sent, a copy of the registered mail revise existing information or provide receipt, certified mail receipt, or re- additional information. Amendments ceipt from a designated delivery serv- containing bioequivalence studies must ice as defined in paragraph (g) of this contain reports of all bioequivalence section. FDA will accept as adequate studies conducted by the applicant on documentation of the date of receipt a the same drug product formulation, un- return receipt, signature proof of deliv- less the information has previously ery by a designated delivery service, or been submitted to FDA in the ANDA. A a letter acknowledging receipt by the complete study report must be sub- person provided the notice. An appli- mitted for any bioequivalence study cant may rely on another form of docu- upon which the applicant relies for ap- mentation only if FDA has agreed to proval. For all other bioequivalence such documentation in advance. A copy studies conducted on the same drug of the notice itself need not be sub- product formulation as defined in mitted to the Agency. § 314.3 of this chapter, the applicant (f) Forty-five day period after receipt of must submit either a complete or sum- notice. If the requirements of this sec- mary report. If a summary report of a tion are met, FDA will presume the no- bioequivalence study is submitted and tice to be complete and sufficient, and FDA determines that there may be bio- it will count the day following the date equivalence issues or concerns with the of receipt of the notice by the patent product, FDA may require that the ap- owner or its representative and by the plicant submit a complete report of the approved NDA holder or its attorney, bioequivalence study to FDA. agent, or other authorized official as (2) Submission of an amendment con- the first day of the 45-day period pro- taining significant data or information vided for in section 505(j)(5)(B)(iii) of before the end of the initial review the Federal Food, Drug, and Cosmetic cycle constitutes an agreement be- Act. FDA may, if the applicant pro- tween FDA and the applicant to extend vides a written statement to FDA that the initial review cycle only for the a later date should be used, count from time necessary to review the signifi- such later date. cant data or information and for no (g) Designated delivery services. (1) For more than 180 days. purposes of this section, the term (b) Field copy. The applicant must ‘‘designated delivery service’’ means submit a field copy of each amendment any delivery service provided by a under § 314.94(a)(9). The applicant, other

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than a foreign applicant, must include § 314.97 Supplements and other in its submission of each such amend- changes to an approved ANDA. ment to FDA a statement certifying (a) General requirements. The appli- that a field copy of the amendment has cant must comply with the require- been sent to the applicant’s home FDA ments of §§ 314.70 and 314.71 regarding district office. the submission of supplemental ANDAs (c) Different listed drug. An applicant and other changes to an approved may not amend an ANDA to seek ap- ANDA. proval of a drug referring to a listed (b) Different listed drug. An applicant drug that is different from the ref- may not supplement an ANDA to seek erence listed drug identified in the approval of a drug referring to a listed ANDA. This paragraph (c) applies if, at drug that is different from the current any time before the approval of the reference listed drug identified in the ANDA, a different listed drug is ap- ANDA. This paragraph (b) applies if proved that is the pharmaceutical changes are proposed in a supplement equivalent to the product in the ANDA to the ANDA such that the proposed and is designated as a reference listed product is a pharmaceutical equivalent drug. This paragraph (c) also applies if to a different listed drug than the ref- changes are proposed in an amendment erence listed drug identified in the to the ANDA such that the proposed ANDA. A change of reference listed drug must be submitted in a new product is a pharmaceutical equivalent ANDA. However, notwithstanding the to a different listed drug than the ref- limitation described in this paragraph erence listed drug identified in the (b), an applicant may supplement the ANDA. A change of the reference listed ANDA to seek approval of a different drug must be submitted in a new strength. ANDA. However, notwithstanding the limitation described in this paragraph [81 FR 69653, Oct. 6, 2016] (c), an applicant may amend the ANDA to seek approval of a different § 314.98 Postmarketing reports. strength. (a) Each applicant having an ap- (d)(1) Patent certification requirements. proved abbreviated new drug applica- An amendment to an ANDA is required tion under § 314.94 that is effective to contain an appropriate patent cer- must comply with the requirements of tification or statement described in § 314.80 regarding the reporting and rec- § 314.94(a)(12) or a recertification for a ordkeeping of adverse drug experi- previously submitted paragraph IV cer- ences. tification if approval is sought for any (b) Each applicant must make the re- of the following types of amendments: ports required under § 314.81 and section 505(k) of the Federal Food, Drug, and (i) To add a new indication or other Cosmetic Act for each of its approved condition of use; abbreviated applications. (ii) To add a new strength; (iii) To make other than minor [79 FR 33089, June 10, 2014] changes in product formulation; or § 314.99 Other responsibilities of an (iv) To change the physical form or applicant of an ANDA. crystalline structure of the active in- (a) An applicant must comply with gredient. the requirements of § 314.65 regarding (2) If the amendment to the ANDA withdrawal by the applicant of an un- does not contain a patent certification approved ANDA and § 314.72 regarding a or statement, the applicant must change in ownership of an ANDA. verify that the proposed change de- (b) An applicant may ask FDA to scribed in the amendment is not one of waive under this section any require- the types of amendments described in ment that applies to the applicant paragraph (d)(1) of this section. under §§ 314.92 through 314.99. The appli- [57 FR 17983, Apr. 28, 1992, as amended at 58 cant must comply with the require- FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999; ments for a waiver under § 314.90. If 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16, FDA grants the applicant’s waiver re- 2009; 81 FR 69652, Oct. 6, 2016] quest with respect to a requirement

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under §§ 314.92 through 314.99, the paragraph IV acknowledgment letter. waived requirement will not constitute The date of filing will be the date 60 a basis for refusal to approve an ANDA days after the date FDA received the under § 314.127. NDA. The date of filing begins the 180- 81 FR 69653, Oct. 6, 2016] day period described in section 505(c) of the Federal Food, Drug, and Cosmetic Subpart D—FDA Action on Appli- Act. This 180-day period is called the ‘‘filing clock.’’ cations and Abbreviated Ap- (3) If FDA refuses to file the NDA, plications the Agency will notify the applicant in writing and state the reason under SOURCE: 50 FR 7493, Feb. 22, 1985, unless paragraph (d) or (e) of this section for otherwise noted. Redesignated at 57 FR 17983, the refusal. If FDA refuses to file the Apr. 28, 1992. NDA under paragraph (d) of this sec- § 314.100 Timeframes for reviewing ap- tion, the applicant may request in plications and abbreviated applica- writing within 30 days of the date of tions. the Agency’s notification an informal (a) Except as provided in paragraph conference with the Agency about (c) of this section, within 180 days of whether the Agency should file the receipt of an application for a new drug NDA. If, following the informal con- under section 505(b) of the act or an ab- ference, the applicant requests that breviated application for a new drug FDA file the NDA (with or without under section 505(j) of the act, FDA amendments to correct the defi- will review it and send the applicant ei- ciencies), the Agency will file the NDA ther an approval letter under § 314.105 over protest under paragraph (a)(2) of or a complete response letter under this section, notify the applicant in § 314.110. This 180-day period is called writing, and review it as filed. If the the ‘‘initial review cycle.’’ NDA is filed over protest, the date of (b) At any time before approval, an filing will be the date 60 days after the applicant may withdraw an application date the applicant requested the infor- under § 314.65 or an abbreviated applica- mal conference. The applicant need not tion under § 314.99 and later submit it resubmit a copy of an NDA that is filed again for consideration. over protest. If FDA refuses to file the (c) The initial review cycle may be NDA under paragraph (e) of this sec- adjusted by mutual agreement between tion, the applicant may amend the FDA and an applicant or as provided in NDA and resubmit it, and the Agency §§ 314.60 and 314.96, as the result of a will make a determination under this major amendment. section whether it may be filed. [73 FR 39609, July 10, 2008] (b)(1) Receiving an ANDA. An ANDA will be evaluated after it is submitted § 314.101 Filing an NDA and receiving to determine whether the ANDA may an ANDA. be received. Receipt of an ANDA means (a) Filing an NDA. (1) Within 60 days that FDA has made a threshold deter- after FDA receives an NDA, the Agen- mination that the abbreviated applica- cy will determine whether the NDA tion is substantially complete. may be filed. The filing of an NDA (2) If FDA finds that none of the rea- means that FDA has made a threshold sons in paragraphs (d) and (e) of this determination that the NDA is suffi- section for considering the ANDA not ciently complete to permit a sub- to have been received applies, the stantive review. ANDA is substantially complete and (2) If FDA finds that none of the rea- the Agency will receive the ANDA and sons in paragraphs (d) and (e) of this notify the applicant in writing. If FDA section for refusing to file the NDA determines, upon evaluation, that an apply, the Agency will file the NDA ANDA was substantially complete as of and notify the applicant in writing. In the date it was submitted to FDA, FDA the case of a 505(b)(2) application that will consider the ANDA to have been contains a paragraph IV certification, received as of the date of submission. the applicant will be notified via a In the case of an ANDA that contains a

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paragraph IV certification, the appli- (7) The NDA or ANDA does not con- cant will be notified via a paragraph IV tain a statement for each clinical acknowledgment letter. study that the study was conducted in (3) If FDA considers the ANDA not to compliance with the institutional re- have been received under paragraph (d) view board regulations in part 56 of or (e) of this section, FDA will notify this chapter, or was not subject to the applicant of the refuse-to-receive those regulations, and that it was con- decision. The applicant may then: ducted in compliance with the in- (i) Withdraw the ANDA under § 314.99; formed consent regulations in part 50 or of this chapter, or, if the study was (ii) Correct the deficiencies and re- subject to but was not conducted in submit the ANDA; or compliance with those regulations, the (iii) Take no action, in which case NDA or ANDA does not contain a brief FDA may consider the ANDA with- statement of the reason for the non- drawn after 1 year. compliance. (8) The drug product that is the sub- (c) [Reserved] ject of the submission is already cov- (d) NDA or ANDA deficiencies. FDA ered by an approved NDA or ANDA and may refuse to file an NDA or may not the applicant of the submission: consider an ANDA to be received if any (i) Has an approved NDA or ANDA for of the following applies: the same drug product; or (1) The NDA or ANDA does not con- (ii) Is merely a distributor and/or retain a completed application form. packager of the already approved drug (2) The NDA or ANDA is not sub- product. mitted in the form required under (9) The NDA is submitted as a § 314.50 or § 314.94. 505(b)(2) application for a drug that is a (3) The NDA or ANDA is incomplete duplicate of a listed drug and is eligible because it does not on its face contain for approval under section 505(j) of the information required under section Federal Food, Drug, and Cosmetic Act. 505(b) or section 505(j) of the Federal (e) Regulatory deficiencies. The Agen- Food, Drug, and Cosmetic Act and cy will refuse to file an NDA or will § 314.50 or § 314.94. In determining consider an ANDA not to have been re- whether an ANDA is incomplete on its ceived if any of the following applies: face, FDA will consider the nature (1) The drug product is subject to li- (e.g., major or minor) of the defi- censing by FDA under the Public ciencies, including the number of defi- Health Service Act (42 U.S.C. 201 et ciencies in the ANDA. seq.) and subchapter F of this chapter. (4) The applicant fails to submit a (2) Submission of a 505(b)(2) applica- complete environmental assessment, tion or an ANDA is not permitted which addresses each of the items spec- under section 505(c)(3)(E)(ii), ified in the applicable format under 505(j)(5)(F)(ii), 505A(b)(1)(A)(i)(I), § 25.40 of this chapter or fails to provide 505A(c)(1)(A)(i)(I), or 505E(a) of the Fed- sufficient information to establish that eral Food, Drug, and Cosmetic Act. the requested action is subject to cat- (f) Outcome of FDA review. (1) Within egorical exclusion under § 25.30 or § 25.31 180 days after the date of filing, plus of this chapter. the period of time the review period (5) The NDA or ANDA does not con- was extended (if any), FDA will either: tain an accurate and complete English (i) Approve the NDA; or translation of each part of the NDA or (ii) Issue a notice of opportunity for ANDA that is not in English. a hearing if the applicant asked FDA (6) The NDA or ANDA does not con- to provide it an opportunity for a hear- tain a statement for each nonclinical ing on an NDA in response to a com- laboratory study that the study was plete response letter. conducted in compliance with the re- (2) Within 180 days after the date of quirements set forth in part 58 of this receipt, plus the period of time the re- chapter, or, for each study not con- view clock was extended (if any), FDA ducted in compliance with part 58 of will either approve or disapprove the this chapter, a brief statement of the ANDA. If FDA disapproves the ANDA, reason for the noncompliance. FDA will issue a notice of opportunity

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for hearing if the applicant asked FDA (c) Ninety-day conference. Approxi- to provide it an opportunity for a hear- mately 90 days after the agency re- ing on an ANDA in response to a com- ceives the application, FDA will pro- plete response letter. vide applicants with an opportunity to (3) This paragraph (f) does not apply meet with agency reviewing officials. to NDAs or ANDAs that have been The purpose of the meeting will be to withdrawn from FDA review by the ap- inform applicants of the general plicant. progress and status of their applica- [81 FR 69653, Oct. 6, 2016] tions, and to advise applicants of deficiencies that have been identified by § 314.102 Communications between that time and that have not already FDA and applicants. been communicated. This meeting will (a) General principles. During the be available on applications for all new course of reviewing an application or chemical entities and major new indian abbreviated application, FDA shall cations of marketed drugs. Such meet- communicate with applicants about ings will be held at the applicant’s op- scientific, medical, and procedural tion, and may be held by telephone if issues that arise during the review mutually agreed upon. Such meetings process. Such communication may take the form of telephone conversa- would not ordinarily be held on abbre- tions, letters, or meetings, whichever viated applications because they are is most appropriate to discuss the par- not submitted for new chemical enti- ticular issue at hand. Communications ties or new indications. shall be appropriately documented in (d) End-of-review conference. At the the application in accordance with conclusion of FDA’s review of an NDA § 10.65 of this chapter. Further details as designated by the issuance of a com- on the procedures for communication plete response letter, FDA will provide between FDA and applicants are con- the applicant with an opportunity to tained in a staff manual guide that is meet with agency reviewing officials. publicly available. The purpose of the meeting will be to (b) Notification of easily correctable de- discuss what further steps need to be ficiencies. FDA reviewers shall make taken by the applicant before the ap- every reasonable effort to commu- plication can be approved. Requests for nicate promptly to applicants easily such meetings must be directed to the correctable deficiencies found in an ap- director of the division responsible for plication or an abbreviated application reviewing the application. when those deficiencies are discovered, particularly deficiencies concerning (e) Other meetings. Other meetings be- chemistry, manufacturing, and con- tween FDA and applicants may be held, trols issues. The agency will also in- with advance notice, to discuss sci- form applicants promptly of its need entific, medical, and other issues that for more data or information or for arise during the review process. Re- technical changes in the application or quests for meetings shall be directed to the abbreviated application needed to the director of the division responsible facilitate the agency’s review. This for reviewing the application or abbre- early communication is intended to viated application. FDA will make permit applicants to correct such read- every attempt to grant requests for ily identified deficiencies relatively meetings that involve important issues early in the review process and to sub- and that can be scheduled at mutually mit an amendment before the review convenient times. However, ‘‘drop-in’’ period has elapsed. Such early commu- visits (i.e., an unannounced and un- nication would not ordinarily apply to scheduled visit by a company rep- major scientific issues, which require resentative) are discouraged except for consideration of the entire pending ap- urgent matters, such as to discuss an plication or abbreviated application by important new safety issue. agency managers as well as reviewing staff. Instead, major scientific issues [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July will ordinarily be addressed in a com- 1, 1992, as amended at 73 FR 39609, July 10, plete response letter. 2008]

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§ 314.103 Dispute resolution. with the Center Director if the matter (a) General. FDA is committed to re- is still unresolved. Requests for such solving differences between applicants meetings shall be directed to the direc- and FDA reviewing divisions with re- tor of the division responsible for respect to technical requirements for ap- viewing the application or abrreviated plications or abbreviated applications application. FDA will make every at- as quickly and amicably as possible tempt to grant requests for meetings through the cooperative exchange of that involve important issues and that information and views. can be scheduled at mutually conven- (b) Administrative and procedural ient times. issues. When administrative or proce- (3) In requesting a meeting designed dural disputes arise, the applicant to resolve a scientific or medical dis- should first attempt to resolve the pute, applicants may suggest that FDA matter with the division responsible seek the advice of outside experts, in for reviewing the application or abbre- which case FDA may, in its discretion, viated application, beginning with the invite to the meeting one or more of its consumer safety officer assigned to the advisory committee members or other application or abbreviated application. consultants, as designated by the agen- If resolution is not achieved, the appli- cy. Applicants may also bring their cant may raise the matter with the own consultants. For major scientific person designated as ombudsman, and medical policy issues not resolved whose function shall be to investigate by informal meetings, FDA may refer what has happened and to facilitate a the matter to one of its standing advi- timely and equitable resolution. Appro- sory committees for its consideration priate issues to raise with the ombuds- and recommendations. man include resolving difficulties in [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, scheduling meetings, obtaining timely 1985, as amended at 57 FR 17989, Apr. 28, 1992; replies to inquiries, and obtaining 73 FR 39609, July 10, 2008] timely completion of pending reviews. Further details on this procedure are § 314.104 Drugs with potential for abuse. contained in a staff manual guide that is publicly available under FDA’s pub- The Food and Drug Administration lic information regulations in part 20. will inform the Drug Enforcement Ad- (c) Scientific and medical disputes. (1) ministration under section 201(f) of the Because major scientific issues are or- Controlled Substances Act (21 U.S.C. dinarily communicated to applicants 801) when an application or abbreviated in a complete response letter pursuant application is submitted for a drug to § 314.110, the ‘‘end-of-review con- that appears to have an abuse poten- ference’’ described in § 314.102(d) will tial. provide a timely forum for discussing [57 FR 17989, Apr. 28, 1992] and resolving, if possible, scientific and medical issues on which the applicant § 314.105 Approval of an NDA and an disagrees with the agency. In addition, ANDA. the ‘‘ninety-day conference’’ described (a) FDA will approve an NDA and in § 314.102(c) will provide a timely send the applicant an approval letter if forum for discussing and resolving, if none of the reasons in § 314.125 for re- possible, issues identified by that date. fusing to approve the NDA applies. (2) When scientific or medical dis- FDA will issue a tentative approval putes arise at other times during the letter if an NDA otherwise meets the review process, applicants should dis- requirements for approval under the cuss the matter directly with the re- Federal Food, Drug, and Cosmetic Act, sponsible reviewing officials. If nec- but cannot be approved because there essary, applicants may request a meet- is a 7-year period of orphan exclusivity ing with the appropriate reviewing offi- for the listed drug under section 527 of cials and management representatives the Federal Food, Drug, and Cosmetic in order to seek a resolution. Ordi- Act and § 316.31 of this chapter, or if a narily, such meetings would be held 505(b)(2) application otherwise meets first with the Division Director, then the requirements for approval under with the Office Director, and finally the Federal Food, Drug, and Cosmetic

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Act, but cannot be approved until the the statutory standards. FDA makes conditions in § 314.107(b)(3) are met; be- its views on drug products and classes cause there is a period of exclusivity of drugs available through guidance for the listed drug under § 314.108; be- documents, recommendations, and cause there is a period of pediatric ex- other statements of policy. clusivity for the listed drug under sec- (d) FDA will approve an ANDA and tion 505A of the Federal Food, Drug, send the applicant an approval letter if and Cosmetic Act; or because there is a none of the reasons in § 314.127 for re- period of exclusivity for the listed drug fusing to approve the ANDA applies. under section 505E of the Federal Food, FDA will issue a tentative approval Drug, and Cosmetic Act. A drug prod- letter if an ANDA otherwise meets the uct that is granted tentative approval requirements for approval under the is not an approved drug and will not be Federal Food, Drug, and Cosmetic Act, approved until FDA issues an approval but cannot be approved because there after any necessary additional review is a 7-year period of orphan exclusivity of the NDA. FDA’s tentative approval for the listed drug under section 527 of of a drug product is based on informa- the Federal Food, Drug, and Cosmetic tion available to FDA at the time of Act and § 316.31 of this chapter, or can- the tentative approval letter (i.e., in- not be approved until the conditions in formation in the 505(b)(2) application § 314.107(b)(3) or (c) are met; because and the status of current good manu- there is a period of exclusivity for the facturing practices of the facilities listed drug under § 314.108; because used in the manufacturing and testing there is a period of pediatric exclu- of the drug product) and is therefore sivity for the listed drug under section subject to change on the basis of new 505A of the Federal Food, Drug, and information that may come to FDA’s Cosmetic Act; or because there is a pe- attention. A new drug product may not riod of exclusivity for the listed drug be marketed until the date of approval. under section 505E of the Federal Food, (b) FDA will approve an NDA and Drug, and Cosmetic Act. A drug prod- issue the applicant an approval letter uct that is granted tentative approval on the basis of draft labeling if the is not an approved drug and will not be only deficiencies in the NDA concern approved until FDA issues an approval editorial or similar minor deficiencies after any necessary additional review in the draft labeling. Such approval of the ANDA. FDA’s tentative approval will be conditioned upon the applicant of a drug product is based on informa- incorporating the specified labeling tion available to FDA at the time of changes exactly as directed, and upon the tentative approval letter (i.e., in- the applicant submitting to FDA a formation in the ANDA and the status copy of the final printed labeling prior of current good manufacturing practices of the facilities used in the manu- to marketing. facturing and testing of the drug prod- (c) FDA will approve an NDA after it uct) and is therefore subject to change determines that the drug meets the on the basis of new information that statutory standards for safety and ef- may come to FDA’s attention. A new fectiveness, manufacturing and con- drug product may not be marketed trols, and labeling, and an ANDA after until the date of approval. it determines that the drug meets the statutory standards for manufacturing [81 FR 69654, Oct. 6, 2016] and controls, labeling, and, where applicable, bioequivalence. While the § 314.106 Foreign data. statutory standards apply to all drugs, (a) General. The acceptance of foreign the many kinds of drugs that are sub- data in an application generally is gov- ject to the statutory standards and the erned by § 312.120 of this chapter. wide range of uses for those drugs de- (b) As sole basis for marketing approval. mand flexibility in applying the stand- An application based solely on foreign ards. Thus FDA is required to exercise clinical data meeting U.S. criteria for its scientific judgment to determine marketing approval may be approved the kind and quantity of data and in- if: (1) The foreign data are applicable formation an applicant is required to to the U.S. population and U.S. med- provide for a particular drug to meet ical practice; (2) the studies have been

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performed by clinical investigators of and none of the reasons in paragraph recognized competence; and (3) the (d) of this section for delaying approval data may be considered valid without applies, the 505(b)(2) application or the need for an on-site inspection by ANDA may be approved as follows: FDA or, if FDA considers such an in- (i) Immediately, if the applicant cer- spection to be necessary, FDA is able tifies under § 314.50(i) or § 314.94(a)(12) to validate the data through an on-site that: inspection or other appropriate means. (A) The applicant is aware of a rel- Failure of an application to meet any evant patent but the patent informa- of these criteria will result in the ap- tion required under section 505(b) or (c) plication not being approvable based on of the Federal Food, Drug, and Cos- the foreign data alone. FDA will apply metic Act has not been submitted to this policy in a flexible manner accord- FDA; or ing to the nature of the drug and the (B) The relevant patent has expired; data being considered. or (c) Consultation between FDA and ap- (C) The relevant patent is invalid, plicants. Applicants are encouraged to unenforceable, or will not be infringed, meet with agency officials in a ‘‘pre- except as provided in paragraphs (b)(3) submission’’ meeting when approval and (c) of this section, and the 45-day based solely on foreign data will be period provided for in section sought. 505(c)(3)(C) and (j)(5)(B)(iii) of the Fed- [50 FR 7493, Feb. 22, 1985, as amended at 55 eral Food, Drug, and Cosmetic Act has FR 11580, Mar. 29, 1990] expired; or (D) There are no relevant patents. § 314.107 Date of approval of a (ii) Immediately, if the applicant 505(b)(2) application or ANDA. submits an appropriate statement (a) General. A drug product may be under § 314.50(i) or § 314.94(a)(12) explain- introduced or delivered for introduc- ing that a method-of-use patent does tion into interstate commerce when not claim an indication or other condi- the 505(b)(2) application or ANDA for tion of use for which the applicant is the drug product is approved. A seeking approval, except that if the ap- 505(b)(2) application or ANDA for a plicant also submits a paragraph IV drug product is approved on the date certification to the patent, then the FDA issues an approval letter under 505(b)(2) application or ANDA may be § 314.105 for the 505(b)(2) application or approved as provided in paragraph ANDA. (b)(1)(i)(C) of this section. (b) Effect of patent(s) on the listed (iii) On the date specified, if the ap- drug. As described in paragraphs (b)(1) plicant certifies under § 314.50(i) or and (2) of this section, the status of § 314.94(a)(12) that the relevant patent patents listed for the listed drug(s) re- will expire on a specified date. lied upon or reference listed drug, as (2) Patent information filed after sub- applicable, must be considered in de- mission of 505(b)(2) application or ANDA. termining the first possible date on If the holder of the approved NDA for which a 505(b)(2) application or ANDA the listed drug submits patent informa- can be approved. The criteria in para- tion required under § 314.53 after the graphs (b)(1) and (2) of this section will date on which the 505(b)(2) application be used to determine, for each relevant or ANDA was submitted to FDA, the patent, the date that patent will no 505(b)(2) applicant or ANDA applicant longer prevent approval. The first pos- must comply with the requirements of sible date on which the 505(b)(2) appli- § 314.50(i)(4) and (6) and § 314.94(a)(12)(vi) cation or ANDA can be approved will and (viii) regarding submission of an be calculated for each patent, and the appropriate patent certification or 505(b)(2) application or ANDA may be statement. If the applicant submits an approved on the last applicable date. amendment certifying under (1) Timing of approval based on patent § 314.50(i)(1)(i)(A)(4) or certification or statement. If none of the § 314.94(a)(12)(i)(A)(4) that the relevant reasons in § 314.125 or § 314.127, as appli- patent is invalid, unenforceable, or will cable, for refusing to approve the not be infringed, and complies with the 505(b)(2) application or ANDA applies, requirements of § 314.52 or § 314.95, the

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505(b)(2) application or ANDA may be applicable, the district court decides approved immediately upon submission that the patent is invalid, unenforce- of documentation of receipt of notice able, or not infringed (including any of paragraph IV certification under substantive determination that there § 314.52(e) or § 314.95(e). The 45-day pe- is no cause of action for patent in- riod provided for in section 505(c)(3)(C) fringement or invalidity), the 505(b)(2) and (j)(5)(B)(iii) of the Federal Food, application or ANDA may be approved Drug, and Cosmetic Act does not apply on: in these circumstances. (A) The date on which the court en- (3) Disposition of patent litigation—(i) ters judgment reflecting the decision; Approval upon expiration of 30-month pe- or riod or 71⁄2 years from date of listed drug (B) The date of a settlement order or approval. (A) Except as provided in consent decree signed and entered by paragraphs (b)(3)(ii) through (viii) of the court stating that the patent that this section, if, with respect to patents is the subject of the certification is infor which required information was valid, unenforceable, or not infringed. submitted under § 314.53 before the date (iii) Appeal of Federal district court on which the 505(b)(2) application or judgment of infringement. If before the ANDA was submitted to FDA (exclud- expiration of the 30-month period, or ing an amendment or supplement to 71⁄2 years where applicable, the district the 505(b)(2) application or ANDA), the court decides that the patent has been applicant certifies under § 314.50(i) or infringed, and if the judgment of the § 314.94(a)(12) that the relevant patent district court is appealed, the 505(b)(2) is invalid, unenforceable, or will not be application or ANDA may be approved infringed, and the patent owner or its on: representative or the exclusive patent (A) The date on which the mandate is licensee brings suit for patent infringe- issued by the court of appeals entering ment within 45 days of receipt of the judgment that the patent is invalid, notice of certification from the appli- unenforceable, or not infringed (includ- cant under § 314.52 or § 314.95, the ing any substantive determination that 505(b)(2) application or ANDA may be there is no cause of action for patent approved 30 months after the later of infringement or invalidity); or the date of the receipt of the notice of (B) The date of a settlement order or certification by any owner of the listed consent decree signed and entered by patent or by the NDA holder (or its the court of appeals stating that the representative(s)) unless the court has patent that is the subject of the certifi- extended or reduced the period because cation is invalid, unenforceable, or not of a failure of either the plaintiff or de- infringed. fendant to cooperate reasonably in ex- (iv) Affirmation or non-appeal of Fed- pediting the action; or eral district court judgment of infringe- (B) If the patented drug product ment. If before the expiration of the 30- qualifies for 5 years of exclusive mar- month period, or 71⁄2 years where appli- keting under § 314.108(b)(2) and the pat- cable, the district court decides that ent owner or its representative or the the patent has been infringed, and if exclusive patent licensee brings suit the judgment of the district court is for patent infringement during the 1- not appealed or is affirmed, the year period beginning 4 years after the 505(b)(2) application or ANDA may be date of approval of the patented drug approved no earlier than the date spec- and within 45 days of receipt of the no- ified by the district court in an order tice of certification from the applicant under 35 U.S.C. 271(e)(4)(A). under § 314.52 or § 314.95, the 505(b)(2) ap- (v) Grant of preliminary injunction by plication or ANDA may be approved at Federal district court. If before the expi- the expiration of the 71⁄2 years from the ration of the 30-month period, or 71⁄2 date of approval of the NDA for the years where applicable, the district patented drug product. court grants a preliminary injunction (ii) Federal district court decision of in- prohibiting the applicant from engag- validity, unenforceability, or non-in- ing in the commercial manufacture or fringement. If before the expiration of sale of the drug product until the court the 30-month period, or 71⁄2 years where decides the issues of patent validity

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and infringement, and if the court later in an approval under paragraph (b)(3) of decides that: this section. (A) The patent is invalid, unenforce- (c) Timing of approval of subsequent able, or not infringed, the 505(b)(2) ap- ANDA. (1) If an ANDA contains a para- plication or ANDA may be approved as graph IV certification for a relevant provided in paragraph (b)(3)(ii) of this patent and the ANDA is not that of a section; or first applicant, the ANDA is regarded (B) The patent is infringed, the as the ANDA of a subsequent applicant. 505(b)(2) application or ANDA may be The ANDA of a subsequent applicant approved as provided in paragraph will not be approved during the period (b)(3)(iii) or (iv) of this section, which- when any first applicant is eligible for ever is applicable. 180-day exclusivity or during the 180- (vi) Written consent to approval by pat- day exclusivity period of a first appli- ent owner or exclusive patent licensee. If cant. Any applicable 180-day exclu- before the expiration of the 30-month sivity period cannot extend beyond the period, or 71⁄2 years where applicable, expiration of the patent upon which the patent owner or the exclusive pat- the 180-day exclusivity period was ent licensee (or their representatives) based. agrees in writing that the 505(b)(2) ap- (2) A first applicant must submit cor- plication or ANDA may be approved respondence to its ANDA notifying any time on or after the date of the FDA within 30 days of the date of its consent, approval may be granted on or first commercial marketing of its drug after that date. product or the reference listed drug. If (vii) Court order terminating 30-month an applicant does not notify FDA, as or 71⁄2-year period. If before the expira- required in this paragraph (c)(2), of this tion of the 30-month period, or 71⁄2 date, the date of first commercial mar- years where applicable, the court en- keting will be deemed to be the date of ters an order requiring the 30-month or the drug product’s approval. 71⁄2-year period to be terminated, the (3) If FDA concludes that a first ap- 505(b)(2) application or ANDA may be plicant is not actively pursuing ap- approved in accordance with the proval of its ANDA, FDA may imme- court’s order. diately approve an ANDA(s) of a subse- (viii) Court order of dismissal without a quent applicant(s) if the ANDA(s) is finding of infringement. If before the ex- otherwise eligible for approval. piration of the 30-month period, or 71⁄2 (d) Delay due to exclusivity. The Agen- years where applicable, the court(s) cy will also delay the approval of a enter(s) an order of dismissal, with or 505(b)(2) application or ANDA if delay without prejudice, without a finding of is required by the exclusivity provi- infringement in each pending suit for sions in § 314.108; section 527 of the Fed- patent infringement brought within 45 eral Food, Drug, and Cosmetic Act and days of receipt of the notice of para- § 316.31 of this chapter; section 505A of graph IV certification sent by the the Federal Food, Drug, and Cosmetic 505(b)(2) or ANDA applicant, the Act; or section 505E of the Federal 505(b)(2) application or ANDA may be Food, Drug, and Cosmetic Act. When approved on or after the date of the the approval of a 505(b)(2) application order. or ANDA is delayed under this section (4) Tentative approval. FDA will issue and § 314.108; section 527 of the Federal a tentative approval letter when ten- Food, Drug, and Cosmetic Act and tative approval is appropriate in ac- § 316.31 of this chapter; section 505A of cordance with this section. In order for the Federal Food, Drug, and Cosmetic a 505(b)(2) application or ANDA to be Act; or section 505E of the Federal approved under paragraph (b)(3) of this Food, Drug, and Cosmetic Act, the section, the applicant must receive an 505(b)(2) application or ANDA will be approval letter from the Agency. Ten- approved on the latest of the days spec- tative approval of an NDA or ANDA ified under this section and § 314.108; does not constitute ‘‘approval’’ of an section 527 of the Federal Food, Drug, NDA or ANDA and cannot, absent an and Cosmetic Act and § 316.31 of this approval letter from the Agency, result chapter; section 505A of the Federal

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Food, Drug, and Cosmetic Act; or sec- ceipt of the applicant’s notice of para- tion 505E of the Federal Food, Drug, graph IV certification by the recipient. and Cosmetic Act, as applicable. When the 45th day falls on Saturday, (e) Notification of court actions or writ- Sunday, or a Federal holiday, the 45th ten consent to approval. (1) The appli- day will be the next day that is not a cant must submit the following infor- Saturday, Sunday, or a Federal holi- mation to FDA, as applicable: day. (i) A copy of any judgment by the (2) Notification of filing of legal action. court (district court or mandate of the (i) The 505(b)(2) or ANDA applicant court of appeals) or settlement order or must notify FDA in writing within 14 consent decree signed and entered by days of the filing of any legal action the court (district court or court of ap- filed within 45 days of receipt of the no- peals) finding a patent described in tice of paragraph IV certification by paragraph (b)(3) of this section invalid, any recipient. A 505(b)(2) applicant unenforceable, or not infringed, or find- must send the notification to its NDA. ing the patent valid and infringed; An ANDA applicant must send the no- (ii) Written notification of whether tification to its ANDA. The notifica- or not any action by the court de- tion to FDA of the legal action must scribed in paragraph (e)(1)(i) of this include: section has been appealed within the (A) The 505(b)(2) application or ANDA time permitted for an appeal; number. (iii) A copy of any order entered by (B) The name of the 505(b)(2) or the court terminating the 30-month or ANDA applicant. 71⁄2-year period as described in paragraph (b)(3)(i), (ii), (vii), or (viii) of this (C) The established name of the drug section; product or, if no established name ex- (iv) A copy of any written consent to ists, the name(s) of the active ingre- approval by the patent owner or exclu- dient(s), the drug product’s strength, sive patent licensee described in para- and dosage form. graph (b)(3)(vi) of this section; (D) A statement that an action for (v) A copy of any preliminary injunc- patent infringement, identified by tion described in paragraph (b)(3)(v) of court, case number, and the patent this section, and a copy of any subse- number(s) of the patent(s) at issue in quent court order lifting the injunc- the action, has been filed in an appro- tion; and priate court on a specified date. (vi) A copy of any court order pursu- (ii) A patent owner or NDA holder (or ant to 35 U.S.C. 271(e)(4)(A) ordering its representative(s)) may also notify that a 505(b)(2) application or ANDA FDA of the filing of any legal action may be approved no earlier than the for patent infringement. The notice date specified (irrespective of whether should contain the information and be the injunction relates to a patent de- sent to the offices or divisions described in paragraph (b)(3) of this sec- scribed in paragraph (f)(2)(i) of this section). tion. (2) All information required by para- (iii) If the 505(b)(2) or ANDA appli- graph (e)(1) of this section must be sent cant, the patent owner(s), the NDA to the applicant’s NDA or ANDA, as ap- holder, or its representative(s) does not propriate, within 14 days of the date of notify FDA in writing before the expi- entry by the court, the date of appeal ration of the 45-day time period or the or expiration of the time for appeal, or completion of the Agency’s review of the date of written consent to ap- the 505(b)(2) application or ANDA, proval, as applicable. whichever occurs later, that a legal ac- (f) Forty-five day period after receipt of tion for patent infringement was filed notice of paragraph IV certification—(1) within 45 days of receipt of the notice Computation of 45-day time clock. The 45- of paragraph IV certification, the day clock described in paragraph (b)(3) 505(b)(2) application or ANDA may be of this section as to each recipient re- approved upon expiration of the 45-day quired to receive notice of paragraph period (if the 505(b)(2) or ANDA appli- IV certification under § 314.52 or § 314.95 cant confirms that a legal action for begins on the day after the date of re- patent infringement has not been filed)

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or upon completion of the Agency’s re- Clinical investigation means any ex- view of the 505(b)(2) application or periment other than a bioavailability ANDA, whichever is later. study in which a drug is administered (3) Waiver. If the patent owner or or dispensed to, or used on, human sub- NDA holder who is an exclusive patent jects. licensee (or its representative(s)) Conducted or sponsored by the appli- waives its opportunity to file a legal cant with regard to an investigation action for patent infringement within means that before or during the inves- 45 days of a receipt of the notice of cer- tigation, the applicant was named in tification and the patent owner or NDA Form FDA–1571 filed with FDA as the holder who is an exclusive patent li- sponsor of the investigational new drug censee (or its representative(s)) sub- application under which the investiga- mits to FDA a valid waiver before the tion was conducted, or the applicant or 45 days elapse, the 505(b)(2) application the applicant’s predecessor in interest, or ANDA may be approved upon com- provided substantial support for the in- pletion of the Agency’s review of the vestigation. To demonstrate ‘‘substan- NDA or ANDA. FDA will only accept a tial support,’’ an applicant must either waiver in the following form: provide a certified statement from a certified public accountant that the ap- (Name of patent owner or NDA holder who is plicant provided 50 percent or more of an exclusive patent licensee or its representative(s)) has received notice from (name of ap- the cost of conducting the study or plicant) under (section 505(b)(3) or 505(j)(2)(B) provide an explanation why FDA of the Federal Food, Drug, and Cosmetic Act) should consider the applicant to have and does not intend to file an action for pat- conducted or sponsored the study if the ent infringement against (name of applicant) applicant’s financial contribution to concerning the drug (name of drug) before the study is less than 50 percent or the (date on which 45 days elapse). (Name of patent applicant did not sponsor the inves- owner or NDA holder who is an exclusive patent tigational new drug. A predecessor in licensee) waives the opportunity provided by (section 505(c)(3)(C) or 505(j)(5)(B)(iii) of the interest is an entity, e.g., a corpora- Federal Food, Drug, and Cosmetic Act) and tion, that the applicant has taken over, does not object to FDA’s approval of (name of merged with, or purchased, or from applicant)’s (505(b)(2) application or ANDA) for which the applicant has purchased all (name of drug) with an approval date on or rights to the drug. Purchase of non- after the date of this submission. exclusive rights to a clinical investiga- (g) Conversion of approval to tentative tion after it is completed is not suffi- approval. If FDA issues an approval let- cient to satisfy this definition. ter in error or a court enters an order Essential to approval means, with re- requiring, in the case of an already ap- gard to an investigation, that there are proved 505(b)(2) application or ANDA, no other data available that could sup- that the date of approval be delayed, port approval of the NDA. FDA will convert the approval to a ten- New chemical entity means a drug that tative approval if appropriate. contains no active moiety that has been approved by FDA in any other [81 FR 69655, Oct. 6, 2016] NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic § 314.108 New drug product exclu- Act. sivity. New clinical investigation means an in- (a) Definitions. The definitions in vestigation in humans the results of § 314.3 and the following definitions of which have not been relied on by FDA terms apply to this section: to demonstrate substantial evidence of Approved under section 505(b) means effectiveness of a previously approved an NDA submitted under section 505(b) drug product for any indication or of and approved on or after October 10, safety for a new patient population and 1962, or an application that was do not duplicate the results of another ‘‘deemed approved’’ under section investigation that was relied on by the 107(c)(2) of Public Law 87–781. agency to demonstrate the effective- Bioavailability study means a study to ness or safety in a new patient popu- determine the bioavailability or the lation of a previously approved drug pharmacokinetics of a drug. product. For purposes of this section,

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data from a clinical investigation pre- tial to approval of the application, for viously submitted for use in the com- a period of 3 years after the date of ap- prehensive evaluation of the safety of a proval of the application, the Agency drug product but not to support the ef- will not approve a 505(b)(2) application fectiveness of the drug product would or an ANDA for the conditions of ap- be considered new. proval of the NDA, or an ANDA sub- (b) Submission of and timing of ap- mitted pursuant to an approved peti- proval of a 505(b)(2) application or ANDA. tion under section 505(j)(2)(C) of the (1) [Reserved] Federal Food, Drug, and Cosmetic Act (2) If a drug product that contains a that relies on the information sup- new chemical entity was approved porting the conditions of approval of after September 24, 1984, in an NDA an original NDA. submitted under section 505(b) of the (5) If a supplemental NDA: Federal Food, Drug, and Cosmetic Act, (i) Was approved after September 24, no person may submit a 505(b)(2) appli- 1984; and cation or ANDA under section 505(j) of (ii) Contained reports of new clinical the Federal Food, Drug, and Cosmetic investigations (other than bio- Act for a drug product that contains availability studies) that were con- the same active moiety as in the new ducted or sponsored by the applicant chemical entity for a period of 5 years that were essential to approval of the from the date of approval of the first supplemental NDA, for a period of 3 approved NDA, except that the 505(b)(2) years after the date of approval of the application or ANDA may be submitted supplemental application, the Agency after 4 years if it contains a certifi- will not approve a 505(b)(2) application cation of patent invalidity or non- or an ANDA for a change, or an ANDA infringement described in submitted pursuant to an approved pe- § 314.50(i)(1)(i)(A)(4) or tition under section 505(j)(2)(C) of the § 314.94(a)(12)(i)(A)(4). Federal Food, Drug, and Cosmetic Act (3) The approval of a 505(b)(2) applica- that relies on the information sup- tion or ANDA described in paragraph porting a change approved in the sup- (b)(2) of this section will occur as pro- plemental NDA. vided in § 314.107(b)(1) or (2), unless the owner of a patent that claims the drug, [59 FR 50368, Oct. 3, 1994, as amended at 81 FR the patent owner’s representative, or 69657, Oct. 6, 2016] exclusive licensee brings suit for patent infringement against the applicant § 314.110 Complete response letter to the applicant. during the 1-year period beginning 48 months after the date of approval of (a) Complete response letter. FDA will the NDA for the new chemical entity send the applicant a complete response and within 45 days after receipt of the letter if the agency determines that we notice described at § 314.52 or § 314.95, in will not approve the application or ab- which case, approval of the 505(b)(2) ap- breviated application in its present plication or ANDA will occur as pro- form for one or more of the reasons vided in § 314.107(b)(3). given in § 314.125 or § 314.127, respec- (4) If an NDA: tively. (i) Was submitted under section (1) Description of specific deficiencies. A 505(b) of the Federal Food, Drug, and complete response letter will describe Cosmetic Act; all of the specific deficiencies that the (ii) Was approved after September 24, agency has identified in an application 1984; or abbreviated application, except as (iii) Was for a drug product that con- stated in paragraph (a)(3) of this sec- tains an active moiety that has been tion. previously approved in another NDA (2) Complete review of data. A com- under section 505(b) of the Federal plete response letter reflects FDA’s Food, Drug, and Cosmetic Act; and complete review of the data submitted (iv) Contained reports of new clinical in an original application or abbre- investigations (other than bio- viated application (or, where appro- availability studies) conducted or spon- priate, a resubmission) and any amend- sored by the applicant that were essen- ments that the agency has reviewed.

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The complete response letter will iden- new review cycle beginning on the date tify any amendments that the agency FDA receives the resubmission. has not yet reviewed. (2) Withdrawal. Withdraw the applica- (3) Inadequate data. If FDA deter- tion or abbreviated application. A deci- mines, after an application is filed or sion to withdraw an application or ab- an abbreviated application is received, breviated application is without preju- that the data submitted are inadequate dice to a subsequent submission. to support approval, the agency might (3) Request opportunity for hearing. issue a complete response letter with- Ask the agency to provide the appli- out first conducting required inspec- cant an opportunity for a hearing on tions and/or reviewing proposed prod- the question of whether there are uct labeling. grounds for denying approval of the ap- (4) Recommendation of actions for application or abbreviated application proval. When possible, a complete re- under section 505(d) or (j)(4) of the act, sponse letter will recommend actions respectively. The applicant must sub- that the applicant might take to place mit the request to the Associate Direc- the application or abbreviated applicator for Policy, Center for Drug Evalua- tion in condition for approval. tion and Research, Food and Drug Ad- (b) Applicant actions. After receiving ministration, 10903 New Hampshire a complete response letter, the appli- Ave., Silver Spring, MD 20993. Within cant must take one of following ac- 60 days of the date of the request for an tions: opportunity for a hearing, or within a (1) Resubmission. Resubmit the appli- different time period to which FDA and cation or abbreviated application, ad- the applicant agree, the agency will ei- dressing all deficiencies identified in the complete response letter. ther approve the application or abbre- (i) A resubmission of an application viated application under § 314.105, or or efficacy supplement that FDA clas- refuse to approve the application under sifies as a Class 1 resubmission con- § 314.125 or abbreviated application stitutes an agreement by the applicant under § 314.127 and give the applicant to start a new 2-month review cycle be- written notice of an opportunity for a ginning on the date FDA receives the hearing under § 314.200 and section resubmission. 505(c)(1)(B) or (j)(5)(c) of the act on the (ii) A resubmission of an application question of whether there are grounds or efficacy supplement that FDA clas- for denying approval of the application sifies as a Class 2 resubmission con- or abbreviated application under sec- stitutes an agreement by the applicant tion 505(d) or (j)(4) of the act, respec- to start a new 6-month review cycle be- tively. ginning on the date FDA receives the (c) Failure to take action. (1) An appli- resubmission. cant agrees to extend the review period (iii) A resubmission of an NDA sup- under section 505(c)(1) or (j)(5)(A) of the plement other than an efficacy supple- act until it takes any of the actions ment constitutes an agreement by the listed in paragraph (b) of this section. applicant to start a new review cycle For an application or abbreviated ap- the same length as the initial review plication, FDA may consider an appli- cycle for the supplement (excluding cant’s failure to take any of such ac- any extension due to a major amend- tions within 1 year after issuance of a ment of the initial supplement), begin- complete response letter to be a re- ning on the date FDA receives the request by the applicant to withdraw the submission. application, unless the applicant has (iv) A major resubmission of an ab- requested an extension of time in breviated application constitutes an which to resubmit the application. agreement by the applicant to start a FDA will grant any reasonable request new 6-month review cycle beginning on for such an extension. FDA may con- the date FDA receives the resubmis- sider an applicant’s failure to resubmit sion. the application within the extended (v) A minor resubmission of an abbre- time period or to request an additional viated application constitutes an extension to be a request by the appli- agreement by the applicant to start a cant to withdraw the application.

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(2) If FDA considers an applicant’s (d) Certain drug products approved failure to take action in accordance for safety and effectiveness that were with paragraph (c)(1) of this section to no longer marketed on September 24, be a request to withdraw the applica- 1984, are not included in the list. Any tion, the agency will notify the appli- person who wishes to obtain marketing cant in writing. The applicant will approval for such a drug product under have 30 days from the date of the noti- an abbreviated new drug application fication to explain why the application must petition FDA for a determination should not be withdrawn and to request whether the drug product was with- an extension of time in which to resub- drawn from the market for safety or ef- mit the application. FDA will grant fectiveness reasons and request that any reasonable request for an exten- the list be amended to include the drug sion. If the applicant does not respond product. A person seeking such a deter- to the notification within 30 days, the mination shall use the petition proce- application will be deemed to be with- dures established in § 10.30 of this chap- drawn. ter. The petitioner shall include in the petition information to show that the [73 FR 39609, July 10, 2008] drug product was approved for safety and effectiveness and all evidence § 314.120 [Reserved] available to the petitioner concerning the reason that marketing of the drug § 314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) pe- product ceased. tition that relies on, a listed drug [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July that is no longer marketed. 1, 1992] (a) An abbreviated new drug application that refers to, or a petition under § 314.125 Refusal to approve an NDA. section 505(j)(2)(C) of the act and (a) The Food and Drug Administra- § 314.93 that relies on, a listed drug that tion will refuse to approve the NDA has been voluntarily withdrawn from and for a new drug give the applicant sale in the United States must be ac- written notice of an opportunity for a companied by a petition seeking a de- hearing under § 314.200 on the question termination whether the listed drug of whether there are grounds for deny- was withdrawn for safety or effective- ing approval of the NDA under section ness reasons. The petition must be sub- 505(d) of the Federal Food, Drug, and mitted under §§ 10.25(a) and 10.30 of this Cosmetic Act, if: chapter and must contain all evidence (1) FDA sends the applicant a com- available to the petitioner concerning plete response letter under § 314.110; the reasons for the withdrawal from (2) The applicant requests an oppor- sale. tunity for hearing for a new drug on (b) When a petition described in para- the question of whether the NDA is ap- graph (a) of this section is submitted, provable; and the agency will consider the evidence (3) FDA finds that any of the reasons in the petition and any other evidence given in paragraph (b) of this section before the agency, and determine apply. whether the listed drug is withdrawn (b) FDA may refuse to approve an from sale for safety or effectiveness NDA for any of the following reasons, reasons, in accordance with the proce- unless the requirement has been dures in § 314.161. waived under § 314.90: (c) An abbreviated new drug applica- (1) The methods to be used in, and tion described in paragraph (a) of this the facilities and controls used for, the section will be disapproved, under manufacture, processing, packing, or § 314.127(a)(11), and a 505(j)(2)(C) peti- holding of the drug substance or the tion described in paragraph (a) of this drug product are inadequate to pre- section will be disapproved, under serve its identity, strength, quality, § 314.93(e)(1)(iv), unless the agency de- purity, stability, and bioavailability. termines that the withdrawal of the (2) The investigations required under listed drug was not for safety or effec- section 505(b) of the Federal Food, tiveness reasons. Drug, and Cosmetic Act do not include

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adequate tests by all methods reason- (14) The NDA does not contain an ex- ably applicable to show whether or not planation of the omission of a report of the drug is safe for use under the condi- any investigation of the drug product tions prescribed, recommended, or sug- sponsored by the applicant, or an ex- gested in its proposed labeling. planation of the omission of other in- (3) The results of the tests show that formation about the drug pertinent to the drug is unsafe for use under the an evaluation of the NDA that is re- conditions prescribed, recommended, ceived or otherwise obtained by the ap- or suggested in its proposed labeling or plicant from any source. the results do not show that the drug (15) A nonclinical laboratory study product is safe for use under those con- that is described in the NDA and that ditions. is essential to show that the drug is (4) There is insufficient information safe for use under the conditions pre- about the drug to determine whether scribed, recommended, or suggested in the product is safe for use under the its proposed labeling was not con- conditions prescribed, recommended, ducted in compliance with the good or suggested in its proposed labeling. laboratory practice regulations in part (5) There is a lack of substantial evi- 58 of this chapter and no reason for the dence consisting of adequate and well- noncompliance is provided or, if it is, controlled investigations, as defined in the differences between the practices § 314.126, that the drug product will used in conducting the study and the have the effect it purports or is rep- good laboratory practice regulations do resented to have under the conditions not support the validity of the study. of use prescribed, recommended, or (16) Any clinical investigation in- suggested in its proposed labeling. volving human subjects described in (6) The proposed labeling is false or the NDA, subject to the institutional misleading in any particular. review board regulations in part 56 of (7) The NDA contains an untrue this chapter or informed consent regu- statement of a material fact. lations in part 50 of this chapter, was (8) The drug product’s proposed label- not conducted in compliance with ing does not comply with the require- those regulations such that the rights ments for labels and labeling in part or safety of human subjects were not 201. adequately protected. (9) The NDA does not contain bioavailability or bioequivalence data re- (17) The applicant or contract required under part 320 of this chapter. search organization that conducted a (10) A reason given in a letter refus- bioavailability or bioequivalence study ing to file the NDA under § 314.101(d), if described in § 320.38 or § 320.63 of this the deficiency is not corrected. chapter that is contained in the NDA (11) The drug will be manufactured in refuses to permit an inspection of fa- whole or in part in an establishment cilities or records relevant to the study that is not registered and not exempt by a properly authorized officer or em- from registration under section 510 of ployee of the Department of Health and the Federal Food, Drug, and Cosmetic Human Services or refuses to submit Act and part 207. reserve samples of the drug products (12) The applicant does not permit a used in the study when requested by properly authorized officer or employee FDA. of the Department of Health and (18) For a new drug, the NDA failed Human Services an adequate oppor- to contain the patent information re- tunity to inspect the facilities, con- quired by section 505(b)(1) of the Fed- trols, and any records relevant to the eral Food, Drug, and Cosmetic Act. NDA. (19) The 505(b)(2) application failed to (13) The methods to be used in, and contain a patent certification or state- the facilities and controls used for, the ment with respect to each listed patent manufacture, processing, packing, or for a drug product approved in an NDA holding of the drug substance or the that: drug product do not comply with the (i) Is pharmaceutically equivalent to current good manufacturing practice the drug product for which the original regulations in parts 210 and 211. 505(b)(2) application is submitted; and

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(ii) Was approved before the original methods of analysis ultimately used. If 505(b)(2) application was submitted. the protocol does not contain a descrip- (c) For drugs intended to treat life- tion of the proposed methods of anal- threatening or severely-debilitating ill- ysis, the study report should describe nesses that are developed in accordance how the methods used were selected. with §§ 312.80 through 312.88 of this (2) The study uses a design that per- chapter, the criteria contained in para- mits a valid comparison with a control graphs (b) (3), (4), and (5) of this section to provide a quantitative assessment of shall be applied according to the con- drug effect. The protocol for the study siderations contained in § 312.84 of this and report of results should describe chapter. the study design precisely; for example, duration of treatment periods, whether [50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28, treatments are parallel, sequential, or 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. crossover, and whether the sample size 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766, is predetermined or based upon some Mar. 6, 2009; 81 FR 60221, Aug. 31, 2016; 81 FR interim analysis. Generally, the fol- 69658, Oct. 6, 2016] lowing types of control are recognized: (i) Placebo concurrent control. The test § 314.126 Adequate and well-controlled drug is compared with an inactive studies. preparation designed to resemble the (a) The purpose of conducting clin- test drug as far as possible. A placebo- ical investigations of a drug is to dis- controlled study may include addi- tinguish the effect of a drug from other tional treatment groups, such as an ac- influences, such as spontaneous change tive treatment control or a dose-com- in the course of the disease, placebo ef- parison control, and usually includes fect, or biased observation. The charac- randomization and blinding of patients teristics described in paragraph (b) of or investigators, or both. this section have been developed over a (ii) Dose-comparison concurrent con- period of years and are recognized by trol. At least two doses of the drug are the scientific community as the essen- compared. A dose-comparison study tials of an adequate and well-con- may include additional treatment trolled clinical investigation. The Food groups, such as placebo control or ac- and Drug Administration considers tive control. Dose-comparison trials these characteristics in determining usually include randomization and whether an investigation is adequate blinding of patients or investigators, or and well-controlled for purposes of sec- both. tion 505 of the act. Reports of adequate (iii) No treatment concurrent control. and well-controlled investigations pro- Where objective measurements of effec- vide the primary basis for determining tiveness are available and placebo ef- whether there is ‘‘substantial evi- fect is negligible, the test drug is com- dence’’ to support the claims of effec- pared with no treatment. No treatment tiveness for new drugs. Therefore, the concurrent control trials usually in- study report should provide sufficient clude randomization. details of study design, conduct, and (iv) Active treatment concurrent con- analysis to allow critical evaluation trol. The test drug is compared with and a determination of whether the known effective therapy; for example, characteristics of an adequate and where the condition treated is such well-controlled study are present. that administration of placebo or no (b) An adequate and well-controlled treatment would be contrary to the in- study has the following characteristics: terest of the patient. An active treat- (1) There is a clear statement of the ment study may include additional objectives of the investigation and a treatment groups, however, such as a summary of the proposed or actual placebo control or a dose-comparison methods of analysis in the protocol for control. Active treatment trials usu- the study and in the report of its re- ally include randomization and blind- sults. In addition, the protocol should ing of patients or investigators, or contain a description of the proposed both. If the intent of the trial is to methods of analysis, and the study re- show similarity of the test and control port should contain a description of the drugs, the report of the study should

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assess the ability of the study to have liable. The protocol for the study and detected a difference between treat- the report of results should explain the ments. Similarity of test drug and ac- variables measured, the methods of ob- tive control can mean either that both servation, and criteria used to assess drugs were effective or that neither response. was effective. The analysis of the study (7) There is an analysis of the results should explain why the drugs should be of the study adequate to assess the ef- considered effective in the study, for fects of the drug. The report of the example, by reference to results in pre- study should describe the results and vious placebo-controlled studies of the the analytic methods used to evaluate active control drug. them, including any appropriate statis- (v) Historical control. The results of tical methods. The analysis should as- treatment with the test drug are com- sess, among other things, the compared with experience historically de- parability of test and control groups rived from the adequately documented with respect to pertinent variables, and natural history of the disease or condi- the effects of any interim data anal- tion, or from the results of active yses performed. treatment, in comparable patients or (c) The Director of the Center for populations. Because historical control Drug Evaluation and Research may, on populations usually cannot be as well the Director’s own initiative or on the assessed with respect to pertinent vari- petition of an interested person, waive ables as can concurrent control popu- in whole or in part any of the criteria lations, historical control designs are in paragraph (b) of this section with re- usually reserved for special cir- spect to a specific clinical investiga- cumstances. Examples include studies tion, either prior to the investigation of diseases with high and predictable or in the evaluation of a completed mortality (for example, certain malig- study. A petition for a waiver is re- nancies) and studies in which the effect quired to set forth clearly and con- of the drug is self-evident (general an- cisely the specific criteria from which esthetics, drug metabolism). waiver is sought, why the criteria are (3) The method of selection of sub- not reasonably applicable to the par- jects provides adequate assurance that ticular clinical investigation, what al- they have the disease or condition ternative procedures, if any, are to be, being studied, or evidence of suscepti- or have been employed, and what re- bility and exposure to the condition sults have been obtained. The petition against which prophylaxis is directed. is also required to state why the clin- (4) The method of assigning patients ical investigations so conducted will to treatment and control groups mini- yield, or have yielded, substantial evi- mizes bias and is intended to assure dence of effectiveness, notwithstanding comparability of the groups with re- nonconformance with the criteria for spect to pertinent variables such as which waiver is requested. age, sex, severity of disease, duration (d) For an investigation to be consid- of disease, and use of drugs or therapy ered adequate for approval of a new other than the test drug. The protocol drug, it is required that the test drug for the study and the report of its re- be standardized as to identity, sults should describe how subjects were strength, quality, purity, and dosage assigned to groups. Ordinarily, in a form to give significance to the results concurrently controlled study, assign- of the investigation. ment is by randomization, with or (e) Uncontrolled studies or partially without stratification. controlled studies are not acceptable as (5) Adequate measures are taken to the sole basis for the approval of minimize bias on the part of the sub- claims of effectiveness. Such studies jects, observers, and analysts of the carefully conducted and documented, data. The protocol and report of the may provide corroborative support of study should describe the procedures well-controlled studies regarding effi- used to accomplish this, such as blind- cacy and may yield valuable data re- ing. garding safety of the test drug. Such (6) The methods of assessment of sub- studies will be considered on their mer- jects’ response are well-defined and re- its in the light of the principles listed

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here, with the exception of the require- (B) No petition to submit an ANDA ment for the comparison of the treated for the drug product with the different subjects with controls. Isolated case re- active ingredient was approved under ports, random experience, and reports § 314.93. lacking the details which permit sci- (4)(i) If the ANDA is for a drug prod- entific evaluation will not be consid- uct whose route of administration, dos- ered. age form, or strength purports to be the same as that of the listed drug re- [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, ferred to in the ANDA, information 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. submitted in the abbreviated new drug 4, 2002] application is insufficient to show that the route of administration, dosage § 314.127 Refusal to approve an ANDA. form, or strength is the same as that of (a) FDA will refuse to approve an the reference listed drug; or ANDA for a new drug under section (ii) If the ANDA is for a drug product 505(j) of the Federal Food, Drug, and whose route of administration, dosage Cosmetic Act for any of the following form, or strength is different from that reasons, unless the requirement has of the listed drug referred to in the ap- been waived under § 314.99: plication, no petition to submit an (1) The methods used in, or the facili- ANDA for the drug product with the ties and controls used for, the manu- different route of administration, dos- facture, processing, and packing of the age form, or strength was approved drug product are inadequate to ensure under § 314.93. and preserve its identity, strength, (5) If the ANDA was submitted under quality, and purity. the approval of a petition under § 314.93, (2) Information submitted with the the ANDA did not contain the informa- ANDA is insufficient to show that each tion required by FDA with respect to of the proposed conditions of use has the active ingredient, route of adminis- been previously approved for the listed tration, dosage form, or strength that drug referred to in the ANDA. is not the same as that of the reference (3)(i) If the reference listed drug has listed drug. only one active ingredient, information (6)(i) Information submitted in the submitted with the ANDA is insuffi- ANDA is insufficient to show that the cient to show that the active ingre- drug product is bioequivalent to the dient is the same as that of the ref- listed drug referred to in the ANDA; or erence listed drug; (ii) If the ANDA was submitted under (ii) If the reference listed drug has a petition approved under § 314.93, in- more than one active ingredient, infor- formation submitted in the ANDA is mation submitted with the ANDA is in- insufficient to show that the active insufficient to show that the active ingredients of the drug product are of the gredients are the same as the active in- same pharmacological or therapeutic gredients of the reference listed drug; class as those of the reference listed or drug and that the drug product can be (iii) If the reference listed drug has expected to have the same therapeutic more than one active ingredient and if effect as the reference listed drug when the ANDAis for a drug product that has administered to patients for each con- an active ingredient different from the dition of use approved for the reference reference listed drug: listed drug. (A) Information submitted with the (7) Information submitted in the ANDA is insufficient to show: ANDA is insufficient to show that the (1) That the other active ingredients labeling proposed for the drug is the are the same as the active ingredients same as the labeling approved for the of the reference listed drug; or listed drug referred to in the ANDA ex- (2) That the different active ingre- cept for changes required because of dient is an active ingredient of a listed differences approved in a petition drug or a drug that does not meet the under § 314.93 or because the drug prod- requirements of section 201(p) of the uct and the reference listed drug are Federal Food, Drug, and Cosmetic Act; produced or distributed by different or manufacturers or because aspects of

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the listed drug’s labeling are protected (3) A change in the composition of a by patent, or by exclusivity, and such parenteral drug product to include an differences do not render the proposed inactive ingredient that has not been drug product less safe or effective than previously approved in a parenteral the listed drug for all remaining, non- drug product. protected conditions of use. (4) A change in composition of a drug (8)(i) Information submitted in the product for ophthalmic use to include ANDA or any other information avail- an inactive ingredient that has not able to FDA shows that: been previously approved in a drug for (A) The inactive ingredients of the ophthalmic use. drug product are unsafe for use, as de- (5) The use of a delivery or a modified scribed in paragraph (a)(8)(ii) of this release mechanism never before ap- section, under the conditions pre- proved for the drug. scribed, recommended, or suggested in (6) A change in composition to in- the labeling proposed for the drug prod- clude a significantly greater content of uct; or one or more inactive ingredients than (B) The composition of the drug prod- previously used in the drug product. uct is unsafe, as described in paragraph (7) If the drug product is intended for (a)(8)(ii) of this section, under the con- topical administration, a change in the ditions prescribed, recommended, or properties of the vehicle or base that suggested in the proposed labeling be- might increase absorption of certain cause of the type or quantity of inac- potentially toxic active ingredients tive ingredients included or the man- thereby affecting the safety of the drug ner in which the inactive ingredients product, or a change in the lipophilic are included. properties of a vehicle or base, e.g., a (ii)(A) FDA will consider the inactive change from an oleaginous to a water ingredients or composition of a drug soluble vehicle or base. product unsafe and refuse to approve (B) FDA will consider an inactive in- an ANDA under paragraph (a)(8)(i) of gredient in, or the composition of, a this section if, on the basis of informa- drug product intended for parenteral tion available to the agency, there is a use to be unsafe and will refuse to ap- reasonable basis to conclude that one prove the ANDA unless it contains the or more of the inactive ingredients of same inactive ingredients, other than the proposed drug or its composition preservatives, buffers, and anti- raises serious questions of safety or ef- oxidants, in the same concentration as ficacy. From its experience with re- the listed drug, and, if it differs from viewing inactive ingredients, and from the listed drug in a preservative, buff- other information available to it, FDA er, or antioxidant, the ANDA contains may identify changes in inactive ingre- sufficient information to demonstrate dients or composition that may ad- that the difference does not affect the versely affect a drug product’s safety safety or efficacy of the drug product. or efficacy. The inactive ingredients or (C) FDA will consider an inactive in- composition of a proposed drug product gredient in, or the composition of, a will be considered to raise serious ques- drug product intended for ophthalmic tions of safety or efficacy if the prod- or otic use unsafe and will refuse to ap- uct incorporates one or more of these prove the ANDA unless it contains the changes. Examples of the changes that same inactive ingredients, other than may raise serious questions of safety or preservatives, buffers, substances to efficacy include, but are not limited to, adjust tonicity, or thickening agents, the following: in the same concentration as the listed (1) A change in an inactive ingredient drug, and if it differs from the listed so that the product does not comply drug in a preservative, buffer, sub- with an official compendium. stance to adjust tonicity, or thickening (2) A change in composition to in- agent, the ANDA contains sufficient clude an inactive ingredient that has information to demonstrate that the not been previously approved in a drug difference does not affect the safety or product for human use by the same efficacy of the drug product and the la- route of administration. beling does not claim any therapeutic

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advantage over or difference from the products used in the study when relisted drug. quested by FDA. (9) Approval of the listed drug re- [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July ferred to in the ANDA has been with- 1, 1992, as amended at 58 FR 25927, Apr. 28, drawn or suspended for grounds de- 1993; 67 FR 77672, Dec. 19, 2002; 81 FR 69658, scribed in § 314.150(a) or FDA has pub- Oct. 6, 2016] lished a notice of opportunity for hearing to withdraw approval of the ref- § 314.150 Withdrawal of approval of an erence listed drug under § 314.150(a). application or abbreviated application. (10) Approval of the listed drug referred to in the ANDA has been with- (a) The Food and Drug Administra- drawn under § 314.151 or FDA has pro- tion will notify the applicant, and, if posed to withdraw approval of the ref- appropriate, all other persons who erence listed drug under § 314.151(a). manufacture or distribute identical, re- (11) FDA has determined that the ref- lated, or similar drug products as de- erence listed drug has been withdrawn fined in §§ 310.6 and 314.151(a) of this from sale for safety or effectiveness chapter and for a new drug afford an opportunity for a hearing on a proposal reasons under § 314.161, or the reference to withdraw approval of the applica- listed drug has been voluntarily with- tion or abbreviated new drug applica- drawn from sale and the agency has tion under section 505(e) of the act and not determined whether the with- under the procedure in § 314.200, if any drawal is for safety or effectiveness of the following apply: reasons, or approval of the reference (1) The Secretary of Health and listed drug has been suspended under Human Services has suspended the ap- § 314.153, or the agency has issued an proval of the application or abbre- initial decision proposing to suspend viated application for a new drug on a the reference listed drug under finding that there is an imminent haz- § 314.153(a)(1). ard to the public health. FDA will (12) The abbreviated new drug appli- promptly afford the applicant an expe- cation does not meet any other re- dited hearing following summary sus- quirement under section 505(j)(2)(A) of pension on a finding of imminent haz- the Federal Food, Drug, and Cosmetic ard to health. Act. (2) FDA finds: (13) The abbreviated new drug appli- (i) That clinical or other experience, cation contains an untrue statement of tests, or other scientific data show material fact. that the drug is unsafe for use under (14) For an ANDA submitted pursu- the conditions of use upon the basis of ant to an approved petition under which the application or abbreviated § 10.30 of this chapter and § 314.93, an application was approved; or NDA subsequently has been approved (ii) That new evidence of clinical ex- for the change described in the ap- perience, not contained in the applica- proved petition. tion or not available to FDA until after (b) FDA may refuse to approve an the application or abbreviated applica- ANDA for a new drug if the applicant tion was approved, or tests by new or contract research organization that methods, or tests by methods not conducted a bioavailability or bio- deemed reasonably applicable when the equivalence study described in § 320.63 application or abbreviated application was approved, evaluated together with of this chapter that is contained in the the evidence available when the appli- ANDA refuses to permit an inspection cation or abbreviated application was of facilities or records relevant to the approved, reveal that the drug is not study by a properly authorized officer shown to be safe for use under the con- or employee of the Department of ditions of use upon the basis of which Health and Human Services or refuses the application or abbreviated applica- to submit reserve samples of the drug tion was approved; or (iii) Upon the basis of new information before FDA with respect to the

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drug, evaluated together with the evi- based on a fair evaluation of all mate- dence available when the application rial facts, is false or misleading in any or abbreviated application was ap- particular, and the labeling was not proved, that there is a lack of substan- corrected by the applicant within a tial evidence from adequate and well- reasonable time after receipt of writ- controlled investigations as defined in ten notice from the agency. § 314.126, that the drug will have the ef- (4) That the applicant has failed to fect it is purported or represented to comply with the notice requirements of have under the conditions of use pre- section 510(j)(2) of the act. scribed, recommended, or suggested in (5) That the applicant has failed to its labeling; or submit bioavailability or bioequiva- (iv) That the application or abbre- lence data required under part 320 of viated application contains any untrue this chapter. statement of a material fact; or (6) The application or abbreviated ap- (v) That the patent information pre- plication does not contain an expla- scribed by section 505(c) of the act was nation of the omission of a report of not submitted within 30 days after the any investigation of the drug product receipt of written notice from FDA sponsored by the applicant, or an ex- specifying the failure to submit such planation of the omission of other in- information; or formation about the drug pertinent to (b) FDA may notify the applicant, an evaluation of the application or ab- and, if appropriate, all other persons breviated application that is received who manufacture or distribute iden- or otherwise obtained by the applicant tical, related, or similar drug products from any source. as defined in § 310.6, and for a new drug afford an opportunity for a hearing on (7) That any nonclinical laboratory a proposal to withdraw approval of the study that is described in the applica- application or abbreviated new drug tion or abbreviated application and application under section 505(e) of the that is essential to show that the drug act and under the procedure in § 314.200, is safe for use under the conditions pre- if the agency finds: scribed, recommended, or suggested in (1) That the applicant has failed to its labeling was not conducted in com- establish a system for maintaining re- pliance with the good laboratory prac- quired records, or has repeatedly or de- tice regulations in part 58 of this chap- liberately failed to maintain required ter and no reason for the noncompli- records or to make required reports ance was provided or, if it was, the dif- under section 505(k) or 507(g) of the act ferences between the practices used in and § 314.80, § 314.81, or § 314.98, or that conducting the study and the good lab- the applicant has refused to permit ac- oratory practice regulations do not cess to, or copying or verification of, support the validity of the study. its records. (8) Any clinical investigation involv- (2) That on the basis of new informa- ing human subjects described in the ap- tion before FDA, evaluated together plication or abbreviated application, with the evidence available when the subject to the institutional review application or abbreviated application board regulations in part 56 of this was approved, the methods used in, or chapter or informed consent regula- the facilities and controls used for, the tions in part 50 of this chapter, was not manufacture, processing, and packing conducted in compliance with those of the drug are inadequate to ensure regulations such that the rights or and preserve its identity, strength, safety of human subjects were not ade- quality, and purity and were not made quately protected. adequate within a reasonable time (9) That the applicant or contract re- after receipt of written notice from the search organization that conducted a agency. bioavailability or bioequivalence study (3) That on the basis of new informa- described in § 320.38 or § 320.63 of this tion before FDA, evaluated together chapter that is contained in the appli- with the evidence available when the cation or abbreviated application re- application or abbreviated application fuses to permit an inspection of facili- was approved, the labeling of the drug, ties or records relevant to the study by

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a properly authorized officer or em- agency’s and the applicant’s views of ployee of the Department of Health and the reasons for withdrawal. Human Services or refuses to submit reserve samples of the drug products [57 FR 17993, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 64 FR 402, Jan. 5, 1999] used in the study when requested by FDA. § 314.151 Withdrawal of approval of an (10) That the labeling for the drug abbreviated new drug application product that is the subject of the ab- under section 505(j)(5) of the act. breviated new drug application is no (a) Approval of an abbreviated new longer consistent with that for the list- drug application approved under ed drug referred to in the abbreviated new drug application, except for dif- § 314.105(d) may be withdrawn when the ferences approved in the abbreviated agency withdraws approval, under new drug application or those dif- § 314.150(a) or under this section, of the ferences resulting from: approved drug referred to in the abbre- (i) A patent on the listed drug issued viated new drug application. If the after approval of the abbreviated new agency proposed to withdraw approval drug application; or of a listed drug under § 314.150(a), the (ii) Exclusivity accorded to the listed holder of an approved application for drug after approval of the abbreviated the listed drug has a right to notice new drug application that do not and opportunity for hearing. The pub- render the drug product less safe or ef- lished notice of opportunity for hearing fective than the listed drug for any re- will identify all drug products approved maining, nonprotected condition(s) of under § 314.105(d) whose applications use. are subject to withdrawal under this (c) FDA will withdraw approval of an section if the listed drug is withdrawn, application or abbreviated application and will propose to withdraw such if the applicant requests its withdrawal drugs. Holders of approved applications because the drug subject to the appli- for the identified drug products will be cation or abbreviated application is no provided notice and an opportunity to longer being marketed, provided none respond to the proposed withdrawal of of the conditions listed in paragraphs their applications as described in para- (a) and (b) of this section applies to the graphs (b) and (c) of this section. drug. FDA will consider a written re- (b)(1) The published notice of oppor- quest for a withdrawal under this para- tunity for hearing on the withdrawal of graph to be a waiver of an opportunity the listed drug will serve as notice to for hearing otherwise provided for in holders of identified abbreviated new this section. Withdrawal of approval of drug applications of the grounds for an application or abbreviated applica- the proposed withdrawal. tion under this paragraph is without (2) Holders of applications for drug prejudice to refiling. products identified in the notice of op- (d) FDA may notify an applicant that portunity for hearing may submit writ- it believes a potential problem associ- ten comments on the notice of oppor- ated with a drug is sufficiently serious tunity for hearing issued on the pro- that the drug should be removed from posed withdrawal of the listed drug. If the market and may ask the applicant an abbreviated new drug application to waive the opportunity for hearing holder submits comments on the notice otherwise provided for under this sec- of opportunity for hearing and a hear- tion, to permit FDA to withdraw ap- ing is granted, the abbreviated new proval of the application or abbre- drug application holder may partici- viated application for the product, and pate in the hearing as a nonparty par- to remove voluntarily the product from ticipant as provided for in § 12.89 of this the market. If the applicant agrees, the chapter. agency will not make a finding under (3) Except as provided in paragraphs paragraph (b) of this section, but will (c) and (d) of this section, the approval withdraw approval of the application of an abbreviated new drug application or abbreviated application in a notice for a drug product identified in the no- published in the FEDERAL REGISTER tice of opportunity for hearing on the that contains a brief summary of the withdrawal of a listed drug will be

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withdrawn when the agency has com- final agency action, reviewable in a ju- pleted the withdrawal of approval of dicial proceeding. the listed drug. (8) Documents in the record will be (c)(1) If the holder of an application publicly available in accordance with for a drug identified in the notice of op- § 10.20(j) of this chapter. Documents portunity for hearing has submitted available for examination or copying timely comments but does not have an will be placed on public display in the opportunity to participate in a hearing Division of Dockets Management because a hearing is not requested or is (HFA–305), Food and Drug Administra- settled, the submitted comments will tion, room. 1–23, 12420 Parklawn Dr., be considered by the agency, which will Rockville, MD 20857, promptly upon re- issue an initial decision. The initial de- ceipt in that office. cision will respond to the comments, (d) If the agency determines, based and contain the agency’s decision upon information submitted by the whether there are grounds to withdraw holder of an abbreviated new drug ap- approval of the listed drug and of the plication, that the grounds for with- abbreviated new drug applications on drawal of the listed drug are not appli- which timely comments were sub- cable to a drug identified in the notice mitted. The initial decision will be of opportunity for hearing, the final de- sent to each abbreviated new drug ap- cision will state that the approval of plication holder that has submitted the abbreviated new drug application comments. for such drug is not withdrawn. (2) Abbreviated new drug application [57 FR 17994, Apr. 28, 1992] holders to whom the initial decision was sent may, within 30 days of the § 314.152 Notice of withdrawal of ap- issuance of the initial decision, submit proval of an application or abbre- written objections. viated application for a new drug. (3) The agency may, at its discretion, If the Food and Drug Administration hold a limited oral hearing to resolve withdraws approval of an application dispositive factual issues that cannot or abbreviated application for a new be resolved on the basis of written sub- drug, FDA will publish a notice in the missions. FEDERAL REGISTER announcing the (4) If there are no timely objections withdrawal of approval. If the applica- to the initial decision, it will become tion or abbreviated application was final at the expiration of 30 days. withdrawn for grounds described in (5) If timely objections are sub- § 314.150(a) or § 314.151, the notice will mitted, they will be reviewed and re- announce the removal of the drug from sponded to in a final decision. the list of approved drugs published (6) The written comments received, under section 505(j)(6) of the act and the initial decision, the evidence relied shall satisfy the requirement of § 314.162(b). on in the comments and in the initial decision, the objections to the initial [57 FR 17994, Apr. 28, 1992] decision, and, if a limited oral hearing has been held, the transcript of that § 314.153 Suspension of approval of an hearing and any documents submitted abbreviated new drug application. therein, shall form the record upon (a) Suspension of approval. The ap- which the agency shall make a final proval of an abbreviated new drug ap- decision. plication approved under § 314.105(d) (7) Except as provided in paragraph shall be suspended for the period stated (d) of this section, any abbreviated new when: drug application whose holder sub- (1) The Secretary of the Department mitted comments on the notice of op- of Health and Human Services, under portunity for hearing shall be with- the imminent hazard authority of sec- drawn upon the issuance of a final deci- tion 505(e) of the act or the authority sion concluding that the listed drug of this paragraph, suspends approval of should be withdrawn for grounds as de- a listed drug referred to in the abbre- scribed in § 314.150(a). The final decision viated new drug application, for the pe- shall be in writing and shall constitute riod of the suspension;

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(2) The agency, in the notice de- by the agency and responded to in a scribed in paragraph (b) of this section, final decision. or in any subsequent written notice (4) The agency may, in its discretion, given an abbreviated new drug applica- hold a limited oral hearing to resolve tion holder by the agency, concludes dispositive factual issues that cannot that the risk of continued marketing be resolved on the basis of written sub- and use of the drug is inappropriate, missions. pending completion of proceedings to (5) If the final decision affirms the withdraw or suspend approval under agency’s initial decision that the listed § 314.151 or paragraph (b) of this sec- drug was withdrawn for reasons of safe- tion; or ty or effectiveness, the decision will be (3) The agency, under the procedures published in the FEDERAL REGISTER in set forth in paragraph (b) of this sec- compliance with § 314.152, and will, ex- tion, issues a final decision stating the cept as provided in paragraph (b)(6) of determination that the abbreviated ap- this section, suspend approval of all ab- plication is suspended because the list- breviated new drug applications identi- ed drug on which the approval of the fied under paragraph (b)(1) of this sec- abbreviated new drug application de- tion and remove from the list the listed pends has been withdrawn from sale for drug and any drug whose approval was reasons of safety or effectiveness or has suspended under this paragraph. The been suspended under paragraph (b) of notice will satisfy the requirement of this section. The suspension will take § 314.162(b). The agency’s final decision effect on the date stated in the decision and copies of materials on which it re- and will remain in effect until the lies will also be filed with the Division agency determines that the marketing of Dockets Management (address in of the drug has resumed or that the paragraph (b)(1) of this section). withdrawal is not for safety or effec- (6) If the agency determines in its tiveness reasons. final decision that the listed drug was (b) Procedures for suspension of abbre- withdrawn for reasons of safety or ef- viated new drug applications when a list- fectiveness but, based upon informa- ed drug is voluntarily withdrawn for safe- tion submitted by the holder of an ab- ty or effectiveness reasons. (1) If a listed breviated new drug application, also drug is voluntarily withdrawn from determines that the reasons for the sale, and the agency determines that withdrawal of the listed drug are not the withdrawal from sale was for rea- relevant to the safety and effectiveness sons of safety or effectiveness, the of the drug subject to such abbreviated agency will send each holder of an ap- new drug application, the final decision proved abbreviated new drug applica- will state that the approval of such ab- tion that is subject to suspension as a breviated new drug application is not result of this determination a copy of suspended. the agency’s initial decision setting (7) Documents in the record will be forth the reasons for the determina- publicly available in accordance with tion. The initial decision will also be § 10.20(j) of this chapter. Documents placed on file with the Division of available for examination or copying Dockets Management (HFA–305), Food will be placed on public display in the and Drug Administration, room 1–23, Division of Dockets Management (ad- 12420 Parklawn Dr., Rockville, MD dress in paragraph (b)(1) of this sec- 20857. tion) promptly upon receipt in that of- (2) Each abbreviated new drug appli- fice. cation holder will have 30 days from the issuance of the initial decision to [57 FR 17995, Apr. 28, 1992] present, in writing, comments and information bearing on the initial deci- § 314.160 Approval of an application or sion. If no comments or information is abbreviated application for which received, the initial decision will be- approval was previously refused, come final at the expiration of 30 days. suspended, or withdrawn. (3) Comments and information re- Upon the Food and Drug Administra- ceived within 30 days of the issuance of tion’s own initiative or upon request of the initial decision will be considered an applicant, FDA may, on the basis of

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new data, approve an application or ab- that marketing of the drug has re- breviated application which it had pre- sumed or that the withdrawal is not for viously refused, suspended, or with- safety or effectiveness reasons. A de- drawn approval. FDA will publish a no- termination that the drug is not with- tice in the FEDERAL REGISTER announc- drawn for safety or effectiveness rea- ing the approval. sons may be made at any time after its [57 FR 17995, Apr. 28, 1992] removal from the list, upon the agency’s initiative, or upon the submission § 314.161 Determination of reasons for of a petition under §§ 10.25(a) and 10.30 voluntary withdrawal of a listed of this chapter. If the agency deter- drug. mines that the drug is not withdrawn (a) A determination whether a listed for safety or effectiveness reasons, the drug that has been voluntarily with- agency shall publish a notice of this de- drawn from sale was withdrawn for termination in the FEDERAL REGISTER. safety or effectiveness reasons may be The notice will also announce that the made by the agency at any time after drug is relisted, under § 314.162(c). The the drug has been voluntarily with- notice will also serve to reinstate ap- drawn from sale, but must be made: (1) Prior to approving an abbreviated proval of all suspended abbreviated new new drug application that refers to the drug applications that referred to the listed drug; listed drug. (2) Whenever a listed drug is volun- [57 FR 17995, Apr. 28, 1992] tarily withdrawn from sale and abbreviated new drug applications that re- § 314.162 Removal of a drug product ferred to the listed drug have been ap- from the list. proved; and (a) FDA will remove a previously ap- (3) When a person petitions for such a proved new drug product from the list determination under §§ 10.25(a) and 10.30 of this chapter. for the period stated when: (b) Any person may petition under (1) The agency withdraws or suspends §§ 10.25(a) and 10.30 of this chapter for a approval of a new drug application or determination whether a listed drug an abbreviated new drug application has been voluntarily withdrawn for under § 314.150(a) or § 314.151 or under safety or effectiveness reasons. Any the imminent hazard authority of sec- such petition must contain all evidence tion 505(e) of the act, for the same pe- available to the petitioner concerning riod as the withdrawal or suspension of the reason that the drug is withdrawn the application; or from sale. (2) The agency, in accordance with (c) If the agency determines that a the procedures in § 314.153(b) or § 314.161, listed drug is withdrawn from sale for issues a final decision stating that the safety or effectiveness reasons, the listed drug was withdrawn from sale agency will, except as provided in para- for safety or effectiveness reasons, or graph (d) of this section, publish a no- suspended under § 314.153(b), until the tice of the determination in the FED- agency determines that the withdrawal ERAL REGISTER. from the market has ceased or is not (d) If the agency determines under for safety or effectiveness reasons. paragraph (a) of this section that a listed drug is withdrawn from sale for (b) FDA will publish in the FEDERAL safety and effectiveness reasons and REGISTER a notice announcing the re- there are approved abbreviated new moval of a drug from the list. drug applications that are subject to (c) At the end of the period specified suspension under section 505(j)(5) of the in paragraph (a)(1) or (a)(2) of this sec- act, FDA will initiate a proceeding in tion, FDA will relist a drug that has accordance with § 314.153(b). been removed from the list. The agency (e) A drug that the agency deter- will publish in the FEDERAL REGISTER a mines is withdrawn for safety or effec- notice announcing the relisting of the tiveness reasons will be removed from drug. the list, under § 314.162. The drug may be relisted if the agency has evidence [57 FR 17996, Apr. 28, 1992]

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§ 314.170 Adulteration and mis- the notice to file a written notice of branding of an approved drug. participation and request for hearing. All drugs, including those the Food The applicant, or other persons subject and Drug Administration approves to the notice under § 310.6, who fails to under section 505 of the act and this file a written notice of participation part, are subject to the adulteration and request for hearing within 30 days, and misbranding provisions in sections waives the opportunity for a hearing. 501, 502, and 503 of the act. FDA is au- (3) It is the responsibility of every thorized to regulate approved new manufacturer and distributor of a drug drugs by regulations issued through in- product to review every notice of op- formal rulemaking under sections 501, portunity for a hearing published in 502, and 503 of the act. the FEDERAL REGISTER to determine whether it covers any drug product [50 FR 7493, Feb. 22, 1985. Redesignated at 57 that person manufactures or distrib- FR 17983, Apr. 28, 1992, and amended at 64 FR 402, Jan. 5, 1999] utes. Any person may request an opinion of the applicability of a notice to a specific product that may be identical, Subpart E—Hearing Procedures for related, or similar to a product listed New Drugs in a notice by writing to the Division of New Drugs and Labeling Compli- SOURCE: 50 FR 7493, Feb. 22, 1985, unless ance, Office of Compliance, Center for otherwise noted. Redesignated at 57 FR 17983, Drug Evaluation and Research, Food Apr. 28, 1992. and Drug Administration, 10903 New § 314.200 Notice of opportunity for Hampshire Ave., Silver Spring, MD hearing; notice of participation and 20993–0002. A person shall request an request for hearing; grant or denial opinion within 30 days of the date of of hearing. publication of the notice to be eligible (a) Notice of opportunity for hearing. for an opportunity for a hearing under The Director of the Center for Drug the notice. If a person requests an opin- Evaluation and Research, Food and ion, that person’s time for filing an ap- Drug Administration, will give the appearance and request for a hearing and plicant, and all other persons who man- supporting studies and analyses begins ufacture or distribute identical, re- on the date the person receives the lated, or similar drug products as de- opinion from FDA. fined in § 310.6 of this chapter, notice (b) FDA will provide the notice of op- and an opportunity for a hearing on the portunity for a hearing to applicants Center’s proposal to refuse to approve and to other persons subject to the no- an application or to withdraw the ap- tice under § 310.6, as follows: proval of an application or abbreviated (1) To any person who has submitted application under section 505(e) of the an application or abbreviated applica- act. The notice will state the reasons tion, by delivering the notice in person for the action and the proposed or by sending it by registered or cer- grounds for the order. tified mail to the last address shown in (1) The notice may be general (that the application or abbreviated applica- is, simply summarizing in a general tion. way the information resulting in the (2) To any person who has not sub- notice) or specific (that is, either refer- mitted an application or abbreviated ring to specific requirements in the application but who is subject to the statute and regulations with which notice under § 310.6 of this chapter, by there is a lack of compliance, or pro- publication of the notice in the FED- viding a detailed description and anal- ERAL REGISTER. ysis of the specific facts resulting in (c)(1) Notice of participation and re- the notice). quest for a hearing, and submission of (2) FDA will publish the notice in the studies and comments. The applicant, or FEDERAL REGISTER and will state that any other person subject to the notice the applicant, and other persons sub- under § 310.6, who wishes to participate ject to the notice under § 310.6, who in a hearing, shall file with the Divi- wishes to participate in a hearing, has sion of Dockets Management (HFA– 30 days after the date of publication of 305), Food and Drug Administration,

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5630 Fishers Lane, rm. 1061, Rockville, prove an application is not required to MD 20852, (i) within 30 days after the submit additional studies and analyses date of the publication of the notice (or if the studies upon which the person re- of the date of receipt of an opinion relies have been submitted in the appli- quested under paragraph (a)(3) of this cation and in the format and con- section) a written notice of participa- taining the summaries required under tion and request for a hearing and (ii) § 314.50. within 60 days after the date of publi- (1) If the grounds for FDA’s proposed cation of the notice, unless a different action concern the effectiveness of the period of time is specified in the notice drug, each request for hearing is re- of opportunity for a hearing, the stud- quired to be supported only by ade- ies on which the person relies to justify quate and well-controlled clinical stud- a hearing as specified in paragraph (d) ies meeting all of the precise require- of this section. The applicant, or other ments of § 314.126 and, for combination person, may incorporate by reference drug products, § 300.50, or by other stud- the raw data underlying a study if the ies not meeting those requirements for data were previously submitted to FDA which a waiver has been previously as part of an application, abbreviated granted by FDA under § 314.126. Each application, or other report. person requesting a hearing shall sub- (2) FDA will not consider data or mit all adequate and well-controlled analyses submitted after 60 days in de- clinical studies on the drug product, in- termining whether a hearing is war- cluding any unfavorable analyses, ranted unless they are derived from views, or judgments with respect to the well-controlled studies begun before studies. No other data, information, or the date of the notice of opportunity studies may be submitted. for hearing and the results of the studies were not available within 60 days (2) The submission is required to in- after the date of publication of the no- clude a factual analysis of all the stud- tice. Nevertheless, FDA may consider ies submitted. If the grounds for FDA’s other studies on the basis of a showing proposed action concern the effective- by the person requesting a hearing of ness of the drug, the analysis is re- inadvertent omission and hardship. quired to specify how each study ac- The person requesting a hearing shall cords, on a point-by-point basis, with list in the request for hearing all stud- each criterion required for an adequate ies in progress, the results of which the well-controlled clinical investigation person intends later to submit in sup- established under § 314.126 and, if the port of the request for a hearing. The product is a combination drug product, person shall submit under paragraph with each of the requirements for a (c)(1)(ii) of this section a copy of the combination drug established in complete protocol, a list of the partici- § 300.50, or the study is required to be pating investigators, and a brief status accompanied by an appropriate waiver report of the studies. previously granted by FDA. If a study (3) Any other interested person who concerns a drug or dosage form or con- is not subject to the notice of oppor- dition of use or mode of administration tunity for a hearing may also submit other than the one in question, that comments on the proposal to withdraw fact is required to be clearly stated. approval of the application or abbre- Any study conducted on the final mar- viated application. The comments are keted form of the drug product is re- requested to be submitted within the quired to be clearly identified. time and under the conditions specified (3) Each person requesting a hearing in this section. shall submit an analysis of the data (d) The person requesting a hearing is upon which the person relies, except required to submit under paragraph that the required information relating (c)(1)(ii) of this section the studies (in- either to safety or to effectiveness may cluding all protocols and underlying be omitted if the notice of opportunity raw data) on which the person relies to for hearing does not raise any issue justify a hearing with respect to the with respect to that aspect of the drug; drug product. Except, a person who re- information on compliance with § 300.50 quests a hearing on the refusal to ap- may be omitted if the drug product is

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not a combination drug product. A fi- permitted in § 314.200(c)(2)) all studies and in- nancial certification or disclosure formation specified in § 314.200(d). statement or both as required by part (WARNING: A willfully false statement is a 54 of this chapter must accompany all criminal offense, 18 U.S.C. 1001.) clinical data submitted. FDA can most (e) Contentions that a drug product is efficiently consider submissions made not subject to the new drug requirements. in the following format. A notice of opportunity for a hearing I. Safety data. encompasses all issues relating to the A. Animal safety data. legal status of each drug product sub- 1. Individual active components. ject to it, including identical, related, a. Controlled studies. and similar drug products as defined in b. Partially controlled or uncontrolled § 310.6. A notice of appearance and re- studies. quest for a hearing under paragraph 2. Combinations of the individual active (c)(1)(i) of this section is required to components. contain any contention that the prod- a. Controlled studies. b. Partially controlled or uncontrolled uct is not a new drug because it is gen- studies. erally recognized as safe and effective B. Human safety data. within the meaning of section 201(p) of 1. Individual active components. the act, or because it is exempt from a. Controlled studies. part or all of the new drug provisions b. Partially controlled or uncontrolled of the act under the exemption for studies. products marketed before June 25, 1938, c. Documented case reports. contained in section 201(p) of the act or d. Pertinent marketing experiences that may influence a determination about the under section 107(c) of the Drug safety of each individual active component. Amendments of 1962, or for any other 2. Combinations of the individual active reason. Each contention is required to components. be supported by a submission under a. Controlled studies. paragraph (c)(1)(ii) of this section and b. Partially controlled or uncontrolled the Commissioner of Food and Drugs studies. will make an administrative deter- c. Documented case reports. mination on each contention. The fail- d. Pertinent marketing experiences that may influence a determination about the ure of any person subject to a notice of safety of each individual active component. opportunity for a hearing, including II. Effectiveness data. any person who manufactures or dis- A. Individual active components: Con- tributes an identical, related, or simi- trolled studies, with an analysis showing lar drug product as defined in § 310.6, to clearly how each study satisfies, on a point- submit a notice of participation and re- by-point basis, each of the criteria required quest for hearing or to raise all such by § 314.126. contentions constitutes a waiver of any B. Combinations of individual active components. contentions not raised. 1. Controlled studies with an analysis (1) A contention that a drug product showing clearly how each study satisfies on is generally recognized as safe and ef- a point-by-point basis, each of the criteria fective within the meaning of section required by § 314.126. 201(p) of the act is required to be sup- 2. An analysis showing clearly how each reported by submission of the same quan- quirement of § 300.50 has been satisfied. tity and quality of scientific evidence III. A summary of the data and views set- that is required to obtain approval of ting forth the medical rationale and purpose for the drug and its ingredients and the sci- an application for the product, unless entific basis for the conclusion that the drug FDA has waived a requirement for ef- and its ingredients have been proven safe fectiveness (under § 314.126) or safety, and/or effective for the intended use. If there or both. The submission should be in is an absence of controlled studies in the ma- the format and with the analyses re- terial submitted or the requirements of any quired under paragraph (d) of this sec- element of § 300.50 or § 314.126 have not been tion. A person who fails to submit the fully met, that fact is required to be stated required scientific evidence required clearly and a waiver obtained under § 314.126 is required to be submitted. under paragraph (d) waives the conten- IV. A statement signed by the person re- tion. General recognition of safety and sponsible for such submission that it in- effectiveness shall ordinarily be based cludes in full (or incorporates by reference as upon published studies which may be

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corroborated by unpublished studies A. A copy of each pertinent document or and other data and information. record to establish the exact date the drug (2) A contention that a drug product was initially marketed. is exempt from part or all of the new B. A statement whether such marketing has at any subsequent time been discon- drug provisions of the act under the ex- tinued. If such marketing has been discon- emption for products marketed before tinued, the exact date of each such dis- June 25, 1938, contained in section continuance should be submitted, together 201(p) of the act, or under section 107(c) with a copy of each pertinent document or of the Drug Amendments of 1962, is re- record to establish each such date. quired to be supported by evidence of IV. Verification. past and present quantitative for- A statement signed by the person respon- mulas, labeling, and evidence of mar- sible for such submission, that all appro- keting. A person who makes such a priate records have been searched and to the best of that person’s knowledge and belief it contention should submit the formulas, includes a true and accurate presentation of labeling, and evidence of marketing in the facts. the following format. (WARNING: A willfully false statement is a I. Formulation. criminal offense, 18 U.S.C. 1001.) A. A copy of each pertinent document or (3) The Food and Drug Administra- record to establish the exact quantitative formulation of the drug (both active and in- tion will not find a drug product, inactive ingredients) on the date of initial cluding any active ingredient, which is marketing of the drug. identical, related, or similar, as de- B. A statement whether such formulation scribed in § 310.6, to a drug product, in- has at any subsequent time been changed in cluding any active ingredient for which any manner. If any such change has been an application is or at any time has made, the exact date, nature, and rationale been effective or deemed approved, or for each change in formulation, including approved under section 505 of the act, any deletion or change in the concentration to be exempt from part or all of the of any active ingredient and/or inactive in- new drug provisions of the act. gredient, should be stated, together with a copy of each pertinent document or record to (4) A contention that a drug product establish the date and nature of each such is not a new drug for any other reason change, including, but not limited to, the is required to be supported by submis- formula which resulted from each such sion of the factual records, data, and change. If no such change has been made, a information that are necessary and ap- copy of representative documents or records propriate to support the contention. showing the formula at representative points (5) It is the responsibility of every in time should be submitted to support the statement. person who manufactures or distrib- II. Labeling. utes a drug product in reliance upon a A. A copy of each pertinent document or ‘‘grandfather’’ provision of the act to record to establish the identity of each item maintain files that contain the data of written, printed, or graphic matter used and information necessary fully to doc- as labeling on the date the drug was initially ument and support that status. marketed. (f) Separation of functions. Separation B. A statement whether such labeling has of functions commences upon receipt of at any subsequent time been discontinued or a request for hearing. The Director of changed in any manner. If such discontinuance or change has been made, the exact the Center for Drug Evaluation and Re- date, nature, and rationale for each dis- search, Food and Drug Administration, continuance or change and a copy of each will prepare an analysis of the request pertinent document or record to establish and a proposed order ruling on the each such discontinuance or change should matter. The analysis and proposed be submitted, including, but not limited to, order, the request for hearing, and any the labeling which resulted from each such proposed order denying a hearing and discontinuance or change. If no such dis- response under paragraph (g) (2) or (3) continuance or change has been made, a copy of representative documents or records show- of this section will be submitted to the ing labeling at representative points in time Office of the Commissioner of Food and should be submitted to support the state- Drugs for review and decision. When ment. the Center for Drug Evaluation and Re- III. Marketing. search recommends denial of a hearing

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on all issues on which a hearing is re- drawal of approval of the application or quested, no representative of the Cen- abbreviated application; for example, ter will participate or advise in the re- no adequate and well-controlled clin- view and decision by the Commis- ical investigations meeting each of the sioner. When the Center for Drug Eval- precise elements of § 314.126 and, for a uation and Research recommends that combination drug product, § 300.50 of a hearing be granted on one or more this chapter, showing effectiveness issues on which a hearing is requested, have been identified. Any order enter- separation of functions terminates as ing summary judgment is required to to those issues, and representatives of set forth the Commissioner’s findings the Center may participate or advise in and conclusions in detail and is re- the review and decision by the Com- quired to specify why each study sub- missioner on those issues. The Com- mitted fails to meet the requirements missioner may modify the text of the of the statute and regulations or why issues, but may not deny a hearing on the request for hearing does not raise a those issues. Separation of functions genuine and substantial issue of fact. continues with respect to issues on (2) When following a general notice of which the Center for Drug Evaluation opportunity for a hearing (as defined in and Research has recommended denial paragraph (a)(1) of this section) the Di- of a hearing. The Commissioner will rector of the Center for Drug Evalua- neither evaluate nor rule on the Cen- tion and Research concludes that sum- ter’s recommendation on such issues mary judgment against a person re- and such issues will not be included in questing a hearing should be consid- the notice of hearing. Participants in ered, the Director will serve upon the the hearing may make a motion to the person requesting a hearing by reg- presiding officer for the inclusion of istered mail a proposed order denying a any such issue in the hearing. The rul- hearing. This person has 60 days after ing on such a motion is subject to re- receipt of the proposed order to review in accordance with § 12.35(b). Fail- spond with sufficient data, informa- ure to so move constitutes a waiver of tion, and analyses to demonstrate that the right to a hearing on such an issue. there is a genuine and substantial issue Separation of functions on all issues resumes upon issuance of a notice of of fact which justifies a hearing. hearing. The Office of the General (3) When following a general or spe- Counsel, Department of Health and cific notice of opportunity for a hear- Human Services, will observe the same ing a person requesting a hearing sub- separation of functions. mits data or information of a type re- (g) Summary judgment. A person who quired by the statute and regulations, requests a hearing may not rely upon and the Director of the Center for Drug allegations or denials but is required to Evaluation and Research concludes set forth specific facts showing that that summary judgment against the there is a genuine and substantial issue person should be considered, the Direc- of fact that requires a hearing with re- tor will serve upon the person by reg- spect to a particular drug product spec- istered mail a proposed order denying a ified in the request for hearing. hearing. The person has 60 days after (1) Where a specific notice of oppor- receipt of the proposed order to re- tunity for hearing (as defined in para- spond with sufficient data, informa- graph (a)(1) of this section) is used, the tion, and analyses to demonstrate that Commissioner will enter summary there is a genuine and substantial issue judgment against a person who re- of fact which justifies a hearing. quests a hearing, making findings and (4) If review of the data, information, conclusions, denying a hearing, if it and analyses submitted show that the conclusively appears from the face of grounds cited in the notice are not the data, information, and factual valid, for example, that substantial analyses in the request for the hearing evidence of effectiveness exists, the that there is no genuine and substan- Commissioner will enter summary tial issue of fact which precludes the judgment for the person requesting the refusal to approve the application or hearing, and rescind the notice of op- abbreviated application or the with- portunity for hearing.

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(5) If the Commissioner grants a quired to include the requests for hear- hearing, it will begin within 90 days ing together with the data and infor- after the expiration of the time for re- mation submitted and the Commis- questing the hearing unless the parties sioner’s findings and conclusion. otherwise agree in the case of denial of (b) A manufacturer or distributor of approval, and as soon as practicable in an identical, related, or similar drug the case of withdrawal of approval. product under § 310.6 may seek judicial (6) The Commissioner will grant a review of an order withdrawing ap- hearing if there exists a genuine and proval of a new drug application, substantial issue of fact or if the Com- whether or not a hearing has been held, missioner concludes that a hearing in a United States court of appeals would otherwise be in the public inter- under section 505(h) of the act. est. (7) If the manufacturer or distributor of an identical, related, or similar drug Subpart F [Reserved] product requests and is granted a hearing, the hearing may consider whether Subpart G—Miscellaneous the product is in fact identical, related, Provisions or similar to the drug product named in the notice of opportunity for a hear- SOURCE: 50 FR 7493, Feb. 22, 1985, unless ing. otherwise noted. Redesignated at 57 FR 17983, (8) A request for a hearing, and any Apr. 28, 1992. subsequent grant or denial of a hearing, applies only to the drug products § 314.410 Imports and exports of new named in such documents. drugs. (h) FDA will issue a notice with- (a) Imports. (1) A new drug may be im- drawing approval and declaring all ported into the United States if: (i) It products unlawful for drug products is the subject of an approved applica- subject to a notice of opportunity for a tion under this part; or (ii) it complies hearing, including any identical, re- with the regulations pertaining to in- lated, or similar drug product under vestigational new drugs under part 312; § 310.6, for which an opportunity for a and it complies with the general regu- hearing is waived or for which a hear- lations pertaining to imports under ing is denied. The Commissioner may subpart E of part 1. defer or stay the action pending a ruling on any related request for a hear- (2) A drug substance intended for use ing or pending any related hearing or in the manufacture, processing, or re- other administrative or judicial pro- packing of a new drug may be imported ceeding. into the United States if it complies with the labeling exemption in § 201.122 [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, pertaining to shipments of drug sub- 1985, as amended at 50 FR 21238, May 23, 1985; stances in domestic commerce. 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, (b) Exports. (1) A new drug may be ex- Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR ported if it is the subject of an ap- 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004; proved application under this part or it 74 FR 13113, Mar. 26, 2009] complies with the regulations pertaining to investigational new drugs § 314.201 Procedure for hearings. under part 312. Parts 10 through 16 apply to hearings (2) A new drug substance that is cov- relating to new drugs under section 505 ered by an application approved under (d) and (e) of the act. this part for use in the manufacture of an approved drug product may be ex- § 314.235 Judicial review. ported by the applicant or any person (a) The Commissioner of Food and listed as a supplier in the approved ap- Drugs will certify the transcript and plication, provided the drug substance record. In any case in which the Com- intended for export meets the speci- missioner enters an order without a fication of, and is shipped with a copy hearing under § 314.200(g), the record of the labeling required for, the ap- certified by the Commissioner is re- proved drug product.

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(3) Insulin or an antibiotic drug may (b) An investigational new drug ap- be exported without regard to the re- plication or an application, abbre- quirements in section 802 of the act if viated application, amendment, or sup- the insulin or antibiotic drug meets plement may incorporate by reference the requirements of section 801(e)(1) of all or part of the contents of any drug the act. master file in support of the submis- [50 FR 7493, Feb. 22, 1985. Redesignated at 57 sion if the holder authorizes the incor- FR 17983, Apr. 28, 1992, and amended at 64 FR poration in writing. Each incorpora- 402, Jan. 5, 1999; 69 FR 18766, Apr. 8, 2004] tion by reference is required to describe the incorporated material by § 314.420 Drug master files. name, reference number, volume, and (a) A drug master file is a submission page number of the drug master file. of information to the Food and Drug (c) A drug master file is required to Administration by a person (the drug be submitted in two copies. The agency master file holder) who intends it to be has prepared guidance that provides in- used for one of the following purposes: formation about how to prepare a well- To permit the holder to incorporate organized drug master file. If the drug the information by reference when the master file holder adds, changes, or de- holder submits an investigational new letes any information in the file, the drug application under part 312 or sub- holder shall notify in writing, each per- mits an application or an abbreviated son authorized to reference that infor- application or an amendment or sup- mation. Any addition, change, or dele- plement to them under this part, or to tion of information in a drug master permit the holder to authorize other file (except the list required under persons to rely on the information to paragraph (d) of this section) is re- support a submission to FDA without quired to be submitted in two copies the holder having to disclose the information to the person. FDA ordinarily and to describe by name, reference neither independently reviews drug number, volume, and page number the master files nor approves or dis- information affected in the drug mas- approves submissions to a drug master ter file. file. Instead, the agency customarily (d) The drug master file is required to reviews the information only in the contain a complete list of each person context of an application under part currently authorized to incorporate by 312 or this part. A drug master file may reference any information in the file, contain information of the kind re- identifying by name, reference number, quired for any submission to the agen- volume, and page number the informa- cy, including information about the tion that each person is authorized to following: incorporate. If the holder restricts the (1) [Reserved] authorization to particular drug prod- (2) Drug substance, drug substance ucts, the list is required to include the intermediate, and materials used in name of each drug product and the ap- their preparation, or drug product; plication number, if known, to which (3) Packaging materials; the authorization applies. (4) Excipient, colorant, flavor, es- (e) The public availability of data sence, or materials used in their prepa- and information in a drug master file, ration; including the availability of data and (5) FDA-accepted reference informa- information in the file to a person au- tion. (A person wishing to submit in- thorized to reference the file, is deter- formation and supporting data in a mined under part 20 and § 314.430. drug master file (DMF) that is not covered by Types II through IV DMF’s [50 FR 7493, Feb. 22, 1985, as amended at 50 must first submit a letter of intent to FR 21238, May 23, 1985; 53 FR 33122, Aug. 30, the Drug Master File Staff, Food and 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, Drug Administration, 5901–B Jan. 12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR Ammendale Rd., Beltsville, MD 20705– 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004] 1266.) FDA will then contact the person to discuss the proposed submission.

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§ 314.430 Availability for public disclo- (2) Notwithstanding paragraph (d)(1) sure of data and information in an of this section, FDA will make avail- application or abbreviated applica- able to the public upon request the in- tion. formation in the investigational new (a) The Food and Drug Administra- drug application that was required to tion will determine the public avail- be filed in Docket Number 95S–0158 in ability of any part of an application or the Division of Dockets Management abbreviated application under this sec- (HFA–305), Food and Drug Administra- tion and part 20 of this chapter. For tion, 5630 Fishers Lane, rm. 1061, Rock- purposes of this section, the applica- ville, MD 20852, for investigations in- tion or abbreviated application involving an exception from informed cludes all data and information sub- consent under § 50.24 of this chapter. mitted with or incorporated by ref- Persons wishing to request this infor- erence in the application or abbre- mation shall submit a request under viated application, including investiga- the Freedom of Information Act. tional new drug applications, drug (e) After FDA sends an approval let- master files under § 314.420, supple- ter to the applicant, the following data ments submitted under § 314.70 or and information in the application or § 314.97, reports under § 314.80 or § 314.98, abbreviated application are imme- and other submissions. For purposes of diately available for public disclosure, this section, safety and effectiveness unless the applicant shows that ex- data include all studies and tests of a traordinary circumstances exist. A list drug on animals and humans and all of approved applications and abbre- studies and tests of the drug for iden- viated applications, entitled ‘‘Approved tity, stability, purity, potency, and Drug Products with Therapeutic bioavailability. Equivalence Evaluations,’’ is available (b) FDA will not publicly disclose the from the Government Printing Office, existence of an application or abbre- Washington, DC 20402. This list is up- viated application before an approval dated monthly. letter is sent to the applicant under (1) [Reserved] § 314.105 or tentative approval letter is (2) If the application applies to a new sent to the applicant under § 314.107, drug, all safety and effectiveness data unless the existence of the application previously disclosed to the public as or abbreviated application has been previously publicly disclosed or ac- set forth in § 20.81 and a summary or knowledged. summaries of the safety and effective- (c) If the existence of an unapproved ness data and information submitted application or abbreviated application with or incorporated by reference in has not been publicly disclosed or ac- the application. The summaries do not knowledged, no data or information in constitute the full reports of investiga- the application or abbreviated applications under section 505(b)(1) of the act tion is available for public disclosure. (21 U.S.C. 355(b)(1)) on which the safety (d)(1) If the existence of an applica- or effectiveness of the drug may be ap- tion or abbreviated application has proved. The summaries consist of the been publicly disclosed or acknowl- following: edged before the agency sends an ap- (i) For an application approved be- proval letter to the applicant, no data fore July 1, 1975, internal agency or information contained in the appli- records that describe safety and effec- cation or abbreviated application is tiveness data and information, for ex- available for public disclosure before ample, a summary of the basis for ap- the agency sends an approval letter, proval or internal reviews of the data but the Commissioner may, in his or and information, after deletion of the her discretion, disclose a summary of following: selected portions of the safety and ef- (a) Names and any information that fectiveness data that are appropriate would identify patients or test subjects for public consideration of a specific or investigators. pending issue; for example, for consid- (b) Any inappropriate gratuitous eration of an open session of an FDA comments unnecessary to an objective advisory committee. analysis of the data and information.

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(ii) For an application approved on or (1) No work is being or will be under- after July 1, 1975, a Summary Basis of taken to have the application ap- Approval (SBA) document that con- proved. tains a summary of the safety and ef- (2) A final determination is made fectiveness data and information eval- that the application is not approvable uated by FDA during the drug approval and all legal appeals have been ex- process. The SBA is prepared in one of hausted. the following ways: (3) Approval of the application is (a) Before approval of the applica- withdrawn and all legal appeals have tion, the applicant may prepare a draft been exhausted. SBA which the Center for Drug Evalua- (4) A final determination has been tion and Research will review and may made that the drug is not a new drug. revise. The draft may be submitted (5) For applications submitted under with the application or as an amend- section 505(b) of the act, the effective ment. date of the approval of the first abbre- (b) The Center for Drug Evaluation viated application submitted under and Research may prepare the SBA. section 505(j) of the act which refers to (3) A protocol for a test or study, un- such drug, or the date on which the ap- less it is shown to fall within the exemption established for trade secrets proval of an abbreviated application and confidential commercial informa- under section 505(j) of the act which re- tion in § 20.61. fers to such drug could be made effec- (4) Adverse reaction reports, product tive if such an abbreviated application experience reports, consumer com- had been submitted. plaints, and other similar data and in- (6) For abbreviated applications sub- formation after deletion of the fol- mitted under section 505(j) of the act, lowing: when FDA sends an approval letter to (i) Names and any information that the applicant. would identify the person using the (g) The following data and informa- product. tion in an application or abbreviated (ii) Names and any information that application are not available for public would identify any third party involved disclosure unless they have been pre- with the report, such as a physician or viously disclosed to the public as set hospital or other institution. forth in § 20.81 of this chapter or they (5) A list of all active ingredients and relate to a product or ingredient that any inactive ingredients previously has been abandoned and they do not disclosed to the public as set forth in represent a trade secret or confidential § 20.81. commercial or financial information (6) An assay procedure or other ana- under § 20.61 of this chapter: lytical procedure, unless it serves no (1) Manufacturing methods or proc- regulatory or compliance purpose and esses, including quality control proce- is shown to fall within the exemption dures. established for trade secrets and con- (2) Production, sales distribution, fidential commercial information in and similar data and information, ex- § 20.61. cept that any compilation of that data (7) All correspondence and written and information aggregated and pre- summaries of oral discussions between pared in a way that does not reveal FDA and the applicant relating to the data or information which is not avail- application, under the provisions of able for public disclosure under this part 20. provision is available for public disclo- (f) All safety and effectiveness data sure. and information which have been submitted in an application and which (3) Quantitative or semiquantitative have not previously been disclosed to formulas. the public are available to the public, upon request, at the time any one of the following events occurs unless extraordinary circumstances are shown:

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(h) The compilations of information Park North II, HFD–[insert mail code specified in § 20.117 are available for of office or division], 7500 Standish public disclosure. Place, rm. 150, Rockville, MD 20855. The mail code for the Office of Generic [50 FR 7493, Feb. 22, 1985, as amended at 50 Drugs is HFD–600, the mail codes for FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, the Divisions of Chemistry I, II, and III Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR are HFD–620, HFD–640, and HFD–630, 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68 respectively, and the mail code for the FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, Division of Bioequivalence is HFD–650. 2004; 73 FR 39610, July 10, 2008] (3) A request for an opportunity for a hearing under § 314.110 on the question § 314.440 Addresses for applications of whether there are grounds for deny- and abbreviated applications. ing approval of an application, except (a) Applicants shall send applica- an application under paragraph (b) of tions, abbreviated applications, and this section, should be directed to the other correspondence relating to mat- Associate Director for Policy (HFD–5). ters covered by this part, except for (4) The field copy of an application, products listed in paragraph (b) of this an abbreviated application, amend- section, to the appropriate office iden- ments, supplements, resubmissions, re- tified below: quests for waivers, and other cor- (1) Except as provided in paragraph respondence about an application and (a)(4) of this section, an application an abbreviated application shall be under § 314.50 or § 314.54 submitted for sent to the applicant’s home FDA dis- filing should be directed to the Central trict office, except that a foreign appli- Document Room, 5901–B Ammendale cant shall send the field copy to the ap- Rd., Beltsville, MD 20705–1266. Appli- propriate address identified in para- cants may obtain information about graphs (a)(1) and (a)(2) of this section. folders for binding applications on the (b) Applicants shall send applications Internet at http://www.fda.gov/cder/ and other correspondence relating to ddms/binders.htm. After FDA has filed matters covered by this part for the the application, the agency will inform drug products listed below to the Food the applicant which division is respon- and Drug Administration, Center for sible for the application. Amendments, Biologics Evaluation and Research, supplements, resubmissions, requests Document Control Center, 10903 New for waivers, and other correspondence Hampshire Ave., Bldg. 71, Rm. G112, about an application that has been Silver Spring, MD 20993–0002, except ap- filed should be addressed to 5901–B plicants shall send a request for an op- Ammendale Rd., Beltsville, MD 20705– portunity for a hearing under § 314.110 1266, to the attention of the appro- on the question of whether there are priate division. grounds for denying approval of an application to the Center for Biologics (2) Except as provided in paragraph Evaluation and Research, ATTN: Di- (a)(4) of this section, an abbreviated ap- rector, at the same address. plication under § 314.94, and amend- (1) Ingredients packaged together ments, supplements, and resubmissions with containers intended for the collec- should be directed to the Office of Ge- tion, processing, or storage of blood neric Drugs (HFD–600), Center for Drug and blood components; Evaluation and Research, Food and (2) Plasma volume expanders and hy- Drug Administration, Metro Park droxyethyl starch for leukapheresis; North VII, 7620 Standish Pl., Rockville, (3) Blood component processing solu- MD 20855. This includes items sent by tions and shelf life extenders; and parcel post or overnight courier serv- (4) Oxygen carriers. ice. Correspondence not associated with an abbreviated application should [50 FR 7493, Feb. 22, 1985, as amended at 50 be addressed specifically to the in- FR 21238, May 23, 1985; 55 FR 11581, Mar. 29, tended office or division and to the per- 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR son as follows: Office of Generic Drugs, 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005; Center for Drug Evaluation and Re- 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. search, Food and Drug Administration, 26, 2009; 75 FR 37295, June 29, 2010; 80 FR Attn: [insert name of person], Metro 18091, Apr. 3, 2015]

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§ 314.445 Guidance documents. Approval under this section will be (a) FDA has made available guidance subject to the requirement that the ap- documents under § 10.115 of this chapter plicant study the drug further, to to help you to comply with certain re- verify and describe its clinical benefit, quirements of this part. where there is uncertainty as to the re- (b) The Center for Drug Evaluation lation of the surrogate endpoint to and Research (CDER) maintains a list clinical benefit, or of the observed clin- of guidance documents that apply to ical benefit to ultimate outcome. Post- CDER’s regulations. The list is main- marketing studies would usually be tained on the Internet and is published studies already underway. When re- annually in the FEDERAL REGISTER. A quired to be conducted, such studies request for a copy of the CDER list must also be adequate and well-con- should be directed to the Office of trolled. The applicant shall carry out Training and Communications, Divi- any such studies with due diligence. sion of Drug Information, Center for Drug Evaluation and Research, Food § 314.520 Approval with restrictions to assure safe use. and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD (a) If FDA concludes that a drug 20993–0002. product shown to be effective can be safely used only if distribution or use [65 FR 56480, Sept. 19, 2000, as amended at 74 is restricted, FDA will require such FR 13113, Mar. 26, 2009] postmarketing restrictions as are needed to assure safe use of the drug prod- Subpart H—Accelerated Approval uct, such as: of New Drugs for Serious or (1) Distribution restricted to certain Life-Threatening Illnesses facilities or physicians with special training or experience; or SOURCE: 57 FR 58958, Dec. 11, 1992, unless (2) Distribution conditioned on the otherwise noted. performance of specified medical procedures. § 314.500 Scope. (b) The limitations imposed will be This subpart applies to certain new commensurate with the specific safety drug products that have been studied concerns presented by the drug prod- for their safety and effectiveness in uct. treating serious or life-threatening illnesses and that provide meaningful § 314.530 Withdrawal procedures. therapeutic benefit to patients over ex- (a) For new drugs approved under isting treatments (e.g., ability to treat §§ 314.510 and 314.520, FDA may with- patients unresponsive to, or intolerant draw approval, following a hearing as of, available therapy, or improved pa- provided in part 15 of this chapter, as tient response over available therapy). modified by this section, if: [57 FR 58958, Dec. 11, 1992, as amended at 64 (1) A postmarketing clinical study FR 402, Jan. 5, 1999] fails to verify clinical benefit; (2) The applicant fails to perform the § 314.510 Approval based on a surro- required postmarketing study with due gate endpoint or on an effect on a diligence; clinical endpoint other than sur- (3) Use after marketing demonstrates vival or irreversible morbidity. that postmarketing restrictions are in- FDA may grant marketing approval adequate to assure safe use of the drug for a new drug product on the basis of product; adequate and well-controlled clinical (4) The applicant fails to adhere to trials establishing that the drug prod- the postmarketing restrictions agreed uct has an effect on a surrogate end- upon; point that is reasonably likely, based (5) The promotional materials are on epidemiologic, therapeutic, patho- false or misleading; or physiologic, or other evidence, to pre- (6) Other evidence demonstrates that dict clinical benefit or on the basis of the drug product is not shown to be an effect on a clinical endpoint other safe or effective under its conditions of than survival or irreversible morbidity. use.

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(b) Notice of opportunity for a hearing. agency action from which the appli- The Director of the Center for Drug cant may petition for judicial review. Evaluation and Research will give the Before requesting an order from a applicant notice of an opportunity for court for a stay of action pending re- a hearing on the Center’s proposal to view, an applicant must first submit a withdraw the approval of an applica- petition for a stay of action under tion approved under § 314.510 or § 314.520. § 10.35 of this chapter. The notice, which will ordinarily be a [57 FR 58958, Dec. 11, 1992, as amended at 64 letter, will state generally the reasons FR 402, Jan. 5, 1999] for the action and the proposed grounds for the order. § 314.540 Postmarketing safety report- (c) Submission of data and information. ing. (1) If the applicant fails to file a writ- Drug products approved under this ten request for a hearing within 15 days program are subject to the post- of receipt of the notice, the applicant marketing recordkeeping and safety waives the opportunity for a hearing. reporting applicable to all approved (2) If the applicant files a timely re- drug products, as provided in §§ 314.80 quest for a hearing, the agency will and 314.81. publish a notice of hearing in the FED- ERAL REGISTER in accordance with § 314.550 Promotional materials. §§ 12.32(e) and 15.20 of this chapter. (3) An applicant who requests a hear- For drug products being considered ing under this section must, within 30 for approval under this subpart, unless days of receipt of the notice of oppor- otherwise informed by the agency, ap- tunity for a hearing, submit the data plicants must submit to the agency for and information upon which the appli- consideration during the preapproval cant intends to rely at the hearing. review period copies of all promotional (d) Separation of functions. Separation materials, including promotional label- of functions (as specified in § 10.55 of ing as well as advertisements, intended this chapter) will not apply at any for dissemination or publication within point in withdrawal proceedings under 120 days following marketing approval. this section. After 120 days following marketing ap- (e) Procedures for hearings. Hearings proval, unless otherwise informed by held under this section will be con- the agency, the applicant must submit ducted in accordance with the provi- promotional materials at least 30 days sions of part 15 of this chapter, with prior to the intended time of initial the following modifications: dissemination of the labeling or initial (1) An advisory committee duly con- publication of the advertisement. stituted under part 14 of this chapter will be present at the hearing. The § 314.560 Termination of requirements. committee will be asked to review the If FDA determines after approval issues involved and to provide advice that the requirements established in and recommendations to the Commis- § 314.520, § 314.530, or § 314.550 are no sioner of Food and Drugs. longer necessary for the safe and effec- (2) The presiding officer, the advisory tive use of a drug product, it will so no- committee members, up to three rep- tify the applicant. Ordinarily, for drug resentatives of the applicant, and up to products approved under § 314.510, these three representatives of the Center requirements will no longer apply when may question any person during or at FDA determines that the required the conclusion of the person’s presen- postmarketing study verifies and de- tation. No other person attending the scribes the drug product’s clinical ben- hearing may question a person making efit and the drug product would be ap- a presentation. The presiding officer propriate for approval under tradi- may, as a matter of discretion, permit tional procedures. For drug products questions to be submitted to the pre- approved under § 314.520, the restric- siding officer for response by a person tions would no longer apply when FDA making a presentation. determines that safe use of the drug (f) Judicial review. The Commis- product can be assured through appro- sioner’s decision constitutes final priate labeling. FDA also retains the

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discretion to remove specific post- animals to provide substantial evi- approval requirements upon review of a dence of the effectiveness of these petition submitted by the sponsor in products only when: accordance with § 10.30. (1) There is a reasonably well-understood pathophysiological mechanism of Subpart I—Approval of New Drugs the toxicity of the substance and its When Human Efficacy Studies prevention or substantial reduction by Are Not Ethical or Feasible the product; (2) The effect is demonstrated in SOURCE: 67 FR 37995, May 31, 2002, unless more than one animal species expected otherwise noted. to react with a response predictive for humans, unless the effect is dem- § 314.600 Scope. onstrated in a single animal species This subpart applies to certain new that represents a sufficiently well- drug products that have been studied characterized animal model for pre- for their safety and efficacy in amelio- dicting the response in humans; rating or preventing serious or life- (3) The animal study endpoint is threatening conditions caused by expo- clearly related to the desired benefit in sure to lethal or permanently disabling humans, generally the enhancement of toxic biological, chemical, radio- survival or prevention of major mor- logical, or nuclear substances. This bidity; and subpart applies only to those new drug (4) The data or information on the ki- products for which: Definitive human netics and pharmacodynamics of the efficacy studies cannot be conducted product or other relevant data or infor- because it would be unethical to delib- mation, in animals and humans, allows erately expose healthy human volun- selection of an effective dose in hu- teers to a lethal or permanently dis- mans. abling toxic biological, chemical, radi- (b) Approval under this subpart will ological, or nuclear substance; and be subject to three requirements: field trials to study the product’s effec- (1) Postmarketing studies. The appli- tiveness after an accidental or hostile cant must conduct postmarketing exposure have not been feasible. This studies, such as field studies, to verify subpart does not apply to products that and describe the drug’s clinical benefit can be approved based on efficacy and to assess its safety when used as standards described elsewhere in FDA’s regulations (e.g., accelerated approval indicated when such studies are fea- based on surrogate markers or clinical sible and ethical. Such postmarketing endpoints other than survival or irre- studies would not be feasible until an versible morbidity), nor does it address exigency arises. When such studies are the safety evaluation for the products feasible, the applicant must conduct to which it does apply. such studies with due diligence. Appli- cants must include as part of their ap- § 314.610 Approval based on evidence plication a plan or approach to post- of effectiveness from studies in ani- marketing study commitments in the mals. event such studies become ethical and (a) FDA may grant marketing ap- feasible. proval for a new drug product for which (2) Approval with restrictions to ensure safety has been established and for safe use. If FDA concludes that a drug which the requirements of § 314.600 are product shown to be effective under met based on adequate and well-con- this subpart can be safely used only if trolled animal studies when the results distribution or use is restricted, FDA of those animal studies establish that will require such postmarketing re- the drug product is reasonably likely strictions as are needed to ensure safe to produce clinical benefit in humans. use of the drug product, commensurate In assessing the sufficiency of animal with the specific safety concerns pre- data, the agency may take into ac- sented by the drug product, such as: count other data, including human (i) Distribution restricted to certain data, available to the agency. FDA will facilities or health care practitioners rely on the evidence from studies in with special training or experience;

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(ii) Distribution conditioned on the posal to withdraw the approval of an performance of specified medical proce- application approved under this sub- dures, including medical followup; and part. The notice, which will ordinarily (iii) Distribution conditioned on be a letter, will state generally the rea- specified recordkeeping requirements. sons for the action and the proposed (3) Information to be provided to patient grounds for the order. recipients. For drug products or specific (c) Submission of data and information. indications approved under this sub- (1) If the applicant fails to file a writ- part, applicants must prepare, as part ten request for a hearing within 15 days of their proposed labeling, labeling to of receipt of the notice, the applicant be provided to patient recipients. The waives the opportunity for a hearing. patient labeling must explain that, for (2) If the applicant files a timely re- ethical or feasibility reasons, the quest for a hearing, the agency will drug’s approval was based on efficacy publish a notice of hearing in the FED- studies conducted in animals alone and ERAL REGISTER in accordance with must give the drug’s indication(s), di- §§ 12.32(e) and 15.20 of this chapter. rections for use (dosage and adminis- (3) An applicant who requests a hear- tration), contraindications, a descrip- ing under this section must, within 30 tion of any reasonably foreseeable days of receipt of the notice of oppor- risks, adverse reactions, anticipated tunity for a hearing, submit the data benefits, drug interactions, and any and information upon which the appli- other relevant information required by cant intends to rely at the hearing. FDA at the time of approval. The pa- (d) Separation of functions. Separation tient labeling must be available with of functions (as specified in § 10.55 of the product to be provided to patients this chapter) will not apply at any prior to administration or dispensing point in withdrawal proceedings under of the drug product for the use ap- this section. proved under this subpart, if possible. (e) Procedures for hearings. Hearings held under this section will be con- § 314.620 Withdrawal procedures. ducted in accordance with the provi- (a) Reasons to withdraw approval. For sions of part 15 of this chapter, with new drugs approved under this subpart, the following modifications: FDA may withdraw approval, following (1) An advisory committee duly con- a hearing as provided in part 15 of this stituted under part 14 of this chapter chapter, as modified by this section, if: will be present at the hearing. The (1) A postmarketing clinical study committee will be asked to review the fails to verify clinical benefit; issues involved and to provide advice (2) The applicant fails to perform the and recommendations to the Commis- postmarketing study with due dili- sioner of Food and Drugs. gence; (2) The presiding officer, the advisory (3) Use after marketing demonstrates committee members, up to three rep- that postmarketing restrictions are in- resentatives of the applicant, and up to adequate to ensure safe use of the drug three representatives of CDER may product; question any person during or at the (4) The applicant fails to adhere to conclusion of the person’s presen- the postmarketing restrictions applied tation. No other person attending the at the time of approval under this sub- hearing may question a person making part; a presentation. The presiding officer (5) The promotional materials are may, as a matter of discretion, permit false or misleading; or questions to be submitted to the pre- (6) Other evidence demonstrates that siding officer for response by a person the drug product is not shown to be making a presentation. safe or effective under its conditions of (f) Judicial review. The Commissioner use. of Food and Drugs’ decision constitutes (b) Notice of opportunity for a hearing. final agency action from which the ap- The Director of the Center for Drug plicant may petition for judicial re- Evaluation and Research (CDER) will view. Before requesting an order from a give the applicant notice of an oppor- court for a stay of action pending re- tunity for a hearing on CDER’s pro- view, an applicant must first submit a

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petition for a stay of action under PART 315—DIAGNOSTIC § 10.35 of this chapter. RADIOPHARMACEUTICALS § 314.630 Postmarketing safety report- Sec. ing. 315.1 Scope. Drug products approved under this 315.2 Definition. subpart are subject to the post- 315.3 General factors relevant to safety and marketing recordkeeping and safety effectiveness. reporting requirements applicable to 315.4 Indications. all approved drug products, as provided 315.5 Evaluation of effectiveness. 315.6 Evaluation of safety. in §§ 314.80 and 314.81. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, § 314.640 Promotional materials. 355, 371, 374, 379e; sec. 122, Pub. L. 105–115, 111 Stat. 2322 (21 U.S.C. 355 note). For drug products being considered for approval under this subpart, unless SOURCE: 64 FR 26667, May 17, 1999, unless otherwise noted. otherwise informed by the agency, applicants must submit to the agency for § 315.1 Scope. consideration during the preapproval The regulations in this part apply to review period copies of all promotional radiopharmaceuticals intended for in materials, including promotional label- vivo administration for diagnostic and ing as well as advertisements, intended monitoring use. They do not apply to for dissemination or publication within radiopharmaceuticals intended for 120 days following marketing approval. therapeutic purposes. In situations After 120 days following marketing ap- where a particular radiopharma- proval, unless otherwise informed by ceutical is proposed for both diagnostic the agency, the applicant must submit and therapeutic uses, the radiopharma- promotional materials at least 30 days ceutical must be evaluated taking into prior to the intended time of initial account each intended use. dissemination of the labeling or initial publication of the advertisement. § 315.2 Definition. For purposes of this part, diagnostic § 314.650 Termination of requirements. radiopharmaceutical means: If FDA determines after approval (a) An article that is intended for use under this subpart that the require- in the diagnosis or monitoring of a dis- ments established in §§ 314.610(b)(2), ease or a manifestation of a disease in 314.620, and 314.630 are no longer nec- humans and that exhibits spontaneous essary for the safe and effective use of disintegration of unstable nuclei with a drug product, FDA will so notify the the emission of nuclear particles or applicant. Ordinarily, for drug products photons; or approved under § 314.610, these require- (b) Any nonradioactive reagent kit or ments will no longer apply when FDA nuclide generator that is intended to determines that the postmarketing be used in the preparation of such arti- study verifies and describes the drug cle as defined in paragraph (a) of this product’s clinical benefit. For drug section. products approved under § 314.610, the § 315.3 General factors relevant to restrictions would no longer apply safety and effectiveness. when FDA determines that safe use of FDA’s determination of the safety the drug product can be ensured and effectiveness of a diagnostic radio- through appropriate labeling. FDA also pharmaceutical includes consideration retains the discretion to remove spe- of the following: cific postapproval requirements upon (a) The proposed use of the diagnostic review of a petition submitted by the radiopharmaceutical in the practice of sponsor in accordance with § 10.30 of medicine, this chapter. (b) The pharmacological and toxicological activity of the diagnostic radiopharmaceutical (including any

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carrier or ligand component of the di- in diagnostic or therapeutic patient agnostic radiopharmaceutical), and management. (c) The estimated absorbed radiation (5) For a claim that does not fall dose of the diagnostic radiopharma- within the indication categories identi- ceutical. fied in § 315.4, the applicant or sponsor should consult FDA on how to estab- § 315.4 Indications. lish the effectiveness of the diagnostic (a) For diagnostic radiopharma- radiopharmaceutical for the claim. ceuticals, the categories of proposed (b) The accuracy and usefulness of indications for use include, but are not the diagnostic information is deter- limited to, the following: mined by comparison with a reliable (1) Structure delineation; assessment of actual clinical status. A (2) Functional, physiological, or bio- reliable assessment of actual clinical chemical assessment; status may be provided by a diagnostic (3) Disease or pathology detection or standard or standards of demonstrated assessment; and accuracy. In the absence of such diag- (4) Diagnostic or therapeutic patient nostic standard(s), the actual clinical management. status must be established in another (b) Where a diagnostic radiopharma- manner, e.g., patient followup. ceutical is not intended to provide dis- § 315.6 Evaluation of safety. ease-specific information, the proposed indications for use may refer to a bio- (a) Factors considered in the safety chemical, physiological, anatomical, or assessment of a diagnostic radio- pathological process or to more than pharmaceutical include, among others, one disease or condition. the following: (1) The radiation dose; § 315.5 Evaluation of effectiveness. (2) The pharmacology and toxicology (a) The effectiveness of a diagnostic of the radiopharmaceutical, including radiopharmaceutical is assessed by any radionuclide, carrier, or ligand; evaluating its ability to provide useful (3) The risks of an incorrect diag- clinical information related to its pro- nostic determination; posed indications for use. The method (4) The adverse reaction profile of the of this evaluation varies depending drug; upon the proposed indication(s) and (5) Results of human experience with may use one or more of the following the radiopharmaceutical for other uses; criteria: and (1) The claim of structure delineation (6) Results of any previous human ex- is established by demonstrating in a perience with the carrier or ligand of defined clinical setting the ability to the radiopharmaceutical when the locate anatomical structures and to same chemical entity as the carrier or characterize their anatomy. ligand has been used in a previously (2) The claim of functional, physio- studied product. logical, or biochemical assessment is (b) The assessment of the adverse re- established by demonstrating in a de- action profile includes, but is not lim- fined clinical setting reliable measure- ited to, an evaluation of the potential ment of function(s) or physiological, of the diagnostic radiopharmaceutical, biochemical, or molecular process(es). including the carrier or ligand, to elic- (3) The claim of disease or pathology it the following: detection or assessment is established (1) Allergic or hypersensitivity re- by demonstrating in a defined clinical sponses, setting that the diagnostic radio- (2) Immunologic responses, pharmaceutical has sufficient accuracy (3) Changes in the physiologic or bio- in identifying or characterizing the dis- chemical function of the target and ease or pathology. nontarget tissues, and (4) The claim of diagnostic or thera- (4) Clinically detectable signs or peutic patient management is estab- symptoms. lished by demonstrating in a defined (c)(1) To establish the safety of a di- clinical setting that the test is useful agnostic radiopharmaceutical, FDA

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may require, among other information, Subpart C—Designation of an Orphan the following types of data: Drug (i) Pharmacology data, 316.20 Content and format of a request for (ii) Toxicology data, orphan-drug designation. (iii) Clinical adverse event data, and 316.21 Verification of orphan-drug status. (iv) Radiation safety assessment. 316.22 Permanent-resident agent for foreign (2) The amount of new safety data re- sponsor. 316.23 Timing of requests for orphan-drug quired will depend on the characteris- designation; designation of already ap- tics of the product and available infor- proved drugs. mation regarding the safety of the di- 316.24 Deficiency letters and granting or- agnostic radiopharmaceutical, and its phan-drug designation. carrier or ligand, obtained from other 316.25 Refusal to grant orphan-drug designa- studies and uses. Such information tion. may include, but is not limited to, the 316.26 Amendment to orphan-drug designation. dose, route of administration, fre- 316.27 Change in ownership of orphan-drug quency of use, half-life of the ligand or designation. carrier, half-life of the radionuclide, 316.28 Publication of orphan-drug designa- and results of clinical and preclinical tions. studies. FDA will establish categories 316.29 Revocation of orphan-drug designa- of diagnostic radiopharmaceuticals tion. based on defined characteristics rel- 316.30 Annual reports of holder of orphan- drug designation. evant to risk and will specify the amount and type of safety data that Subpart D—Orphan-Drug Exclusive are appropriate for each category (e.g., Approval required safety data may be limited for diagnostic radiopharmaceuticals with 316.31 Scope of orphan-drug exclusive ap- a well established, low-risk profile). proval. 316.34 FDA recognition of exclusive ap- Upon reviewing the relevant product proval. characteristics and safety information, 316.36 Insufficient quantities of orphan FDA will place each diagnostic radio- drugs. pharmaceutical into the appropriate safety risk category. Subpart E—Open Protocols for (d) Radiation safety assessment. The Investigations radiation safety assessment must es- 316.40 Treatment use of a designated orphan tablish the radiation dose of a diag- drug. nostic radiopharmaceutical by radiation dosimetry evaluations in humans Subpart F—Availability of Information and appropriate animal models. The maximum tolerated dose need not be 316.50 Guidance documents. 316.52 Availability for public disclosure of established. data and information in requests and applications.

PART 316—ORPHAN DRUGS AUTHORITY: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

Subpart A—General Provisions SOURCE: 57 FR 62085, Dec. 29, 1992, unless otherwise noted. Sec. 316.1 Scope of this part. EDITORIAL NOTE: Nomenclature changes to 316.2 Purpose. part 316 appear at 69 FR 13717, Mar. 24, 2004. 316.3 Definitions. 316.4 Address for submissions. Subpart A—General Provisions Subpart B—Written Recommendations for § 316.1 Scope of this part. Investigations of Orphan Drugs (a) This part implements sections 525, 316.10 Content and format of a request for 526, 527, and 528 of the act and provides written recommendations. procedures to encourage and facilitate 316.12 Providing written recommendations. the development of drugs for rare dis- 316.14 Refusal to provide written rec- eases or conditions, including biologi- ommendations. cal products and antibiotics. This part

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sets forth the procedures and require- rate) of the molecule, responsible for ments for: the physiological or pharmacological (1) Submissions to FDA of: action of the drug substance. (i) Requests for recommendations for (3) Clinically superior means that a investigations of drugs for rare dis- drug is shown to provide a significant eases or conditions; therapeutic advantage over and above (ii) Requests for designation of a drug that provided by an approved drug for a rare disease or condition; and (that is otherwise the same drug) in (iii) Requests for gaining exclusive one or more of the following ways: approval for a drug for a rare disease or (i) Greater effectiveness than an ap- condition. proved drug (as assessed by effect on a (2) Allowing a sponsor to provide an clinically meaningful endpoint in ade- investigational drug under a treatment quate and well controlled clinical protocol to patients who need the drug trials). Generally, this would represent for treatment of a rare disease or con- the same kind of evidence needed to dition. support a comparative effectiveness (b) This part does not apply to food, claim for two different drugs; in most medical devices, or drugs for veteri- cases, direct comparative clinical nary use. trials would be necessary; or (c) References in this part to regulatory sections of the Code of Federal (ii) Greater safety in a substantial Regulations are to chapter I of title 21, portion of the target populations, for unless otherwise noted. example, by the elimination of an ingredient or contaminant that is associ- [57 FR 62085, Dec. 29, 1992, as amended at 78 ated with relatively frequent adverse FR 35132, June 12, 2013] effects. In some cases, direct comparative clinical trials will be necessary; or § 316.2 Purpose. (iii) In unusual cases, where neither The purpose of this part is to estab- greater safety nor greater effectiveness lish standards and procedures for deter- has been shown, a demonstration that mining eligibility for the benefits pro- the drug otherwise makes a major con- vided for in section 2 of the Orphan tribution to patient care. Drug Act, including written rec- (4) Director means the Director of ommendations for investigations of or- FDA’s Office of Orphan Products Devel- phan drugs, a 7-year period of exclusive opment. marketing, and treatment use of investigational orphan drugs. This part is (5) FDA means the Food and Drug also intended to satisfy Congress’ re- Administration. quirements that FDA promulgate pro- (6) Holder means the sponsor in whose cedures for the implementation of sec- name an orphan drug is designated and tions 525(a) and 526(a) of the act. approved. (7) IND means an investigational new § 316.3 Definitions. drug application under part 312 of this (a) The definitions and interpreta- chapter. tions contained in section 201 of the act (8) Manufacturer means any person or apply to those terms when used in this agency engaged in the manufacture of part. a drug that is subject to investigation (b) The following definitions of terms and approval under the act or the bio- apply to this part: logics provisions of the Public Health (1) Act means the Federal Food, Drug, Service Act (42 U.S.C. 262–263). and Cosmetic Act as amended by sec- (9) Marketing application means an ap- tion 2 of the Orphan Drug Act (sections plication for approval of a new drug 525–528 (21 U.S.C. 360aa–360dd)). filed under section 505(b) of the act or (2) Active moiety means the molecule an application for a biologics license or ion, excluding those appended por- submitted under section 351 of the Pub- tions of the molecule that cause the lic Health Service Act (42 U.S.C. 262). drug to be an ester, salt (including a (10) Orphan drug means a drug in- salt with hydrogen or coordination tended for use in a rare disease or con- bonds), or other noncovalent derivative dition as defined in section 526 of the (such as a complex, chelate, or clath- act.

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(11) Orphan-drug designation means in structure between them were due to FDA’s act of granting a request for des- post-translational events or infidelity ignation under section 526 of the act. of translation or transcription or were (12) Orphan-drug exclusive approval or minor differences in amino acid se- exclusive approval means that, effective quence; other potentially important on the date of FDA approval as stated differences, such as different glycosyl- in the approval letter of a marketing ation patterns or different tertiary application for a sponsor of a des- structures, would not cause the drugs ignated orphan drug, no approval will to be considered different unless the be given to a subsequent sponsor of the differences were shown to be clinically same drug for the same use or indica- superior. tion for 7 years, except as otherwise (B) Two polysaccharide drugs would provided by law or in this part. A des- be considered the same if they had ignated drug will receive orphan-drug identical saccharide repeating units, exclusive approval only if the same even if the number of units were to drug has not already been approved for vary and even if there were postpolym- the same use or indication. erization modifications, unless the sub- (13) Orphan subset of a non-rare disease sequent drug could be shown to be or condition (‘‘orphan subset’’) means clinically superior. that use of the drug in a subset of per- (C) Two polynucleotide drugs con- sons with a non-rare disease or condition may be appropriate but use of the sisting of two or more distinct nucleo- drug outside of that subset (in the re- tides would be considered the same if maining persons with the non-rare dis- they had an identical sequence of pu- ease or condition) would be inappro- rine and pyrimidine bases (or their de- priate owing to some property(ies) of rivatives) bound to an identical sugar the drug, for example, drug toxicity, backbone (ribose, deoxyribose, or modi- mechanism of action, or previous clin- fications of these sugars), unless the ical experience with the drug. subsequent drug were shown to be (14) Same drug means: clinically superior. (i) If it is a drug composed of small (D) Closely related, complex partly molecules, a drug that contains the definable drugs with similar thera- same active moiety as a previously ap- peutic intent, such as two live viral proved drug and is intended for the vaccines for the same indication, would same use as the previously approved be considered the same unless the sub- drug, even if the particular ester or sequent drug was shown to be clini- salt (including a salt with hydrogen or cally superior. coordination bonds) or other (15) Sponsor means the entity that as- noncovalent derivative such as a com- sumes responsibility for a clinical or plex, chelate or clathrate has not been nonclinical investigation of a drug, in- previously approved, except that if the cluding the responsibility for compli- subsequent drug can be shown to be ance with applicable provisions of the clinically superior to the first drug, it act and regulations. A sponsor may be will not be considered to be the same an individual, partnership, corporation, drug. or Government agency and may be a (ii) If it is a drug composed of large manufacturer, scientific institution, or molecules (macromolecules), a drug an investigator regularly and lawfully that contains the same principal mo- engaged in the investigation of drugs. lecular structural features (but not For purposes of the Orphan Drug Act, necessarily all of the same structural FDA considers the real party or parties features) and is intended for the same in interest to be a sponsor. use as a previously approved drug, except that, if the subsequent drug can be [57 FR 62085, Dec. 29, 1992, as amended at 64 shown to be clinically superior, it will FR 402, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; not be considered to be the same drug. 78 FR 35132, June 12, 2013] This criterion will be applied as follows to different kinds of macromolecules: § 316.4 Address for submissions. (A) Two protein drugs would be con- All correspondence and requests for sidered the same if the only differences FDA action under the provisions of

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this rule should be addressed as fol- (if the product is the subject of an IND lows: Office of Orphan Products Devel- or a marketing application, the IND or opment, Food and Drug Administra- marketing application numbers should tion, Bldg. 32, Rm. 5271, 10903 New be stated and the investigational or ap- Hampshire Ave., Silver Spring, MD proved indication or indications for use 20993. specified); [78 FR 35133, June 12, 2013] (ii) Known marketing experience or investigational status outside the Subpart B—Written Recommenda- United States; (iii) So far as is known or can be de- tions for Investigations of Or- termined, all indications previously or phan Drugs currently under investigation anywhere; § 316.10 Content and format of a request for written recommendations. (iv) All adverse regulatory actions taken by the United States or foreign (a) A sponsor’s request for written authorities. recommendations from FDA concerning the nonclinical and clinical in- (8) The basis for concluding that the vestigations necessary for approval of a drug is for a disease or condition that marketing application shall be sub- is rare in the United States, including mitted in the form and contain the in- the following: formation required in this section. (i) The size and other known demo- FDA may require the sponsor to sub- graphic characteristics of the patient mit information in addition to that population affected and the source of specified in paragraph (b) of this sec- this information. tion if FDA determines that the spon- (ii) For drugs intended for diseases or sor’s initial request does not contain conditions affecting 200,000 or more adequate information on which to base people in the United States, or for a recommendations. vaccine, diagnostic drug, or preventive (b) A sponsor shall submit two copies drug that would be given to 200,000 or of a completed, dated, and signed re- more persons per year, a summary of quest for written recommendations the sponsor’s basis for believing that that contains the following: the disease or condition described in (1) The sponsor’s name and address. paragraph (b)(6) of this section occurs (2) A statement that the sponsor is so infrequently that there is no reason- requesting written recommendations able expectation that the costs of drug on orphan-drug development under sec- development and marketing will be re- tion 525 of the act. covered in future sales of the drug in (3) The name of the sponsor’s pri- the United States. The estimated costs mary contact person and/or resident and sales data should be submitted as agent, and the person’s title, address, provided for in § 316.21(c). and telephone number. (9) A summary and analysis of avail- (4) The generic name and trade name, able data on the pharmacologic effects if any, of the drug and a list of the drug of the drug. product’s components or description of (10) A summary and analysis of avail- the drug product’s formulation, and able nonclinical and clinical data perti- chemical and physical properties. nent to the drug and the disease to be (5) The proposed dosage form and studied including copies of pertinent route of administration. published reports. When a drug pro- (6) A description of the disease or posed for orphan drug designation is in- condition for which the drug is pro- tended to treat a life-threatening or se- posed to be investigated and the pro- verely debilitating illness, especially posed indication or indications for use where no satisfactory alternative ther- for such disease or condition. apy exists, the sponsor may wish vol- (7) Current regulatory and marketing untarily to provide this information. A status and history of the drug product, sponsor of such a drug may be entitled including: to expeditious development, evalua- (i) Whether the product is the subject tion, and marketing under 21 CFR part of an IND or a marketing application 312, subpart E.

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(11) An explanation of how the data § 316.14 Refusal to provide written rec- summarized and analyzed under para- ommendations. graphs (b)(9) and (b)(10) of this section (a) FDA may refuse to provide writ- support the rationale for use of the ten recommendations concerning the drug in the rare disease or condition. nonclinical laboratory studies and clin- (12) A definition of the population ical investigations necessary for ap- from which subjects will be identified proval of a marketing application for for clinical trials, if known. any of the following reasons: (13) A detailed outline of any proto- (1) The information required to be cols under which the drug has been or submitted by § 316.10(b) has not been is being studied for the rare disease or submitted, or the information sub- condition and a summary and analysis mitted is incomplete. of any available data from such stud- (2) There is insufficient information about: ies. (i) The drug to identify the active (14) The sponsor’s proposal as to the moiety and its physical and chemical scope of nonclinical and clinical inves- properties, if these characteristics can tigations needed to establish the safety be determined; or and effectiveness of the drug. (ii) The disease or condition to deter- (15) Detailed protocols for each pro- mine that the disease or condition is posed United States or foreign clinical rare in the United States; or investigation, if available. (iii) The reasons for believing that (16) Specific questions to be ad- the drug may be useful for treating the dressed by FDA in its recommenda- rare disease or condition with that tions for nonclinical laboratory studies drug; or and clinical investigations. (iv) The regulatory and marketing history of the drug to determine the [57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, scope and type of investigations that 1993] have already been conducted on the drug for the rare disease or condition; § 316.12 Providing written rec- or ommendations. (v) The plan of study for establishing (a) FDA will provide the sponsor with the safety and effectiveness of the drug written recommendations concerning for treatment of the rare disease or the nonclinical laboratory studies and condition. clinical investigations necessary for (3) The specific questions for which approval of a marketing application if the sponsor seeks the advice of the none of the reasons described in § 316.14 agency are unclear or are not suffi- for refusing to do so applies. ciently specific. (b) When a sponsor seeks written rec- (4) On the basis of the information ommendations at a stage of drug devel- submitted and on other information opment at which advice on any clinical available to the agency, FDA deter- investigations, or on particular inves- mines that the disease or condition for tigations would be premature, FDA’s which the drug is intended is not rare in the United States. response may be limited to written rec- (5) On the basis of the information ommendations concerning only non- submitted and on other information clinical laboratory studies, or only cer- available to the agency, FDA deter- tain of the clinical studies (e.g., Phase mines that there is an inadequate basis 1 studies as described in § 312.21 of this for permitting investigational use of chapter). Prior to providing written the drug under part 312 of this chapter recommendations for the clinical infor the rare disease or condition. vestigations required to achieve mar- (6) The request for information con- keting approval, FDA may require that tains an untrue statement of material the results of the nonclinical labora- fact. tory studies or completed early clinical (b) A refusal to provide written rec- studies be submitted to FDA for agen- ommendations will be in writing and cy review. will include a statement of the reason for FDA’s refusal. Where practicable,

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FDA will describe the information or (2) The name and address of the spon- material it requires or the conditions sor; the name of the sponsor’s primary the sponsor must meet for FDA to pro- contact person and/or resident agent vide recommendations. including title, address, telephone (c) Within 90 days after the date of a number, and email address; the generic letter from FDA requesting additional and trade name, if any, of the drug, or, information or material or setting if neither is available, the chemical forth the conditions that the sponsor is name or a meaningful descriptive name asked to meet, the sponsor shall either: of the drug; and the name and address (1) Provide the information or mate- of the source of the drug if it is not rial or amend the request for written manufactured by the sponsor. recommendations to meet the condi- (3) A description of the rare disease tions sought by FDA; or or condition for which the drug is being (2) Withdraw the request for written or will be investigated, the proposed recommendations. FDA will consider a use of the drug, and the reasons why sponsor’s failure to respond within 90 such therapy is needed. days to an FDA letter requesting information or material or setting forth (4) A description of the drug, to in- conditions to be met to be a with- clude the identity of the active moiety drawal of the request for written rec- if it is a drug composed of small mol- ommendations. ecules, or of the principal molecular structural features if it is composed of macromolecules; its physical and Subpart C—Designation of an chemical properties, if these character- Orphan Drug istics can be determined; and a discus- § 316.20 Content and format of a re- sion of the scientific rationale to es- quest for orphan-drug designation. tablish a medically plausible basis for the use of the drug for the rare disease (a) A sponsor that submits a request or condition, including all relevant for orphan-drug designation of a drug data from in vitro laboratory studies, for a specified rare disease or condition preclinical efficacy studies conducted shall submit each request in the form in an animal model for the human dis- and containing the information re- ease or condition, and clinical experi- quired in paragraph (b) of this section. ence with the drug in the rare disease A sponsor may request orphan-drug or condition that are available to the designation of a previously unapproved sponsor, whether positive, negative, or drug, or of a new use for an already marketed drug. In addition, a sponsor inconclusive. Animal toxicology stud- of a drug that is otherwise the same ies are generally not relevant to a re- drug as an already approved drug may quest for orphan-drug designation. Cop- seek and obtain orphan-drug designa- ies of pertinent unpublished and pub- tion for the subsequent drug for the lished papers are also required. same rare disease or condition if it can (5) Where the sponsor of a drug that present a plausible hypothesis that its is otherwise the same drug as an al- drug may be clinically superior to the ready approved drug seeks orphan-drug first drug. More than one sponsor may designation for the subsequent drug for receive orphan-drug designation of the the same rare disease or condition, an same drug for the same rare disease or explanation of why the proposed vari- condition, but each sponsor seeking or- ation may be clinically superior to the phan-drug designation must file a com- first drug. plete request for designation as pro- (6) Where a sponsor requests orphan- vided in paragraph (b) of this section. drug designation for a drug for only a (b) A sponsor shall submit two copies subset of persons with a particular dis- of a completed, dated, and signed re- ease or condition that otherwise affects quest for designation that contains the 200,000 or more people (‘‘orphan sub- following: set’’), a demonstration that, due to one (1) A statement that the sponsor re- or more properties of the drug, the requests orphan-drug designation for a maining persons with such disease or rare disease or condition, which shall condition would not be appropriate be identified with specificity. candidates for use of the drug.

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(7) A summary of the regulatory sta- expectation that the sales of the drug tus and marketing history of the drug will be sufficient to offset the costs of in the United States and in foreign developing the drug for the U.S. mar- countries, e.g., IND and marketing ap- ket and the costs of making the drug plication status and dispositions, what available in the United States. uses are under investigation and in (b) For the purpose of documenting what countries; for what indication is that the number of people affected by the drug approved in foreign countries; the disease or condition for which the what adverse regulatory actions have drug is to be developed is less than been taken against the drug in any 200,000 persons, ‘‘prevalence’’ is defined country. as the number of persons in the United (8) Documentation, with appended States who have been diagnosed as hav- authoritative references, to dem- ing the disease or condition at the time onstrate that: of the submission of the request for or- (i) The disease or condition for which phan-drug designation. To document the drug is intended affects fewer than the number of persons in the United 200,000 people in the United States or, States who have the disease or condi- if the drug is a vaccine, diagnostic tion for which the drug is to be devel- drug, or preventive drug, the persons to oped, the sponsor shall submit to FDA whom the drug will be administered in evidence showing: the United States are fewer than 200,000 (1) The estimated prevalence of the per year as specified in § 316.21(b), or (ii) For a drug intended for diseases disease or condition for which the drug or conditions affecting 200,000 or more is being developed, together with a list people, or for a vaccine, diagnostic of the sources (including dates of infor- drug, or preventive drug to be adminis- mation provided and literature cita- tered to 200,000 or more persons per tions) for the estimate; year in the United States, there is no (2) Upon request by FDA, the esti- reasonable expectation that costs of re- mated prevalence of any other disease search and development of the drug for or condition for which the drug has al- the indication can be recovered by ready been approved or for which the sales of the drug in the United States drug is currently being developed, to- as specified in § 316.21(c). gether with an explanation of the bases (c) Any of the information previously of these estimates; and provided by the sponsor to FDA under (3) The estimated number of people subpart B of this part may be ref- to whom the drug will be administered erenced by specific page or location if annually if the drug is a vaccine or is it duplicates information required else- a drug intended for diagnosis or pre- where in this section. vention of a rare disease or condition, together with an explanation of the [57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013] bases of these estimates (including dates of information provided and lit- § 316.21 Verification of orphan-drug erature citations). status. (c) When submitting documentation (a) So that FDA can determine that there is no reasonable expectation whether a drug qualifies for orphan- that costs of research and development drug designation under section 526(a) of of the drug for the disease or condition the act, the sponsor shall include in its can be recovered by sales of the drug in request to FDA for orphan-drug des- the United States, the sponsor shall ignation under § 316.20 either: submit to FDA: (1) Documentation as described in (1) Data on all costs that the sponsor paragraph (b) of this section that the has incurred in the course of devel- number of people affected by the dis- oping the drug for the U.S. market. ease or condition for which the drug is These costs shall include, but are not to be developed is fewer than 200,000 limited to, nonclinical laboratory stud- persons; or ies, clinical studies, dosage form devel- (2) Documentation as described in opment, record and report mainte- paragraph (c) of this section that dem- nance, meetings with FDA, determina- onstrates that there is no reasonable tion of patentability, preparation of

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designation request, IND/marketing ap- cases where the extent of these future plication preparation, distribution of development costs are not clear, the the drug under a ‘‘treatment’’ protocol, sponsor should request FDA’s advice licensing costs, liability insurance, and and assistance in estimating the scope overhead and depreciation. Further- of nonclinical laboratory studies and more, the sponsor shall demonstrate clinical investigations and other data the reasonableness of the cost data. that are needed to support marketing For example, if the sponsor has in- approval. Based on these recommenda- curred costs for clinical investigations, tions, a cost estimate should be pre- the sponsor shall provide information pared. on the number of investigations, the (5) A statement of and justification years in which they took place, and on for production and marketing costs the scope, duration, and number of pa- that the sponsor has incurred in the tients that were involved in each inves- past and expects to incur during the tigation. first 7 years that the drug is marketed. (2) If the drug was developed wholly (6) An estimate of and justification or in part outside the United States, in for the expected revenues from sales of addition to the documentation listed in the drug in the United States during paragraph (c)(1) of this section: its first 7 years of marketing. The jus- (i) Data on and justification for all tification should assume that the total costs that the sponsor has incurred market for the drug is equal to the outside of the United States in the prevalence of the disease or condition course of developing the drug for the that the drug will be used to treat. The U.S. market. The justification, in addi- justification should include: tion to demonstrating the reasonable- (i) An estimate of the expected mar- ness of the cost data, must also explain ket share of the drug in each of the the method that was used to determine first 7 years that it is marketed, to- which portion of the foreign develop- gether with an explanation of the basis ment costs should be applied to the for that estimate; U.S. market, and what percent these (ii) A projection of and justification costs are of total worldwide develop- for the price at which the drug will be ment costs. Any data submitted to for- sold; and eign government authorities to support (iii) Comparisons with sales of simi- drug pricing determinations must be larly situated drugs, where available. included with this information. (7) The name of each country where (ii) Data that show which foreign de- the drug has already been approved for velopment costs were recovered marketing for any indication, the dates through cost recovery procedures that of approval, the indication for which are allowed during drug development in the drug is approved, and the annual some foreign countries. For example, if sales and number of prescriptions in the sponsor charged patients for the each country since the first approval drug during clinical investigations, the date. revenues collected by the sponsor must (8) A report of an independent cer- be reported to FDA. tified public accountant in accordance (3) In cases where the drug has al- with Statement on Standards for At- ready been approved for marketing for testation established by the American any indication or in cases where the Institute of Certified Public Account- drug is currently under investigation ants on agreed upon procedures per- for one or more other indications (in formed with respect to the data esti- addition to the indication for which or- mates and justifications submitted phan-drug designation is being sought), pursuant to this section. Cost data a clear explanation of and justification shall be determined in accordance with for the method that is used to appor- generally accepted accounting prin- tion the development costs among the ciples. various indications. (d) A sponsor that is requesting or- (4) A statement of and justification phan-drug designation for a drug de- for any development costs that the signed to treat a disease or condition sponsor expects to incur after the sub- that affects 200,000 or more persons mission of the designation request. In shall, at FDA’s request, allow FDA or

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FDA-designated personnel to examine or contains inaccurate or incomplete at reasonable times and in a reasonable information. FDA may consider a des- manner all relevant financial records ignation request voluntarily with- and sales data of the sponsor and man- drawn if the sponsor fails to respond to ufacturer. the deficiency letter within 1 year of issuance of the deficiency letter, unless [57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013] within that same timeframe the sponsor requests in writing an extension of § 316.22 Permanent-resident agent for time to respond. This request must in- foreign sponsor. clude the reason(s) for the requested Every foreign sponsor that seeks or- extension and the length of time of the phan-drug designation shall name a requested extension. FDA will grant all permanent resident of the United reasonable requests for an extension. In the event FDA denies a request for States as the sponsor’s agent upon an extension of time, FDA may con- whom service of all processes, notices, sider the designation request volun- orders, decisions, requirements, and tarily withdrawn. In the event FDA other communications may be made on considers a designation request volun- behalf of the sponsor. Notifications of tarily withdrawn, FDA will so notify changes in such agents or changes of the sponsor in writing. address of agents should preferably be (b) FDA will grant the request for or- provided in advance, but not later than phan-drug designation if none of the 60 days after the effective date of such reasons described in § 316.25 for requir- changes. The permanent-resident agent ing or permitting refusal to grant such may be an individual, firm, or domestic a request applies. corporation and may represent any (c) When a request for orphan-drug number of sponsors. The name of the designation is granted, FDA will notify permanent-resident agent, address, the sponsor in writing and will pub- telephone number, and email address licize the orphan-drug designation in shall be provided to: Office of Orphan accordance with § 316.28. Products Development, Food and Drug (d) A sponsor may voluntarily with- Administration, Bldg. 32, rm. 5271, 10903 draw an orphan-drug designation re- New Hampshire Ave., Silver Spring, quest or an orphan-drug designation at MD 20993. any time after the request is submitted [78 FR 35133, June 12, 2013] or granted, respectively, by submitting a written request for withdrawal to § 316.23 Timing of requests for orphan- FDA. FDA will acknowledge such with- drug designation; designation of al- drawal in a letter to the sponsor. Any ready approved drugs. benefits attendant to designation (such (a) A sponsor may request orphan- as orphan-exclusive approval) will drug designation at any time in its cease once designation is voluntarily drug development process prior to the withdrawn, from the date of FDA’s ac- time that sponsor submits a marketing knowledgement letter. If a sponsor vol- application for the drug for the same untarily withdraws designation, FDA rare disease or condition. will publicize such withdrawal in ac- (b) A sponsor may request orphan- cordance with § 316.28. drug designation of an already approved drug for an unapproved use [57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013] without regard to whether the prior marketing approval was for a rare dis- § 316.25 Refusal to grant orphan-drug ease or condition. designation. [78 FR 35133, June 12, 2013] (a) FDA will refuse to grant a request for orphan-drug designation if any of § 316.24 Deficiency letters and grant- the following reasons apply: ing orphan-drug designation. (1) The drug is not intended for a rare (a) FDA will send a deficiency letter disease or condition because: to the sponsor if the request for or- (i) There is insufficient evidence to phan-drug designation lacks informa- support the estimate that the drug is tion required under §§ 316.20 and 316.21, intended for treatment of a disease or

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condition in fewer than 200,000 people the orphan-drug designation to the rein the United States, or that the drug sults of unanticipated research find- is intended for use in prevention or in ings, to unforeseen developments in the diagnosis in fewer than 200,000 people treatment or diagnosis of the disease annually in the United States; or or condition, or to changes based on (ii) Where the drug is intended for FDA recommendations, and that, as of prevention, diagnosis, or treatment of the date of the submission of the a disease or condition affecting 200,000 amendment request, the amendment or more people in the United States, would not result in exceeding the prev- the sponsor has failed to demonstrate alence or cost recovery thresholds in that there is no reasonable expectation § 316.21(a)(1) or (a)(2) upon which the that development and production costs drug was originally designated. will be recovered from sales of the drug [78 FR 35134, June 12, 2013] for such disease or condition in the United States. A sponsor’s failure to § 316.27 Change in ownership of or- comply with § 316.21 shall constitute a phan-drug designation. failure to make the demonstration re- (a) A sponsor may transfer ownership quired in this paragraph. of or any beneficial interest in the or- (2) There is insufficient information phan-drug designation of a drug to a about the drug, or the disease or condi- new sponsor. At the time of the trans- tion for which it is intended, to estab- fer, the new and former owners are re- lish a medically plausible basis for ex- quired to submit the following infor- pecting the drug to be effective in the mation to FDA: prevention, diagnosis, or treatment of (1) The former owner or assignor of that disease or condition. rights shall submit a letter or other (3) The drug is otherwise the same document that states that all or some drug as an already approved drug for rights to the orphan-drug designation the same rare disease or condition and of the drug have been transferred to the sponsor has not submitted a medi- the new owner or assignee and that a cally plausible hypothesis for the pos- complete copy of the request for or- sible clinical superiority of the subse- phan-drug designation, including any quent drug. amendments to the request, supple- (b) FDA may refuse to grant a re- ments to the granted request, and cor- quest for orphan-drug designation if respondence relevant to the orphan- the request for designation contains an drug designation, has been provided to untrue statement of material fact or the new owner or assignee. omits material information or if the (2) The new owner or assignee of request is otherwise ineligible under rights shall submit a statement accept- this part. ing orphan-drug designation and a let- [57 FR 62085, Dec. 29, 1992, as amended at 78 ter or other document containing the FR 35133, June 12, 2013] following: (i) The date that the change in own- § 316.26 Amendment to orphan-drug ership or assignment of rights is effec- designation. tive; (a) At any time prior to approval of a (ii) A statement that the new owner marketing application for a designated has a complete copy of the request for orphan drug, the sponsor holding des- orphan-drug designation including any ignation may apply for an amendment amendments to the request, supple- to the designated use if the proposed ments to the granted request, and cor- change is due to new and unexpected respondence relevant to the orphan- findings in research on the drug, infor- drug designation; and mation arising from FDA recommenda- (iii) A specific description of the tions, or unforeseen developments in rights that have been assigned and treatment or diagnosis of the disease those that have been reserved. This or condition. may be satisfied by the submission of (b) FDA will grant the amendment if either a list of rights assigned and re- it finds that the initial designation reserved or copies of all relevant agree- quest was made in good faith and that ments between assignors and assignees; the amendment is intended to conform and

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(iv) The name and address of a new (c) Where a drug has been designated primary contact person or resident as an orphan drug because the preva- agent. lence of a disease or condition (or, in (b) No sponsor may relieve itself of the case of vaccines, diagnostic drugs, responsibilities under the Orphan Drug or preventive drugs, the target popu- Act or under this part by assigning lation) is under 200,000 in the United rights to another person without: States at the time of designation, its (1) Assuring that the sponsor or the designation will not be revoked on the assignee will carry out such respon- ground that the prevalence of the dis- sibilities; or ease or condition (or the target popu- (2) Obtaining prior permission from lation) becomes more than 200,000 per- FDA. sons. (d) If FDA revokes orphan-drug des- [57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, ignation, FDA will publicize that the 1993] drug is no longer designated in accord- § 316.28 Publication of orphan-drug ance with § 316.28(e). designations. [57 FR 62085, Dec. 29, 1992, as amended at 78 Each month FDA will update a pub- FR 35134, June 12, 2013] licly available cumulative posting of § 316.30 Annual reports of holder of or- all drugs designated as orphan drugs. phan-drug designation. These postings will contain the following information: Within 14 months after the date on (a) The name and address of the spon- which a drug was designated as an or- sor; phan drug and annually thereafter (b) The generic name and trade name, until marketing approval, the sponsor if any, or, if neither is available, the of a designated drug shall submit a chemical name or a meaningful de- brief progress report to the FDA Office of Orphan Products Development on scriptive name of the drug; the drug that includes: (c) The date of the granting of or- (a) A short account of the progress of phan-drug designation; drug development including a review of (d) The designated use in the rare dis- preclinical and clinical studies initi- ease or condition; and ated, ongoing, and completed and a (e) If the drug loses designation after short summary of the status or results August 12, 2013, the date of it no longer of such studies. having designation. (b) A description of the investiga- [78 FR 35134, June 12, 2013] tional plan for the coming year, as well as any anticipated difficulties in devel- § 316.29 Revocation of orphan-drug opment, testing, and marketing; and designation. (c) A brief discussion of any changes (a) FDA may revoke orphan-drug des- that may affect the orphan-drug status ignation for any drug if the agency of the product. For example, for prod- finds that: ucts nearing the end of the approval (1) The request for designation con- process, sponsors should discuss any tained an untrue statement of material disparity between the probable mar- fact; or keting indication and the designated (2) The request for designation omit- indication as related to the need for an ted material information required by amendment to the orphan-drug des- this part; or ignation pursuant to § 316.26. (3) FDA subsequently finds that the drug in fact had not been eligible for Subpart D—Orphan-drug orphan-drug designation at the time of Exclusive Approval submission of the request therefor. (b) For an approved drug, revocation § 316.31 Scope of orphan-drug exclu- of orphan-drug designation also sus- sive approval. pends or withdraws the sponsor’s exclu- (a) FDA may approve a sponsor’s sive marketing rights for the drug but marketing application for a designated not the approval of the drug’s mar- orphan drug for use in the rare disease keting application. or condition for which the drug was

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designated, or for select indication(s) FDA will so notify the sponsor in writ- or use(s) within the rare disease or con- ing. dition for which the drug was des- [57 FR 62085, Dec. 29, 1992, as amended at 78 ignated. Unless FDA previously ap- FR 35134, June 12, 2013] proved the same drug for the same use or indication, FDA will not approve an- § 316.34 FDA recognition of exclusive other sponsor’s marketing application approval. for the same drug for the same use or (a) FDA will send the sponsor (or, the indication before the expiration of 7 permanent-resident agent, if applica- years from the date of such approval as ble) timely written notice recognizing stated in the approval letter from FDA, exclusive approval once the marketing except that such a marketing applica- application for a designated orphan- tion can be approved sooner if, and at drug product has been approved, if the such time as, any of the following oc- same drug has not already been ap- curs: proved for the same use or indication. (1) Withdrawal of exclusive approval The written notice will inform the or revocation of orphan-drug designa- sponsor of the requirements for main- tion by FDA under any provision of taining orphan-drug exclusive approval this part; or for the full 7-year term of exclusive approval. (2) Withdrawal for any reason of the (b) When a marketing application is marketing application for the drug in approved under section 505 of the Fed- question; or eral Food, Drug, and Cosmetic Act (21 (3) Consent by the holder of exclusive U.S.C. 355) for a designated orphan approval to permit another marketing drug that qualifies for exclusive ap- application to gain approval; or proval, FDA will publish in its publica- (4) Failure of the holder of exclusive tion entitled ‘‘Approved Drug Products approval to assure a sufficient quantity With Therapeutic Equivalence Evalua- of the drug under section 527 of the act tions’’ information identifying the and § 316.36. sponsor, the drug, and the date of ter- (b) Orphan-drug exclusive approval mination of the orphan-drug exclusive protects only the approved indication approval. A subscription to this publi- or use of a designated drug. If such ap- cation and its monthly cumulative sup- proval is limited to only particular in- plements is available from the Super- dication(s) or uses(s) within the rare intendent of Documents, Government disease or condition for which the drug Printing Office, Washington, DC 20402– was designated, FDA may later ap- 9325, and is also available online at prove the drug for additional indica- http://www.accessdata.fda.gov/scripts/ tion(s) or uses(s) within the rare dis- cder/ob/default.cfm. ease or condition not protected by the (c) If a drug is otherwise the same drug as a previously approved drug for exclusive approval. If the sponsor who the same use or indication, FDA will obtains approval for these new indica- not recognize orphan-drug exclusive tion(s) or uses(s) has orphan-drug des- approval if the sponsor fails to dem- ignation for the drug for the rare dis- onstrate upon approval that the drug is ease or condition, FDA will recognize a clinically superior to the previously new orphan-drug exclusive approval for approved drug. these new (not previously approved) indication(s) or use(s) from the date of [78 FR 35135, June 12, 2013] approval of the drug for such new indi- § 316.36 Insufficient quantities of or- cation(s) or use(s). phan drugs. (c) If a sponsor’s marketing applica- (a) Under section 527 of the act, tion for a drug product is determined whenever the Director has reason to not to be approvable because approval believe that the holder of exclusive ap- is barred under section 527 of the Fed- proval cannot assure the availability of eral Food, Drug, and Cosmetic Act sufficient quantities of an orphan drug until the expiration of the period of ex- to meet the needs of patients with the clusive marketing of another drug, disease or condition for which the drug

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was designated, the Director will so no- Subpart F—Availability of tify the holder of this possible insuffi- Information ciency and will offer the holder one of the following options, which must be § 316.50 Guidance documents. exercised by a time that the Director FDA’s Office of Orphan Products De- specifies: velopment will maintain and make (1) Provide the Director in writing, or publicly available a list of guidance orally, or both, at the Director’s dis- documents that apply to the regula- cretion, views and data as to how the tions in this part. The list is main- holder can assure the availability of tained on the Internet and is published sufficient quantities of the orphan drug annually in the FEDERAL REGISTER. A within a reasonable time to meet the request for a copy of the list should be needs of patients with the disease or directed to the Office of Orphan Prod- condition for which the drug was des- ucts Development, Food and Drug Ad- ignated; or ministration, Bldg. 32, rm. 5271, 10903 (2) Provide the Director in writing New Hampshire Ave., Silver Spring, the holder’s consent for the approval of MD 20993. other marketing applications for the [78 FR 35135, June 12, 2013] same drug before the expiration of the 7-year period of exclusive approval. § 316.52 Availability for public disclo- (b) If, within the time that the Direc- sure of data and information in re- tor specifies, the holder fails to consent quests and applications. to the approval of other marketing ap- (a) FDA will not publicly disclose the plications and if the Director finds that existence of a request for orphan-drug the holder has not shown that it can designation under section 526 of the act assure the availability of sufficient prior to final FDA action on the re- quantities of the orphan drug to meet quest unless the existence of the re- the needs of patients with the disease quest has been previously publicly dis- or condition for which the drug was closed or acknowledged. designated, the Director will issue a (b) Whether or not the existence of a written order withdrawing the drug pending request for designation has product’s exclusive approval. This been publicly disclosed or acknowl- order will embody the Director’s find- edged, no data or information in the re- ings and conclusions and will con- quest are available for public disclo- stitute final agency action. An order sure prior to final FDA action on the withdrawing the sponsor’s exclusive request. marketing rights may issue whether or (c) Upon final FDA action on a re- not there are other sponsors that can quest for designation, FDA will deter- assure the availability of alternative mine the public availability of data sources of supply. Once withdrawn and information in the request in ac- under this section, exclusive approval cordance with part 20 and § 314.430 of may not be reinstated for that drug. this chapter and other applicable statutes and regulations. Subpart E—Open Protocols for (d) In accordance with § 316.28, FDA will make a cumulative list of all or- Investigations phan drug designations available to the public and update such list monthly. § 316.40 Treatment use of a designated orphan drug. (e) FDA will not publicly disclose the existence of a pending marketing appli- Prospective investigators seeking to cation for a designated orphan drug for obtain treatment use of designated or- the use for which the drug was des- phan drugs may do so as provided in ignated unless the existence of the ap- subpart I of this chapter. plication has been previously publicly [74 FR 40945, Aug. 13, 2009] disclosed or acknowledged. (f) FDA will determine the public availability of data and information contained in pending and approved

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marketing applications for a des- PART 320—BIOAVAILABILITY AND ignated orphan drug for the use for BIOEQUIVALENCE REQUIREMENTS which the drug was designated in accordance with part 20 and § 314.430 of Subpart A—General Provisions this chapter and other applicable statutes and regulations. Sec. 320.1 Definitions.

PART 317—QUALIFYING Subpart B—Procedures for Determining the PATHOGENS Bioavailability or Bioequivalence of Drug Products Sec. 320.21 Requirements for submission of bio- 317.1 [Reserved] availability and bioequivalence data. 317.2 List of qualifying pathogens that have 320.22 Criteria for waiver of evidence of in the potential to pose a serious threat to vivo bioavailability or bioequivalence. public health. 320.23 Basis for measuring in vivo bio- AUTHORITY: 21 U.S.C. 355f, 371. availability or demonstrating bioequivalence. SOURCE: 79 FR 32480, June 5, 2014, unless 320.24 Types of evidence to measure bio- otherwise noted. availability or establish bioequivalence. 320.25 Guidelines for the conduct of an in § 317.1 [Reserved] vivo bioavailability study. 320.26 Guidelines on the design of a single- § 317.2 List of qualifying pathogens dose in vivo bioavailability or bioequiva- that have the potential to pose a se- lence study. rious threat to public health. 320.27 Guidelines on the design of a mul- The term ‘‘qualifying pathogen’’ in tiple-dose in vivo bioavailability study. 320.28 Correlation of bioavailability with an section 505E(f) of the Federal Food, acute pharmacological effect or clinical Drug, and Cosmetic Act is defined to evidence. mean any of the following: 320.29 Analytical methods for an in vivo (a) Acinetobacter species. bioavailability or bioequivalence study. (b) Aspergillus species. 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- (c) Burkholderia cepacia complex. view of protocols by the Food and Drug (d) Campylobacter species. Administration. (e) Candida species. 320.31 Applicability of requirements regard- (f) Clostridium difficile. ing an ‘‘Investigational New Drug Appli- (g) Coccidioides species. cation.’’ 320.32 Procedures for establishing or amend- (h) Cryptococcus species. ing a bioequivalence requirement. (i) Enterobacteriaceae. 320.33 Criteria and evidence to assess actual (j) Enterococcus species. or potential bioequivalence problems. (k) Helicobacter pylori. 320.34 Requirements for batch testing and (l) Mycobacterium tuberculosis com- certification by the Food and Drug Ad- ministration. plex. 320.35 Requirements for in vitro testing of (m) Neisseria gonorrhoeae. each batch. (n) Neisseria meningitidis. 320.36 Requirements for maintenance of (o) Non-tuberculous mycobacteria records of bioequivalence testing. species. 320.38 Retention of bioavailability samples. (p) Pseudomonas species. 320.63 Retention of bioequivalence samples. (q) Staphylococcus aureus. AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. (r) Streptococcus agalactiae. (s) Streptococcus pneumoniae. Subpart A—General Provisions (t) Streptococcus pyogenes. (u) Vibrio cholerae. § 320.1 Definitions. The definitions contained in § 314.3 of this chapter apply to those terms when used in this part. [81 FR 69658, Oct. 6, 2016]

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Subpart B—Procedures for Deter- process, including a change in product mining the Bioavailability or formulation or dosage strength, beyond Bioequivalence of Drug Prod- the variations provided for in the ap- ucts proved application. (2) A change in the labeling to provide for a new indication for use of the SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth- drug product, if clinical studies are re- erwise noted. quired to support the new indication § 320.21 Requirements for submission for use. of bioavailability and bioequiva- (3) A change in the labeling to pro- lence data. vide for a new dosage regimen or for an (a) Any person submitting a full new additional dosage regimen for a special drug application to the Food and Drug patient population, e.g., infants, if clin- Administration (FDA) shall include in ical studies are required to support the the application either: new or additional dosage regimen. (1) Evidence measuring the in vivo (d) FDA may approve a full new drug bioavailability of the drug product that application, or a supplemental applica- is the subject of the application; or tion proposing any of the changes set (2) Information to permit FDA to forth in paragraph (c) of this section, waive the submission of evidence meas- that does not contain evidence of in uring in vivo bioavailability. vivo bioavailability or information to (b) Any person submitting an abbre- permit waiver of the requirement for in viated new drug application to FDA vivo bioavailability data, if all of the shall include in the application either: following conditions are met. (1) Evidence demonstrating that the (1) The application is otherwise ap- drug product that is the subject of the provable. abbreviated new drug application is (2) The application agrees to submit, bioequivalent to the reference listed within the time specified by FDA, ei- drug (defined in § 314.3(b) of this chap- ther: ter). A complete study report must be (i) Evidence measuring the in vivo submitted for the bioequivalence study bioavailability and demonstrating the upon which the applicant relies for ap- in vivo bioequivalence of the drug proval. For all other bioequivalence product that is the subject of the appli- studies conducted on the same drug cation; or product formulation, the applicant must submit either a complete or sum- (ii) Information to permit FDA to mary report. If a summary report of a waive measurement of in vivo bio- bioequivalence study is submitted and availability. FDA determines that there may be bio- (e) Evidence measuring the in vivo equivalence issues or concerns with the bioavailability and demonstrating the product, FDA may require that the ap- in vivo bioequivalence of a drug prod- plicant submit a complete report of the uct shall be obtained using one of the bioequivalence study to FDA; or approaches for determining bio- (2) Information to show that the drug availability set forth in § 320.24. product is bioequivalent to the ref- (f) Information to permit FDA to erence listed drug which would permit waive the submission of evidence meas- FDA to waive the submission of evi- uring the in vivo bioavailability or dence demonstrating in vivo bioequiva- demonstrating the in vivo bioequivalence as provided in paragraph (f) of lence shall meet the criteria set forth this section. in § 320.22. (c) Any person submitting a supple- (g) Any person holding an approved mental application to FDA shall in- full or abbreviated new drug applica- clude in the supplemental application tion shall submit to FDA a supple- the evidence or information set forth mental application containing new evi- in paragraphs (a) and (b) of this section dence measuring the in vivo bio- if the supplemental application pro- availability or demonstrating the in poses any of the following changes: vivo bioequivalence of the drug product (1) A change in the manufacturing that is the subject of the application if site or a change in the manufacturing notified by FDA that:

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(1) There are data demonstrating if the product meets one of the fol- that the dosage regimen in the labeling lowing criteria: is based on incorrect assumptions or (1) The drug product: facts regarding the pharmacokinetics (i) Is a parenteral solution intended of the drug product and that following solely for administration by injection, this dosage regimen could potentially or an ophthalmic or otic solution; and result in subtherapeutic or toxic levels; (ii) Contains the same active and in- or active ingredients in the same con- (2) There are data measuring signifi- centration as a drug product that is the cant intra-batch and batch-to-batch subject of an approved full new drug variability, e.g., plus or minus 25 per- application or abbreviated new drug cent, in the bioavailability of the drug application. product. (2) The drug product: (h) The requirements of this section (i) Is administered by inhalation as a regarding the submission of evidence gas, e.g., a medicinal or an inhalation measuring the in vivo bioavailability anesthetic; and or demonstrating the in vivo bio- (ii) Contains an active ingredient in equivalence apply only to a full or ab- the same dosage form as a drug product breviated new drug application or a that is the subject of an approved full supplemental application for a finished new drug application or abbreviated dosage formulation. new drug application. (3) The drug product: [57 FR 17998, Apr. 28, 1992, as amended at 67 (i) Is a solution for application to the FR 77672, Dec. 19, 2002; 74 FR 2862, Jan. 16, skin, an oral solution, elixir, syrup, 2009] tincture, a solution for aerosolization or nebulization, a nasal solution, or § 320.22 Criteria for waiver of evidence similar other solubilized form; and of in vivo bioavailability or bioequivalence. (ii) Contains an active drug ingredient in the same concentration and (a) Any person submitting a full or dosage form as a drug product that is abbreviated new drug application, or a the subject of an approved full new supplemental application proposing drug application or abbreviated new any of the changes set forth in drug application; and § 320.21(c), may request FDA to waive (iii) Contains no inactive ingredient the requirement for the submission of or other change in formulation from evidence measuring the in vivo bio- the drug product that is the subject of availability or demonstrating the in the approved full new drug application vivo bioequivalence of the drug product or abbreviated new drug application that is the subject of the application. that may significantly affect absorp- An applicant shall submit a request for tion of the active drug ingredient or waiver with the application. Except as active moiety for products that are provided in paragraph (f) of this sec- systemically absorbed, or that may sig- tion, FDA shall waive the requirement nificantly affect systemic or local for the submission of evidence of in availability for products intended to vivo bioavailability or bioequivalence act locally. if the drug product meets any of the (c) FDA shall waive the requirement provisions of paragraphs (b), (c), (d), or for the submission of evidence meas- (e) of this section. uring the in vivo bioavailability or (b) For certain drug products, the in demonstrating the in vivo bioequiva- vivo bioavailability or bioequivalence lence of a solid oral dosage form (other of the drug product may be self-evi- than a delayed release or extended re- dent. FDA shall waive the requirement lease dosage form) of a drug product for the submission of evidence obtained determined to be effective for at least in vivo measuring the bioavailability one indication in a Drug Efficacy or demonstrating the bioequivalence of Study Implementation notice or which these drug products. A drug product’s is identical, related, or similar to such in vivo bioavailability or bioequiva- a drug product under § 310.6 of this lence may be considered self-evident chapter unless FDA has evaluated the based on other data in the application drug product under the criteria set

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forth in § 320.33, included the drug prod- (ii) Both drug products meet an ap- uct in the Approved Drug Products propriate in vitro test approved by with Therapeutic Equivalence Evalua- FDA. tions List, and rated the drug product (e) FDA, for good cause, may waive a as having a known or potential bio- requirement for the submission of evi- equivalence problem. A drug product so dence of in vivo bioavailability or bio- rated reflects a determination by FDA equivalence if waiver is compatible that an in vivo bioequivalence study is with the protection of the public required. health. For full new drug applications, (d) For certain drug products, bio- FDA may defer a requirement for the availability may be measured or bio- submission of evidence of in vivo bioequivalence may be demonstrated by availability if deferral is compatible evidence obtained in vitro in lieu of in with the protection of the public vivo data. FDA shall waive the require- health. ment for the submission of evidence (f) FDA, for good cause, may require obtained in vivo measuring the bio- evidence of in vivo bioavailability or availability or demonstrating the bio- bioequivalence for any drug product if equivalence of the drug product if the the agency determines that any dif- drug product meets one of the fol- ference between the drug product and a lowing criteria: listed drug may affect the bio- (1) [Reserved] availability or bioequivalence of the drug product. (2) The drug product is in the same dosage form, but in a different [57 FR 17998, Apr. 28, 1992, as amended at 67 strength, and is proportionally similar FR 77673, Dec. 19, 2002] in its active and inactive ingredients to another drug product for which the § 320.23 Basis for measuring in vivo bioavailability or demonstrating same manufacturer has obtained ap- bioequivalence. proval and the conditions in paragraphs (d)(2)(i) through (d)(2)(iii) of (a)(1) The in vivo bioavailability of a this section are met: drug product is measured if the prod- (i) The bioavailability of this other uct’s rate and extent of absorption, as drug product has been measured; determined by comparison of measured parameters, e.g., concentration of the (ii) Both drug products meet an ap- active drug ingredient in the blood, propriate in vitro test approved by urinary excretion rates, or pharma- FDA; and cological effects, do not indicate a sig- (iii) The applicant submits evidence nificant difference from the reference showing that both drug products are material’s rate and extent of absorp- proportionally similar in their active tion. For drug products that are not in- and inactive ingredients. tended to be absorbed into the blood- (iv) Paragraph (d) of this section does stream, bioavailability may be as- not apply to delayed release or ex- sessed by scientifically valid measure- tended release products. ments intended to reflect the rate and (3) The drug product is, on the basis extent to which the active ingredient of scientific evidence submitted in the or active moiety becomes available at application, shown to meet an in vitro the site of action. test that has been correlated with in (2) Statistical techniques used must vivo data. be of sufficient sensitivity to detect (4) The drug product is a reformu- differences in rate and extent of ab- lated product that is identical, except sorption that are not attributable to for a different color, flavor, or preserv- subject variability. ative that could not affect the bio- (3) A drug product that differs from availability of the reformulated prod- the reference material in its rate of ab- uct, to another drug product for which sorption, but not in its extent of ab- the same manufacturer has obtained sorption, may be considered to be bio- approval and the following conditions available if the difference in the rate of are met: absorption is intentional, is appro- (i) The bioavailability of the other priately reflected in the labeling, is not product has been measured; and essential to the attainment of effective

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body drug concentrations on chronic product. Applicants shall conduct bio- use, and is considered medically insig- availability and bioequivalence testing nificant for the drug product. using the most accurate, sensitive, and (b)(1) Two drug products will be con- reproducible approach available among sidered bioequivalent drug products if those set forth in paragraph (b) of this they are pharmaceutical equivalents or section. The method used must be ca- pharmaceutical alternatives whose pable of measuring bioavailability or rate and extent of absorption do not establishing bioequivalence, as appro- show a significant difference when ad- priate, for the product being tested. ministered at the same molar dose of (b) The following in vivo and in vitro the active moiety under similar experi- approaches, in descending order of ac- mental conditions, either single dose or curacy, sensitivity, and reproduc- multiple dose. Some pharmaceutical ibility, are acceptable for determining equivalents or pharmaceutical alter- the bioavailability or bioequivalence of natives may be equivalent in the ex- a drug product. tent of their absorption but not in their rate of absorption and yet may be (1)(i) An in vivo test in humans in considered bioequivalent because such which the concentration of the active differences in the rate of absorption are ingredient or active moiety, and, when intentional and are reflected in the la- appropriate, its active metabolite(s), in beling, are not essential to the attain- whole blood, plasma, serum, or other ment of effective body drug concentra- appropriate biological fluid is meas- tions on chronic use, and are consid- ured as a function of time. This ap- ered medically insignificant for the proach is particularly applicable to particular drug product studied. dosage forms intended to deliver the (2) For drug products that are not inactive moiety to the bloodstream for tended to be absorbed into the blood- systemic distribution within the body; stream, bioequivalence may be dem- or onstrated by scientifically valid meth- (ii) An in vitro test that has been ods that are expected to detect a sig- correlated with and is predictive of nificant difference between the drug human in vivo bioavailability data; or and the listed drug in safety and thera- (2) An in vivo test in humans in peutic effect. which the urinary excretion of the ac- [57 FR 17999, Apr. 28, 1992, as amended at 67 tive moiety, and, when appropriate, its FR 77673, Dec. 19, 2002, 81 FR 69658, Oct. 6, active metabolite(s), are measured as a 2016] function of time. The intervals at which measurements are taken should § 320.24 Types of evidence to measure bioavailability or establish bio- ordinarily be as short as possible so equivalence. that the measure of the rate of elimination is as accurate as possible. De- (a) Bioavailability may be measured pending on the nature of the drug prod- or bioequivalence may be demonstrated by several in vivo and in uct, this approach may be applicable to vitro methods. FDA may require in the category of dosage forms described vivo or in vitro testing, or both, to in paragraph (b)(1)(i) of this section. measure the bioavailability of a drug This method is not appropriate where product or establish the bioequivalence urinary excretion is not a significant of specific drug products. Information mechanism of elimination. on bioequivalence requirements for (3) An in vivo test in humans in specific products is included in the cur- which an appropriate acute pharma- rent edition of FDA’s publication ‘‘Ap- cological effect of the active moiety, proved Drug Products with Thera- and, when appropriate, its active me- peutic Equivalence Evaluations’’ and tabolite(s), are measured as a function any current supplement to the publica- of time if such effect can be measured tion. The selection of the method used with sufficient accuracy, sensitivity, to meet an in vivo or in vitro testing and reproducibility. This approach is requirement depends upon the purpose applicable to the category of dosage of the study, the analytical methods forms described in paragraph (b)(1)(i) of available, and the nature of the drug this section only when appropriate

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methods are not available for measure- mans of a product at any time if the ment of the concentration of the moi- agency has evidence that the product: ety, and, when appropriate, its active (1) May not produce therapeutic ef- metabolite(s), in biological fluids or ex- fects comparable to a pharmaceutical cretory products but a method is avail- equivalent or alternative with which it able for the measurement of an appro- is intended to be used interchangeably; priate acute pharmacological effect. (2) May not be bioequivalent to a This approach may be particularly ap- pharmaceutical equivalent or alter- plicable to dosage forms that are not native with which it is intended to be intended to deliver the active moiety used interchangeably; or to the bloodstream for systemic dis- (3) Has greater than anticipated po- tribution. tential toxicity related to pharmaco- (4) Well-controlled clinical trials that kinetic or other characteristics. establish the safety and effectiveness [57 FR 17999, Apr. 28, 1992; 57 FR 29354, July of the drug product, for purposes of 1, 1992, as amended at 67 FR 77673, Dec. 19, measuring bioavailability, or appro- 2002] priately designed comparative clinical trials, for purposes of demonstrating § 320.25 Guidelines for the conduct of an in vivo bioavailability study. bioequivalence. This approach is the least accurate, sensitive, and reproduc- (a) Guiding principles. (1) The basic ible of the general approaches for principle in an in vivo bioavailability measuring bioavailability or dem- study is that no unnecessary human re- onstrating bioequivalence. For dosage search should be done. forms intended to deliver the active (2) An in vivo bioavailability study is moiety to the bloodstream for systemic generally done in a normal adult popu- distribution, this approach may be con- lation under standardized conditions. sidered acceptable only when analyt- In some situations, an in vivo bio- ical methods cannot be developed to availability study in humans may pref- permit use of one of the approaches erably and more properly be done in outlined in paragraphs (b)(1)(i) and suitable patients. Critically ill patients (b)(2) of this section, when the ap- shall not be included in an in vivo bio- proaches described in paragraphs availability study unless the attending (b)(1)(ii), (b)(1)(iii), and (b)(3) of this physician determines that there is a section are not available. This ap- potential benefit to the patient. (b) The basic design of proach may also be considered suffi- Basic design. an in vivo bioavailability study is de- ciently accurate for measuring bio- termined by the following: availability or demonstrating bio- (1) The scientific questions to be an- equivalence of dosage forms intended swered. to deliver the active moiety locally, (2) The nature of the reference mate- e.g., topical preparations for the skin, rial and the dosage form to be tested. eye, and mucous membranes; oral dos- (3) The availability of analytical age forms not intended to be absorbed, methods. e.g., an antacid or radiopaque medium; (4) Benefit-risk considerations in re- and bronchodilators administered by gard to testing in humans. inhalation if the onset and duration of (c) Comparison to a reference material. pharmacological activity are defined. In vivo bioavailability testing of a drug (5) A currently available in vitro test product shall be in comparison to an acceptable to FDA (usually a dissolu- appropriate reference material unless tion rate test) that ensures human in some other approach is more appro- vivo bioavailability. priate for valid scientific reasons. (6) Any other approach deemed ade- (d) Previously unmarketed active drug quate by FDA to measure bio- ingredients or therapeutic moieties. (1) An availability or establish bioequiva- in vivo bioavailability study involving lence. a drug product containing an active (c) FDA may, notwithstanding prior drug ingredient or therapeutic moiety requirements for measuring bio- that has not been approved for mar- availability or establishing bioequiva- keting can be used to measure the fol- lence, require in vivo testing in hu- lowing pharmacokinetic data:

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(i) The bioavailability of the formu- marketed drug product, and the data lation proposed for marketing; and needed to establish dosage rec- (ii) The essential pharmacokinetic ommendations. characteristics of the active drug in- (3) The reference material should be gredient or therapeutic moiety, such as taken from a current batch of a drug the rate of absorption, the extent of ab- product that is the subject of an ap- sorption, the half-life of the thera- proved new drug application and that peutic moiety in vivo, and the rate of contains the same active drug ingre- excretion and/or metabolism. Dose pro- dient or therapeutic moiety, if the new portionality of the active drug ingre- formulation, new dosage form, or new dient or the therapeutic moiety needs salt or ester is intended to be com- to be established after single-dose ad- parable to or to meet any comparative ministration and in certain instances after multiple-dose administration. labeling claims made in relation to the This characterization is a necessary drug product that is the subject of an part of the investigation of the drug to approved new drug application. support drug labeling. (f) Extended release formulations. (1) (2) The reference material in such a The purpose of an in vivo bio- bioavailability study should be a solu- availability study involving a drug tion or suspension containing the same product for which an extended release quantity of the active drug ingredient claim is made is to determine if all of or therapeutic moiety as the formula- the following conditions are met: tion proposed for marketing. (i) The drug product meets the ex- (3) The reference material should be tended release claims made for it. administered by the same route as the (ii) The bioavailability profile estab- formulation proposed for marketing lished for the drug product rules out unless an alternative or additional the occurrence of any dose dumping. route is necessary to answer the sci- (iii) The drug product’s steady-state entific question under study. For ex- performance is equivalent to a cur- ample, in the case of an active drug in- rently marketed nonextended release gredient or therapeutic moiety that is or extended release drug product that poorly absorbed after oral administra- contains the same active drug ingre- tion, it may be necessary to compare the oral dosage form proposed for mar- dient or therapeutic moiety and that is keting with the active drug ingredient subject to an approved full new drug or therapeutic moiety administered in application. solution both orally and intravenously. (iv) The drug product’s formulation (e) New formulations of active drug in- provides consistent pharmacokinetic gredients or therapeutic moieties approved performance between individual dosage for marketing. (1) An in vivo bio- units. availability study involving a drug (2) The reference material(s) for such product that is a new dosage form, or a a bioavailability study shall be chosen new salt or ester of an active drug in- to permit an appropriate scientific gredient or therapeutic moiety that evaluation of the extended release has been approved for marketing can claims made for the drug product. The be used to: reference material shall be one of the (i) Measure the bioavailability of the following or any combination thereof: new formulation, new dosage form, or (i) A solution or suspension of the ac- new salt or ester relative to an appro- tive drug ingredient or therapeutic priate reference material; and moiety. (ii) Define the pharmacokinetic pa- (ii) A currently marketed noncon- rameters of the new formulation, new dosage form, or new salt or ester to es- trolled release drug product containing tablish dosage recommendation. the same active drug ingredient or (2) The selection of the reference ma- therapeutic moiety and administered terial(s) in such a bioavailability study according to the dosage recommenda- depends upon the scientific questions tions in the labeling of the noncon- to be answered, the data needed to es- trolled release drug product. tablish comparability to a currently

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(iii) A currently marketed extended tivity of the test, the reference mate- release drug product subject to an ap- rial in a bioavailability study may be a proved full new drug application con- placebo if: taining the same active drug ingre- (1) The study measures the thera- dient or therapeutic moiety and admin- peutic or acute pharmacological effect istered according to the dosage rec- of the active drug ingredient or thera- ommendations in the labeling proposed peutic moiety; or for the extended release drug product. (2) The study is a clinical trial to es- (iv) A reference material other than tablish the safety and effectiveness of one set forth in paragraph (f)(2) (i), (ii) the drug product. or (iii) of this section that is appro- (i) Standards for test drug product and priate for valid scientific reasons. reference material. (1) Both the drug (g) Combination drug products. (1) Gen- product to be tested and the reference erally, the purpose of an in vivo bio- material, if it is another drug product, availability study involving a combina- shall be shown to meet all compendial tion drug product is to determine if the or other applicable standards of iden- rate and extent of absorption of each tity, strength, quality, and purity, inactive drug ingredient or therapeutic cluding potency and, where applicable, moiety in the combination drug prod- content uniformity, disintegration uct is equivalent to the rate and extent times, and dissolution rates. of absorption of each active drug ingre- (2) Samples of the drug product to be dient or therapeutic moiety adminis- tested shall be manufactured using the tered concurrently in separate single- same equipment and under the same ingredient preparations. conditions as those used for full-scale (2) The reference material in such a production. bioavailability study should be two or [42 FR 1648, Jan. 7, 1977, as amended at 67 FR more currently marketed, single-ingre- 77674, Dec. 19, 2002] dient drug products each of which contains one of the active drug ingredients § 320.26 Guidelines on the design of a or therapeutic moieties in the com- single-dose in vivo bioavailability bination drug product. The Food and or bioequivalence study. Drug Administration may, for valid (a) Basic principles. (1) An in vivo bio- scientific reasons, specify that the ref- availability or bioequivalence study erence material shall be a combination should be a single-dose comparison of drug product that is the subject of an the drug product to be tested and the approved new drug application. appropriate reference material con- (3) The Food and Drug Administra- ducted in normal adults. tion may permit a bioavailability (2) The test product and the reference study involving a combination drug material should be administered to product to determine the rate and ex- subjects in the fasting state, unless tent of absorption of selected, but not some other approach is more appro- all, active drug ingredients or thera- priate for valid scientific reasons. peutic moieties in the combination (b) Study design. (1) A single-dose drug product. The Food and Drug Ad- study should be crossover in design, ministration may permit this deter- unless a parallel design or other design mination if the pharmacokinetics and is more appropriate for valid scientific the interactions of the active drug in- reasons, and should provide for a drug gredients or therapeutic moieties in elimination period. the combination drug product are well (2) Unless some other approach is ap- known and the therapeutic activity of propriate for valid scientific reasons, the combination drug product is gen- the drug elimination period should be erally recognized to reside in only one either: of the active drug ingredients or thera- (i) At least three times the half-life peutic moieties, e.g., ampicillin in an of the active drug ingredient or thera- ampicillin-probenecid combination peutic moiety, or its metabolite(s), drug product. measured in the blood or urine; or (h) Use of a placebo as the reference (ii) At least three times the half-life material. Where appropriate or where of decay of the acute pharmacological necessary to demonstrate the sensi- effect.

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(c) Collection of blood samples. (1) some other approach is more appro- When comparison of the test product priate for valid scientific reasons. and the reference material is to be (2) The use of an acute pharma- based on blood concentration time cological effect to determine bio- curves, unless some other approach is availability may further require dem- more appropriate for valid scientific onstration of dose-related response. In reasons, blood samples should be taken such a case, bioavailability may be de- with sufficient frequency to permit an termined by comparison of the dose-re- estimate of both: sponse curves as well as the total area (i) The peak concentration in the under the acute pharmacological ef- blood of the active drug ingredient or fect-time curves for any given dose. therapeutic moiety, or its metabolite(s), measured; and [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] (ii) The total area under the curve for a time period at least three times the § 320.27 Guidelines on the design of a half-life of the active drug ingredient multiple-dose in vivo bioavailability or therapeutic moiety, or its metabo- study. lite(s), measured. (a) Basic principles. (1) In selected cir- (2) In a study comparing oral dosage cumstances it may be necessary for the forms, the sampling times should be test product and the reference material identical. to be compared after repeated adminis- (3) In a study comparing an intra- tration to determine steady-state lev- venous dosage form and an oral dosage els of the active drug ingredient or form, the sampling times should be therapeutic moiety in the body. those needed to describe both: (i) The distribution and elimination (2) The test product and the reference phase of the intravenous dosage form; material should be administered to and subjects in the fasting or nonfasting (ii) The absorption and elimination state, depending upon the conditions phase of the oral dosage form. reflected in the proposed labeling of (4) In a study comparing drug deliv- the test product. ery systems other than oral or intra- (3) A multiple-dose study may be re- venous dosage forms with an appro- quired to determine the bioavailability priate reference standard, the sampling of a drug product in the following cir- times should be based on valid sci- cumstances: entific reasons. (i) There is a difference in the rate of (d) Collection of urine samples. When absorption but not in the extent of ab- comparison of the test product and the sorption. reference material is to be based on cu- (ii) There is excessive variability in mulative urinary excretion-time bioavailability from subject to subject. curves, unless some other approach is (iii) The concentration of the active more appropriate for valid scientific drug ingredient or therapeutic moiety, reasons, samples of the urine should be or its metabolite(s), in the blood re- collected with sufficient frequency to sulting from a single dose is too low for permit an estimate of the rate and ex- accurate determination by the analyt- tent of urinary excretion of the active ical method. drug ingredient or therapeutic moiety, (iv) The drug product is an extended or its metabolite(s), measured. release dosage form. (e) Measurement of an acute pharma- (b) Study design. (1) A multiple-dose cological effect. (1) When comparison of study should be crossover in design, the test product and the reference ma- unless a parallel design or other design terial is to be based on acute pharma- is more appropriate for valid scientific cological effect-time curves, measure- reasons, and should provide for a drug ments of this effect should be made elimination period if steady-state con- with sufficient frequency to permit a ditions are not achieved. reasonable estimate of the total area (2) A multiple-dose study is not re- under the curve for a time period at quired to be of crossover design if the least three times the half-life of decay study is to establish dose proportion- of the pharmacological effect, unless ality under a multiple-dose regimen or

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to establish the pharmacokinetic pro- clearances obtained in a single-dose file of a new drug product, a new drug study to support adequate dosage rec- delivery system, or an extended release ommendations. dosage form. (2) In a linear system, the area under (3) If a drug elimination period is re- the blood concentration-time curve quired, unless some other approach is during a dosing interval in a multiple- more appropriate for valid scientific dose steady-state study is directly pro- reasons, the drug elimination period portional to the fraction of the dose ab- should be either: sorbed and is equal to the cor- (i) At least five times the half-life of responding ‘‘zero to infinity’’ area the active drug ingredient or thera- under the curve for a single-dose study. peutic moiety, or its active metabo- Therefore, when steady-state condi- lite(s), measured in the blood or urine; tions are achieved, a comparison of or blood concentrations during a dosing (ii) At least five times the half-life of interval may be used to define the frac- decay of the acute pharmacological ef- tion of the active drug ingredient or fect. therapeutic moiety absorbed. (c) Achievement of steady-state condi- (3) Other methods based on valid sci- tions. Whenever a multiple-dose study entific reasons should be used to deter- is conducted, unless some other ap- mine the bioavailability of a drug prod- proach is more appropriate for valid uct having dose-dependent kinetics scientific reasons, sufficient doses of (non-linear system). the test product and reference material (f) Measurement of an acute pharma- should be administered in accordance cological effect. When comparison of the with the labeling to achieve steady- test product and the reference material state conditions. is to be based on acute pharma- (d) Collection of blood or urine samples. cological effect-time curves, measure- (1) Whenever comparison of the test ments of this effect should be made product and the reference material is with sufficient frequency to dem- to be based on blood concentration- onstrate a maximum effect and a lack time curves at steady state, appro- of significant difference between the priate dosage administration and sam- test product and the reference mate- pling should be carried out to docu- rial. ment attainment of steady state. (2) Whenever comparison of the test [42 FR 1648, Jan. 7, 1977, as amended at 67 FR product and the reference material is 77674, Dec. 19, 2002] to be based on cumulative urinary ex- § 320.28 Correlation of bioavailability cretion-time curves at steady state, ap- with an acute pharmacological ef- propriate dosage administration and fect or clinical evidence. sampling should be carried out to document attainment of steady state. Correlation of in vivo bioavailability (3) A more complete characterization data with an acute pharmacological ef- of the blood concentration or urinary fect or clinical evidence of safety and excretion rate during the absorption effectiveness may be required if needed and elimination phases of a single dose to establish the clinical significance of administered at steady-state is encour- a special claim, e.g., in the case of an aged to permit estimation of the total extended release preparation. area under concentration-time curves [42 FR 1648, Jan. 7, 1977, as amended at 67 FR or cumulative urinary excretion-time 77674, Dec. 19, 2002] curves and to obtain pharmacokinetic information, e.g., half-life or blood § 320.29 Analytical methods for an in clearance, that is essential in pre- vivo bioavailability or bioequiva- paring adequate labeling for the drug lence study. product. (a) The analytical method used in an (e) Steady-state parameters. (1) In cer- in vivo bioavailability or bioequiva- tain instances, e.g., in a study involv- lence study to measure the concentra- ing a new drug entity, blood clearances tion of the active drug ingredient or at steady-state obtained in a multiple- therapeutic moiety, or its active me- dose study should be compared to blood tabolite(s), in body fluids or excretory

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products, or the method used to meas- (2) General inquiries relating to bio- ure an acute pharmacological effect equivalence requirements and method- shall be demonstrated to be accurate ology shall be submitted to the Food and of sufficient sensitivity to meas- and Drug Administration, Center for ure, with appropriate precision, the ac- Drug Evaluation and Research, Divi- tual concentration of the active drug sion of Bioequivalence (HFD–650), 7500 ingredient or therapeutic moiety, or its Standish Pl., Rockville, MD 20855–2773. active metabolite(s), achieved in the body. [57 FR 18000, Apr. 28, 1992, as amended at 67 FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26, (b) When the analytical method is 2009] not sensitive enough to measure accurately the concentration of the active § 320.31 Applicability of requirements drug ingredient or therapeutic moiety, regarding an ‘‘Investigational New or its active metabolite(s), in body Drug Application.’’ fluids or excretory products produced (a) Any person planning to conduct by a single dose of the test product, an in vivo bioavailability or bioequiva- two or more single doses may be given lence study in humans shall submit an together to produce higher concentra- ‘‘Investigational New Drug Applica- tion if the requirements of § 320.31 are tion’’ (IND) if: met. (1) The test product contains a new [42 FR 1648, Jan. 7, 1977, as amended at 67 FR chemical entity as defined in 77674, Dec. 19, 2002] § 314.108(a) of this chapter; or (2) The study involves a radioactively § 320.30 Inquiries regarding bio- labeled drug product; or availability and bioequivalence requirements and review of protocols (3) The study involves a cytotoxic by the Food and Drug Administra- drug product. tion. (b) Any person planning to conduct a (a) The Commissioner of Food and bioavailability or bioequivalence study Drugs strongly recommends that, to in humans using a drug product that avoid the conduct of an improper study contains an already approved, non-new and unnecessary human research, any chemical entity shall submit an IND if person planning to conduct a bio- the study is one of the following: availability or bioequivalence study (1) A single-dose study in normal sub- submit the proposed protocol for the jects or patients where either the max- study to FDA for review prior to the imum single or total daily dose exceeds initiation of the study. that specified in the labeling of the (b) FDA may review a proposed pro- drug product that is the subject of an tocol for a bioavailability or bioequiva- approved new drug application or ab- lence study and will offer advice with breviated new drug application. respect to whether the following condi- (2) A multiple-dose study in normal tions are met: subjects or patients where either the (1) The design of the proposed bio- single or total daily dose exceeds that availability or bioequivalence study is specified in the labeling of the drug appropriate. product that is the subject of an ap- (2) The reference material to be used proved new drug application or abbre- in the bioavailability or bioequivalence viated new drug application. study is appropriate. (3) A multiple-dose study on an ex- (3) The proposed chemical and statis- tended release product on which no sin- tical analytical methods are adequate. gle-dose study has been completed. (c)(1) General inquiries relating to in (c) The provisions of parts 50, 56, and vivo bioavailability requirements and 312 of this chapter are applicable to methodology shall be submitted to the any bioavailability or bioequivalence Food and Drug Administration, Center study in humans conducted under an for Drug Evaluation and Research, Of- IND. fice of Clinical Pharmacology, 10903 (d) A bioavailability or bioequiva- New Hampshire Ave., Silver Spring, lence study in humans other than one MD 20993–0002. described in paragraphs (a) through (c)

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of this section is exempt from the re- the study, including any contract requirements of part 312 of this chapter if search organization, must submit to the following conditions are satisfied: FDA any additional data or informa- (1) If the study is one described under tion that the agency deems necessary, § 320.38(b) or § 320.63, the person con- as soon as possible, but in no case later ducting the study, including any con- than 15 calendar days after receiving tract research organization, must re- the request. tain reserve samples of any test article and reference standard used in the [57 FR 18000, Apr. 28, 1992, as amended at 58 study and release the reserve samples FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, to FDA upon request, in accordance 2002; 75 FR 59963, Sept. 29, 2010] with, and for the period specified in, § 320.38; § 320.32 Procedures for establishing or amending a bioequivalence require- (2) An in vivo bioavailability or bio- ment. equivalence study in humans must be conducted in compliance with the re- (a) The Food and Drug Administra- quirements for institutional review set tion, on its own initiative or in re- forth in part 56 of this chapter, and in- sponse to a petition by an interested formed consent set forth in part 50 of person, may propose and promulgate a this chapter; and regulation to establish a bioequiva- (3) The person conducting the study, lence requirement for a product not including any contract research orga- subject to section 505(j) of the act if it nization, must notify FDA and all par- finds there is well-documented evi- ticipating investigators of any serious dence that specific pharmaceutical adverse event, as defined in § 312.32(a), equivalents or pharmaceutical alter- observed during the conduct of the natives intended to be used inter- study as soon as possible but in no case changeably for the same therapeutic later than 15 calendar days after be- effect: coming aware of its occurrence. Each (1) Are not bioequivalent drug prod- report must be submitted on FDA ucts; or Form 3500A or in an electronic format that FDA can process, review, and ar- (2) May not be bioequivalent drug chive. FDA will periodically issue guid- products based on the criteria set forth ance on how to provide the electronic in § 320.33; or submission (e.g., method of trans- (3) May not be bioequivalent drug mission, media, file formats, prepara- products because they are members of tion and organization of files). Each re- a class of drug products that have close port must bear prominent identifica- structural similarity and similar phys- tion of its contents, i.e., ‘‘bio- icochemical or pharmacokinetic prop- availability/bioequivalence safety re- erties to other drug products in the port.’’ The person conducting the same class that FDA finds are not bio- study, including any contract research equivalent drug products. organization, must also notify FDA of (b) FDA shall include in a proposed any fatal or life-threatening adverse rule to establish a bioequivalence re- event from the study as soon as pos- quirement the evidence and criteria set sible but in no case later than 7 cal- forth in § 320.33 that are to be consid- endar days after becoming aware of its ered in determining whether to issue occurrence. Each notification under the proposal. If the rulemaking is pro- this paragraph must be submitted to posed in response to a petition, FDA the Director, Office of Generic Drugs in shall include in the proposal a sum- the Center for Drug Evaluation and Re- mary and analysis of the relevant in- search at FDA. Relevant followup information that was submitted in the formation to a bioavailability/bioequivalence safety report must be sub- petition as well as other available in- mitted as soon as the information is formation to support the establishment available and must be identified as of a bioequivalence requirement. such, i.e., ‘‘Followup bioavailability/ (c) FDA, on its own initiative or in bioequivalence safety report.’’ Upon re- response to a petition by an interested quest from FDA, the person conducting person, may propose and promulgate

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an amendment to a bioequivalence re- minute in 900 milliliters of distilled or quirement established under this sub- deionized water at 37 °C, or differs sig- part. nificantly from that of an appropriate [57 FR 18000, Apr. 28, 1992] reference material such as an identical drug product that is the subject of an § 320.33 Criteria and evidence to as- approved full new drug application. sess actual or potential bioequiva- (3) The particle size and/or surface lence problems. area of the active drug ingredient is The Commissioner of Food and Drugs critical in determining its bio- shall consider the following factors, availability. when supported by well-documented (4) Certain physical structural char- evidence, to identify specific pharma- acteristics of the active drug ingre- ceutical equivalents and pharma- dient, e.g., polymorphic forms, con- ceutical alternatives that are not or forms, solvates, complexes, and crystal may not be bioequivalent drug prod- modifications, dissolve poorly and this ucts. poor dissolution may affect absorption. (a) Evidence from well-controlled (5) Such drug products have a high clinical trials or controlled observa- ratio of excipients to active ingredi- tions in patients that such drug prod- ents, e.g., greater than 5 to 1. ucts do not give comparable thera- (6) Specific inactive ingredients, e.g., peutic effects. hydrophilic or hydrophobic excipients (b) Evidence from well-controlled and lubricants, either may be required bioequivalence studies that such prod- for absorption of the active drug ingre- ucts are not bioequivalent drug prod- dient or therapeutic moiety or, alter- ucts. natively, if present, may interfere with (c) Evidence that the drug products such absorption. exhibit a narrow therapeutic ratio, (f) Pharmacokinetic evidence that: e.g., there is less than a 2-fold difference in median lethal dose (LD ) (1) The active drug ingredient, thera- 50 peutic moiety, or its precursor is ab- and median effective dose (ED50) values, or have less than a 2-fold dif- sorbed in large part in a particular seg- ference in the minimum toxic con- ment of the gastrointestinal tract or is centrations and minimum effective absorbed from a localized site. concentrations in the blood, and safe (2) The degree of absorption of the ac- and effective use of the drug products tive drug ingredient, therapeutic moi- requires careful dosage titration and ety, or its precursor is poor, e.g., less patient monitoring. than 50 percent, ordinarily in compari- (d) Competent medical determination son to an intravenous dose, even when that a lack of bioequivalence would it is administered in pure form, e.g., in have a serious adverse effect in the solution. treatment or prevention of a serious (3) There is rapid metabolism of the disease or condition. therapeutic moiety in the intestinal (e) Physicochemical evidence that: wall or liver during the process of ab- (1) The active drug ingredient has a sorption (first-pass metabolism) so the low solubility in water, e.g., less than 5 therapeutic effect and/or toxicity of milligrams per 1 milliliter, or, if dis- such drug product is determined by the solution in the stomach is critical to rate as well as the degree of absorp- absorption, the volume of gastric fluids tion. required to dissolve the recommended (4) The therapeutic moiety is rapidly dose far exceeds the volume of fluids metabolized or excreted so that rapid present in the stomach (taken to be 100 dissolution and absorption are required milliliters for adults and prorated for for effectiveness. infants and children). (5) The active drug ingredient or (2) The dissolution rate of one or therapeutic moiety is unstable in spe- more such products is slow, e.g., less cific portions of the gastrointestinal than 50 percent in 30 minutes when tract and requires special coatings or tested using either a general method formulations, e.g., buffers, enteric specified in an official compendium or coatings, and film coatings, to assure a paddle method at 50 revolutions per adequate absorption.

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(6) The drug product is subject to product meets a bioequivalence re- dose dependent kinetics in or near the quirement shall be maintained by the therapeutic range, and the rate and ex- manufacturer for at least 2 years after tent of absorption are important to the expiration date of the batch and bioequivalence. submitted to the Food and Drug Ad- ministration on request. [42 FR 1635, Jan. 7, 1977. Redesignated and amended at 57 FR 18001, Apr. 28, 1992; 81 FR (b) Any person who contracts with 17066, Mar. 28, 2016] another party to conduct a bioequivalence study from which the data are in- § 320.34 Requirements for batch test- tended to be submitted to FDA as part ing and certification by the Food of an application submitted under part and Drug Administration. 314 of this chapter shall obtain from (a) If the Commissioner determines the person conducting the study suffi- that individual batch testing by the cient accurate financial information to Food and Drug Administration is nec- allow the submission of complete and essary to assure that all batches of the accurate financial certifications or dis- same drug product meet an appropriate closure statements required under part in vitro test, he shall include in the 54 of this chapter and shall maintain bioequivalence requirement a require- that information and all records relat- ment for manufacturers to submit sam- ing to the compensation given for that ples of each batch to the Food and study and all other financial interest Drug Administration and to withhold information required under part 54 of distribution of the batch until notified this chapter for 2 years after the date by the Food and Drug Administration of approval of the application. The per- that the batch may be introduced into son maintaining these records shall, interstate commerce. upon request for any properly author- (b) The Commissioner will ordinarily ized officer or employee of the Food terminate a requirement for a manu- and Drug Administration, at reason- facturer to submit samples for batch able time, permit such officer or em- testing on a finding that the manufac- ployee to have access to and copy and turer has produced four consecutive verify these records. batches that were tested by the Food and Drug Administration and found to [42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992, as amended at 63 FR meet the bioequivalence requirement, 5252, Feb. 2, 1998] unless the public health requires that batch testing be extended to additional § 320.38 Retention of bioavailability batches. samples. [42 FR 1635, Jan. 7, 1977. Redesignated at 57 (a) The applicant of an application or FR 18001, Apr. 28, 1992] supplemental application submitted under section 505 of the Federal Food, § 320.35 Requirements for in vitro test- Drug, and Cosmetic Act, or, if bio- ing of each batch. availability testing was performed If a bioequivalence requirement under contract, the contract research specifies a currently available in vitro organization shall retain an appro- test or an in vitro bioequivalence priately identified reserve sample of standard comparing the drug product the drug product for which the appli- to a reference standard, the manufac- cant is seeking approval (test article) turer shall conduct the test on a sam- and of the reference standard used to ple of each batch of the drug product to perform an in vivo bioavailability assure batch-to-batch uniformity. study in accordance with and for the [42 FR 1635, Jan. 7, 1977. Redesignated at 57 studies described in paragraph (b) of FR 18001, Apr. 28, 1992] this section that is representative of each sample of the test article and ref- § 320.36 Requirements for mainte- erence standard provided by the appli- nance of records of bioequivalence cant for the testing. testing. (b) Reserve samples shall be retained (a) All records of in vivo or in vitro for the following test articles and ref- tests conducted on any marketed batch erence standards and for the studies de- of a drug product to assure that the scribed:

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(1) If the formulation of the test arti- ple from which the reserve sample was cle is the same as the formulation(s) obtained was used. used in the clinical studies dem- (f) Authorized FDA personnel will or- onstrating substantial evidence of safe- dinarily collect reserve samples di- ty and effectiveness for the test arti- rectly from the applicant or contract cle’s claimed indications, a reserve research organization at the storage sample of the test article used to con- site during a preapproval inspection. If duct an in vivo bioavailability study authorized FDA personnel are unable comparing the test article to a ref- to collect samples, FDA may require erence oral solution, suspension, or in- the applicant or contract research or- jection. ganization to submit the reserve sam- (2) If the formulation of the test arti- ples to the place identified in the agen- cle differs from the formulation(s) used cy’s request. If FDA has not collected in the clinical studies demonstrating or requested delivery of a reserve sam- substantial evidence of safety and ef- ple, or if FDA has not collected or re- fectiveness for the test article’s quested delivery of any portion of a re- claimed indications, a reserve sample serve sample, the applicant or contract of the test article and of the reference research organization shall retain the standard used to conduct an in vivo bioequivalence study comparing the sample or remaining sample for the 5- test article to the formulation(s) (ref- year period specified in paragraph (e) erence standard) used in the clinical of this section. studies. (g) Upon release of the reserve sam- (3) For a new formulation, new dos- ples to FDA, the applicant or contract age form, or a new salt or ester of an research organization shall provide a active drug ingredient or therapeutic written assurance that, to the best moiety that has been approved for mar- knowledge and belief of the individual keting, a reserve sample of the test ar- executing the assurance, the reserve ticle and of the reference standard used samples came from the same samples to conduct an in vivo bioequivalence as used in the specific bioavailability study comparing the test article to a or bioequivalence study identified by marketed product (reference standard) the agency. The assurance shall be exe- that contains the same active drug in- cuted by an individual authorized to gredient or therapeutic moiety. act for the applicant or contract re- (c) Each reserve sample shall consist search organization in releasing the re- of a sufficient quantity to permit FDA serve samples to FDA. to perform five times all of the release (h) A contract research organization tests required in the application or may contract with an appropriate, supplemental application. independent third party to provide (d) Each reserve sample shall be ade- storage of reserve samples provided quately identified so that the reserve that the sponsor of the study has been sample can be positively identified as notified in writing of the name and ad- having come from the same sample as dress of the facility at which the re- used in the specific bioavailability serve samples will be stored. study. (i) If a contract research organization (e) Each reserve sample shall be conducting a bioavailability or bio- stored under conditions consistent equivalence study that requires reserve with product labeling and in an area sample retention under this section or segregated from the area where testing § 320.63 goes out of business, it shall is conducted and with access limited to transfer its reserve samples to an ap- authorized personnel. Each reserve propriate, independent third party, and sample shall be retained for a period of shall notify in writing the sponsor of at least 5 years following the date on the study of the transfer and provide which the application or supplemental the study sponsor with the name and application is approved, or, if such ap- address of the facility to which the re- plication or supplemental application serve samples have been transferred. is not approved, at least 5 years following the date of completion of the [58 FR 25927, Apr. 28, 1993, as amended at 64 bioavailability study in which the sam- FR 402, Jan. 5, 1999]

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§ 320.63 Retention of bioequivalence § 328.3 Definitions. samples. As used in this part: The applicant of an abbreviated ap- (a) Alcohol means the substance plication or a supplemental application known as ethanol, ethyl alcohol, or Al- submitted under section 505 of the Fed- cohol, USP. eral Food, Drug, and Cosmetic Act, or, (b) Inactive ingredient means any com- if bioequivalence testing was per- ponent of a product other than an ac- formed under contract, the contract re- tive ingredient as defined in § 210.3(b)(7) search organization shall retain re- of this chapter. serve samples of any test article and reference standard used in conducting an in vivo or in vitro bioequivalence Subpart B—Ingredients study required for approval of the abbreviated application or supplemental § 328.10 Alcohol. application. The applicant or contract (a) Any over-the-counter (OTC) drug research organization shall retain the product intended for oral ingestion reserve samples in accordance with, shall not contain alcohol as an inactive and for the period specified in, § 320.38 ingredient in concentrations that ex- and shall release the reserve samples to ceed those established in this part, un- FDA upon request in accordance with less a specific exemption, as provided § 320.38. in paragraph (e) or (f) of this section, [58 FR 25928, Apr. 28, 1993, as amended at 64 has been approved. FR 402, Jan. 5, 1999] (b) For any OTC drug product intended for oral ingestion and labeled PART 328—OVER-THE-COUNTER for use by adults and children 12 years DRUG PRODUCTS INTENDED FOR of age and over, the amount of alcohol in the product shall not exceed 10 per- ORAL INGESTION THAT CONTAIN cent. ALCOHOL (c) For any OTC drug product intended for oral ingestion and labeled Subpart A—General Provisions for use by children 6 to under 12 years Sec. of age, the amount of alcohol in the 328.1 Scope. product shall not exceed 5 percent. 328.3 Definitions. (d) For any OTC drug product intended for oral ingestion and labeled Subpart B—Ingredients for use by children under 6 years of 328.10 Alcohol. age, the amount of alcohol in the product shall not exceed 0.5 percent. Subpart C—Labeling (e) The Food and Drug Administra- tion will grant an exemption from 328.50 Principal display panel of all OTC drug products intended for oral ingestion paragraphs (b), (c), and (d) of this sec- that contain alcohol. tion where appropriate, upon petition under the provisions of § 10.30 of this AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, chapter. Appropriate cause, such as a 701 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371). specific solubility or manufacturing problem, must be adequately docu- SOURCE: 60 FR 13595, Mar. 13, 1995, unless mented in the petition. Decisions with otherwise noted. respect to requests for exemption shall EDITORIAL NOTE: Nomenclature changes to be maintained in a permanent file for part 328 appear at 69 FR 13717, Mar. 24, 2004. public review by the Division of Dock- ets Management (HFA–305), Food and Subpart A—General Provisions Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. § 328.1 Scope. (f) Ipecac syrup is exempt from the Reference in this part to regulatory provisions of paragraph (d) of this sec- sections of the Code of Federal Regula- tion. tions are to chapter I of title 21 unless (g) The following drugs are tempo- otherwise noted. rarily exempt from the provisions of

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paragraphs (b), (c), and (d) of this sec- over 5 percent alcohol and labeled for tion: use by adults and children 12 years of (1) Aromatic Cascara Fluidextract. age and over, the labeling shall contain (2) Cascara Sagrada Fluidextract. the following statement in the direc- (3) Orally ingested homeopathic drug tions section: ‘‘Consult a physician for products. use in children under 12 years of age.’’ (g) For any OTC drug product in- [60 FR 13595, Mar. 13, 1995, as amended at 61 FR 58630, Nov. 18, 1996; 68 FR 24879, May 9, tended for oral ingestion containing 2003] over 0.5 percent alcohol and labeled for use by children ages 6 to under 12 years Subpart C—Labeling of age, the labeling shall contain the following statement in the directions § 328.50 Principal display panel of all section: ‘‘Consult a physician for use in OTC drug products intended for children under 6 years of age.’’ oral ingestion that contain alcohol. (h) When the direction regarding age (a) The amount (percentage) of alco- in paragraph (e) or (f) of this section hol present in a product shall be stated differs from an age-limiting direction in terms of percent volume of absolute contained in any OTC drug monograph alcohol at 60 °F (15.56 °C) in accordance in this chapter, the direction con- with § 201.10(d)(2) of this chapter. taining the more stringent age limita- (b) A statement expressing the tion shall be used. amount (percentage) of alcohol present in a product shall appear prominently PART 329—NONPRESCRIPTION and conspicuously on the ‘‘principal HUMAN DRUG PRODUCTS SUB- display panel,’’ as defined in § 201.60 of JECT TO SECTION 760 OF THE this chapter. For products whose prin- FEDERAL FOOD, DRUG, AND cipal display panel is on the immediate COSMETIC ACT container label and that are not marketed in another retail package (e.g., an outer box), the statement of the per- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, centage of alcohol present in the prod- 355, 371, 379aa. uct shall appear prominently and con- SOURCE: 79 FR 33089, June 10, 2014, unless spicuously on the ‘‘principal display otherwise noted. panel’’ of the immediate container label. § 329.100 Postmarketing reporting of adverse drug events under section (c) For products whose principal dis- 760 of the Federal Food, Drug, and play panel is on the retail package and Cosmetic Act. the retail package is not the immediate container, the statement of the (a) Reporting requirements. Reports of percentage of alcohol present in the serious adverse events required by sec- product shall also appear on the imme- tion 760 of the Federal Food, Drug, and diate container label; it may appear Cosmetic Act (FD&C Act) must include anywhere on that label in accord with the information specified in this sec- section 502(e) of the Federal Food, tion, as applicable. Except as provided Drug, and Cosmetic Act. in paragraph (c)(2) of this section, (d) The statement expressing the these reports must be submitted to the amount (percentage) of alcohol present Agency in electronic format as de- in the product shall be in a size reason- scribed in paragraph (c)(1) of this sec- ably related to the most prominent tion. printed matter on the panel or label on (b) Contents of reports. For purposes of which it appears, and shall be in lines reporting serious adverse events under generally parallel to the base on which section 760 of the FD&C Act, an indi- the package rests as it is designed to be vidual case safety report (ICSR) con- displayed. stitutes the MedWatch form required (e) For a product to state in its label- to be submitted by section 760(d) of the ing that it is ‘‘alcohol free,’’ it must FD&C Act. ICSRs include the following contain no alcohol (0 percent). information: (f) For any OTC drug product in- (1) Patient information. tended for oral ingestion containing (i) Patient identification code;

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(ii) Patient age at the time of adverse (vii) Unique case identification num- drug experience, or date of birth; ber, which must be the same in the ini- (iii) Patient gender; and tial report and any subsequent fol- (iv) Patient weight. lowup report(s). (2) Adverse event. (c) Electronic format for submissions. (1) (i) Outcome attributed to adverse Each report required to be submitted drug event; to FDA under section 760 of the FD&C (ii) Date of adverse drug event; Act, accompanied by a copy of the (iii) Date of ICSR submission; label on or within the retail package of (iv) Description of adverse drug event the drug and any other documentation (including a concise medical nar- (as ICSR attachments), must be in an rative); electronic format that FDA can proc- (v) Adverse drug event term(s); ess, review, and archive. FDA will issue (vi) Description of relevant tests, in- guidance on how to provide the elec- cluding dates and laboratory data; and tronic submission (e.g., method of (vii) Other relevant patient history, transmission, media, file formats, prep- including preexisting medical condi- aration, and organization of files). tions. (2) The responsible person may re- (3) Suspect medical product(s). quest, in writing, a temporary waiver (i) Name; of the requirements in paragraph (c)(1) (ii) Dose, frequency, and route of ad- of this section. These waivers will be ministration used; granted on a limited basis for good (iii) Therapy dates; cause shown. FDA will issue guidance (iv) Diagnosis for use (indication); on requesting a waiver of the require- (v) Whether the product is a comments in paragraph (c)(1) of this sec- bination product as defined in § 3.2(e) of tion. this chapter; (d) Patient privacy. The responsible (vi) Whether the product is a pre- person should not include in reports scription or nonprescription product; under this section the names and ad- (vii) Whether adverse drug event dresses of individual patients; instead, abated after drug use stopped or dose the responsible person should assign a reduced; unique code for identification of the (viii) Whether adverse drug event re- patient. The responsible person should appeared after reintroduction of drug; include the name of the reporter from (ix) Lot number; whom the information was received as (x) Expiration date; part of the initial reporter informa- (xi) National Drug Code (NDC) num- tion, even when the reporter is the pa- ber; and tient. The names of patients, health (xii) Concomitant medical products care professionals, hospitals, and geo- and therapy dates. graphical identifiers in adverse drug (4) Initial reporter information. event reports are not releasable to the (i) Name, address, and telephone public under FDA’s public information number; regulations in part 20 of this chapter. (ii) Whether the initial reporter is a health care professional; and (iii) Occupation, if a health care pro- PART 330—OVER-THE-COUNTER fessional. (OTC) HUMAN DRUGS WHICH (5) Responsible person (as defined in ARE GENERALLY RECOGNIZED section 760(b) of the FD&C Act) informa- AS SAFE AND EFFECTIVE AND tion. NOT MISBRANDED (i) Name and contact office address; (ii) Telephone number; Subpart A—General Provisions (iii) Report source, such as spontaneous; Sec. (iv) Date the report was received by 330.1 General conditions for general rec- responsible person; ognition as safe, effective and not misbranded. (v) Whether the ICSR is a 15-day re- 330.2 Pregnancy-nursing warning. port; 330.3 Imprinting of solid oral dosage form (vi) Whether the ICSR is an initial drug products. report or followup report; and 330.5 Drug categories.

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Subpart B—Administrative Procedures Food, Drug, and Cosmetic Act (the act) and subchapter C et seq. of this chapter, 330.10 Procedures for classifying OTC drugs including the format and content re- as generally recognized as safe and effective and not misbranded, and for estab- quirements in § 201.66 of this chapter. lishing monographs. An OTC drug product that is not in 330.11 NDA deviations from applicable compliance with chapter V and sub- monograph. chapter C, including § 201.66 of this 330.12 Status of over-the-counter (OTC) chapter, is subject to regulatory ac- drugs previously reviewed under the tion. For purposes of § 201.61(b) of this Drug Efficacy Study (DESI). chapter, the statement of identity of 330.13 Conditions for marketing ingredients recommended for over-the-counter (OTC) the product shall be the term or phrase use under the OTC drug review. used in the applicable OTC drug mono- 330.14 Additional criteria and procedures for graph established in this part. classifying OTC drugs as generally recog- (2) The ‘‘Uses’’ section of the label nized as safe and effective and not mis- and labeling of the product shall con- branded. tain the labeling describing the ‘‘Indi- 330.15 Timelines for FDA review and action cations’’ that have been established in on time and extent applications and safe- an applicable OTC drug monograph or ty and effectiveness data submissions. alternative truthful and nonmisleading AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, statements describing only those indi- 360, 360fff–6, 371. cations for use that have been estab- SOURCE: 39 FR 11741, Mar. 29, 1974, unless lished in an applicable monograph, sub- otherwise noted. ject to the provisions of section 502 of EDITORIAL NOTE: Nomenclature changes to the act relating to misbranding and the part 330 appear at 69 FR 13717, Mar. 24, 2004. prohibition in section 301(d) of the act against the introduction or delivery for Subpart A—General Provisions introduction into interstate commerce of unapproved new drugs in violation of § 330.1 General conditions for general section 505(a) of the act. Any other la- recognition as safe, effective and beling under this subchapter and sub- not misbranded. chapter C et seq. of this chapter shall be An over-the-counter (OTC) drug list- stated in the exact language where ed in this subchapter is generally rec- exact language has been established ognized as safe and effective and is not and identified by quotation marks in misbranded if it meets each of the con- an applicable OTC drug monograph or ditions contained in this part and each by regulation (e.g., § 201.63 of this chap- of the conditions contained in any ap- ter), except as provided in paragraphs plicable monograph. Any product (i) and (j) of this section. which fails to conform to each of the (d) The advertising for the product conditions contained in this part and prescribes, recommends, or suggests its in an applicable monograph is liable to use only under the conditions stated in regulatory action. the labeling. (a) The product is manufactured in (e) The product contains only suit- compliance with current good manu- able inactive ingredients which are facturing practices, as established by safe in the amounts administered and parts 210 and 211 of this chapter. do not interfere with the effectiveness (b) The establishment(s) in which the of the preparation or with suitable drug product is manufactured is reg- tests or assays to determine if the istered, and the drug product is listed, product meets its professed standards in compliance with part 207 of this of identity, strength, quality, and pu- chapter. It is requested but not re- rity. Color additives may be used only quired that the number assigned to the in accordance with section 721 of the product pursuant to part 207 of this act and subchapter A of this chapter. chapter appear on all drug labels and in (f) The product container and con- all drug labeling. If this number is tainer components meet the require- used, it shall be placed in the manner ments of § 211.94 of this chapter. set forth in part 207 of this chapter. (g) The labeling for all drugs contains (c)(1) The product is labeled in com- the general warning: ‘‘Keep out of pliance with chapter V of the Federal reach of children.’’ [highlighted in bold

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type]. The labeling of drugs shall also (12) ‘‘Before a doctor is consulted’’ or state as follows: For drugs used by oral ‘‘without first consulting your doctor’’ administration, ‘‘In case of overdose, or ‘‘consult your doctor before’’. get medical help or contact a Poison (13) ‘‘Beverages’’ or ‘‘drinks’’. Control Center right away’’; for drugs (14) ‘‘Clean’’ or ‘‘cleanse’’. used topically, rectally, or vaginally (15) ‘‘Consulting’’ or ‘‘advising’’. and not intended for oral ingestion, ‘‘If (16) ‘‘Continue(s)’’ or ‘‘persist(s)’’ or swallowed, get medical help or contact ‘‘is persistent’’ or ‘‘do(es) not go away’’ a Poison Control Center right away’’; or ‘‘last(s)’’. and for drugs used topically and in- (17) ‘‘Daily’’ or ‘‘every day’’. tended for oral use, ‘‘If more than used (18) ‘‘Develop(s)’’ or ‘‘begin(s)’’ or for’’ (insert intended use, e.g., pain) ‘‘is ‘‘occur(s)’’. accidentally swallowed, get medical (19) ‘‘Difficulty’’ or ‘‘trouble’’. help or contact a Poison Control Cen- (20) ‘‘Difficulty in urination’’ or ter right away.’’ The Food and Drug ‘‘trouble urinating’’. Administration will grant an exemp- (21) ‘‘Discard’’ or ‘‘throw away’’. tion from these general warnings where (22) ‘‘Discontinue’’ or ‘‘stop’’ or appropriate upon petition, which shall ‘‘quit’’. be maintained in a permanent file for (23) ‘‘Doctor’’ or ‘‘physician’’. public review by the Division of Dock- (24) ‘‘Drowsiness’’ or ‘‘the drowsiness ets Management, Food and Drug Ad- effect’’. ministration, 5630 Fishers Lane, rm. (25) ‘‘Drowsiness may occur’’ or ‘‘you 1061, Rockville, MD 20852. may get drowsy’’. (h) Where no maximum daily dosage (26) ‘‘Enlargement of the’’ or ‘‘an en- limit for an active ingredient is estab- larged’’. lished in this part, it is used in a prod- (27) ‘‘Especially in children’’ or espe- uct at a level that does not exceed the cially children’’. amount reasonably required to achieve (28) ‘‘Exceed’’ or ‘‘use more than’’ or its intended effect. ‘‘go beyond’’. (i) The following terms may be used (29) ‘‘Exceed recommended dosage’’ interchangeably in the labeling of OTC or ‘‘use more than directed’’. drug products, provided such use does (30) ‘‘Excessive’’ or ‘‘too much’’. not alter the meaning of the labeling (31) ‘‘Excitability may occur’’ or that has been established and identi- ‘‘you may get excited’’. fied in an applicable monograph or by (32) ‘‘Experience’’ or ‘‘feel’’. regulation. The following terms shall (33) ‘‘For relief of’’ or ‘‘relieves’’. not be used to change in any way the (34) ‘‘For temporary reduction of’’ or title, headings, and subheadings re- ‘‘temporarily reduces’’. quired under § 201.66(c)(1) through (c)(9) (35) ‘‘For the temporary relief of’’ or of this chapter: ‘‘temporarily relieves’’. (1) ‘‘Abdominal’’ or ‘‘stomach’’ (in (36) ‘‘For the treatment of’’ or context only). ‘‘treats’’. (2) ‘‘Administer’’ or ‘‘give’’. (37) ‘‘Frequently’’ or ‘‘often’’. (3) ‘‘Aggravate(s)’’ or ‘‘make(s) (38) ‘‘Give to’’ or ‘‘use in’’. worse’’. (39) ‘‘Immediately’’ or ‘‘right away’’ or ‘‘directly’’. (4) ‘‘Application of this product’’ or (40) ‘‘Immediately’’ or ‘‘as soon as’’. ‘‘applying’’. (41) ‘‘Immediately following’’ or (5) ‘‘Are uncertain’’ or ‘‘do not ‘‘right after’’. know’’. (42) ‘‘Improve(s)’’ or ‘‘get(s) better’’ (6) ‘‘Ask’’ or ‘‘consult’’ or ‘‘contact’’. or ‘‘make(s) better’’. (7) ‘‘Asking’’ or ‘‘consulting’’. (43) ‘‘Increased’’ or ‘‘more’’. (8) ‘‘Assistance’’ or ‘‘help’’ or ‘‘aid’’. (44) ‘‘Increase your risk of’’ or (9) ‘‘Associated with’’ or ‘‘due to’’ or ‘‘cause’’. ‘‘caused by’’. (45) ‘‘Indication(s)’’ or ‘‘Use(s)’’. (10) ‘‘Avoid contact with eyes’’ or ‘‘do (46) ‘‘Inhalation’’ or ‘‘puff’’. not get into eyes’’. (47) ‘‘In persons who’’ or ‘‘if you’’ or (11) ‘‘Avoid inhaling’’ or ‘‘do not in- ‘‘if the child’’. hale’’. (48) ‘‘Instill’’ or ‘‘put’’.

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(49) ‘‘Is (are) accompanied by’’ or shall not be used to change in any way ‘‘you also have’’ (in context only) or the specific title, headings, and sub- ‘‘(optional: that) occur(s) with’’. headings required under § 201.66(c)(1) (50) ‘‘Longer’’ or ‘‘more’’. through (c)(9) of this chapter: (51) ‘‘Lung’’ or ‘‘pulmonary’’. (l) ‘‘And’’. (52) ‘‘Medication(s)’’ or ‘‘medicine(s)’’ (2) ‘‘As may occur with’’. or ‘‘drug(s)’’. (3) ‘‘Associated’’ or ‘‘to be associ- (53) ‘‘Nervousness, dizziness, or sleep- ated’’. lessness occurs’’ or ‘‘you get nervous, (4) ‘‘Consult a doctor’’. dizzy, or sleepless’’. (5) ‘‘Discontinue use’’. (54) ‘‘Not to exceed’’ or ‘‘do not ex- (6) ‘‘Drug Interaction Precaution’’. ceed’’ or ‘‘not more than’’. (7) ‘‘Due to’’. (55) ‘‘Obtain(s)’’ or ‘‘get(s)’’. (8) ‘‘Except under the advice and su- (56) ‘‘Passages’’ or ‘‘passageways’’ or pervision of a physician’’. ‘‘tubes’’. (9) ‘‘If this occurs’’. (57) ‘‘Perforation of’’ or ‘‘hole in’’. (10) ‘‘In case of’’. (58) ‘‘Persistent’’ or ‘‘that does not go (11) ‘‘Notice’’. away’’ or ‘‘that continues’’ or ‘‘that (12) ‘‘Or’’. lasts’’. (13) ‘‘Occurring with’’. (59) ‘‘Per day’’ or ‘‘daily’’. (14) ‘‘Or as directed by a doctor’’. (60) ‘‘Presently’’ or ‘‘now’’. (15) ‘‘Such as’’. (61) ‘‘Produce(s)’’ or ‘‘cause(s)’’. (16) ‘‘Such as occurs with’’. (62) ‘‘Prompt(ly)’’ or ‘‘quick(ly)’’ or (17) ‘‘Tends to’’. (18) ‘‘This product’’. ‘‘right away’’. (19) ‘‘Unless directed by a doctor’’. (63) ‘‘Reduce’’ or ‘‘minimize’’. (20) ‘‘While taking this product’’ or (64) ‘‘Referred to as’’ or ‘‘of’’. ‘‘before taking this product’’. (65) ‘‘Sensation’’ or ‘‘feeling’’. (21) ‘‘Within’’. (66) ‘‘Solution’’ or ‘‘liquid’’. (67) ‘‘Specifically’’ or ‘‘definitely’’. [39 FR 11741, Mar. 29, 1974, as amended at 40 (68) ‘‘Take’’ or ‘‘use’’ or ‘‘give’’. FR 11718, Mar. 13, 1975; 40 FR 13496, Mar. 27, (69) ‘‘Tend(s) to recur’’ or ‘‘reoc- 1975; 42 FR 15674, Mar. 22, 1977; 46 FR 8459, cur(s)’’ or ‘‘return(s)’’ or ‘‘come(s) Jan. 27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR 16266, May 1, 1986; 55 FR 11581, Mar. 29, 1990; back’’. 59 FR 4000, Jan. 28, 1994; 59 FR 14365, Mar. 28, (70) ‘‘To avoid contamination’’ or 1994; 64 FR 13294, Mar. 17, 1999; 68 FR 24879, ‘‘avoid contamination’’ or ‘‘do not con- May 9, 2003] taminate’’. (71) ‘‘To help’’ or ‘‘helps’’. § 330.2 Pregnancy-nursing warning. (72) ‘‘Unless directed by a doctor’’ or A pregnancy-nursing warning for ‘‘except under the advice of a doctor’’ OTC drugs is set forth under § 201.63 of or ‘‘unless told to do so by a doctor’’. this chapter. (73) ‘‘Use caution’’ or ‘‘be careful’’. (74) ‘‘Usually’’ or ‘‘generally’’ (in con- [47 FR 54758, Dec. 3, 1982] text only). § 330.3 Imprinting of solid oral dosage (75) ‘‘You’’ (‘‘Your’’) or ‘‘the child’’ form drug products. (‘‘the child’s’’). A requirement to imprint an identi- (76) ‘‘You also have’’ or ‘‘occurs fication code on solid oral dosage form with’’. drug products is set forth under part (77) ‘‘When practical’’ or ‘‘if pos- 206 of this chapter. sible’’. (78) ‘‘Whether’’ or ‘‘if’’. [58 FR 47959, Sept. 13, 1993] (79) ‘‘Worsen(s)’’ or ‘‘get(s) worse’’ or ‘‘make(s) worse’’. § 330.5 Drug categories. (j) The following connecting terms Monographs promulgated pursuant to may be deleted from the labeling of the provisions of this part shall be es- OTC drug products, provided such dele- tablished in this part 330 and following tion does not alter the meaning of the parts and shall cover the following des- labeling that has been established and ignated categories: identified in an applicable monograph (a) Antacids. or by regulation. The following terms (b) Laxatives.

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(c) Antidiarrheal products. will be considered by a panel. The (d) Emetics. members of a panel shall be qualified (e) Antiemetics. experts (appointed by the Commis- (f) Antiperspirants. sioner) and may include persons from (g) Sunburn prevention and treat- lists submitted by organizations rep- ment products. resenting professional, consumer, and (h) Vitamin-mineral products. industry interests. The Commissioner (i) Antimicrobial products. shall designate the chairman of each (j) Dandruff products. panel. Summary minutes of all meet- (k) Oral hygiene aids. ings shall be made. (l) Hemorrhoidal products. (2) Request for data and views. The (m) Hematinics. Commissioner will publish a notice in (n) Bronchodilator and antiasthmatic the FEDERAL REGISTER requesting in- products. terested persons to submit, for review (o) Analgesics. and evaluation by an advisory review (p) Sedatives and sleep aids. panel, published and unpublished data (q) Stimulants. and information pertinent to a des- (r) Antitussives. ignated category of OTC drugs. Data (s) Allergy treatment products. and information submitted pursuant to (t) Cold remedies. a published notice, and falling within (u) Antirheumatic products. the confidentiality provisions of 18 (v) Ophthalmic products. U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. (w) Contraceptive products. 331(j), shall be handled by the advisory (x) Miscellaneous dermatologic prod- review panel and the Food and Drug ucts. Administration as confidential until (y) Dentifrices and dental products publication of a proposed monograph such as analgesics, antiseptics, etc. and the full report(s) of the panel or (z) Miscellaneous (all other OTC until the Commissioner places the pan- drugs not falling within one of the el’s recommendations on public display above therapeutic categories). at the office of the Division of Dockets Management. Thirty days thereafter Subpart B—Administrative such data and information shall be Procedures made publicly available and may be viewed at the office of the Division of § 330.10 Procedures for classifying Dockets Management of the Food and OTC drugs as generally recognized Drug Administration, except to the ex- as safe and effective and not misbranded, and for establishing mono- tent that the person submitting it graphs. demonstrates that it still falls within the confidentiality provisions of one or For purposes of classifying over-the- more of those statutes. To be consid- counter (OTC) drugs as drugs generally ered, eight copies of the data and/or recognized among qualified experts as views on any marketed drug within the safe and effective for use and as not class must be submitted, preferably misbranded drugs, the following regu- bound, indexed, and on standard sized lations shall apply: paper (approximately 81⁄2 × 11 inches). (a) Procedure for establishing OTC drug When requested, abbreviated submis- monographs—(1) Advisory review panels. sions should be sent. All submissions The Commissioner shall appoint advi- must be in the following format: sory review panels of qualified experts to evaluate the safety and effectiveness OTC DRUG REVIEW INFORMATION of OTC drugs, to review OTC drug labeling, and to advise him on the pro- I. Label(s) and all labeling (preferably mounted and filed with the other data—fac- mulgation of monographs establishing simile labeling is acceptable in lieu of actual conditions under which OTC drugs are container labeling). generally recognized as safe and effec- II. A statement setting forth the quan- tive and not misbranded. A single advi- tities of active ingredients of the drug. sory review panel shall be established III. Animal safety data. for each designated category of OTC A. Individual active components. drugs and every OTC drug category 1. Controlled studies.

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2. Partially controlled or uncontrolled 4. Pertinent marketing experiences that studies. may influence a determination on the effi- B. Combinations of the individual active cacy of combinations of the individual active components. components. 1. Controlled studies. 5. Pertinent medical and scientific lit- 2. Partially controlled or uncontrolled erature. studies. C. Finished drug product. C. Finished drug product. 1. Controlled studies. 1. Controlled studies. 2. Partially controlled or uncontrolled 2. Partially controlled or uncontrolled studies. studies. 3. Documented case reports. Identify ex- IV. Human safety data. pected or frequently reported side effects. A. Individual active components. 4. Pertinent marketing experiences that 1. Controlled studies. may influence a determination on the effi- 2. Partially controlled or uncontrolled cacy of the finished drug product. studies. 5. Pertinent medical and scientific lit- 3. Documented case reports. Identify ex- erature. VI. A summary of the data and views set- pected or frequently reported side effects. ting forth the medical rationale and purpose 4. Pertinent marketing experiences that (or lack thereof) for the drug and its ingredi- may influence a determination as to the ents and the scientific basis (or lack thereof) safety of each individual active component. for the conclusion that the drug and its in- 5. Pertinent medical and scientific lit- gredients have been proven safe and effective erature. for the intended use. If there is an absence of B. Combinations of the individual active controlled studies in the material submitted, components. an explanation as to why such studies are 1. Controlled studies. not considered necessary must be included. 2. Partially controlled or uncontrolled VII. An official United States Pharma- studies. copeia (USP)–National Formulary (NF) drug 3. Documented case reports. Identify ex- monograph for the active ingredient(s) or bo- pected or frequently reported side effects. tanical drug substance(s), or a proposed 4. Pertinent marketing experiences that standard for inclusion in an article to be rec- may influence a determination as to the ognized in an official USP-NF drug mono- safety of combinations of the individual ac- graph for the active ingredient(s) or botan- tive components. ical drug substance(s). Include information 5. Pertinent medical and scientific lit- showing that the official or proposed erature. compendial monograph for the active ingre- C. Finished drug product. dient or botanical drug substance is con- 1. Controlled studies. sistent with the active ingredient or botan- 2. Partially controlled or uncontrolled ical drug substance used in the studies estab- studies. lishing safety and effectiveness and with the 3. Documented case reports. Identify ex- active ingredient or botanical drug sub- pected or frequently reported side effects. stance marketed in the OTC product(s) to a 4. Pertinent marketing experiences that material extent and for a material time. If may influence a determination as to the differences exist, explain why. safety of the finished drug product. 5. Pertinent medical and scientific lit- (3) Deliberations of an advisory review erature. panel. An advisory review panel will V. Efficacy data. meet as often and for as long as is ap- A. Individual active components. propriate to review the data submitted 1. Controlled studies. to it and to prepare a report containing 2. Partially controlled or uncontrolled its conclusions and recommendations studies. to the Commissioner with respect to 3. Documented case reports. Identify expected or frequently reported side effects. the safety and effectiveness of the 4. Pertinent marketing experiences that drugs in a designated category of OTC may influence a determination on the effi- drugs. A panel may consult any indi- cacy of each individual active component. vidual or group. Any interested person 5. Pertinent medical and scientific lit- may request an opportunity to present erature. oral views to the panel; such request B. Combinations of the individual active may be granted or denied by the panel. components. Such requests for oral presentations 1. Controlled studies. 2. Partially controlled or uncontrolled should be in written form including a studies. summarization of the data to be pre- 3. Documented case reports. Identify ex- sented to the panel. Any interested pected or frequently reported side effects. person may present written data and

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views which shall be considered by the cant human experience during mar- panel. This information shall be pre- keting. Isolated case reports, random sented to the panel in the format set experience, and reports lacking the de- forth in paragraph (a)(2) of this section tails which permit scientific evalua- and within the time period established tion will not be considered. General for the drug category in the notice for recognition of effectiveness shall ordi- review by a panel. narily be based upon published studies (4) Standards for safety, effectiveness, which may be corroborated by unpub- and labeling. The advisory review panel, lished studies and other data. in reviewing the data submitted to it (iii) The benefit-to-risk ratio of a and preparing its conclusions and rec- drug shall be considered in determining ommendations, and the Commissioner, safety and effectiveness. in reviewing the conclusions and rec- (iv) An OTC drug may combine two ommendations of the panel and the or more safe and effective active ingre- published proposed, tentative, and the dients and may be generally recognized final monographs, shall apply the fol- as safe and effective when each active lowing standards to determine general ingredient makes a contribution to the recognition that a category of OTC claimed effect(s); when combining of drugs is safe and effective and not mis- the active ingredients does not de- branded: crease the safety or effectiveness of (i) Safety means a low incidence of any of the individual active ingredi- adverse reactions or significant side ef- ents; and when the combination, when fects under adequate directions for use used under adequate directions for use and warnings against unsafe use as and warnings against unsafe use, pro- well as low potential for harm which vides rational concurrent therapy for a may result from abuse under condi- significant proportion of the target tions of widespread availability. Proof population. of safety shall consist of adequate tests (v) Labeling shall be clear and truth- by methods reasonably applicable to ful in all respects and may not be false show the drug is safe under the pre- or misleading in any particular. It scribed, recommended, or suggested shall state the intended uses and re- conditions of use. This proof shall in- sults of the product; adequate direc- clude results of significant human ex- tions for proper use; and warnings perience during marketing. General against unsafe use, side effects, and ad- recognition of safety shall ordinarily verse reactions in such terms as to be based upon published studies which render them likely to be read and un- may be corroborated by unpublished derstood by the ordinary individual, in- studies and other data. cluding individuals of low comprehen- (ii) Effectiveness means a reasonable sion, under customary conditions of expectation that, in a significant pro- purchase and use. portion of the target population, the (vi) A drug shall be permitted for pharmacological effect of the drug, OTC sale and use by the laity unless, when used under adequate directions because of its toxicity or other poten- for use and warnings against unsafe tial for harmful effect or because of the use, will provide clinically significant method or collateral measures nec- relief of the type claimed. Proof of ef- essary to its use, it may safely be sold fectiveness shall consist of controlled and used only under the supervision of clinical investigations as defined in a practitioner licensed by law to ad- § 314.126(b) of this chapter, unless this minister such drugs. requirement is waived on the basis of a (5) Advisory review panel report to the showing that it is not reasonably appli- Commissioner. An advisory review panel cable to the drug or essential to the va- may submit to the Commissioner a re- lidity of the investigation and that an port containing its conclusions and alternative method of investigation is recommendations with respect to the adequate to substantiate effectiveness. conditions under which OTC drugs fall- Investigations may be corroborated by ing within the category covered by the partially controlled or uncontrolled panel are generally recognized as safe studies, documented clinical studies by and effective and not misbranded. In- qualified experts, and reports of signifi- cluded within this report shall be:

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(i) A recommended monograph or tion that the available data are insuffi- monographs covering the category of cient to classify such conditions under OTC drugs and establishing conditions either paragraph (a)(6)(i) or (ii) of this under which the drugs involved are section (Category III). generally recognized as safe and effec- (iv) The full report(s) of the panel to tive and not misbranded (Category I). the Commissioner. The proposed order This monograph may include any con- shall specify a reasonable period of ditions relating to active ingredients, time within which conditions falling labeling indications, warnings and ade- within paragraph (a)(6)(iii) of this sec- quate directions for use, prescription tion may be continued in marketed or OTC status, and any other condi- products while the data necessary to tions necessary and appropriate for the support them are being obtained for safety and effectiveness of drugs cov- evaluation by the Food and Drug Ad- ered by the monograph. ministration. The summary minutes of (ii) A statement of active ingredi- the panel meetings shall be made avail- ents, labeling claims or other state- able to interested persons upon re- ments, or other conditions reviewed quest. Any interested person may, and excluded from the monograph on within 90 days after publication of the the basis of the panel’s determination proposed order in the FEDERAL REG- that they would result in the drug’s ISTER, file with the Division of Dockets not being generally recognized as safe Management of the Food and Drug Ad- and effective or would result in mis- ministration written comments in trip- branding (Category II). licate. Comments may be accompanied (iii) A statement of active ingredi- by a memorandum or brief in support ents, labeling claims or other state- thereof. All comments may be reviewed ments, or other conditions reviewed and excluded from the monograph on at the office of the Division of Dockets the basis of the panel’s determination Management between the hours of 9 that the available data are insufficient a.m. and 4 p.m., Monday through Fri- to classify such condition under either day. Within 30 days after the final day paragraph (a)(5) (i) or (ii) of this sec- for submission of comments, reply tion and for which further testing is comments may be filed with the Divi- therefore required (Category III). The sion of Dockets Management; these report may recommend the type of fur- comments shall be utilized to reply to ther testing required and the time pe- comments made by other interested riod within which it might reasonably persons and not to reiterate a position. be concluded. The Commissioner may satisfy this re- (6) Proposed monograph. After review- quirement by publishing in the FED- ing the conclusions and recommenda- ERAL REGISTER a proposed order sum- tions of the advisory review panel, the marizing the full report of the advisory Commissioner shall publish in the FED- review panel, containing its conclu- ERAL REGISTER a proposed order con- sions and recommendations, to obtain taining: full public comment before under- (i) A monograph or monographs es- taking his own evaluation and decision tablishing conditions under which a on the matters involved. category of OTC drugs or a specific or (7) Tentative final monograph. (i) After specific OTC drugs are generally recog- reviewing all comments, reply com- nized as safe and effective and not mis- ments, and any new data and informa- branded (Category I). tion or, alternatively, after reviewing a (ii) A statement of the conditions ex- panel’s recommendations, the Commis- cluded from the monograph on the sioner shall publish in the FEDERAL basis of the Commissioner’s determina- REGISTER a tentative order containing tion that they would result in the a monograph establishing conditions drug’s not being generally recognized under which a category of OTC drugs as safe and effective or would result in or specific OTC drugs are generally rec- misbranding (Category II). ognized as safe and effective and not (iii) A statement of the conditions misbranded. Within 90 days, any inter- excluded from the monograph on the ested person may file with the Division basis of the Commissioner’s determina- of Dockets Management, Food and

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Drug Administration, written com- monograph and will be considered by ments or written objections specifying the Commissioner only after a final with particularity the omissions or ad- monograph has been published in the ditions requested. These objections are FEDERAL REGISTER unless the to be supported by a brief statement of Commisisoner finds that good cause the grounds therefor. A request for an has been shown that warrants earlier oral hearing may accompany such ob- consideration. jections. (8) Oral hearing before the Commis- (ii) The Commissioner may also pub- sioner. After reviewing objections filed lish in the FEDERAL REGISTER a sepa- in response to the tentative final rate tentative order containing a state- monograph, the Commissioner, if he ment of those active ingredients re- finds reasonable grounds in support viewed and proposed to be excluded thereof, shall by notice in the FEDERAL from the monograph on the basis of the REGISTER schedule an oral hearing. The Commissioner’s determination that notice scheduling an oral hearing shall they would result in a drug product not specify the length of the hearing and being generally recognized as safe and how the time shall be divided among effective or would result in mis- the parties requesting the hearing. The branding. This order may be published hearing shall be conducted by the Com- when no substantive comments in op- missioner and may not be delegated. position to the panel report or new (9) Final monograph. After reviewing data and information were received by the objections, the entire administra- the Food and Drug Administration tive record including all new data and under paragraph (a)(6)(iv) of this sec- information and comments, and consid- tion or when the Commissioner has ering the arguments made at any oral evaluated and concurs with a panel’s hearing, the Commissioner shall pub- recommendation that a condition be lish in the FEDERAL REGISTER a final excluded from the monograph. Within order containing a monograph estab- 90 days, any interested person may file lishing conditions under which a cat- with the Division of Dockets Manage- egory of OTC drugs or a specific or spe- ment, Food and Drug Administration, cific OTC drugs are generally recog- written objections specifying with par- nized as safe and effective and not mis- ticularity the provision of the ten- branded. The monograph shall become tative order to which objection is effective as specified in the order. made. These objections are to be sup- (10) Administrative record. (i) All data ported by a brief statement of the and information to be considered in grounds therefor. A request for an oral any proceeding pursuant to this sec- hearing may accompany such objection shall be submitted in response to tions. the request for data and views pursu- (iii) Within 12 months after pub- ant to paragraph (a)(2) of this section, lishing a tentative order pursuant to in response to any other notice pub- paragraph (a)(7)(i) of this section, any lished in the FEDERAL REGISTER, or ac- interested person may file with the Di- cepted by the panel during its delibera- vision of Dockets Management, Food tions pursuant to paragraph (a)(3) of and Drug Administration, new data this section or submitted to the Divi- and information to support a condition sion of Dockets Management as part of excluded from the monograph in the the comments during the 90-day period tentative order. and 30-day rebuttal comment period (iv) Within 60 days after the final day permitted pursuant to paragraph (a)(6) for submission of new data and infor- of this section or submitted to the Di- mation, comments on the new data and vision of Dockets Management during information may be filed with the Divi- the 12-month period or as part of the sion of Dockets Management, Food and comments during the 60-day period per- Drug Administration. mitted pursuant to paragraph (a)(7) of (v) New data and information sub- this section. mitted after the time specified in this (ii) The Commissioner shall make all paragraph but prior to the establish- decisions and issue all orders pursuant ment of a final monograph will be con- to this section solely on the basis of sidered as a petition to amend the the administrative record, and shall

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not consider data or information not paragraph (a)(11) of this section shall included as part of the administrative apply), or the Commissioner may pub- record. lish a proposed amendment or repeal in (iii) The administrative record shall the FEDERAL REGISTER if the Commis- consist solely of the following mate- sioner finds general recognition of safe- rial: All notices and orders published in ty and effectiveness employing the the FEDERAL REGISTER, all data and standards in paragraph (a)(4) of this views submitted in response to the re- section. Any interested person may, quest published pursuant to paragraph within 90 days after publication of the (a)(2) of this section, in response to any proposed order in the FEDERAL REG- other notice published in the FEDERAL ISTER, file with the Division of Dockets REGISTER, or accepted by the panel Management, Food and Drug Adminis- during its deliberations pursuant to tration, written comments in trip- paragraph (a)(3) of this section, all licate. Comments may be accompanied minutes of panel meetings, the panel by a memorandum or brief in support report(s), all comments and rebuttal thereof. All comments may be reviewed comments submitted on the proposed in the Division of Dockets Management monograph and all new data and infor- between the hours of 9 a.m. and 4 p.m., mation submitted pursuant to para- Monday through Friday. After review- graph (a)(6) of this section, all objec- ing the comments, the Commissioner tions submitted on the tentative final shall publish a final order amending monograph and all new data and infor- the monograph established under the mation and comments submitted pur- provisions of paragraph (a)(9) of this suant to paragraph (a)(7) of this sec- section or withdraw the proposal if tion, the complete record of any oral comments opposing the amendment public hearing conducted pursuant to are persuasive. A new drug application paragraph (a)(8) of this section, all may be submitted in lieu of, or in addi- other comments requested at any time tion to, a petition under this para- by the Commissioner, all data and in- graph. formation for which the Commissioner (ii) A new drug application may be has reopened the administrative submitted in lieu of a petition to record, and all other material that the amend the OTC drug monograh only if Commissioner includes in the administrative record as part of the basis for the drug product with the condition the Commissioner’s decision. that is the subject of the new drug ap- (11) Court appeal. The monograph plication has not been marketed on an contained in the final order constitutes interim basis (such as under the provi- final agency action from which appeal sions of paragraph (a)(6)(iii) of this sec- lies to the courts. The Food and Drug tion), all clinical testing has been con- Administration will request consolida- ducted pursuant to a new drug application of all appeals in a single court. tion plan, and no marketing of the Upon court appeal, the Commissioner product with the condition for which may, at his discretion, stay the effec- approval is sought is undertaken prior tive date for part or all of the mono- to approval of the new drug applica- graph pending appeal and final court tion. The Food and Drug Administra- adjudication. tion shall handle a new drug applica- (12) Amendment of monographs. (i) The tion as a petition for amendment of a Commissioner may propose on the monograph, and shall review it on that Commissioner’s own initiative to basis, if the provisions of this para- amend or repeal any monograph estab- graph preclude approval of a new drug lished pursuant to this section. Any in- application but permit the granting of terested person may petition the Com- such a petition. missioner for such proposal pursuant (b) Regulatory action. Any product to § 10.30 of this chapter. The Commis- which fails to conform to an applicable sioner may deny the petition if the monograph after its effective date is Commissioner finds a lack of safety or liable to regulatory action. effectiveness employing the standards (c) Information and data submitted in paragraph (a)(4) of this section (in under this section shall include, with which case the appeal provisions of respect to each nonclinical laboratory

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study contained in the application, ei- § 330.12 Status of over-the-counter ther a statement that the study was (OTC) drugs previously reviewed conducted in compliance with the good under the Drug Efficacy Study laboratory practice regulations set (DESI). forth in part 58 of this chapter, or, if (a) There were 420 OTC drugs re- the study was not conducted in compli- viewed in the Drug Efficacy Study (a ance with such regulations, a brief review of drugs introduced to the mar- statement of the reason for the non- ket through new drug procedures be- compliance. tween 1938 and 1962). A careful review (d) [Reserved] has been made of the reports on these (e) Institutional review and informed drugs to determine those drugs for consent. Information and data sub- which implementation may be deferred mitted under this section after July 27, without significant risk to the public 1981, shall include statements regard- health, pending review by appropriate ing each clinical investigation involv- OTC drug advisory review panels and ing human subjects, from which the in- promulgation of a monograph. formation and data are derived, that it (b) On and after April 20, 1972, a num- either was conducted in compliance ber of notices were published in the with the requirements for institutional FEDERAL REGISTER concerning previously unpublished OTC drugs re- review set forth in part 56 of this chap- viewed by the National Academy of ter, or was not subject to such require- Sciences-National Research Council ments in accordance with §§ 56.104 or Drug Efficacy Study Group. Only the 56.105, and that it was conducted in evaluations and comments of the pan- compliance with the requirements for els were published, with no conclusions informed consent set forth in part 50 of of the Commissioner of Food and this chapter. Drugs. Those publications were for the (f) Financial certification or disclosure purpose of giving interested persons statement. Any clinical data submitted the benefit of the Academy’s opinions. under this section must be accom- For those products, and also for OTC panied by financial certifications or drug products previously published disclosure statements or both as re- with the Commissioner’s conclusions quired by part 54 of this chapter. (except for the products listed in paragraphs (b) (1) and (2) of this section, all [39 FR 11741, Mar. 29, 1974, as amended at 39 FR 39556, Nov. 8, 1974; 42 FR 19141, Apr. 12, requests for data, revised labeling, re- 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, quests for new drug applications, ab- 8955, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; breviated new drug applications, updat- 46 FR 21360, Apr. 10, 1981; 46 FR 47738, Sept. ing supplements, data to support less 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, than effective claims, if any, etc., are Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR deferred, and such OTC drug products 3073, Jan. 23, 2002] are instead subject to the OTC drug review in their appropriate classes pursu- § 330.11 NDA deviations from applica- ant to the procedures established in ble monograph. this subpart. A new drug application requesting (1) The requirements of the following approval of an OTC drug deviating in DESI announcements are not deferred any respect from a monograph that has (the reference document may also per- become final shall be in the form retain to prescription drugs): quired by § 314.50 of this chapter, but (i) Certain Surgical Sutures (DESI shall include a statement that the 4725), published in the FEDERAL REG- product meets all conditions of the ap- ISTER of November 11, 1971 (36 FR plicable monograph except for the devi- 21612). ation for which approval is requested (ii) Absorbable Dusting Powder and may omit all information except (DESI 6264), published in the FEDERAL that pertinent to the deviation. REGISTER of May 25, 1971 (36 FR 9475). (iii) Certain Insulin Preparations [39 FR 11741, Mar. 29, 1974, as amended at 55 (DESI 4286), published in the FEDERAL FR 11581, Mar. 29, 1990] REGISTER of April 9, 1971 (36 FR 6842).

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(iv) Sulfo-Van Ointment (DESI 2230), published in the FEDERAL REGISTER of published in the FEDERAL REGISTER of August 28, 1971 (36 FR 17368): October 8, 1970 (35 FR 15860). (a) Rhulitol Solution, containing tan- (v) Antiperspirants and Deodorants nic acid, chlorobutanol, phenol, cam- Containing Neomycin Sulfate (DESI phor, alum, and isopropyl alcohol. 11048) for which an order revoking pro- (b) Zirnox Topical Lotion, containing visions for certification or release was phenyitoloxamine citrate and zir- published in the FEDERAL REGISTER of conium oxide. December 5, 1972 (37 FR 25820) and has (iv) Menacyl Tablets, containing as- been stayed by the filing of objections. pirin, menadione, and ascorbic acid (vi) Thorexin Cough Medicine (DESI (DESI 6363), for which notice of with- 11160) for which a notice of opportunity drawal of approval of the new drug ap- for hearing was published in the FED- plication was published in the FEDERAL ERAL REGISTER of February 2, 1973 (38 REGISTER of July 23, 1970 (35 FR 11827). FR 3210). (v) Curad Medicated Adhesive Ban- (vii) Antibiotic susceptibility discs dage containing sulfathiazole (DESI (DESI 90235) for which an order pro- 4964), for which notice of withdrawal of viding for certain discs to be certified approval of the new drug application and removing provisions for certifi- was published in the FEDERAL REG- cation of other discs was published in ISTER of December 31, 1969 (34 FR 20441). the FEDERAL REGISTER of September (vi) Drugs Containing Rutin, Quer- 30, 1972 (37 FR 20525) and has been cetin, Hesperidin, or any Bioflavonoids stayed by the filing of objections no- (DESI 5960), for which notice of with- tice of which was published in the FED- drawal of approval of new drug applica- ERAL REGISTER of March 15, 1973 (38 FR tions was published in the FEDERAL 7007). REGISTER of July 3, 1970 (35 FR 10872, (2) Deferral of requirements is not ap- 10873) and October 17, 1970 (35 FR 16332). propriate when an announcement has A further notice of opportunity for been published and has been followed hearing with respect to the drugs cov- by a final order classifying a drug ei- ered by the October 17, 1970 FEDERAL ther as lacking substantial evidence of REGISTER notice will be published at a effectiveness or as not shown to be later date. safe. These products will be removed (vii) Antibiotics in Combination with from the market, if they have not al- Other Drugs for Nasal Use (DESI 7561), ready been removed. Regulatory action for which an order revoking provision will also be undertaken against iden- for certification was published in the tical, similar and related products (21 FEDERAL REGISTER of August 6, 1971 (36 CFR 310.6). Deferral of requirements is FR 14469) and confirmed in the FED- not appropriate for the following (the ERAL REGISTER of October 28, 1971 (36 referenced document may also pertain FR 20686). to prescription drugs): (viii) Antibiotic Troches (DESI 8328), (i) Certain Sulfonamide-Deconges- for which an order revoking provision tant Nasal Preparation (DESI 4850), for for certification was published in the which notice of withdrawal of approval FEDERAL REGISTER of July 14, 1971 (36 of new drug applications was published FR 13089) and confirmed in the FED- in the FEDERAL REGISTER of October 24, ERAL REGISTER of October 9, 1971 (36 FR 1970 (35 FR 16605, 16606). 19695). (ii) Eskay’s Theranates, containing (ix) Certain Drugs Containing Oxy- strychnine, sodium, and calcium glyc- phenisatin or Oxyphenisatin Acetate erophosphates, thiamine hydro- (DESI 10732), for which notices of with- chloride, alcohol, and phosphoric acid drawal of approval of new drug applica- (DESI 2220), for which notice of with- tions were published in the FEDERAL drawal of approval of the new drug ap- REGISTER of February 1, 1972 (37 FR plication was published in the FEDERAL 2460), and March 9, 1973 (38 FR 6419). REGISTER of February 18, 1971 (36 FR (x) Curad Medicated Adhesive Ban- 3152). dage containing tyrothricin-nitrofu- (iii) The following topical drugs razone (DESI 6898), for which an order (DESI 1726), for which notice of with- revoking provision for certification drawal of new drug applications was was published March 14, 1972 (37 FR

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5294), and confirmed in the FEDERAL changes, the Food and Drug Adminis- REGISTER of July 6, 1972 (37 FR 13254). tration will not take legal action (xi) Candette Cough Gel (DESI 11562), against any OTC drug, other than those for which notice of withdrawal of ap- not deferred, based on a charge that proval of the new drug application was the product is a new drug and not published in the FEDERAL REGISTER of grandfathered under the act as a result November 19, 1972 (37 FR 25249). of the changes if the changes in formu- (xii) Certain OTC Multiple-Vitamin lation and/or labeling are of the fol- Preparations for Oral Use containing lowing kind: excessive amounts of vitamin D and/or (1) The addition to the labeling of vitamin A (DESI 97), for which notice warning, contraindications, side ef- of withdrawal of approval of the new fects, and/or precaution information. drug applications was published in the (2) The deletion from the labeling of FEDERAL REGISTER of November 29, 1972 false, misleading, or unsupported indi- (37 FR 25249). cations for use or claims of effective- (xiii) Certain Sulfonamide-Con- ness. taining Preparations for Topical Oph- (3) Changes in the components or thalmic or Otic Use (DESI 368, for composition of the drug that will give which a notice of withdrawal of ap- increased assurance that the drug will proval was published in the FEDERAL have its intended effect, yet not raise REGISTER of February 2, 1973 (38 FR or contribute any added safety ques- 3208). tions. (xiv) Those parts of the publication (4) Changes in the components or entitled ‘‘Certain Mouthwash and Gar- composition of the drug which may gle Preparations’’ (DESI 2855) per- reasonably be concluded to improve the taining to Tyrolaris Mouthwash, con- safety of the drug, without diminishing taining tyrothricin, panthenol, and al- its effectiveness. cohol, for which an order revoking pro- (e) The forbearance from legal action vision for certification was published for lack of grandfather protection is an in the FEDERAL REGISTER of February interim procedure designed to encour- 2, 1967 (32 FR 1172) prior to the drug ef- age appropriate change in formulation ficacy study implementation. and/or labeling during the time period (c) Manufacturers and distributors required to review the various classes should take notice that the informa- of OTC drugs. At such time as an appli- tion on OTC drugs provided by the cable OTC drug monograph becomes ef- Drug Efficacy Study review is valuable fective, the interim procedure will information as to the deficiencies in automatically be terminated and any the data available to support indica- appropriate regulatory action will be tions for use. They are encouraged to initiated. perform studies to obtain adequate evidence of effectiveness for the review of § 330.13 Conditions for marketing in- OTC drugs which is already in progress. gredients recommended for over- In the interim it is in the public inter- the-counter (OTC) use under the est that manufacturers and distribu- OTC drug review. tors of all OTC drugs effect changes in (a) Before the publication in the FED- their formulations and/or labeling to ERAL REGISTER of an applicable pro- bring the products into conformity posed monograph, an OTC drug product with current medical knowledge and that contains: (1) An active ingredient experience. limited, on or after May 11, 1972, to pre- (d) Manufacturers and distributors of scription use for the indication and OTC drugs may be reluctant to make route of administration under consider- appropriate formulation and/or label- ation by an OTC advisory review panel, ing changes for fear of losing the pro- and not thereafter exempted from such tection of the so-called ‘‘grandfather’’ limitation pursuant to § 310.200 of this provisions of the 1938 Federal Food, chapter, or Drug, and Cosmetic Act (sec. 201(p)(1)) (2) An active ingredient at a dosage and the 1962 amendments to the act level higher than that available in an (sec. 107(c) of those amendments). To OTC drug product on December 4, 1975, encourage and facilitate prompt shall be regarded as a new drug within

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the meaning of section 201(p) of the act (2) An active ingredient at a dosage for which an approved new drug appli- level higher than that available in any cation is required. OTC drug product on December 4, 1975, (b)(1) An OTC drug product that con- which ingredient and/or dosage level is tains: (i) An active ingredient limited, classified by the panel in category II on or after May 11, 1972, to prescription (conditions subject to § 330.10(a)(6)(ii)), use for the indication and route of ad- may be marketed only after: ministration under consideration by an (i) The Center for Drug Evaluation OTC advisory review panel, and not and Research or the Commissioner ten- thereafter exempted from such limita- tatively determines that the ingredient tion pursuant to § 310.200 of this chap- is generally recognized as safe and ef- ter, or fective, and the Commissioner states (ii) An active ingredient at a dosage by notice in the FEDERAL REGISTER level higher than that available in an (separately or as part of another docu- OTC drug product on December 4, 1975, ment) that marketing under specified which ingredient and/or dosage level is conditions will be permitted; classified by the panel in category I (ii) The ingredient is determined by (conditions subject to § 330.10(a)(6)(i)) the Commissioner to be generally rec- shall be regarded as a new drug within ognized as safe and effective and is in- the meaning of section 201(p) of the act cluded in the appropriate published for which an approved new drug appli- OTC drug final monograph; or cation is required if marketed for OTC (iii) A new drug application for the use prior to the date of publication in product has been approved. the FEDERAL REGISTER of a proposed (d) An OTC drug product that con- monograph. tains: (1) An active ingredient limited, (2) An OTC drug product covered by on or after May 11, 1972, to prescription paragraph (b)(1) of this section which is use for the indication and route of ad- marketed after the date of publication ministration under consideration by an in the FEDERAL REGISTER of a proposed OTC advisory review panel, and not monograph but prior to the effective thereafter exempted from such limita- date of a final monograph shall be sub- tion pursuant to § 310.200 of this chap- ject to the risk that the Commissioner ter, or may not accept the panel’s rec- (2) An active ingredient at a dosage ommendation and may instead adopt a level higher than that available in any different position that may require re- OTC drug product on December 4, 1975, labeling, recall, or other regulatory ac- which ingredient and/or dosage level is tion. The Commissioner may state classified by the panel in category III such position at any time by notice in (conditions subject to § 330.10(a)(6)(iii)), the FEDERAL REGISTER, either sepa- may be marketed only after: rately or as part of another document; (i) The Center for Drug Evaluation appropriate regulatory action will and Research or the Commissioner ten- commence immediately and will not tatively determines that the ingredient await publication of a final monograph. is generally recognized as safe and ef- Marketing of such a product with a for- fective, and the Commissioner states mulation or labeling not in accord with by notice in the FEDERAL REGISTER a proposed monograph or tentative (separately or as part of another docu- final monograph also may result in ment) that marketing under specified regulatory action against the product, conditions will be permitted; the marketer, or both. (ii) The ingredient is determined by (c) An OTC drug product that con- the Commissioner to be generally rec- tains: (1) An active ingredient limited, ognized as safe and effective and is in- on or after May 11, 1972, to prescription cluded in the appropriate published use for the indication and route of ad- OTC drug final monograph; or ministration under consideration by an (iii) A new drug application for the OTC advisory review panel, and not product has been approved. thereafter exempted from such limita- (e) This section applies only to condition pursuant to § 310.200 of this chap- tions under consideration as part of the ter, or OTC drug review initiated on May 11,

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1972, and evaluated under the proce- has filed the submission over protest dures set forth in § 330.10. Section (this date will be no later than 30 days 330.14(h) applies to the marketing of all after the request that FDA file the sub- conditions under consideration and mission over protest). evaluated using the criteria and proce- (4) Feedback letter means a letter dures set forth in § 330.14. issued by the agency in accordance with paragraph (g)(4) of this section [41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 FR 8996, Mar. 6, that informs the sponsor and other in- 1985; 55 FR 11581, Mar. 29, 1990; 67 FR 3074, terested persons who have submitted Jan. 23, 2002] data under paragraph (f) of this section that a condition is initially determined § 330.14 Additional criteria and proce- not to be generally recognized as safe dures for classifying OTC drugs as and effective (GRASE). generally recognized as safe and ef- (5) Safety and effectiveness data sub- fective and not misbranded. mission means a data package sub- This section sets forth additional cri- mitted by a sponsor or other interested teria and procedures by which over- person that includes safety and effec- the-counter (OTC) drugs initially mar- tiveness data and information under keted in the United States after the paragraph (f) of this section and that is OTC drug review began in 1972 and OTC represented by the submitter as being a drugs without any U.S. marketing ex- complete submission. perience can be considered in the OTC (6) Sponsor means the person that drug monograph system. This section submitted a time and extent applica- also addresses conditions regulated as tion (TEA) under paragraph (c) of this a cosmetic or dietary supplement in a section. foreign country that would be regu- (7) Time and extent application (TEA) lated as OTC drugs in the United means a submission by a sponsor under States. Section 330.15 sets forth paragraph (c) of this section, which timelines for FDA review and action. will be evaluated by the agency to de- (a) Definitions. The definitions and in- termine eligibility of a condition for terpretations contained in section 201 consideration in the OTC drug mono- of the Federal Food, Drug, and Cos- graph system. metic Act and the following definitions (b) Criteria. To be considered for in- of terms apply to this section and to clusion in the OTC drug monograph § 330.15. system, the condition must meet the (1) Botanical drug substance means a following criteria: drug substance derived from one or (1) The condition must be marketed more plants, algae, or macroscopic for OTC purchase by consumers. If the fungi, but does not include a highly pu- condition is marketed in another coun- rified or chemically modified substance try in a class of OTC drug products derived from such a source. that may be sold only in a pharmacy, (2) Condition means an active ingre- with or without the personal involve- dient or botanical drug substance (or a ment of a pharmacist, it must be estab- combination of active ingredients or lished that this marketing restriction botanical drug substances), dosage does not indicate safety concerns about form, dosage strength, or route of ad- the condition’s toxicity or other poten- ministration, marketed for a specific tiality for harmful effect, the method OTC use, except as excluded in para- of its use, or the collateral measures graph (b)(2) of this section. necessary to its use. (3) Date of filing means the date of the (2) The condition must have been notice from FDA stating that FDA has marketed OTC for a minimum of 5 con- made a threshold determination that tinuous years in the same country and the safety and effectiveness data sub- in sufficient quantity, as determined in mission is sufficiently complete to per- paragraphs (c)(2)(ii), (c)(2)(iii), and mit a substantive review; or, if the sub- (c)(2)(iv) of this section. Depending on mission is filed over protest in accord- the condition’s extent of marketing in ance with paragraph (j)(3) of this sec- only one country with 5 continuous tion, the date of filing is the date of years of marketing, marketing in more the notice from FDA stating that FDA than one country may be necessary.

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(c) Time and extent application. Cer- the following information for each tain information must be provided country. (For a condition that has been when requesting that a condition sub- marketed OTC in 5 or more countries ject to this section be considered for with a minimum of 5 continuous years inclusion in the OTC drug monograph of marketing in at least one country, system. The following information the sponsor may submit information in must be provided in the format of a accordance with paragraph (c)(4) of this time and extent application (TEA): section): (1) Basic information about the con- (i) How the condition has been mar- dition that includes a description of keted (e.g., OTC general sales direct- the active ingredient(s) or botanical to-consumer; sold only in a pharmacy, drug substance(s), pharmacologic with or without the personal involve- class(es), intended OTC use(s), OTC ment of a pharmacist; dietary supple- strength(s) and dosage form(s), route(s) ment; or cosmetic). If the condition has of administration, directions for use, been marketed as a nonprescription and the applicable existing OTC drug pharmacy-only product, establish that monograph(s) under which the condi- this marketing restriction does not in- tion would be marketed or the request dicate safety concerns about its tox- and rationale for creation of a new OTC icity or other potentiality for harmful drug monograph(s). effect, the method of its use, or the col- (i) A detailed chemical description of lateral measures necessary to its use. the active ingredient(s) that includes a (ii) The cumulative total number of full description of the drug substance, dosage units (e.g., tablets, capsules, including its physical and chemical ounces) sold for each dosage form of characteristics, the method of syn- the condition. Manufacturers or sup- thesis (or isolation) and purification of pliers of OTC active ingredients may the drug substance, and any specifica- provide dosage unit information as the tions and analytical methods necessary total weight of active ingredient sold. to ensure the identity, strength, qual- List the various package sizes for each ity, and purity of the drug substance. dosage form in which the condition is (ii) For a botanical drug substance(s), marketed OTC. Provide an estimate of a detailed description of the botanical the minimum number of potential con- ingredient (including proper identifica- sumer exposures to the condition using tion of the plant, plant part(s), alga, or one of the following calculations: macroscopic fungus used; a certificate of authenticity; and information on the (A) Divide the total number of dosage grower/supplier, growing conditions, units sold by the number of dosage harvest location and harvest time); a units in the largest package size mar- qualitative description (including the keted, or name, appearance, physical/chemical (B) Divide the total weight of the ac- properties, chemical constituents, active ingredient sold by the total weight tive constituent(s) (if known), and bio- of the active ingredient in the largest logical activity (if known)); a quan- package size marketed. titative description of the chemical (iii) A description of the population constituents, including the active con- demographics (percentage of various stituent(s) or other chemical marker(s) racial/ethnic groups) and the source(s) (if known and measurable); the type of from which this information has been manufacturing process (e.g., aqueous compiled, to ensure that the condi- extraction, pulverization); and infor- tion’s use(s) can be reasonably extrapo- mation on any further processing of lated to the U.S. population. the botanical substance (e.g., addition (iv) If the use pattern (i.e., how often of excipients or blending). it is to be used (according to the label) (iii) Reference to the current edition and for how long) varies between coun- of the U.S. Pharmacopeia (USP)–Na- tries based on the condition’s pack- tional Formulary (NF) or foreign com- aging and labeling, or changes in use pendiums may help satisfy the require- pattern have occurred over time in one ments in this section. or more countries, describe the use pat- (2) A list of all countries in which the tern for each country and explain why condition has been marketed. Include there are differences or changes.

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(v) A description of the country’s sys- be provided in a table format. The la- tem for identifying adverse drug expe- beling required by paragraph (c)(3) of riences, especially those found in OTC this section must be attached to the marketing experience, including meth- table. od of collection if applicable. (8) For OTC drugs that have been (3) A statement of how long the con- marketed for more than 5 years in the dition has been marketed in each coun- United States under a new drug appli- try and how long the current product cation, the information requested in labeling has been in use, accompanied paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), by a copy of the current product label- (c)(3), and (c)(5) of this section need not ing. All labeling that is not in English be provided. must be translated to English in ac- (d) Submission of information; confiden- cordance with § 10.20(c)(2) of this chap- tiality. The sponsor must submit three ter. State whether the current product copies of the TEA to the Central Docu- labeling has or has not been author- ment Room, 5630 Fishers Lane, rm. ized, accepted, or approved by a regu- 1061, Rockville, MD 20852. The Food and latory body in each country where the Drug Administration will handle the condition is marketed. TEA as confidential until such time as (4) For a condition that has been a decision is made on the eligibility of marketed OTC in five or more coun- the condition for consideration in the tries with a minimum of 5 continuous OTC drug monograph system. If the years of marketing in at least one condition is found eligible, the TEA country, the sponsor may select at will be placed on public display in the least five of these countries from which Division of Dockets Management after to submit information in accord with deletion of information deemed con- paragraphs (c)(2)(i) through (c)(2)(iv) of fidential under 18 U.S.C. 1905, 5 U.S.C. this section. Selected countries must 552(b), or 21 U.S.C. 331(j). Sponsors include the country with a minimum of must identify information that is con- 5 continuous years of OTC marketing, sidered confidential under these statu- countries that have the longest dura- tory provisions. If the condition is not tion of marketing, and countries hav- found eligible, the TEA will not be ing the most support for extent of mar- placed on public display, but a letter keting, i.e., a large volume of sales from the agency to the sponsor stating with cultural diversity among users of why the condition was not found ac- the product. If the condition meets ceptable will be placed on public dis- these criteria in countries listed in sec- play in the Division of Dockets Man- tion 802(b)(1)(A) of the Federal Food, agement. Drug, and Cosmetic Act, some of these (e) Notice of eligibility. If the condition countries should be included among the is found eligible, the agency will pub- five selected. Sponsors should provide lish a notice of eligibility in the FED- information from more than five coun- ERAL REGISTER and provide the sponsor tries if they believe that it is needed to and other interested parties an oppor- support eligibility. Sponsors should ex- tunity to submit data to demonstrate plain the basis for the countries se- safety and effectiveness. When the no- lected in the TEA. tice of eligibility is published, the (5) A list of all countries where the agency will place the TEA on public condition is marketed only as a pre- display in the Division of Dockets Man- scription drug and the reasons why its agement. marketing is restricted to prescription (f) Safety and effectiveness data submis- in these countries. sion. The notice of eligibility will re- (6) A list of all countries in which the quest a safety and effectiveness data condition has been withdrawn from submission that includes published and marketing or in which an application unpublished data to demonstrate the for OTC marketing approval has been safety and effectiveness of the condi- denied. Include the reasons for such tion for its intended OTC use(s), as well withdrawal or application denial. as the submission of any other relevant (7) The information requested in data and views. These data will be sub- paragraphs (c)(2), (c)(2)(i) through mitted to a docket established in the (c)(2)(iv), and (c)(3) of this section must Division of Dockets Management and

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will be publicly available for viewing (3) If the condition is initially deter- at that office, except data deemed con- mined to be generally recognized as fidential under 18 U.S.C. 1905, 5 U.S.C. safe and effective for OTC use in the 552(b), or 21 U.S.C. 331(j). Data consid- United States, the agency will propose ered confidential under these provi- to include it in an appropriate OTC sions must be clearly identified. Any drug monograph(s), either by amending proposed compendial standards for the an existing monograph(s) or estab- condition will not be considered con- lishing a new monograph(s), if nec- fidential. The safety and effectiveness essary. data submission must be sufficiently (4) If the condition is initially deter- complete to be filed by the agency mined not to be GRASE for OTC use in under paragraph (j)(2) of this section. the United States, the agency will in- Safety and effectiveness data and other form the sponsor and other interested information submitted under this para- persons who have submitted data of its graph are subject to the requirements determination by feedback letter, a in § 330.10(c), (e), and (f). The safety and copy of which will be placed on public effectiveness data submission must in- display in the docket established in the clude the following: Division of Dockets Management. The (1) All data and information listed in agency will publish a notice of pro- § 330.10(a)(2) under the outline ‘‘OTC posed rulemaking to include the condi- Drug Review Information,’’ items III tion in § 310.502 of this chapter. through VII. (5) Interested parties will have an op- (2) All serious adverse drug experi- portunity to submit comments and new ences as defined in §§ 310.305 and 314.80 data. The agency will subsequently of this chapter, from each country publish a final rule (or reproposal if where the condition has been or is cur- necessary) in the FEDERAL REGISTER. rently marketed as a prescription drug or as an OTC drug or product. Provide (h) Marketing. A condition submitted individual adverse drug experience re- under this section for consideration in ports (FDA Form 3500A or equivalent) the OTC drug monograph system may along with a summary of all serious ad- be marketed in accordance with an ap- verse drug experiences and expected or plicable final OTC drug monograph(s) frequently reported side effects for the only after the agency determines that condition. Individual reports that are the condition is generally recognized as not in English must be translated to safe and effective and includes it in the English in accordance with § 10.20(c)(2) appropriate OTC drug final mono- of this chapter. graph(s), and the condition complies (g) Administrative procedures. The with paragraph (i) of this section. agency may use an advisory review When an OTC drug monograph has not panel to evaluate the safety and effec- been finalized and finalization is not tiveness data in accord with the provi- imminent, after the agency has evalu- sions of § 330.10(a)(3). Alternatively, the ated the comments to a proposed rule agency may evaluate the data in con- to include a new condition in a ten- junction with the advisory review tative final monograph as generally panel or on its own without using an recognized as safe and effective and the advisory review panel. The agency will agency has not changed its position as use the safety, effectiveness, and label- a result of the comments, and the con- ing standards in § 330.10(a)(4)(i) through dition complies with paragraph (i) of (a)(4)(vi) in evaluating the data. this section, the agency may publish a (1) If the agency uses an advisory re- notice of enforcement policy that al- view panel to evaluate the data, the lows marketing to begin pending com- panel may submit its recommendations pletion of the final monograph subject in its official minutes of meeting(s) or to the risk that the agency may, prior by a report under the provisions of to or in the final monograph, adopt a § 330.10(a)(5). different position that could require re- (2) The agency may act on an advi- labeling, recall, or other regulatory ac- sory review panel’s recommendations tion. using the procedures in §§ 330.10(a)(2) (i) Compendial monograph. Any active and 330.10(a)(6) through (a)(10). ingredient or botanical drug substance

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included in a final OTC drug mono- and review the submission as filed. The graph or the subject of an enforcement submitter must have a meeting before notice described in paragraph (h) of requesting that FDA file the submis- this section must be recognized in an sion over protest but need not resubmit official USP-NF drug monograph that a copy of a safety and effectiveness sets forth its standards of identity, data submission that is filed over pro- strength, quality, and purity. Sponsors test. A safety and effectiveness data must include an official or proposed submission and the corresponding compendial monograph as part of the TEA-eligible condition are both not safety and effectiveness data submis- deemed under consideration if FDA re- sion listed in § 330.10(a)(2) under item fuses to file the safety and effective- VII of the outline entitled ‘‘OTC DRUG ness data submission, and it is not filed REVIEW INFORMATION.’’ over protest; the condition remains eli- (j) Filing determination. (1) After FDA gible for consideration and the sponsor receives a safety and effectiveness data or any interested person can pursue submission, the agency will determine consideration of the condition in the whether the submission may be filed. future by submitting a new safety and The filing of a submission means that FDA has made a threshold determina- effectiveness data submission. tion that the submission is sufficiently (4) FDA may refuse to file a safety complete to permit a substantive re- and effectiveness data submission if view. any of the following applies: (2) If FDA finds that none of the rea- (i) The submission is incomplete be- sons in paragraph (j)(4) of this section cause it does not contain information for refusing to file the safety and effec- required under paragraph (f) of this tiveness data submission apply, the section. If the submission does not con- agency will file the submission and no- tain required information because such tify the submitter in writing. FDA will information or data are not relevant to post a copy of the notice to the docket. the condition, the submission must The date of filing begins the FDA clearly identify and provide an expla- timelines described in § 330.15(c)(3) and nation for the omission. (4). Data submitted after the date of (ii) The submission is not organized filing will be considered before the or formatted in a manner to enable the issuance of a notice of proposed rule- agency to readily determine whether it making if there is adequate time for is sufficiently complete to permit a review; otherwise, the data will be con- substantive review. sidered as comments to the proposed (iii) The submission does not contain rule after issuance of a notice of pro- a signed statement that the submission posed rulemaking. represents a complete safety and effec- (3) If FDA refuses to file the safety tiveness data submission and that the and effectiveness data submission, the submission includes all the safety and agency will notify the submitter in effectiveness data and information writing and state the reason(s) under available to the submitter at the time paragraph (j)(4) of this section for the refusal. The submitter may request in of the submission, whether positive or writing, within 30 days of the date of negative. the agency’s notification, a meeting (iv) The submission does not contain with the agency about whether the an analysis and summary of the data agency should file the submission, and and other supporting information, or- FDA will convene the meeting within ganized by clinical or nonclinical area, 30 days of the request. If, within 120 such as clinical efficacy data, clinical days after the meeting, the submitter safety data, clinical pharmacology, ad- requests that FDA file the submission verse event reports, animal toxicology, (with or without correcting the defi- chemistry data, and compendial status. ciencies), the agency will file the safe- (v) The submission does not contain a ty and effectiveness data submission supporting document summarizing the over protest under paragraph (j)(2) of strategy used for literature searches, this section, notify the submitter in including search terms, sources, dates writing and post a copy to the docket, accessed, and years reviewed.

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(vi) The submission does not contain this section, FDA will notify the per- a reference list of supporting informa- son that submitted the submission. If, tion, such as published literature, un- within 90 days from the date of the no- published information, abstracts and tice from FDA, the submitter requests case reports, and a copy of the sup- that FDA not withdraw consideration porting information. of the submission, FDA will not deem (vii) The submission includes data or the submission to be withdrawn. information relevant for making a (3) If FDA withdraws consideration of GRASE determination marked as con- a submission under paragraph (k)(1) of fidential without a statement that the this section, FDA will post a notice of information may be released to the withdrawal to the docket, except in the public. case of a TEA submission that is with- (viii) The submission does not con- drawn from consideration before tain a complete environmental assess- issuance of a notice of eligibility, in ment under § 25.40 of this chapter or which case, the notice of withdrawal fails to provide sufficient information will only be provided to the sponsor. to establish that the requested action Information that has been posted to is subject to categorical exclusion the public docket for the condition at under § 25.30 or § 25.31 of this chapter. the time of the withdrawal (such as a (ix) The submission does not contain notice of eligibility or a safety and ef- a statement for each nonclinical lab- fectiveness data submission that has oratory study that the study was con- been accepted for filing and posted to ducted in compliance with the require- the docket) will remain in the public ments set forth in part 58 of this chap- docket. If the condition has been found ter, or, if it was not conducted in com- eligible through issuance of a notice of pliance with part 58 of this chapter, a eligibility, the condition remains eligi- brief statement of the reason for the ble for consideration and the sponsor noncompliance. or any interested person can pursue (x) The submission does not contain a consideration of the condition in the statement for each clinical investiga- future by submitting a new safety and tion involving human subjects that the effectiveness data submission. investigation was conducted in compli- (4) If FDA withdraws consideration of ance with the institutional review a submission under paragraph (k)(1) of board regulations in part 56 of this this section, the timelines under chapter, or was not subject to those § 330.15(c) will no longer apply as of the regulations, and that the investigation date of withdrawal, and the submission was conducted in compliance with the will not be included in the metrics informed consent regulations in part 50 under § 330.15(b). of this chapter. [67 FR 3074, Jan. 23, 2002, as amended at 81 (xi) The submission does not include FR 84475, Nov. 23, 2016] financial certification or disclosure statements, or both, as required by § 330.15 Timelines for FDA review and part 54 of this chapter, accompanying action on time and extent applica- any clinical data submitted. tions and safety and effectiveness (k) Withdrawal of consideration. (1) data submissions. Notwithstanding paragraph (g) of this (a) Applicability. This section applies section, FDA may withdraw consider- to the review of a condition in a time ation of a TEA submission or a safety and extent application (TEA) sub- and effectiveness data submission if: mitted under § 330.14 for consideration (i) The person that submitted the in the over-the-counter (OTC) drug submission requests that its submis- monograph system. This section does sion be withdrawn from consideration; not apply to: or (1) A sunscreen active ingredient or (ii) FDA deems the submission to be combination of sunscreen active ingre- withdrawn from consideration due to dients, and other conditions for such the submitter’s failure to respond to ingredients; or communications from FDA. (2) A non-sunscreen active ingredient (2) Before FDA deems a submission or combination of non-sunscreen active withdrawn under paragraph (k)(1)(ii) of ingredients, and other conditions for

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such ingredients submitted in a TEA submission, FDA will issue a notice of under § 330.14 before November 27, 2014, proposed rulemaking to either: subject to section 586F(a)(1)(C) of the (i) Include the condition in an appro- Federal Food, Drug, and Cosmetic Act. priate OTC monograph(s), either by (b) Metrics. FDA will maintain and amending an existing monograph(s) or update annually, a publicly available establishing a new monograph(s), if posting of metrics for the review of necessary; or TEAs and safety and effectiveness data (ii) Include the condition in § 310.502 submissions that are subject to the of this chapter. timelines in this section. The posting (5) Within 912 days of the closing of will contain the following information the docket of the proposed rulemaking for tracking the extent to which the under paragraph (c)(4) of this section, timelines set forth in paragraph (c) of this section were met during the pre- FDA will issue a final rule. vious calendar year. [81 FR 84477, Nov. 23, 2016] (1) Number and percent of eligibility notices or ineligibility letters issued PART 331—ANTACID PRODUCTS within 180 days of submission of a TEA; FOR OVER-THE-COUNTER (OTC) (2) Number and percent of filing determinations issued within 90 days of HUMAN USE submission of a safety and effectiveness data submission; Subpart A—General Provisions (3) If applicable, number and percent Sec. of feedback letters issued within 730 331.1 Scope. days from the date of filing; (4) Number and percent of notices for Subpart B—Active Ingredients proposed rulemaking issued within 1,095 days from the date of filing; 331.10 Antacid active ingredients. 331.11 Listing of specific active ingredients. (5) Number and percent of final rules 331.15 Combination with nonantacid active issued within 912 days of closing of the ingredients. docket of the proposed rulemaking; and (6) Total number of TEAs submitted Subpart C—Testing Procedures under § 330.14. (c) Timelines for FDA review and ac- 331.20 Determination of percent contribution. FDA will review and take an action of active ingredients. tion within the following timelines: 331.21 Test Modifications. (1) Within 180 days of submission of a Subpart D—Labeling TEA under § 330.14(c), FDA will issue a notice of eligibility or post to the 331.30 Labeling of antacid products. docket a letter of ineligibility, in ac- 331.80 Professional labeling. cordance with § 330.14(d) and (e). AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (2) Within 90 days of submission of a 360, 371. safety and effectiveness data submission, in accordance with § 330.14(j), FDA SOURCE: 39 FR 19874, June 4, 1974, unless will issue a filing determination. The otherwise noted. date of filing begins the FDA timelines in paragraphs (c)(3) and (4) of this sec- Subpart A—General Provisions tion. (3) Within 730 days from the date of § 331.1 Scope. filing, if the condition is initially de- An over-the-counter antacid product termined not to be GRASE for OTC use in a form suitable for oral administra- in the United States, FDA will inform tion is generally recognized as safe and the sponsor and other interested per- effective and is not misbranded if it sons who have submitted data of its de- meets each of the following conditions termination by feedback letter in ac- and each of the general conditions es- cordance with § 330.14(g)(4). tablished in § 330.1 of this chapter. (4) Within 1,095 days from the date of filing of a safety and effectiveness data

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Subpart B—Active Ingredients (4) Bismuth subgallate. (5) Bismuth subnitrate. § 331.10 Antacid active ingredients. (d) Calcium-containing active ingre- (a) The active antacid ingredients of dients: Calcium, as carbonate or phos- the product consist of one or more of phate; maximum daily dosage limit 160 the ingredients permitted in § 331.11 mEq. calcium (e.g., 8 grams calcium within any maximum daily dosage carbonate). limit established, each ingredient is in- (e) Citrate-containing active ingredi- cluded at a level that contributes at ents: Citrate ion, as citric acid or salt; least 25 percent of the total acid neu- maximum daily dosage limit 8 grams. tralizing capacity of the product, and (f) Glycine (aminoacetic acid). the finished product contains at least 5 (g) Magnesium-containing active in- meq of acid neutralizing capacity as gredients: measured by the procedure provided in (1) Hydrate magnesium aluminate ac- the United States Pharmacopeia 23/Na- tivated sulfate. tional Formulary 18. The method es- (2) Magaldrate. tablished in § 331.20 shall be used to de- (3) Magnesium aluminosilicates. termine the percent contribution of (4) Magnesium carbonate. each antacid active ingredient. (5) Magnesium glycinate. (b) This section does not apply to an (6) Magnesium hydroxide. antacid ingredient specifically added as (7) Magnesium oxide. a corrective to prevent a laxative or (8) Magnesium trisilicate. constipating effect. (h) Milk solids, dried. (i) Phosphate-containing active in- [39 FR 19874, June 4, 1974, as amended at 61 FR 4822, Feb. 8, 1996] gredients: (1) Aluminum phosphate; maximum § 331.11 Listing of specific active in- daily dosage limit 8 grams. gredients. (2) Mono or dibasic calcium salt; (a) Aluminum-containing active in- maximum daily dosage limit 2 grams. gredients: (3) Tricalcium phosphate; maximum (1) Basic aluminum carbonate gel. daily dosage limit 24 grams. (2) Aluminum hydroxide (or as alu- (j) Potassium-containing active in- minum hydroxide-hexitol stabilized gredients: polymer, aluminum hydroxide-magne- (1) Potassium bicarbonate (or car- sium carbonate codried gel, aluminum bonate when used as a component of an hydroxide-magnesium trisilicate effervescent preparation); maximum codried gel, aluminum-hydroxide su- daily dosage limit 200 mEq. of bicar- crose powder hydrated). bonate ion for persons up to 60 years (3) Dihydroxyaluminum amino- old and 100 mEq. of bicarbonate ion for acetate and dihydroxyaluminum ami- persons 60 years or older. noacetic acid. (2) Sodium potassium tartrate. (4) Aluminum phosphate gel when (k) Sodium-containing active ingre- used as part of an antacid combination dients: product and contributing at least 25 (1) Sodium bicarbonate (or carbonate percent of the total acid neutralizing when used as a component of an effer- capacity; maximum daily dosage limit vescent preparation); maximum daily is 8 grams. dosage limit 200 mEq. of sodium for (5) Dihydroxyaluminum sodium car- persons up to 60 years old and 100 mEq. bonate. of sodium for persons 60 years or older, (b) Bicarbonate-containing active in- and 200 mEq. of bicarbonate ion for per- gredients: Bicarbonate ion; maximum sons up to 60 years old and 100 mEq. of daily dosage limit 200 mEq. for persons bicarbonate ion for persons 60 years or up to 60 years old and 100 mEq. for per- older. That part of the warning re- sons 60 years or older. quired by § 330.1(g), which states, ‘‘Keep (c) Bismuth-containing active ingre- this and all drugs out of the reach of dients: children’’ is not required on a product (1) Bismuth aluminate. which contains only sodium bicarbon- (2) Bismuth carbonate. ate powder and which is intended pri- (3) Bismuth subcarbonate. marily for other than drug uses.

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(2) Sodium potassium tartrate. Percent contribution = (Total mEq. (l) Silicates: Antacid Active Ingredient × 100)/(Total (1) Magnesium aluminosilicates. mEq. Antacid Product). (2) Magnesium trisilicate. [61 FR 4823, Feb. 8, 1996] (m) Tartrate-containing active ingredients. Tartaric acid or its salts; max- § 331.21 Test modifications. imum daily dosage limit 200 mEq. (15 grams) of tartrate. The formulation or mode of administration of certain products may require [39 FR 19874, June 4, 1974, as amended at 51 a modification of the United States FR 27763, Aug. 1, 1986; 55 FR 19859, May 11, Pharmacopeia 23/National Formulary 1990] 18 acid neutralizing capacity test. Any § 331.15 Combination with nonantacid proposed modification and the data to active ingredients. support it shall be submitted as a petition under the rules established in (a) An antacid may contain any gen- § 10.30 of this chapter. All information erally recognized as safe and effective submitted will be subject to the disclo- nonantacid laxative ingredient to cor- sure rules in part 20 of this chapter. rect for constipation caused by the antacid. No labeling claim of the laxative [61 FR 4823, Feb. 8, 1996] effect may be used for such a product. (b) An antacid may contain any gen- Subpart D—Labeling erally recognized as safe and effective analgesic ingredient(s), if it is indi- § 331.30 Labeling of antacid products. cated for use solely for the concurrent symptoms involved, e.g., headache and (a) Statement of identity. The labeling acid indigestion, and is marketed in a of the product contains the established form intended for ingestion as a solu- name of the drug, if any, and identifies tion. the product as an ‘‘antacid.’’ (c) An antacid may contain any gen- (b) Indications. The labeling of the erally recognized as safe and effective product states, under the heading ‘‘In- antiflatulent ingredient if it is indi- dications,’’ the following: ‘‘For the re- cated for use solely for the concurrent lief of’’ (optional, any or all of the fol- symptoms of gas associated with heart- lowing:) ‘‘heartburn,’’ ‘‘sour stomach,’’ burn, sour stomach or acid indigestion. and/or ‘‘acid indigestion’’ (which may be followed by the optional statement:) Subpart C—Testing Procedures ‘‘and upset stomach associated with’’ (optional, as appropriate) ‘‘this symp- § 331.20 Determination of percent con- tom’’ or ‘‘these symptoms.’’ Other tribution of active ingredients. truthful and nonmisleading state- To determine the percent contribu- ments, describing only the indications tion of an antacid active ingredient, for use that have been established and place an accurately weighed amount of listed in this paragraph (b), may also the antacid active ingredient equal to be used, as provided in § 330.1(c)(2) of the amount present in a unit dose of this chapter, subject to the provisions the product into a 250-milliliter (mL) of section 502 of the act relating to beaker. If wetting is desired, add not misbranding and the prohibition in sec- more than 5 mL of alcohol (neutralized tion 301(d) of the act against the intro- to an apparent pH of 3.5), and mix to duction or delivery for introduction wet the sample thoroughly. Add 70 mL into interstate commerce of unap- of water, and mix on a magnetic stirrer proved new drugs in violation of sec- at 300 ±30 r.p.m. for 1 minute. Analyze tion 505(a) of the act. the acid neutralizing capacity of the (c) Warnings. The labeling of the sample according to the procedure pro- product contains the following warn- vided in the United States Pharma- ings, under the heading ‘‘Warnings’’, copeia 23/National Formulary 18 and which may be combined but not rear- calculate the percent contribution of ranged to eliminate duplicative words the antacid active ingredient in the or phrases if the resulting warning is total product as follows: clear and understandable:

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(1) ‘‘Do not take more than (max- tion of sodium bicarbonate powder imum recommended daily dosage, bro- products identified in § 331.11(k)(1), the ken down by age groups if appropriate, labeling must continue to bear the first expressed in units such as tablets or part of the general warning in § 330.1(g) teaspoonfuls) in a 24–hour period, or of this chapter, which states, ‘‘Keep use the maximum dosage of this prod- this and all drugs out of the reach of uct for more than 2 weeks, except children.’’ under the advice and supervision of a (g) [Reserved] physician.’’ (h) The word ‘‘doctor’’ may be sub- (2) For products which cause constituted for the word ‘‘physician’’ in stipation in 5 percent or more of per- any of the labeling statements in this sons who take the maximum rec- section. ommended dosage: ‘‘May cause constipation.’’ [39 FR 19874, June 4, 1974, as amended at 47 FR 38484, Aug. 31, 1982; 51 FR 16266, May 1, (3) For products which cause laxation 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, in 5 percent or more of persons who Mar. 13, 1987; 55 FR 11581, Mar. 29, 1990; 58 FR take the maximum recommended dos- 45208, Aug. 26, 1993; 59 FR 60556, Nov. 25, 1994; age: ‘‘May have laxative effect.’’ 61 FR 17806, Apr. 22, 1996; 64 FR 13295, Mar. 17, (4) For products containing more 1999; 69 FR 13734, Mar. 24, 2004] than 5 gm per day lactose in a maximum daily dosage: ‘‘Do not use this § 331.80 Professional labeling. product except under advice and super- (a) The labeling of the product provision of a physician if you are allergic vided to health professionals (but not to milk or milk products.’’ to the general public): (d) Drug interaction precaution. The (1) Shall contain the neutralizing ca- labeling of the product contains the pacity of the product as calculated following statement ‘‘Ask a doctor or using the procedure set forth in United pharmacist before use if you are [bul- States Pharmacopeia 23/National For- let] 1 presently taking a prescription mulary 18 expressed in terms of the drug. Antacids may interact with cer- dosage recommended per minimum tain prescription drugs.’’ time interval or, if the labeling rec- (e) Directions for use. The labeling of ommends more than one dosage, in the product contains the recommended terms of the minimum dosage rec- dosage, under the heading ‘‘Direc- ommended per minimum time interval. tions’’, per time interval (e.g., every 4 (2) May contain an indication for the hours) or time period (e.g., 4 times a symptomatic relief of hyperacidity as- day) broken down by age groups if ap- sociated with the diagnosis of peptic propriate, followed by ‘‘or as directed ulcer, gastritis, peptic esophagitis, gas- by a physician.’’ tric hyperacidity, and hiatal hernia. (f) Exemption from the general acci- (3) For products containing basic alu- dental overdose warning. The labeling minum carbonate gel identified in for antacid drug products containing § 331.11(a)(1)—Indication. ‘‘For the the active ingredients identified in treatment, control, or management of § 331.11(a), (b), and (d) through (m); per- hyperphosphatemia, or for use with a mitted combinations of these ingredi- low phosphate diet to prevent forma- ents provided for in § 331.10; and any of tion of phosphate urinary stones, these ingredients or combinations of through the reduction of phosphates in these ingredients in combination with the serum and urine.’’ simethicone (identified in § 332.10 of (4) For products containing aluminum this chapter and provided for in identified in § 331.11(a)—Warnings. (i) § 331.15(c)), are exempt from the re- Prolonged use of aluminum-containing quirement in § 330.1(g) of this chapter antacids in patients with renal failure that the labeling bear the general may result in or worsen dialysis osteo- warning statement ‘‘In case of acci- malacia. Elevated tissue aluminum dental overdose, seek professional as- levels contribute to the development of sistance or contact a poison control the dialysis encephalopathy and osteo- center immediately.’’ With the excep- malacia syndromes. Small amounts of aluminum are absorbed from the gas- 1 See § 201.66(b)(4) of this chapter. trointestinal tract and renal excretion

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of aluminum is impaired in renal fail- safe and effective and is not mis- ure. Aluminum is not well removed by branded if it meets each of the fol- dialysis because it is bound to albumin lowing conditions and each of the gen- and transferrin, which do not cross di- eral conditions established in § 330.1 of alysis membranes. As a result, alu- this chapter. minum is deposited in bone, and dialysis osteomalacia may develop when § 332.3 Definitions. large amounts of aluminum are in- As used in this part: gested orally by patients with impaired Antigas. A term that may be used renal function. interchangeably with the term anti- (ii) Aluminum forms insoluble com- flatulent. Neither term should be con- plexes with phosphate in the gastro- sidered as describing the mechanism of intestinal tract, thus decreasing phos- action of the active ingredient con- phate absorption. Prolonged use of alu- tained in the product. minum-containing antacids by normo- phosphatemic patients may result in [61 FR 8838, Mar. 5, 1996] hypophosphatemia if phosphate intake is not adequate. In its more severe Subpart B—Active Ingredients forms, hypophosphatemia can lead to anorexia, malaise, muscle weakness, § 332.10 Antiflatulent active ingredients. and osteomalacia. (b) Professional labeling for an ant- Simethicone; maximum daily dose acid-antiflatulent combination may 500 mg. There is no dosage limitation contain the information allowed for at this time for professional labeling. health professionals for antacids and antiflatulents. § 332.15 Combination with non-antiflatulent active ingredients. [39 FR 19874, June 4, 1974. Redesignated and An antiflatulent may contain any amended at 55 FR 19859, May 11, 1990] generally recognized as safe and effective antacid ingredient(s) if it is indi- PART 332—ANTIFLATULENT PROD- cated for use solely for the concurrent UCTS FOR OVER-THE-COUNTER symptoms of gas associated with heart- HUMAN USE burn, sour stomach or acid indigestion.

Subpart A—General Provisions Subpart C—Labeling Sec. 332.1 Scope. § 332.30 Labeling of antiflatulent drug 332.3 Definitions. products. (a) Statement of identity. The labeling Subpart B—Active Ingredients of the product contains the established 332.10 Antiflatulent active ingredients. name of the drug, if any, and identifies 332.15 Combination with non-antiflatulent the product as an ‘‘antiflatulent,’’ active ingredients. ‘‘antigas,’’ or ‘‘antiflatulent (antigas).’’ (b) Indications. The labeling of the Subpart C—Labeling product states, under the heading ‘‘In- 332.30 Labeling of antiflatulent products. dications,’’ one or more of the phrases 332.31 Professional labeling. listed in this paragraph (b), as appropriate. Other truthful and nonmis- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, leading statements, describing only the 360, 371. indications for use that have been es- SOURCE: 39 FR 19877, June 4, 1974, unless tablished and listed in this paragraph otherwise noted. (b), may also be used, as provided in § 330.1(c)(2) of this chapter, subject to Subpart A—General Provisions the provisions of section 502 of the Fed- eral Food, Drug, and Cosmetic Act (the § 332.1 Scope. act) relating to misbranding and the An over-the-counter antiflatulent prohibition in section 301(d) of the act product in a form suitable for oral ad- against the introduction or delivery for ministration is generally recognized as introduction into interstate commerce

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of unapproved new drugs in violation of 333.103 Definitions. section 505(a) of the act. 333.110 First aid antibiotic active ingredi- (1) (Select one of the following: ‘‘Al- ents. leviates or Relieves’’) ‘‘the symptoms 333.120 Permitted combinations of active ingredients. referred to as gas.’’ 333.150 Labeling of first aid antibiotic drug (2) (Select one of the following: ‘‘Al- products. leviates’’ or ‘‘Relieves’’) (select one or 333.160 Labeling of permitted combinations more of the following: ‘‘bloating,’’ of active ingredients. ‘‘pressure,’’ ‘‘fullness,’’ or ‘‘stuffed feeling’’) ‘‘commonly referred to as gas.’’ Subpart C—Topical Antifungal Drug (c) Exemption from the general acci- Products dental overdose warning. The labeling for antiflatulent drug products con- 333.201 Scope. 333.203 Definitions. taining simethicone identified in 333.210 Antifungal active ingredients. § 332.10 and antacid/antiflatulent com- 333.250 Labeling of antifungal drug prod- bination drug products provided for in ucts. § 332.15, containing the active ingredi- 333.280 Professional labeling. ents identified in § 331.11(a), (b), and (d) through (m) of this chapter are exempt Subpart D—Topical Acne Drug Products from the requirement in § 330.1(g) of 333.301 Scope. this chapter that the labeling bear the 333.303 Definitions. general warning statement ‘‘In case of 333.310 Acne active ingredients. accidental overdose, seek professional 333.320 Permitted combinations of active in- assistance or contact a poison control gredients. center immediately.’’ The labeling 333.350 Labeling of acne drug products. must continue to bear the first part of AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, the general warning in § 330.1(g) of this 360, 371. chapter, which states, ‘‘Keep this and all drugs out of the reach of children.’’ SOURCE: 52 FR 47322, Dec. 11, 1987, unless otherwise noted. [39 FR 19877, June 4, 1974, as amended at 40 FR 11719, Mar. 13, 1975; 51 FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Subpart A [Reserved] Mar. 13, 1987; 61 FR 8838, Mar. 5, 1996] Subpart B—First Aid Antibiotic § 332.31 Professional labeling. Drug Products (a) The labeling of the product provided to health professionals (but not § 333.101 Scope. to the general public) may contain as (a) An over-the-counter first aid anti- additional indications postoperative biotic drug product in a form suitable gas pain or for use in endoscopic exam- for topical administration is generally ination. recognized as safe and effective and is (b) Professional labeling for an anti- not misbranded if it meets each of the flatulent-antacid combination may conditions in this subpart and each of contain information allowed for health the general conditions established in professionals for antacids and anti- § 330.1. flatulents. (b) References in this subpart to regulatory sections of the Code of Federal PART 333—TOPICAL ANTI- Regulations are to chapter I of title 21 MICROBIAL DRUG PRODUCTS unless otherwise noted. FOR OVER-THE-COUNTER HUMAN USE § 333.103 Definitions. As used in this subpart: Subpart A [Reserved] First aid antibiotic. An antibiotic-containing drug product applied topically Subpart B—First Aid Antibiotic Drug to the skin to help prevent infection in Products minor cuts, scrapes, and burns. Sec. [52 FR 47322, Dec. 11, 1987, as amended at 64 333.101 Scope. FR 403, Jan. 5, 1999]

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§ 333.110 First aid antibiotic active in- hicle, packaged in a pressurized con- gredients. tainer with suitable inert gases. The product consists of any of the (4) Bacitracin zinc-neomycin sulfate following active ingredients within the ointment containing, in each gram, 500 specified concentration established for units of bacitracin and 3.5 milligrams each ingredient and in the specified of neomycin in a suitable ointment dosage form: base. (a) Bacitracin ointment containing, (5) Bacitracin zinc-neomycin sulfate- in each gram, 500 units of bacitracin in polymyxin B sulfate ointment con- a suitable ointment base. taining, in each gram, in a suitable (b) Bacitracin zinc ointment con- ointment base the following: taining, in each gram, 500 units of baci- (i) 400 units of bacitracin, 3 milli- tracin zinc in a suitable ointment base. grams of neomycin, and 8,000 units of (c) Chlortetracycline hydrochloride polymyxin B; or ointment containing, in each gram, 30 (ii) 400 units of bacitracin, 3.5 milli- milligrams of chlortetracycline hydro- grams of neomycin, and 5,000 units of chloride in a suitable ointment base. polymyxin B; or (d) Neomycin sulfate ointment con- (iii) 500 units of bacitracin, 3.5 milli- taining, in each gram, 3.5 milligrams of grams of neomycin, and 5,000 units of neomycin in a suitable water soluble or polymyxin B; or oleaginous ointment base. (iv) 500 units of bacitracin, 3.5 milli- (e) Neomycin sulfate cream con- grams of neomycin, and 10,000 units of taining, in each gram, 3.5 milligrams of polymyxin B; neomycin in a suitable cream base. (6) Bacitracin zinc-polymyxin B sul- (f) Tetracycline hydrochloride oint- fate ointment containing, in each ment containing, in each gram, 30 mil- gram, 500 units of bacitracin and 10,000 ligrams of tetracycline hydrochloride units of polymyxin B in a suitable oint- in a suitable ointment base. ment base. [52 FR 47322, Dec. 11, 1987, as amended at 53 (7) Bacitracin zinc-polymyxin B sul- FR 18838, May 25, 1988; 64 FR 403, Jan. 5, 1999] fate topical aerosol containing, in each gram, 120 units of bacitracin and 2,350 § 333.120 Permitted combinations of units of polymyxin B in a suitable ve- active ingredients. hicle, packaged in a pressurized con- The following combinations are per- tainer with suitable inert gases. mitted provided each active ingredient (8) Bacitracin zinc-polymyxin B sul- is present within the established con- fate topical powder containing, in each centration and in the specified dosage gram, 500 units of bacitracin and 10,000 form, and the product is labeled in ac- units of polymyxin B in a suitable cordance with § 333.160. base. (a) Combinations of antibiotic active in- (9) Neomycin sulfate-polymyxin B gredients. (1) Bacitracin-neomycin sul- sulfate ointment containing, in each fate ointment containing, in each gram, 3.5 milligrams of neomycin and gram, 500 units of bacitracin and 3.5 5,000 units of polymyxin B in a suitable milligrams of neomycin in a suitable water miscible base. ointment base. (10) Neomycin sulfate-polymyxin B (2) Bacitracin-neomycin sulfate-poly- sulfate cream containing, in each myxin B sulfate ointment containing, gram, 3.5 milligrams of neomycin and in each gram, in a suitable ointment 10,000 units of polymyxin B in a suit- base the following: able vehicle. (i) 500 units of bacitracin, 3.5 milli- (11) Oxytetracycline hydrochloride- grams of neomycin, and 5,000 units of polymyxin B sulfate ointment con- polymyxin B; or taining, in each gram, 30 milligrams of (ii) 400 units of bacitracin, 3.5 milli- oxytetracycline and 10,000 units of grams of neomycin, and 5,000 units of polymyxin B in a suitable ointment polymyxin B; base. (3) Bacitracin-polymyxin B sulfate (12) Oxytetracycline hydrochloride- topical aerosol containing, in each polymyxin B sulfate topical powder gram, 500 units of bacitracin and 5,000 containing, in each gram, 30 milli- units of polymyxin B in a suitable ve- grams of oxytetracycline and 10,000

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units of polymyxin B with a suitable myxin B, and any single generally rec- filler. ognized as safe and effective amine or (b) Combinations of first aid antibiotic ‘‘caine’’-type local anesthetic active active ingredients and local anesthetic ac- ingredient; tive ingredients. (1) Bacitracin ointment (5) Bacitracin zinc-polymyxin B sul- containing, in each gram, 500 units of fate ointment containing, in each bacitracin and any single generally gram, 500 units of bacitracin, 10,000 recognized as safe and effective amine units of polymyxin B, and any single or ‘‘caine’’-type local anesthetic active generally recognized as safe and effec- ingredient in a suitable ointment base. tive amine or ‘‘caine’’-type local anes- (2) Bacitracin-neomycin sulfate-poly- thetic active ingredient in a suitable myxin B sulfate ointment containing, ointment base. in each gram, in a suitable ointment (6) Neomycin sulfate-polymyxin B base the following: sulfate cream containing, in each (i) 500 units of bacitracin, 3.5 milligram, 3.5 milligrams of neomycin, grams of neomycin, 5,000 units of poly- 10,000 units of polymyxin B, and any myxin B, and any single generally rec- single generally recognized as safe and ognized as safe and effective amine or effective amine or ‘‘caine’’-type local ‘‘caine’’-type local anesthetic active anesthetic active ingredient in a suit- ingredient; or able vehicle. (ii) 400 units of bacitracin, 3.5 milli- [52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. grams of neomycin, 5,000 units of poly- 24, 1987, as amended at 53 FR 18838, May 25, myxin B, and any single generally rec- 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, ognized as safe and effective amine or Oct. 3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR ‘‘caine’’-type local anesthetic active 403, Jan. 5, 1999] ingredient. (3) Bacitracin-polymyxin B sulfate § 333.150 Labeling of first aid anti- topical aerosol containing, in each biotic drug products. gram, 500 units of bacitracin and 5,000 (a) Statement of identity. The labeling units of polymyxin B and any single of the product contains the established generally recognized as safe and effec- name of the drug, if any, and identifies tive amine or ‘‘caine’’-type local anes- the product as a ‘‘first aid antibiotic.’’ thetic active ingredient in a suitable (b) Indications. The labeling of the vehicle, packaged in a pressurized con- product states, under the heading ‘‘In- tainer with suitable inert gases. dications,’’ the following: ‘‘First aid to (4) Bacitracin zinc-neomycin sulfate- help’’ [select one of the following: polymyxin B sulfate ointment con- ‘‘prevent,’’ (‘‘decrease’’ (‘‘the risk of’’ taining, in each gram, in a suitable or ‘‘the chance of’’)), (‘‘reduce’’ (‘‘the ointment base the following: risk of’’ or ‘‘the chance of’’)), ‘‘guard (i) 400 units of bacitracin, 3 milli- against,’’ or ‘‘protect against’’] [select grams of neomycin, 8,000 units of poly- one of the following: ‘‘infection,’’ myxin B, and any single generally rec- ‘‘bacterial contamination,’’ or ‘‘skin ognized as safe and effective amine or infection’’] ‘‘in minor cuts, scrapes, ‘‘caine’’-type local anesthetic active and burns.’’ Other truthful and nonmis- ingredient; or leading statements describing only the (ii) 400 units of bacitracin, 3.5 milli- indications for use that have been es- grams of neomycin, 5,000 units of poly- tablished and listed in this paragraph myxin B, and any single generally rec- (b), may also be used, as provided in ognized as safe and effective amine or § 330.1(c)(2), subject to the provisions of ‘‘caine’’-type local anesthetic active section 502 of the act relating to mis- ingredient; or branding and the prohibition in section (iii) 500 units of bacitracin, 3.5 milli- 301(d) of the act against the introduc- grams of neomycin, 5,000 units of poly- tion or delivery for introduction into myxin B, and any single generally rec- interstate commerce of unapproved ognized as safe and effective amine or new drugs in violation of section 505(a) ‘‘caine’’-type local anesthetic active of the act. ingredient; or (c) Warnings. The labeling of the (iv) 500 units of bacitracin, 3.5 milli- product contains the following warn- grams of neomycin, 10,000 units of poly- ings under the heading ‘‘Warnings’’:

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(1) ‘‘For external use only. Do not use tablished name, the labeling of the in the eyes or apply over large areas of product states the established name of the body. In case of deep or puncture the combination drug product, followed wounds, animal bites, or serious burns, by the statement of identity for each consult a doctor.’’ ingredient in the combination, as es- (2) For products containing chlortetra- tablished in the statement of identity cycline hydrochloride or tetracycline hy- sections of the applicable OTC drug drochloride.‘‘Stop use and consult a monographs. For a combination drug doctor if the condition persists or gets product that does not have an estab- worse. Do not use longer than 1 week lished name, the labeling of the prod- unless directed by doctor.’’ uct states the statement of identity for (3) For any product containing baci- each ingredient in the combination, as tracin, bacitracin zinc, neomycin, neomy- established in the statement of iden- cin sulfate, polymyxin B, and/or poly- tity sections of the applicable OTC myxin B sulfate. ‘‘Stop use and consult drug monographs. a doctor if the condition persists or (b) Indications. The labeling of the gets worse, or if a rash or other allergic product states, under the heading ‘‘In- reaction develops. Do not use if you are dications,’’ the indication(s) for each allergic to any of the ingredients. Do ingredient in the combination, as es- not use longer than 1 week unless di- tablished in the ‘‘Indications’’ sections rected by a doctor.’’ of the applicable OTC drug mono- (d) Directions. The labeling of the graphs, unless otherwise stated in this product contains the following state- paragraph. Other truthful and nonmis- ments under the heading ‘‘Directions’’: leading statements, describing only the (1) For ointment and cream products. indications for use that have been es- ‘‘Clean the affected area. Apply a small tablished and listed in this paragraph amount of this product (an amount (b), may also be used, as provided in equal to the surface area of the tip of § 330.1(c)(2), subject to the provisions of a finger) on the area 1 to 3 times daily. May be covered with a sterile ban- section 502 of the act relating to mis- dage.’’ branding and the prohibition in section (2) For powder products. ‘‘Clean the af- 301(d) of the act against the introduc- fected area. Apply a light dusting of tion or delivery for introduction into the powder on the area 1 to 3 times interstate commerce of unapproved daily. May be covered with a sterile new drugs in violation of section 505(a) bandage.’’ of the act. (3) For aerosol products. ‘‘Clean the af- (1) For permitted combinations identi- fected area. Spray a small amount of fied in § 333.120(a). The indications in this product on the area 1 to 3 times § 333.150 should be used. daily. May be covered with a sterile (2) For permitted combinations identi- bandage.’’ fied in § 333.120(b). In addition to the re- (e) The word ‘‘doctor’’ may be sub- quired indication identified in § 333.150, stituted for the word ‘‘physician’’ in the labeling of the product may state, any of the labeling statements in this under the heading ‘‘Indications,’’ the subpart. following additional indication: ‘‘First aid for the temporary relief of’’ (select [52 FR 47332, Dec. 11, 1987, as amended at 61 FR 58472, Nov. 15, 1996] one of the following: ‘‘pain,’’ ‘‘discomfort,’’ ‘‘pain or discomfort’’ or ‘‘pain § 333.160 Labeling of permitted com- and itching’’) ‘‘in minor cuts, scrapes, binations of active ingredients. and burns.’’ Statements of identity, indications, (c) Warnings. The labeling of the warnings, and directions for use, re- product states, under the heading spectively, applicable to each ingre- ‘‘Warnings,’’ the warning(s) for each in- dient in the product may be combined gredient in the combination, as estab- to eliminate duplicative words or lished in the warnings sections of the phrases so that the resulting informa- applicable OTC drug monographs. tion is clear and understandable. (d) Directions. The labeling of the (a) Statement of identity. For a com- product states, under the heading ‘‘Di- bination drug product that has an es- rections,’’ directions that conform to

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the directions established for each in- § 333.210 Antifungal active ingredi- gredient in the directions sections of ents. the applicable OTC drug monographs. The active ingredient of the product When the time intervals or age limita- consists of any one of the following tions for administrations of the indi- within the specified concentration es- vidual ingredients differ, the directions tablished for each ingredient: for the combination product may not (a) Clioquinol 3 percent. exceed any maximum dosage limits es- (b) Haloprogin 1 percent. tablished for the individual ingredients (c) Miconazole nitrate 2 percent. in the applicable OTC drug monograph. (d) Povidone-iodine 10 percent. (e) Tolnaftate 1 percent. Subpart C—Topical Antifungal (f) Undecylenic acid, calcium Drug Products undecylenate, copper undecylenate, and zinc undecylenate may be used in- SOURCE: 58 FR 49898, Sept. 23, 1993, unless dividually or in any ratio that provides otherwise noted. a total undecylenate concentration of 10 to 25 percent. § 333.201 Scope. (g) Clotrimazole 1 percent. (a) An over-the-counter antifungal [58 FR 49898, Sept. 23, 1993, as amended at 67 drug product in a form suitable for top- FR 5943, Feb. 8, 2002] ical administration is generally recognized as safe and effective and is not § 333.250 Labeling of antifungal drug misbranded if it meets each of the con- products. ditions in this subpart and each gen- (a) Statement of identity. The labeling eral condition established in § 330.1 of of the product contains the established this chapter. name of the drug, if any, and identifies (b) Reference in this subpart to regu- the product as an ‘‘antifungal.’’ latory sections of the Code of Federal (b) Indications. The labeling of the Regulations are to chapter I of title 21 product states, under the heading ‘‘In- unless otherwise noted. dications,’’ the phrase listed in paragraph (b)(1)(i) of this section and may § 333.203 Definitions. contain the additional phrase listed in paragraph (b)(1)(ii) of this section. As used in this subpart: Other truthful and nonmisleading (a) Antifungal. A drug which inhibits statements, describing only the indica- the growth and reproduction of fungal tions for use that have been established cells and decreases the number of fungi in paragraph (b) of this section, may present. also be used, as provided in § 330.1(c)(2) (b) Athlete’s foot. An infection of the of this chapter, subject to the provi- feet caused by certain dermatophytic sions of section 502 of the Federal fungi. Food, Drug, and Cosmetic Act (the act) (c) Dermatophyte. A fungus that in- relating to misbranding and the prohi- vades and lives upon the skin or in the bition in section 301(d) of the act hair or nails. against the introduction or delivery for (d) Fungus. Any of a large division of introduction into interstate commerce plants, including dermatophytes, of unapproved new drugs in violation of yeasts, and molds, characterized by a section 505(a) of the act. simple cell structure and the absence (1) For products containing any ingre- of chlorophyll. dient identified in § 333.210 labeled for the (e) Jock itch. A chronic and recurrent treatment of athlete’s foot, jock itch, and infection caused by certain ringworm. (i) (Select one of the fol- dermatophytic fungi; affects the upper, lowing: ‘‘Treats,’’ ‘‘For the treatment inner thighs and sometimes extends to of,’’ ‘‘For effective treatment of,’’ the groin and the pubic area; the condi- ‘‘Cures,’’ ‘‘For the cure of,’’ ‘‘Clears tion most frequently occurs in men, up,’’ or ‘‘Proven clinically effective in but may also occur in women. the treatment of’’) ‘‘most’’ (select one (f) Ringworm. A skin infection caused condition from any one or more of the by certain dermatophytic fungi. following groups of conditions:

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(A) ‘‘Athlete’s foot,’’ athlete’s foot improvement within 4 weeks, dis- (dermatophytosis),’’ ‘‘athlete’s foot continue use and consult a doctor.’’ (tinea pedis),’’ or ‘‘tinea pedis (ath- (3) For products labeled according to lete’s foot)’’; paragraph (b)(1) of this section for the (B) ‘‘Jock itch,’’ ‘‘jock itch (tinea treatment of jock itch. ‘‘If irritation oc- cruris),’’ or ‘‘tinea cruris (jock itch)’’; curs or if there is no improvement or within 2 weeks, discontinue use and (C) ‘‘Ringworm,’’ ‘‘ringworm (tinea consult a doctor.’’ corporis),’’ or ‘‘tinea corporis (4) For products labeled according to (ringworm).’’) paragraph (b)(2) of this section for the (ii) In addition to the information prevention of athlete’s foot. ‘‘If irritation identified in paragraph (b)(1)(i) of this occurs, discontinue use and consult a section, the labeling of the product doctor.’’ may contain the following statement: (5) For products containing the ingre- (Select one of the following: ‘‘Re- dient identified in § 333.210(a) labeled ac- lieves,’’ ‘‘For relief of,’’ ‘‘For effective cording to paragraph (b)(1) of this sec- relief of,’’ or ‘‘Soothes,’’) (select one or tion. The following statements must more of the following: ‘‘Itching,’’ appear in boldface type as the first ‘‘scaling,’’ ‘‘cracking,’’ ‘‘burning,’’ warnings under the ‘‘Warnings’’ head- ‘‘redness,’’ ‘‘soreness,’’ ‘‘irritation,’’ ing. (i) ‘‘Do not use on children under 2 ‘‘discomfort,’’ ‘‘chafing associated with years of age.’’ (This warning is to be jock itch,’’ ‘‘itchy, scaly skin between used in place of the warning in para- the toes,’’ or ‘‘itching, burning feet’’). graph (c)(1)(i) of this section.) (ii) ‘‘Do not use for diaper rash.’’ (2) For products containing the ingre- (d) Directions. The labeling of the dient identified in § 333.210(e) labeled for product contains the following state- the prevention of athlete’s foot. (i) (Se- ments under the heading ‘‘Directions’’: lect one of the following: ‘‘Clinically (1) For products labeled according to proven to prevent,’’ ‘‘Prevents,’’ paragraph (b)(1) of this section for the ‘‘Proven effective in the prevention treatment of athlete’s foot, jock itch, and of,’’ ‘‘Helps prevent,’’ ‘‘For the preven- ringworm. [Select one of the following: tion of,’’ ‘‘For the prophylaxis (preven- ‘‘Clean’’ or ‘‘Wash’’] ‘‘the affected area tion) of,’’ ‘‘Guards against,’’ or ‘‘Pre- and dry thoroughly. Apply’’ (the word vents the recurrence of’’) ‘‘most’’ (se- ‘‘spray’’ may be used to replace the lect one of the following: ‘‘Athlete’s word ‘‘apply’’ for aerosol products) ‘‘a foot,’’ ‘‘athlete’s foot thin layer of the product over affected (dermatophytosis),’’ ‘‘athlete’s foot area twice daily (morning and night) or (tinea pedis),’’ or ‘‘tinea pedis (ath- as directed by a doctor. Supervise chil- lete’s foot)’’) ‘‘with daily use.’’ dren in the use of this product. For (ii) In addition to the information athlete’s foot: Pay special attention to identified in paragraph (b)(2)(i) of this spaces between the toes; wear well-fit- section, the labeling of the product ting, ventilated shoes, and change may contain the following statement: shoes and socks at least once daily. For ‘‘Clears up most athlete’s foot infec- athlete’s foot and ringworm, use daily tion and with daily use helps keep it for 4 weeks; for jock itch, use daily for from coming back.’’ 2 weeks. If condition persists longer, (c) Warnings. The labeling of the consult a doctor. This product is not product contains the following warn- effective on the scalp or nails.’’ ings under the heading ‘‘Warnings’’: (2) For products labeled according to (1) For products containing any ingre- paragraph (b)(2) of this section for the dient identified in § 330.210. (i) ‘‘Do not prevention of athlete’s foot. ‘‘To prevent use on children under 2 years of age un- athlete’s foot,’’ (select one of the fol- less directed by a doctor.’’ lowing: ‘‘clean’’ or ‘‘wash’’) ‘‘the feet (ii) ‘‘For external use only.’’ and dry thoroughly. Apply’’ (the word (iii) ‘‘Avoid contact with the eyes.’’ ‘‘spray’’ may be used to replace the (2) For products labeled according to word ‘‘apply’’ for aerosol products) ‘‘a paragraph (b)(1) of this section for the thin layer of the product to the feet treatment of athlete’s foot and ringworm. once or twice daily (morning and/or ‘‘If irritation occurs or if there is no night). Supervise children in the use of

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this product. Pay special attention to (d) Acne pimple. A small, prominent, spaces between the toes; wear well-fit- inflamed elevation of the skin result- ting, ventilated shoes, and change ing from acne. shoes and socks at least once daily.’’ (e) Blackhead. A condition of the skin (e) The word ‘‘physician’’ may be sub- that occurs in acne and is character- stituted for the word ‘‘doctor’’ in any ized by a black tip. of the labeling statements in this sec- (f) Whitehead. A condition of the skin tion. that occurs in acne and is characterized by a small, firm, whitish elevation [58 FR 49898, Sept. 23, 1993, as amended at 65 of the skin. FR 52305, Aug. 29, 2000] § 333.310 Acne active ingredients. § 333.280 Professional labeling. The active ingredient of the product The labeling provided to health pro- consists of any of the following: fessionals (but not to the general pub- (a) Benzoyl peroxide, 2.5 to 10 per- lic) may contain the following addi- cent. tional indication: (b) Resorcinol, 2 percent, when com- (a) For products containing haloprogin bined with sulfur in accordance with or miconazole nitrate identified in § 333.320(a). § 333.210 (a) and (c). ‘‘For the treatment (c) Resorcinol monoacetate, 3 per- of superficial skin infections caused by cent, when combined with sulfur in ac- yeast (Candida albicans).’’ cordance with § 333.320(b). (b) [Reserved] (d) Salicylic acid, 0.5 to 2 percent. (e) Sulfur, 3 to 10 percent. Subpart D—Topical Acne Drug (f) Sulfur, 3 to 8 percent, when com- Products bined with resorcinol or resorcinol monoacetate in accordance with SOURCE: 56 FR 41019, Aug. 16, 1991, unless § 333.320. otherwise noted. [75 FR 9776, Mar. 4, 2010]

§ 333.301 Scope. § 333.320 Permitted combinations of (a) An over-the-counter acne drug active ingredients. product in a form suitable for topical (a) Resorcinol identified in § 333.310(b) application is generally recognized as may be combined with sulfur identified safe and effective and is not mis- in § 333.310(f). branded if it meets each of the condi- (b) Resorcinol monoacetate identified tions in this subpart and each general in § 333.310(c) may be combined with condition established in § 330.1 of this sulfur identified in § 333.310(f). chapter. [75 FR 9776, Mar. 4, 2010] (b) References in this subpart to regulatory sections of the Code of Federal § 333.350 Labeling of acne drug prod- Regulations are to chapter I of title 21 ucts. unless otherwise noted. (a) Statement of identity. The labeling § 333.303 Definitions. of the product contains the established name of the drug, if any, and identifies As used in this subpart: the product as an ‘‘acne medication,’’ (a) Acne. A disease involving the oil ‘‘acne treatment,’’ ‘‘acne medication’’ glands and hair follicles of the skin (insert dosage form, e.g., ‘‘cream,’’ which is manifested by blackheads, ‘‘gel,’’ ‘‘lotion,’’ or ‘‘ointment’’), or whiteheads, acne pimples, and acne ‘‘acne treatment’’ (insert dosage form, blemishes. e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or (b) Acne blemish. A flaw in the skin ‘‘ointment’’). resulting from acne. (b) Indications. The labeling of the (c) Acne drug product. A drug product product states, under the heading ‘‘In- used to reduce the number of acne dications,’’ the phrase listed in para- blemishes, acne pimples, blackheads, graph (b)(1) of this section and may and whiteheads. contain any of the additional phrases

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listed in paragraph (b)(2) of this sec- (i) The labeling states ‘‘For external tion. Other truthful and nonmisleading use only.’’ statements, describing only the indica- (ii) The labeling states ‘‘When using tions for use that have been established this product [bullet] skin irritation and and listed in paragraph (b) of this sec- dryness is more likely to occur if you tion, may also be used, as provided in use another topical acne medication at § 330.1(c)(2) of this chapter, subject to the same time. If irritation occurs, the provisions of section 502 of the Fed- only use one topical acne medication eral Food, Drug, and Cosmetic Act (the at a time.’’ act) relating to misbranding and the (2) For products containing sulfur iden- prohibition in section 301(d) of the act tified in § 333.310(e) and (f). against the introduction or delivery for (i) The labeling states ‘‘Do not use on introduction into interstate commerce [bullet] broken skin [bullet] large areas of unapproved new drugs in violation of of the skin.’’ section 505(a) of the act. (ii) The labeling states ‘‘When using (1) ‘‘For the’’ (select one of the fol- this product [bullet] apply only to lowing: ‘‘management’’ or ‘‘treat- areas with acne.’’ ment’’) ‘‘of acne.’’ (3) For products containing any com- (2) In addition to the information bination identified in § 333.320. (i) The la- identified in paragraph (b)(1) of this beling states ‘‘When using this product section, the labeling of the product [bullet] rinse right away with water if may contain any one or more of the it gets in eyes.’’ following statements: (ii) The labeling states ‘‘Stop use and (i) (Select one of the following: ask a doctor [bullet] if skin irritation ‘‘Clears,’’ ‘‘Clears up,’’ ‘‘Clears up occurs or gets worse.’’ most,’’ ‘‘Dries,’’ ‘‘Dries up,’’ ‘‘Dries and (4) For products containing benzoyl per- clears,’’ ‘‘Helps clear,’’ ‘‘Helps clear oxide identified in § 333.310(a). up,’’ ‘‘Reduces the number of,’’ or ‘‘Re- (i) The labeling states ‘‘Do not use if duces the severity of’’) (select one or you [bullet] have very sensitive skin more of the following: ‘‘acne blem- [bullet] are sensitive to benzoyl per- ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ oxide.’’ or ‘‘whiteheads’’) which may be fol- (ii) The labeling states ‘‘When using lowed by ‘‘and allows skin to heal.’’ this product [bullet] avoid unnecessary (ii) ‘‘Penetrates pores to’’ (select one sun exposure and use a sunscreen [bul- of the following: ‘‘eliminate most,’’ let] avoid contact with the eyes, lips, ‘‘control,’’ ‘‘clear most,’’ or ‘‘reduce and mouth [bullet] avoid contact with the number of’’) (select one or more of hair and dyed fabrics, which may be the following: ‘‘acne blemishes,’’ ‘‘acne bleached by this product [bullet] skin pimples,’’ ‘‘blackheads,’’ or irritation may occur, characterized by ‘‘whiteheads’’). redness, burning, itching, peeling, or (iii) ‘‘Helps keep skin clear of new’’ possibly swelling. Irritation may be re- (select one or more of the following: duced by using the product less fre- ‘‘acne blemishes,’’ ‘‘acne pimples,’’ quently or in a lower concentration.’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). (iii) The labeling states ‘‘Stop use (iv) ‘‘Helps prevent new’’ (select one and ask a doctor if [bullet] irritation or more of the following: ‘‘acne blem- becomes severe.’’ ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ (d) Directions. The labeling of the or ‘‘whiteheads’’) which may be fol- product contains the following infor- lowed by ‘‘from forming.’’ mation under the heading ‘‘Direc- (v) ‘‘Helps prevent the development tions’’: of new’’ (select one or more of the fol- (1) For products applied containing any lowing: ‘‘acne blemishes,’’ ‘‘acne pim- ingredient identified in § 333.310. The la- ples,’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). beling states ‘‘[bullet] clean the skin (c) Warnings. The labeling of the thoroughly before applying this prod- product contains the following warn- uct [bullet] cover the entire affected ings under the heading ‘‘Warnings’’: area with a thin layer one to three (1) For products containing any ingredi- times daily [bullet] because excessive ents identified in § 330.310. drying of the skin may occur, start

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with one application daily, then gradu- SOURCE: 68 FR 18881, April 17, 2003, unless ally increase to two or three times otherwise noted. daily if needed or as directed by a doctor [bullet] if bothersome dryness or Subpart A—General Provisions peeling occurs, reduce application to once a day or every other day.’’ § 335.1 Scope. (2) For products applied and left on the (a) An over-the-counter antidiarrheal skin containing benzoyl peroxide identi- drug product in a form suitable for oral fied in § 333.310(a). administration is generally recognized (i) The labeling states the directions as safe and effective and is not mis- in paragraph (d)(1) of this section. branded if it meets each condition in (ii) The labeling states ‘‘[bullet] if this part and each general condition es- going outside, apply sunscreen after tablished in § 330.1 of this chapter. using this product. If irritation or sen- (b) References in this part to regu- sitivity develops, stop use of both prod- latory sections of the Code of Federal ucts and ask a doctor.’’ Regulations are to chapter I of title 21 (3) For products applied and removed unless otherwise noted. from the skin containing any ingredient identified in § 333.310. Products, such as § 335.3 Definitions. soaps and masks, may be applied and As used in this part: removed and should include appro- (a) Antidiarrheal. A drug that can be priate directions. All products con- shown by objective measurement to taining benzoyl peroxide should in- treat or control (stop) the symptoms of clude the directions in paragraph diarrhea. (d)(2)(ii) of this section. (b) Diarrhea. A condition character- (4) Optional directions. In addition to ized by increased frequency of loose, the required directions in paragraphs watery stools (three or more daily) (d)(1) and (d)(2) of this section, the during a limited period (24 to 48 hours), product may contain the following op- usually with no identifiable cause. tional labeling: ‘‘Sensitivity Test for a (c) Travelers’ diarrhea. A subset of di- New User. Apply product sparingly to arrhea occurring in travelers that is one or two small affected areas during most commonly caused by an infec- the first 3 days. If no discomfort oc- tious agent. curs, follow the directions stated (select one of the following: ‘elsewhere on [68 FR 18881, Apr. 17, 2003, as amended at 69 this label,’ ‘above,’ or ‘below’).’’ FR 26302, May 12, 2004] [56 FR 41019, Aug. 16, 1991, as amended at 75 FR 9776, Mar. 4, 2010] Subpart B—Active Ingredients § 335.10 Antidiarrheal active ingredi- PART 335—ANTIDIARRHEAL DRUG ents. PRODUCTS FOR OVER-THE- The active ingredient of the product COUNTER HUMAN USE consists of any one of the following when used within the dosage limits es- Subpart A—General Provisions tablished for each ingredient in § 335.50(d): Sec. 335.1 Scope. (a) Bismuth subsalicylate. 335.3 Definitions. (b) Kaolin. Subpart B—Active Ingredients Subpart C—Labeling

335.10 Antidiarrheal active ingredients. § 335.50 Labeling of antidiarrheal drug products. Subpart C—Labeling (a) Statement of identity. The labeling 335.50 Labeling of antidiarrheal drug prod- of the product contains the established ucts. name of the drug, if any, and identifies AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, the product either as an 360, 371. ‘‘antidiarrheal’’ or ‘‘for diarrhea.’’

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(b) Indications. The labeling of the ance with § 201.66(c)(5)(ii) of this chap- product states, under the heading ter. ‘‘Use,’’ one or more of the phrases list- (A) The Reye’s syndrome warning in ed in this paragraph (b), as appropriate. § 201.314(h) of this chapter. Other truthful and nonmisleading (B) ‘‘Allergy alert: Contains salicy- statements, describing only the indica- late. Do not take if you are [bullet] al- tions for use that have been established lergic to salicylates (including aspirin), and listed in this paragraph (b) may [bullet] taking other salicylate prod- also be used, as provided in § 330.1(c)(2) ucts’’. of this chapter, subject to the provi- (ii) ‘‘Do not use if you have [bullet] sions of section 502 of the Federal an ulcer [bullet] a bleeding problem’’. Food, Drug, and Cosmetic Act (the act) (iii) ‘‘Ask a doctor or pharmacist be- relating to misbranding and the prohi- fore use if you are taking any drug for bition in section 301(d) of the act [bullet] anticoagulation (thinning the against the introduction or delivery for blood) [bullet] diabetes [bullet] gout introduction into interstate commerce [bullet] arthritis’’. of unapproved new drugs in violation of (iv) ‘‘When using this product a tem- section 505(a) of the act. porary, but harmless, darkening of the (1) For products containing bismuth stool and/or tongue may occur’’. subsalicylate identified in § 335.10(a). The (v) ‘‘Stop use and ask a doctor if [bul- labeling states [select one of the fol- let] symptoms get worse [bullet] ring- lowing: ‘‘controls’’ or ‘‘relieves’’] [se- ing in the ears or loss of hearing occurs lect one or both of the following: ‘‘di- [bullet] diarrhea lasts more than 2 arrhea’’ or ‘‘travelers’ diarrhea’’]. If days’’. both ‘‘diarrhea’’ and ‘‘travelers’ diar- (3) For products containing kaolin iden- rhea’’ are selected, each shall be pre- tified in § 335.10(b). (i) ‘‘Ask a doctor or ceded by a bullet in accordance with pharmacist before use if you are taking § 201.66(b)(4) and (d)(4) of this chapter any other drugs. Try to use at least 3 and the heading ‘‘Uses’’ shall be used. hours before or after taking any other (2) For products containing kaolin iden- drugs.’’ tified in § 335.10(b). The labeling states (ii) ‘‘Stop use and ask a doctor if ‘‘helps firm stool within 24 to 48 [bullet] symptoms get worse [bullet] hours’’. diarrhea lasts more than 2 days’’. (3) Additional indications—(i) When (d) Directions. The labeling of the any additional indications are used, product contains the following infor- the heading ‘‘Uses’’ shall be used and mation under the heading ‘‘Direc- each listed use shall be preceded by a tions’’: bullet in accord with § 201.66(b)(4) of (1) For products containing any ingre- this chapter. dient identified in § 335.10. The labeling (ii) In addition to the indication in states ‘‘[bullet] drink plenty of clear paragraph (b)(1) of this section, one or fluids to help prevent dehydration both of the following may be used for caused by diarrhea’’. products containing bismuth subsalicy- (2) For products containing bismuth late in § 335.10(a): ‘‘[bullet] reduces subsalicylate identified in § 335.10(a). The number of bowel movements’’ ‘‘[bullet] labeling states ‘‘[bullet] adults and helps firm stool’’. children 12 years and over:’’ 525 milli- (c) Warnings. The labeling of the grams ‘‘every 1⁄2 to 1 hour, or’’ 1,050 product contains the following warn- milligrams ‘‘every hour as needed [bul- ings under the heading ‘‘Warnings’’: let] do not exceed’’ 4,200 milligrams ‘‘in (1) For products containing any ingre- 24 hours [bullet] use until diarrhea dient identified in § 335.10. (i) ‘‘Do not stops but not more than 2 days [bullet] use if you have [bullet] bloody or black children under 12 years: ask a doctor’’. stool’’. (3) For products containing kaolin iden- (ii) ‘‘Ask a doctor before use if you tified in § 335.10(b). The labeling states have [bullet] fever [bullet] mucus in ‘‘[bullet] adults and children 12 years the stool’’. and over:’’ 26.2 grams ‘‘after each loose (2) For products containing bismuth stool [bullet] continue to take every 6 subsalicylate identified in § 335.10(a). (i) hours until stool is firm but not more The following shall appear in accord- than 2 days [bullet] do not exceed’’ [262

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grams] ‘‘in 24 hours [bullet] children Subpart A—General Provisions under 12 years of age: ask a doctor’’. (e) Products that meet the criteria es- § 336.1 Scope. tablished in § 201.66(d)(10) of this chapter. (a) An over-the-counter antiemetic The information described in § 201.66(c) drug product in a form suitable for oral of this chapter shall be printed in ac- administration is generally recognized cordance with the following specifica- as safe and effective and is not mis- tions. branded if it meets each of the condi- (1) The labeling shall meet the re- tions in this part and each of the gen- quirements of § 201.66(c) of this chapter eral conditions established in § 330.1. except that the information in (b) References in this part to regu- § 201.66(c)(3) of this chapter may be latory sections of the Code of Federal omitted, and the information in Regulations are to chapter I of title 21 § 201.66(c)(5) and (c)(6) of this chapter unless otherwise noted. may be presented as follows: § 336.3 Definition. (i) The words ‘‘Contains salicylate.’’ may be omitted from the warning in As used in this part: § 335.50(c)(2)(i)(B). Antiemetic. An agent that prevents or treats nausea and vomiting. (ii) The subheading ‘‘When using this product’’ in § 335.50(c)(2)(iv) may be omitted. Subpart B—Active Ingredients (iii) The words ‘‘continue to’’ may be § 336.10 Antiemetic active ingredients. omitted from the directions in The active ingredient of the product § 335.50(d)(3). consists of any of the following when (2) The labeling shall be printed in used within the dosage limits estab- accordance with the requirements of lished for each ingredient in § 336.50(d): § 201.66(d) of this chapter except that (a) Cyclizine hydrochloride. any requirements related to (b) Dimenhydrinate. § 201.66(c)(3) of this chapter and the bul- (c) Diphenhydramine hydrochloride. let in the warning in § 335.50(c)(1)(i) (d) Meclizine hydrochloride. may be omitted. [68 FR 18881, Apr. 17, 2003, as amended at 69 Subpart C—Labeling FR 26302, May 12, 2004] § 336.50 Labeling of antiemetic drug products. PART 336—ANTIEMETIC DRUG (a) Statement of identity. The labeling PRODUCTS FOR OVER-THE- of the product contains the established COUNTER HUMAN USE name of the drug, if any, and identifies the product as an ‘‘antiemetic.’’ Subpart A—General Provisions (b) Indications. The labeling of the product states the following under the Sec. 336.1 Scope. heading ‘‘Indications,’’ ‘‘For the pre- 336.3 Definition. vention and treatment of the nausea, vomiting, or dizziness associated with Subpart B—Active Ingredients motion sickness.’’ Other truthful and nonmisleading statements, describing 336.10 Antiemetic active ingredients. only the indications for use that have been established and listed in this Subpart C—Labeling paragraph (b), may also be used, as pro- 336.50 Labeling of antiemetic drug products. vided in § 330.1(c)(2), subject to the pro- 336.80 Professional labeling. visions of section 502 of the act relating to misbranding and the prohibition in AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, section 301(d) of the act against the in- 360, 371. troduction or delivery for introduction SOURCE: 52 FR 15892, Apr. 30, 1987, unless into interstate commerce of unap- otherwise noted. proved new drugs in violation of section 505(a) of the act.

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(c) Warnings. The labeling of the this product if you are taking sedatives product contains the following warn- or tranquilizers, without first con- ings under the heading ‘‘Warnings:’’ sulting your doctor. Use caution when (1) For products containing any ingre- driving a motor vehicle or operating dient identified in § 336.10—(i) When la- machinery.’’ beled for use in adults and for those prod- (8) For products containing ucts that can be and are labeled for use in diphenhydramine hydrochloride identified children under 12 years of age. ‘‘Do not in § 336.10(c). ‘‘Do not use [bullet] 1 with take this product, unless directed by a any other product containing doctor, if you have a breathing problem diphenhydramine, including one used such as emphysema or chronic bron- on skin’’. chitis, or if you have glaucoma or dif- (d) Directions. The labeling of the ficulty in urination due to enlargement product contains the following infor- of the prostate gland.’’ mation under the heading ‘‘Direc- (ii) For those products that can be and tions’’: are labeled only for children under 12 (1) For products containing cyclizine years of age. ‘‘Do not give this product hydrochloride identified in § 336.10(a). to children who have a breathing prob- Adults and children 12 years of age and lem such as chronic bronchitis or who over: Oral dosage is 50 milligrams have glaucoma, without first con- every 4 to 6 hours, not to exceed 200 sulting the child’s doctor.’’ milligrams in 24 hours, or as directed (2) For products containing cyclizine by a doctor. Children 6 to under 12 hydrochloride identified in § 336.10(a). years of age: Oral dosage is 25 milli- ‘‘Do not give to children under 6 years grams every 6 to 8 hours, not to exceed of age unless directed by a doctor.’’ 75 milligrams in 24 hours, or as di- (3) For products containing dimenhy- rected by a doctor. drinate identified in § 336.10(b). ‘‘Do not give to children under 2 years of age (2) For products containing dimenhy- unless directed by a doctor.’’ drinate identified in § 336.10(b). Adults (4) For products containing and children 12 years of age and over: diphenhydramine hydrochloride identified Oral dosage is 50 to 100 milligrams in § 336.10(c). ‘‘Do not give to children every 4 to 6 hours, not to exceed 400 under 6 years of age unless directed by milligrams in 24 hours, or as directed a doctor.’’ by a doctor. Children 6 to under 12 (5) For products containing meclizine years of age: Oral dosage is 25 to 50 mil- hydrochloride identified in § 336.10(d). ligrams every 6 to 8 hours, not to ex- ‘‘Do not give to children under 12 years ceed 150 milligrams in 24 hours, or as of age unless directed by a doctor.’’ directed by a doctor. Children 2 to (6) For products containing cyclizine under 6 years of age: Oral dosage is 12.5 hydrochloride identified in § 336.10(a) or to 25 milligrams every 6 to 8 hours, not meclizine hydrochloride identified in to exceed 75 milligrams in 24 hours, or § 330.10(d). ‘‘May cause drowsiness; al- as directed by a doctor. cohol, sedatives, and tranquilizers may (3) For products containing increase the drowsiness effect. Avoid diphenhydramine hydrochloride identified alcoholic beverages while taking this in § 336.10(c). Adults and children 12 product. Do not take this product if years of age and over: Oral dosage is 25 you are taking sedatives or tranquil- to 50 milligrams every 4 to 6 hours, not izers, without first consulting your to exceed 300 milligrams in 24 hours, or doctor. Use caution when driving a as directed by a doctor. Children 6 to motor vehicle or operating machin- under 12 years of age: Oral dosage is ery.’’ 12.5 to 25 milligrams every 4 to 6 hours, (7) For products containing dimenhy- not to exceed 150 milligrams in 24 drinate identified in § 336.10(b) or hours, or as directed by a doctor. diphenhydramine hydrochloride identified (4) For products containing meclizine in § 336.10(c). ‘‘May cause marked hydrochloride identified in § 336.10(d). drowsiness; alcohol, sedatives, and Adults and children 12 years of age and tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages 1 See § 201.66(b)(4) of this chapter for defini- while taking this product. Do not take tion of bullet symbol.

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over: Oral dosage is 25 to 50 milligrams (b) References in this part to regu- once daily, or as directed by a doctor. latory sections of the Code of Federal (e) The word ‘‘physician’’ may be sub- Regulations are to chapter I of title 21 stituted for the word ‘‘doctor’’ in any unless otherwise noted. of the labeling statements in this section. § 338.3 Definition. [52 FR 15892, Apr. 30, 1987, as amended at 53 As used in this part: FR 35809, Sept. 15, 1988; 59 FR 16982, Apr. 11, Nighttime sleep-aid. A drug that is use- 1994; 67 FR 72559, Dec. 6, 2003] ful for the relief of occasional sleeplessness by individuals who have dif- § 336.80 Professional labeling. ficulty falling asleep. The labeling provided to health professionals (but not to the general pub- Subpart B—Active Ingredients lic) may contain the following additional indications. § 338.10 Nighttime sleep-aid active in- (a) For products containing cyclizine gredients. hydrochloride, dimenhydrinate, and The active ingredient of the product diphenhydramine hydrochloride identified consists of any of the following when in § 336.10 (a), (b), and (c). ‘‘For the used within the dosage limits estab- treatment of vertigo of motion sick- lished for each ingredient in § 338.50(d): ness.’’ (a) Diphenhydramine hydrochloride. (b) For products containing meclizine (b) Diphenhydramine citrate. hydrochloride identified in § 336.10(d). ‘‘For the treatment of vertigo.’’ Subpart C—Labeling PART 338—NIGHTTIME SLEEP-AID § 338.50 Labeling of nighttime sleep- DRUG PRODUCTS FOR OVER-THE- aid drug products. COUNTER HUMAN USE (a) Statement of identity. The labeling of the product contains the established name of the drug, if any, and identifies Subpart A—General Provisions the product as a ‘‘nighttime sleep-aid.’’ Sec. (b) Indications. The labeling of the 338.1 Scope. product states, under the heading ‘‘In- 338.3 Definition. dications,’’ one or more of the phrases listed in this paragraph. Other truthful Subpart B—Active Ingredients and nonmisleading statements, de- 338.10 Nighttime sleep-aid active ingredi- scribing only the indications for use ents. that have been established and listed in this paragraph (b), may also be used, as Subpart C—Labeling provided in § 330.1(c)(2) of this chapter, 338.50 Labeling of nighttime sleep-aid drug subject to the provisions of section 502 products. of the act relating to misbranding and the prohibition in section 301(d) of the AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. act against the introduction or delivery for introduction into interstate SOURCE: 54 FR 6826, Feb. 14, 1989, unless commerce of unapproved new drugs in otherwise noted. violation of section 505(a) of the act. (1) (‘‘Helps you’’ or ‘‘Reduces time Subpart A—General Provisions to’’) ‘‘fall asleep if you have difficulty falling asleep.’’ § 338.1 Scope. (2) ‘‘For relief of occasional sleepless- (a) An over-the-counter nighttime ness.’’ sleep-aid drug product in a form suit- (3) ‘‘Helps to reduce difficulty falling able for oral administration is gen- asleep.’’ erally recognized as safe and effective (c) Warnings. The labeling of the and is not misbranded if it meets each product contains the following warn- condition in this part and each general ings under the heading ‘‘Warnings’’: condition established in § 330.1 of this (1) ‘‘Do not give to children under 12 chapter. years of age.’’

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(2) ‘‘If sleeplessness persists continu- Subpart C—Labeling ously for more than 2 weeks, consult your doctor. Insomnia may be a symp- 340.50 Labeling of stimulant drug products. tom of serious underlying medical ill- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, ness.’’ 360, 371. (3) ‘‘Do not take this product, unless SOURCE: 53 FR 6105, Feb. 29, 1988, unless directed by a doctor, if you have a otherwise noted. breathing problem such as emphysema or chronic bronchitis, or if you have glaucoma or difficulty in urination due Subpart A—General Provisions to enlargement of the prostate gland.’’ § 340.1 Scope. (4) ‘‘Avoid alcoholic beverages while taking this product. Do not take this (a) An over-the-counter stimulant product if you are taking sedatives or drug product in a form suitable for oral tranquilizers, without first consulting administration is generally recognized your doctor.’’ as safe and effective and is not mis- (5) ‘‘Do not use [bullet] 1 with any branded if it meets each of the condi- other product containing tions in this part and each of the gen- diphenhydramine, even one used on eral conditions established in § 330.1. skin’’. (b) References in this part to regu- (d) Directions. The labeling of the latory sections of the Code of Federal product contains the following infor- Regulations are to chapter I of title 21 mation under the heading ‘‘Direc- unless otherwise noted. tions’’: (1) For products containing § 340.3 Definition. diphenhydramine hydrochloride identified As used in this part: in § 338.10(a). Adults and children 12 Stimulant. A drug which helps restore years of age and over: Oral dosage is 50 mental alertness or wakefulness during milligrams at bedtime if needed, or as fatigue or drowsiness. directed by a doctor. (2) For products containing diphenhydramine citrate identified in Subpart B—Active Ingredient § 338.10(b). Adults and children 12 years § 340.10 Stimulant active ingredient. of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as di- The active ingredient of the product rected by a doctor. consists of caffeine when used within (e) The word ‘‘physician’’ may be sub- the dosage limits established in stituted for the word ‘‘doctor’’ in any § 340.50(d). of the labeling statements in this section. Subpart C—Labeling [54 FR 6826, Feb. 14, 1989, as amended at 59 FR 16983, Apr. 11, 1994; 67 FR 72559, Dec. 6, § 340.50 Labeling of stimulant drug 2002] products. (a) Statement of identity. The labeling PART 340—STIMULANT DRUG of the product contains the established PRODUCTS FOR OVER-THE- name of the drug, if any, and identifies COUNTER HUMAN USE the product as an ‘‘altertness aid’’ or a ‘‘stimulant.’’ Subpart A—General Provisions (b) Indications. The labeling of the product states, under the heading ‘‘In- Sec. dications,’’ the following: ‘‘Helps re- 340.1 Scope. store mental alertness or wakefulness 340.3 Definition. when experiencing fatigue or drowsi- Subpart B—Active Ingredient ness.’’ Other truthful and nonmisleading statements, describing only the 340.10 Stimulant active ingredient. indications for use that have been established and listed in this paragraph 1 See § 201.66(b)(4) of this chapter for defini- (b), may also be used, as provided in tion of bullet symbol. § 330.1(c)(2), subject to the provisions of

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section 502 of the Act relating to mis- treating concurrent symptoms (in either branding and the prohibition in section a single-ingredient or combination drug 301(d) of the Act against the introduc- product). tion or delivery for introduction into 341.72 Labeling of antihistamine drug prod- interstate commerce of unapproved ucts. 341.74 Labeling of antitussive drug prod- new drugs in violation of section 505(a) ucts. of the Act. 341.76 Labeling of bronchodilator drug prod- (c) Warnings. The labeling of the ucts. product contains the following warn- 341.78 Labeling of expectorant drug prod- ings under the heading ‘‘Warnings’’: ucts. (1) ‘‘The recommended dose of this 341.80 Labeling of nasal decongestant drug product contains about as much caf- products. feine as a cup of coffee. Limit the use 341.85 Labeling of permitted combinations of caffeine-containing medications, of active ingredients. foods, or beverages while taking this 341.90 Professional labeling. product because too much caffeine may AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, cause nervousness, irritability, sleep- 360, 371. lessness, and, occasionally, rapid heart EDITORIAL NOTE: Nomenclature changes to beat.’’ part 341 appear at 69 FR 13717, Mar. 24, 2004. (2) ‘‘For occasional use only. Not intended for use as a substitute for sleep. Subpart A—General Provisions If fatigue or drowsiness persists or continues to recur, consult a’’ (select one § 341.1 Scope. of the following: ‘‘physician’’ or ‘‘doctor’’). (a) An over-the-counter cold, cough, (3) ‘‘Do not give to children under 12 allergy, bronchodilator, or anti- years of age.’’ asthmatic drug product in a form suit- (d) Directions. The labeling of the able for oral, inhalant, or topical ad- product contains the following infor- ministration is generally recognized as mation under the heading ‘‘Direc- safe and effective and is not mis- tions’’: Adults and children 12 years of branded if it meets each of the condi- age and over: Oral dosage is 100 to 200 tions in this part and each of the gen- milligrams not more often than every 3 eral conditions established in § 330.1. to 4 hours. (b) References in this part to regulatory sections of the Code of Federal PART 341—COLD, COUGH, AL- Regulations are to chapter I of title 21 LERGY, BRONCHODILATOR, AND unless otherwise noted. ANTIASTHMATIC DRUG PROD- [51 FR 35339, Oct. 2, 1986] UCTS FOR OVER-THE-COUNTER HUMAN USE § 341.3 Definitions. As used in this part: Subpart A—General Provisions (a) Bronchodilator drug. A drug used to overcome spasms that cause nar- Sec. rowing of the bronchial air tubes, such 341.1 Scope. as in the symptomatic treatment of 341.3 Definitions. the wheezing and shortness of breath of Subpart B—Active Ingredients asthma. (b) Oral antitussive drug. A drug that 341.12 Antihistamine active ingredients. either is taken by mouth or is dis- 341.14 Antitussive active ingredients. solved in the mouth in the form of a 341.16 Bronchodilator active ingredients. 341.18 Expectorant active ingredient. lozenge and acts systemically to re- 341.20 Nasal decongestant active ingredi- lieve cough. ents. (c) Topical antitussive drug. A drug 341.40 Permitted combinations of active in- that relieves cough when inhaled after gredients. being applied topically to the throat or chest in the form of an ointment or Subpart C—Labeling from a steam vaporizer, or when dis- 341.70 Labeling of OTC drug products con- solved in the mouth in the form of a taining ingredients that are used for lozenge for a local effect.

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(d) Expectorant drug. A drug taken (m) Triprolidine hydrochloride. orally to promote or facilitate the re- [57 FR 58374, Dec. 9, 1992, as amended at 59 moval of secretions from the res- FR 4218, Jan. 28, 1994] piratory airways. (e) Antihistamine drug. A drug used § 341.14 Antitussive active ingredients. for the relief of the symptoms of hay The active ingredients of the product fever and upper respiratory allergies consist of any of the following when (allergic rhinitis). used within the dosage limits and in (f) Oral nasal decongestant drug. A the dosage forms established for each drug that is taken by mouth and acts ingredient in § 341.74(d): systemically to reduce nasal conges- (a) Oral antitussives. (1) Chlophedianol tion caused by acute or chronic rhi- hydrochloride. nitis. (2) Codeine ingredients. The following (g) Topical nasal decongestant drug. A ingredients may be used only in com- drug that when applied topically inside bination in accordance with § 290.2 and the nose, in the form of drops, jellies, 21 CFR 1308.15(c). or sprays, or when inhaled intranasally (i) Codeine. reduces nasal congestion caused by (ii) Codeine phosphate. acute or chronic rhinitis. (iii) Codeine sulfate. (h) Calibrated dropper. A dropper cali- (3) Dextromethorphan. brated such that the volume error in- (4) Dextromethorphan hydrobromide. curred in measuring any liquid does (5) Diphenhydramine citrate. not exceed 15 percent under normal use (6) Diphenhydramine hydrochloride. conditions. (b) Topical antitussives. (1) Camphor. (i) Effervescent dosage form. A dosage (2) Menthol. form intended to be dissolved in water [52 FR 30055, Aug. 12, 1987, as amended at 59 before administration. It contains, in FR 29174, June 3, 1994; 67 FR 4907, Feb. 1, 2002] addition to the active ingredient(s), mixtures of acids (citric acid, tartaric § 341.16 Bronchodilator active ingredi- acid) and sodium bicarbonate, which ents. release carbon dioxide when dissolved The active ingredients of the product in water. consist of any of the following when used within the dosage limits estab- [51 FR 35339, Oct. 2, 1986, as amended at 54 FR lished for each ingredient: 8509, Feb. 28, 1989; 55 FR 40382, Oct. 3, 1990; 57 (a) Ephedrine. FR 58374, Dec. 9, 1992; 59 FR 43409, Aug. 23, 1994; 71 FR 43362, Aug. 1, 2006] (b) Ephedrine hydrochloride. (c) Ephedrine sulfate. (d) Epinephrine. Subpart B—Active Ingredients (e) Epinephrine bitartrate. (f) Racephedrine hydrochloride. § 341.12 Antihistamine active ingredi- (g) Racepinephrine hydrochloride. ents. [51 FR 35339, Oct. 2, 1986] The active ingredient of the product consists of any of the following when § 341.18 Expectorant active ingredient. used within the dosage limits established for each ingredient: The active ingredient of the product is guaifenesin when used within the (a) Brompheniramine maleate. dosage limits established in § 341.78(d). (b) Chlorcyclizine hydrochloride. (c) Chlorpheniramine maleate. [54 FR 8509, Feb. 28, 1989] (d) Dexbrompheniramine maleate. § 341.20 Nasal decongestant active in- (e) Dexchlorpheniramine maleate. gredients. (f) Diphenhydramine citrate. The active ingredient of the product (g) Diphenhydramine hydrochloride. consists of any of the following when (h) Doxylamine succinate. used within the dosage limits and in (i) Phenindamine tartrate. the dosage forms established for each (j) Pheniramine maleate. ingredient: (k) Pyrilamine maleate. (a) Oral nasal decongestants. (1) Phen- (l) Thonzylamine hydrochloride. ylephrine hydrochloride.

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(2) Pseudoephedrine hydrochloride. antitussive active ingredient identified (3) Pseudoephedrine sulfate. in § 341.14(a)(1) through (a)(4) provided (4) Phenylephrine bitartrate in an ef- that the product is labeled according to fervescent dosage form. § 341.85(c)(4). Diphenhydramine citrate (b) Topical nasal decongestants. (1) in §§ 341.12(f) and 341.14(a)(5) or Levmetamfetamine. diphenhydramine hydrochloride in (2) Ephedrine. §§ 341.12(g) and 341.14(a)(6) may be both (3) Ephedrine hydrochloride. the antihistamine and the antitussive (4) Ephedrine sulfate. active ingredient provided that the (5) [Reserved] product is labeled according to (6) Naphazoline hydrochloride. § 341.70(a). (7) Oxymetazoline hydrochloride. (e) Any single antihistamine active (8) Phenylephrine hydrochloride. (9) Propylhexedrine. ingredient identified in § 341.12(a) (10) Xylometazoline hydrochloride. through (e) and (h) through (m) may be combined with any single oral [59 FR 43409, Aug. 23, 1994, as amended at 63 antitussive active ingredient identified FR 40650, July 30, 1998; 71 FR 43362, Aug. 1, in § 341.14(a)(1) through (a)(4) and any 2006] single oral nasal decongestant active § 341.40 Permitted combinations of ac- ingredient identified in § 341.20(a) pro- tive ingredients. vided that the product is labeled ac- The following combinations are per- cording to § 341.85(c)(4). mitted provided each active ingredient Diphenhydramine citrate in §§ 341.12(f) is present within the dosage limits es- and 341.14(a)(5) or diphenhydramine hy- tablished in parts 341, 343, and 356 of drochloride in §§ 341.12(g) and this chapter and the product is labeled 341.14(a)(6) may be both the antihis- in accordance with §§ 341.70 or 341.85: tamine and the antitussive active in- (a) Any single antihistamine active gredient provided that the product is ingredient identified in § 341.12 may be labeled according to § 341.70(a). combined with any generally recog- (f) Any single antihistamine active nized as safe and effective single an- ingredient identified in § 341.12(a) algesic-antipyretic active ingredient, through (e) and (h) through (m) may be or any combination of acetaminophen combined with any single oral with other analgesic-antipyretic active antitussive active ingredient identified ingredients, or any aspirin and antacid in § 341.14(a)(1) through (a)(4) and any combination provided that the product generally recognized as safe and effec- is labeled according to § 341.85. tive single analgesic-antipyretic active (b) Any single antihistamine active ingredient, or any combination of acet- ingredient identified in § 341.12 may be aminophen with other analgesic-anti- combined with any single oral nasal de- pyretic active ingredients, or any aspi- congestant active ingredient identified rin and antacid combination provided in § 341.20(a) provided that the product that the product is labeled according to is labeled according to § 341.85. § 341.85(c)(4). Diphenhydramine citrate (c) Any single antihistamine active in §§ 341.12(f) and 341.14(a)(5) or ingredient identified in § 341.12 may be diphenhydramine hydrochloride in combined with any single oral nasal decongestant active ingredient identified §§ 341.12(g) and 341.14(a)(6) may be both in § 341.20(a) and any generally recog- the antihistamine and the antitussive nized as safe and effective single an- active ingredient provided that the algesic-antipyretic active ingredient, product is labeled according to or any combination of acetaminophen § 341.70(a). with other analgesic-antipyretic active (g) Any single antihistamine active ingredients, or any aspirin and antacid ingredient identified in § 341.12(a) combination provided that the product through (e) and (h) through (m) may be is labeled according to § 341.85. combined with any single oral (d) Any single antihistamine active antitussive active ingredient identified ingredient identified in § 341.12(a) in § 341.14(a)(1) through (a)(4) and any through (e) and (h) through (m) may be single oral nasal decongestant active combined with any single oral ingredient identified in § 341.20(a) and

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any generally recognized as safe and ef- (l) Any single oral antitussive active fective single analgesic-antipyretic ac- ingredient identified in § 341.14(a) may tive ingredient, or any combination of be combined with any generally recog- acetaminophen with other analgesic- nized as safe and effective single an- antipyretic active ingredients, or any algesic-antipyretic active ingredient, aspirin and antacid combination pro- or any combination of acetaminophen vided that the product is labeled ac- with other analgesic-antipyretic active cording to § 341.85(c)(4). ingredients, or any aspirin and antacid Diphenhydramine citrate in §§ 341.12(f) combination provided that the product and 341.14(a)(5) or diphenhydramine hy- is labeled according to § 341.85. drochloride in §§ 341.12(g) and (m) Any single oral antitussive ac- 341.14(a)(6) may be both the antihis- tive ingredient identified in § 341.14(a) tamine and the antitussive active in- may be combined with any single oral gredient provided that the product is nasal decongestant active ingredient labeled according to § 341.70(a). identified in § 341.20(a) and any gen- (h) Any single oral antitussive active erally recognized as safe and effective ingredient identified in § 341.14(a)(1) single analgesic-antipyretic active in- through (a)(4) may be combined with gredient, or any combination of acet- any single expectorant active ingre- aminophen with other analgesic-anti- dient identified in § 341.18 provided that pyretic active ingredients, or any aspi- the product is labeled according to rin and antacid combination provided § 341.85. that the product is labeled according to (i) Any single oral antitussive active § 341.85. ingredient identified in § 341.14(a) may (n) Any single oral antitussive active be combined with any single oral nasal ingredient identified in § 341.14(a)(1) decongestant active ingredient identi- through (a)(4) may be combined with fied in § 341.20(a) provided that the any single oral nasal decongestant ac- product is labeled according to § 341.85. tive ingredient identified in § 341.20(a) (j) Any single oral antitussive active and any single expectorant active in- ingredient identified in § 341.14(a)(1) gredient identified in § 341.18 and any through (a)(4) may be combined with generally recognized as safe and effec- any single oral nasal decongestant active single analgesic-antipyretic active tive ingredient identified in § 341.20(a) ingredient, or any combination of acet- and any single expectorant active in- aminophen with other analgesic-anti- gredient identified in § 341.18 provided pyretic active ingredients, or any aspi- that the product is labeled according to rin and antacid combination provided § 341.85. that the product is labeled according to (k) Any single antitussive active in- § 341.85. gredient identified in § 341.14(a) or (b)(2) (o) Any single expectorant active in- may be combined with any generally gredient identified in § 341.18 may be recognized as safe and effective single combined with any generally recog- oral anesthetic/analgesic active ingre- nized as safe and effective single an- dient, or any combination of anes- algesic-antipyretic active ingredient, thetic/analgesic active ingredients pro- or any combination of acetaminophen vided that the product is available in with other analgesic-antipyretic active either a liquid (to be swallowed) or a ingredients, or any aspirin and antacid solid dosage form (to be dissolved in combination provided that the product the mouth and swallowed) and provided is labeled according to § 341.85. that the product is labeled according to (p) Any single expectorant active in- § 341.85. If the combination contains a gredient identified in § 341.18 may be topical antitussive, the product must combined with any single oral nasal de- be formulated in a solid dosage form to congestant active ingredient identified be dissolved in the mouth. Menthol in in § 341.20(a) provided that the product § 341.14(b)(2) and part 356 of this chapter is labeled according to § 341.85. may be both the antitussive and the (q) Any single expectorant active in- anesthetic/analgesic active ingredient gredient identified in § 341.18 may be provided that the product is labeled ac- combined with any single oral nasal de- cording to § 341.70(b). congestant active ingredient identified

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in § 341.20(a) and any generally recog- matics (camphor (54 milligrams (mg)), nized as safe and effective single an- menthol (80 mg), methyl salicylate (11 algesic-antipyretic active ingredient, mg), and lavender oil (4 mg)) provided or any combination of acetaminophen that the product is available only as a with other analgesic-antipyretic active nasal inhaler and provided that the ingredients, or any aspirin and antacid product is labeled according to § 341.85. combination provided that the product (w) Any single antitussive active in- is labeled according to § 341.85. gredient identified in § 341.14(a) or (b)(2) (r) Any single oral nasal deconges- may be combined with any generally tant active ingredient identified in recognized as safe and effective single § 341.20(a) may be combined with any oral demulcent active ingredient pro- generally recognized as safe and effec- vided that the product is available in tive single analgesic-antipyretic active either a liquid (to be swallowed) or a ingredient, or any combination of acet- solid dosage form (to be dissolved in aminophen with other analgesic-anti- the mouth and swallowed) and provided pyretic active ingredients, or any aspirin and antacid combination provided that the product is labeled according to that the product is labeled according to § 341.85. If the combination contains a § 341.85. topical antitussive, the product must (s) Any single oral nasal deconges- be formulated in a solid dosage form to tant active ingredient identified in be dissolved in the mouth. § 341.20(a) may be combined with any (x) Any single oral nasal deconges- generally recognized as safe and effec- tant active ingredient identified in tive single oral anesthetic/analgesic ac- § 341.20(a) may be combined with any tive ingredient identified, or any com- generally recognized as safe and effec- bination of anesthetic/analgesic active tive single oral demulcent active ingre- ingredients provided that the product dient provided that the product is is available in either a liquid (to be available in either a liquid (to be swal- swallowed) or a solid dosage form (to lowed) or a solid dosage form (to be dis- be dissolved in the mouth and swal- solved in the mouth and swallowed) lowed) and provided that the product is and provided that the product is la- labeled according to § 341.85. beled according to § 341.85. (t) Any single oral nasal deconges- (y) Any single antitussive active in- tant active ingredient identified in gredient identified in § 341.14(a) or (b)(2) § 341.20(a) may be combined with any may be combined with any single oral single antitussive active ingredient nasal decongestant active ingredient identified in § 341.14(a) or (b)(2) and any identified in § 341.20(a) and any gen- generally recognized as safe and effec- erally recognized as safe and effective tive single oral anesthetic/analgesic ac- single oral demulcent active ingredient tive ingredient, or any combination of provided that the product is available anesthetic/analgesic active ingredients in either a liquid (to be swallowed) or a provided that the product is available solid dosage form (to be dissolved in in either a liquid (to be swallowed) or a the mouth and swallowed) and provided solid dosage form (to be dissolved in the mouth and swallowed) and provided that the product is labeled according to that the product is labeled according to § 341.85. If the combination contains a § 341.85. If the combination contains a topical antitussive, the product must topical antitussive, the product must be formulated in a solid dosage form to be formulated in a solid dosage form to be dissolved in the mouth. be dissolved in the mouth. (z) Any single antitussive active in- (u) Camphor identified in § 341.14(b)(1) gredient identified in § 341.14(a) or (b)(2) may be combined with menthol identi- may be combined with any generally fied in § 341.14(b)(2) and eucalyptus oil recognized as safe and effective single (1.2 to 1.3 percent) provided that the oral anesthetic/analgesic active ingre- product is available only in a suitable dient or any combination of anesthetic/ ointment vehicle and provided that the analgesic active ingredients and any product is labeled according to § 341.85. generally recognized as safe and effec- (v) Levmetamfetamine identified in tive single oral demulcent active ingre- § 341.20(b)(1) may be combined with aro- dient provided that the product is

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available in either a liquid (to be swal- phrases so that the resulting informa- lowed) or a solid dosage form (to be dis- tion is clear and understandable. solved in the mouth and swallowed) (a) For products containing and provided that the product is la- diphenhydramine citrate and beled according to § 341.85. If the com- diphenhydramine hydrochloride identified bination contains a topical antitussive, in § 341.14(a)(5) and (a)(6). The labeling the product must be formulated in a of the product contains the established solid dosage form to be dissolved in the name of the drug, if any, and identifies mouth. the product as an ‘‘antihistamine/ (aa) Any single oral nasal deconges- cough suppressant’’ or ‘‘antihistamine/ tant active ingredient identified in antitussive (cough suppressant).’’ The § 341.20(a) may be combined with any indications shall be combined from generally recognized as safe and effec- §§ 341.72(b) and 341.74(b). The warnings tive single oral anesthetic/analgesic ac- shall be combined from §§ 341.72(c)(1), tive ingredient or any combination of (c)(2), (c)(4), and (c)(6) and 341.74(c)(1), oral anesthetic/analgesic active ingre- (c)(2), (c)(3), and (c)(4). Alternatively, dients and any generally recognized as all of the warnings in § 341.74(c) shall be safe and effective single oral demulcent used. The directions for OTC labeling active ingredient provided that the shall follow §§ 341.74(d)(1)(iv) or product is available in either a liquid (d)(1)(v), as applicable. The directions (to be swallowed) or a solid dosage for professional labeling shall follow form (to be dissolved in the mouth and § 341.90(j) or (k), as applicable. swallowed) and provided that the prod- (b) For products containing menthol uct is labeled according to § 341.85. identified in §§ 341.14(b)(2) and 356.12(f) of (bb) Any single antitussive active in- this chapter. The product contains 5 to gredient identified in § 341.14(a) or (b)(2) 10 milligrams menthol. The labeling of may be combined with any single oral the product contains the established nasal decongestant active ingredient name of the drug, if any, and identifies identified in § 341.20(a) and any gen- the product as a ‘‘cough suppressant/ erally recognized as safe and effective oral anesthetic’’ or ‘‘antitussive (cough single oral anesthetic/analgesic active suppressant)/oral anesthetic.’’ The in- ingredient identified or any combina- dications shall be combined from tion of anesthetic/analgesic active in- § 341.74(b) and part 356 of this chapter. gredients and any generally recognized The warnings shall be combined from as safe and effective single oral demul- § 341.74(c)(1), (c)(2), and (c)(3) and part cent active ingredient provided that 356 of this chapter. The directions shall the product is available in either a liq- be: ‘‘Directions [in bold type] [bullet] 1 uid (to be swallowed) or a solid dosage adults and children 2 years and over: form (to be dissolved in the mouth and dissolve lozenge slowly in the mouth. swallowed) and provided that the prod- Repeat every 2 hours as needed or as uct is labeled according to § 341.85. If directed by a doctor. [bullet] children the combination contains a topical under 2 years of age: ask a doctor’’. antitussive, the product must be formulated in a solid dosage form to be [61 FR 15703, Apr. 9, 1996, as amended at 67 dissolved in the mouth. FR 78170, Dec. 23, 2002; 68 FR 17881, Apr. 14, 2003] [67 FR 78168, Dec. 23, 2002] § 341.72 Labeling of antihistamine Subpart C—Labeling drug products. (a) Statement of identity. The labeling § 341.70 Labeling of OTC drug products containing ingredients that are of the product contains the established used for treating concurrent symp- name of the drug, if any, and identifies toms (in either a single-ingredient the product as an ‘‘antihistamine.’’ or combination drug product). (b) Indications. The labeling of the The statements of identity, indica- product states, under the heading ‘‘In- tions, warnings, and directions for use, dications,’’ any of the phrases listed in respectively, applicable to each ingredient in the product may be combined 1 See § 201.66(b)(4) of this chapter for defini- to eliminate duplicative words or tion of bullet symbol.

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paragraph (b) of this section, as appro- this product if you are taking sedatives priate. Other truthful and nonmis- or tranquilizers, without first con- leading statements, describing only the sulting your doctor. Use caution when indications for use that have been es- driving a motor vehicle or operating tablished and listed in this paragraph, machinery.’’ may also be used, as provided in (4) For products containing § 330.1(c)(2) of this chapter, subject to diphenhydramine citrate, the provisions of section 502 of the Fed- diphenhydramine hydrochloride, or eral Food, Drug, and Cosmetic Act (the doxylamine succinate identified in act) relating to misbranding and the § 341.12(f), (g), and (h). ‘‘May cause prohibition in section 301(d) of the act marked drowsiness; alcohol, sedatives, against the introduction or delivery for and tranquilizers may increase the introduction into interstate commerce drowsiness effect. Avoid alcoholic bev- of unapproved new drugs in violation of erages while taking this product. Do section 505(a) of the act. not take this product if you are taking (1) ‘‘Temporarily’’ (select one of the sedatives or tranquilizers, without first following: ‘‘relieves,’’ ‘‘alleviates,’’ consulting your doctor. Use caution ‘‘decreases,’’ ‘‘reduces,’’ or ‘‘dries’’) when driving a motor vehicle or oper- ‘‘runny nose and’’ (select one of the fol- ating machinery.’’ lowing: ‘‘relieves,’’ ‘‘alleviates,’’ ‘‘de- (5) For products containing creases,’’ or ‘‘reduces’’) ‘‘sneezing, phenindamine tartrate identified in itching of the nose or throat, and § 341.12(i). ‘‘May cause nervousness and itchy, watery eyes due to hay fever’’ insomnia in some individuals.’’ (which may be followed by one or both (6) For products that are labeled only of the following: ‘‘or other upper res- for use by children under 12 years of age. piratory allergies’’ or ‘‘(allergic rhi- The labeling of the product contains nitis)’’). only the warnings identified in para- (2) ‘‘For the temporary relief of graphs (c)(1) and (c)(5) of this section as runny nose, sneezing, itching of the well as the following: nose or throat, and itchy, watery eyes due to hay fever’’ (which may be fol- (i) ‘‘Do not give this product to chil- lowed by one or both of the following: dren who have a breathing problem ‘‘or other upper respiratory allergies’’ such as chronic bronchitis, or who have or ‘‘(allergic rhinitis)’’). glaucoma, without first consulting the (c) Warnings. The labeling of the child’s doctor.’’ product contains the following warn- (ii) For products containing ings, under the heading ‘‘Warnings’’: brompheniramine maleate, (1) ‘‘May cause excitability especially chlorpheniramine maleate, in children.’’ dexbrompheniramine maleate, (2) ‘‘Do not take this product, unless dexchlorpheniramine maleate, directed by a doctor, if you have a phenindamine tartrate, pheniramine male- breathing problem such as emphysema ate, pyrilamine maleate, thonzylamine hy- or chronic bronchitis, or if you have drochloride, or triprolidine hydrochloride glaucoma or difficulty in urination due identified in § 341.12(a), (c), (d), (e), (i), to enlargement of the prostate gland.’’ (j), (k), (l), and (m). ‘‘May cause drowsi- (3) For products containing ness. Sedatives and tranquilizers may brompheniramine maleate, chlorcyclizine increase the drowsiness effect. Do not hydrochloride, chlorpheniramine maleate, give this product to children who are dexbrompheniramine maleate, taking sedatives or tranquilizers, with- dexchlorpheniramine maleate, out first consulting the child’s doctor.’’ phenindamine tartrate, pheniramine male- (iii) For products containing ate, pyrilamine maleate, thonzylamine hy- diphenhydramine citrate, drochloride, or triprolidine hydrochloride diphenhydramine hydrochloride, or identified in § 341.12(a), (b), (c), (d), (e), doxylamine succinate identified in (i), (j), (k), (l), and (m). ‘‘May cause § 341.12(f), (g), and (h). ‘‘May cause drowsiness; alcohol, sedatives, and marked drowsiness. Sedatives and tranquilizers may increase the drowsi- tranquilizers may increase the drowsiness effect. Avoid alcoholic beverages ness effect. Do not give this product to while taking this product. Do not take children who are taking sedatives or

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tranquilizers, without first consulting grams every 4 to 6 hours, not to exceed the child’s doctor.’’ 12 milligrams in 24 hours, or as di- (iv) For products containing rected by a doctor. Children 6 to under diphenhydramine citrate or 12 years of age: oral dosage is 1 milli- diphenhydramine hydrochloride identified gram every 4 to 6 hours, not to exceed in § 341.12(f) and (g). ‘‘Do not use [bul- 6 milligrams in 24 hours, or as directed let] 1 with any other product con- by a doctor. Children under 6 years of taining diphenhydramine, even one age: consult a doctor. used on skin’’. (5) For products containing (7) For products containing dexchlorpheniramine maleate identified in diphenhydramine citrate or § 341.12(e). Adults and children 12 years diphenhydramine hydrochloride identified of age and over: oral dosage is 2 milli- in § 341.12(f) and (g). ‘‘Do not use [bul- grams every 4 to 6 hours, not to exceed let] with any other product containing 12 milligrams in 24 hours, or as di- diphenhydramine, even one used on rected by a doctor. Children 6 to under skin’’. 12 years of age: oral dosage is 1 milli- (d) Directions. The labeling of the gram every 4 to 6 hours, not to exceed product contains the following infor- 6 milligrams in 24 hours, or as directed mation under the heading ‘‘Direc- by a doctor. Children under 6 years of tions’’: age: consult a doctor. (1) For products containing (6) For products containing brompheniramine maleate identified in diphenhydramine citrate identified in § 341.12(a). Adults and children 12 years § 341.12(f). Adults and children 12 years of age and over: oral dosage is 4 milli- of age and over: oral dosage is 38 to 76 grams every 4 to 6 hours, not to exceed milligrams every 4 to 6 hours, not to 24 milligrams in 24 hours, or as di- exceed 456 milligrams in 24 hours, or as rected by a doctor. Children 6 to under directed by a doctor. Children 6 to 12 years of age: oral dosage is 2 milli- under 12 years of age: oral dosage is 19 grams every 4 to 6 hours, not to exceed to 38 milligrams every 4 to 6 hours, not 12 milligrams in 24 hours, or as di- to exceed 228 milligrams in 24 hours, or rected by a doctor. Children under 6 as directed by a doctor. Children under years of age: consult a doctor. 6 years of age: consult a doctor. (2) For products containing (7) For products containing chlorcyclizine hydrochloride identified in diphenhydramine hydrochloride identified § 341.12(b). Adults and children 12 years in § 341.12(g). Adults and children 12 of age and over: oral dosage is 25 milli- years of age and over: oral dosage is 25 grams every 6 to 8 hours, not to exceed to 50 milligrams every 4 to 6 hours, not 75 milligrams in 24 hours, or as di- to exceed 300 milligrams in 24 hours, or rected by a doctor. Children under 12 as directed by a doctor. Children 6 to years of age: consult a doctor. under 12 years of age: oral dosage is (3) For products containing 12.5 to 25 milligrams every 4 to 6 hours, chlorpheniramine maleate identified in not to exceed 150 milligrams in 24 § 341.12(c). Adults and children 12 years hours, or as directed by a doctor. Chil- of age and over: oral dosage is 4 milli- dren under 6 years of age: consult a grams every 4 to 6 hours, not to exceed doctor. 24 milligrams in 24 hours, or as di- (8) For products containing doxylamine rected by a doctor. Children 6 to under succinate identified in § 341.12(h). Adults 12 years of age: oral dosage is 2 milli- and children 12 years of age and over: grams every 4 to 6 hours, not to exceed oral dosage is 7.5 to 12.5 milligrams 12 milligrams in 24 hours, or as di- every 4 to 6 hours, not to exceed 75 mil- rected by a doctor. Children under 6 ligrams in 24 hours, or as directed by a years of age: consult a doctor. doctor. Children 6 to under 12 years of (4) For products containing age: oral dosage is 3.75 to 6.25 milli- dexbrompheniramine maleate identified in grams every 4 to 6 hours, not to exceed § 341.12(d). Adults and children 12 years 37.5 milligrams in 24 hours, or as di- of age and over: oral dosage is 2 milli- rected by a doctor. Children under 6 years of age: consult a doctor. 1 See § 201.66(b)(4) of this chapter for defini- (9) For products containing tion of bullet symbol. phenindamine tartrate identified in

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§ 341.12(i). Adults and children 12 years (e) The word ‘‘physician’’ may be sub- of age and over: oral dosage is 25 milli- stituted for the word ‘‘doctor’’ in any grams every 4 to 6 hours, not to exceed of the labeling statements in this sec- 150 milligrams in 24 hours, or as dition. rected by a doctor. Children 6 to under 12 years of age: oral dosage is 12.5 milli- [57 FR 58374, Dec. 9, 1992, as amended at 59 FR 4218, Jan. 28, 1994; 67 FR 72559, Dec. 6, grams every 4 to 6 hours, not to exceed 2002] 75 milligrams in 24 hours, or as directed by a doctor. Children under 6 § 341.74 Labeling of antitussive drug years of age: consult a doctor. products. (10) For products containing (a) The labeling pheniramine maleate identified in Statement of identity. § 341.12(j). Adults and children 12 years of the product contains the established of age and over: oral dosage is 12.5 to 25 name of the drug, if any, and identifies milligrams every 4 to 6 hours, not to the product as a ‘‘cough suppressant’’ exceed 150 milligrams in 24 hours, or as or an ‘‘antitussive (cough suppres- directed by a doctor. Children 6 to sant).’’ under 12 years of age: oral dosage is (b) Indications. The labeling of the 6.25 to 12.5 milligrams every 4 to 6 product states, under the heading ‘‘In- hours, not to exceed 75 milligrams in 24 dications,’’ any of the phrases listed in hours, or as directed by a doctor. Chil- this paragraph (b), as appropriate. dren under 6 years of age: consult a Other truthful and nonmisleading doctor. statements, describing only the indica- (11) For products containing pyrilamine tions for use that have been established maleate identified in § 341.12(k). Adults and listed in this paragraph, may also and children 12 years of age and over: be used, as provided in § 330.1(c)(2), sub- oral dosage is 25 to 50 milligrams every ject to the provisions of section 502 of 6 to 8 hours, not to exceed 200 milli- the act relating to misbranding and the grams in 24 hours, or as directed by a prohibition in section 301(d) of the act doctor. Children 6 to under 12 years of against the introduction or delivery for age: oral dosage is 12.5 to 25 milligrams introduction into interstate commerce every 6 to 8 hours, not to exceed 100 of unapproved new drugs in violation of milligrams in 24 hours, or as directed section 505(a) of the act. by a doctor. Children under 6 years of (1) ‘‘Temporarily’’ (select one of the age: consult a doctor. following: ‘‘alleviates,’’ ‘‘calms,’’ (12) For products containing thonzyl- ‘‘controls,’’ ‘‘decreases,’’ ‘‘quiets,’’ amine hydrochloride identified in ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) § 341.12(l). Adults and children 12 years ‘‘cough due to’’ (select one of the fol- of age and over: oral dosage is 50 to 100 lowing: ‘‘minor bronchial irritation’’ or milligrams every 4 to 6 hours, not to ‘‘minor throat and bronchial irrita- exceed 600 milligrams in 24 hours, or as tion’’) (select one of the following: ‘‘as directed by a doctor. Children 6 to may occur with,’’ ‘‘associated with,’’ or under 12 years of age: oral dosage is 25 ‘‘occurring with’’) (select one of the to 50 milligrams every 4 to 6 hours, not following: ‘‘A cold’’ or ‘‘the common to exceed 300 milligrams in 24 hours, or cold’’) ‘‘or inhaled irritants.’’ as directed by a doctor. Children under (2) ‘‘Temporarily’’ (select one of the 6 years of age: consult a doctor. following: ‘‘alleviates,’’ ‘‘calms,’’ (13) For products containing triprolidine ‘‘controls,’’ ‘‘decreases,’’ ‘‘quiets,’’ hydrochloride identified in § 341.12(m). ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) Adults and children 12 years of age and ‘‘cough’’ (select one of the following: over: oral dosage is 2.5 milligrams ‘‘as may occur with,’’ ‘‘associated every 4 to 6 hours, not to exceed 10 mil- with,’’ or ‘‘occurring with’’) (select one ligrams in 24 hours, or as directed by a of the following: ‘‘A cold,’’ ‘‘the com- doctor. Children 6 to under 12 years of mon cold,’’ or ‘‘inhaled irritants’’). age: oral dosage is 1.25 milligrams (3) In addition to the required infor- every 4 to 6 hours, not to exceed 5 mil- mation identified in paragraphs (b) (1) ligrams in 24 hours, or as directed by a and (2) of this section, the labeling of doctor. Children under 6 years of age: the product may contain any (one or consult a doctor. more) of the following statements:

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(i) ‘‘Cough suppressant which tempo- product for persistent or chronic cough rarily’’ (select one of the following: such as occurs with smoking, asthma, ‘‘Alleviates,’’ ‘‘controls,’’ ‘‘decreases,’’ or emphysema, or if cough is accom- ‘‘reduces,’’ ‘‘relieves,’’ or ‘‘suppresses’’) panied by excessive phlegm (mucus) ‘‘the impulse to cough.’’ unless directed by a doctor.’’ (ii) ‘‘Temporarily helps you cough (3) For oral and topical antitussives la- less.’’ beled only for children under 12 years of (iii) ‘‘Temporarily helps to’’ (select age. ‘‘Do not give this product for per- one of the following: ‘‘Alleviate,’’ sistent or chronic cough such as occurs ‘‘control,’’ ‘‘decrease,’’ ‘‘reduce,’’ ‘‘re- with asthma or if cough is accom- lieve,’’ or ‘‘suppress’’) ‘‘the cough re- panied by excessive phlegm (mucus) flex that causes coughing.’’ unless directed by a doctor.’’ (iv) ‘‘Temporarily’’ (select one of the (4) Oral antitussives—(i) For products following: ‘‘Alleviates,’’ ‘‘controls,’’ containing codeine ingredients identified ‘‘decreases,’’ ‘‘reduces,’’ ‘‘relieves,’’ or in § 341.14(a)(2). ‘‘May cause or aggra- ‘‘suppresses’’) ‘‘the intensity of vate constipation.’’ coughing.’’ (ii) For products containing codeine in- (v) (Select one of the following: ‘‘Al- gredients identified in § 341.14(a)(2) when leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ labeled only for adults. ‘‘Do not take ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- this product if you have a chronic pul- presses’’) (select one of the following: monary disease or shortness of breath ‘‘Cough,’’ ‘‘the impulse to cough,’’ or unless directed by a doctor.’’ ‘‘your cough’’) ‘‘to help you’’ (select (iii) For products containing codeine in- one of the following: ‘‘Get to sleep,’’ gredients identified in § 341.14(a)(2) when ‘‘sleep,’’ or ‘‘rest’’). labeled only for children under 12 years of (vi) For products containing age. ‘‘Do not give this product to chil- chlophedianol hydrochloride, codeine in- dren who have a chronic pulmonary gredients, dextromethorphan, or disease, shortness of breath, or who are dextromethorphan hydrobromide identi- taking other drugs unless directed by a fied in § 341.14(a) (1), (2), (3), and (4). doctor.’’ ‘‘Calms the cough control center and (iv) For products containing codeine in- relieves coughing.’’ gredients identified in § 341.14(a)(2) when (vii) For products containing labeled for use in adults and children chlophedianol hydrochloride, under 12 years of age. ‘‘Adults and chil- dextromethorphan, dextromethorphan dren who have a chronic pulmonary hydrobromide, camphor, or menthol iden- disease or shortness of breath, or chil- tified in § 341.14(a) (1), (3), (4) and (b) (1) dren who are taking other drugs, and (2). (a) ‘‘Nonnarcotic cough sup- should not take this product unless di- pressant for the temporary’’ (select one rected by a doctor.’’ of the following: ‘‘alleviation,’’ ‘‘con- (v) For products containing trol,’’ ‘‘decrease,’’ ‘‘reduction,’’ ‘‘re- dextromethorphan or dextromethorphan lief,’’ or ‘‘suppression’’) ‘‘of cough.’’ hydrobromide as identified in § 341.14 (b) (Select one of the following: ‘‘Al- (a)(3) and (a)(4) when labeled for adults leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ or for adults and children under 12 years ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- of age. Drug interaction precaution. ‘‘Do presses’’) ‘‘cough impulses without nar- not use if you are now taking a pre- cotics.’’ scription monoamine oxidase inhibitor (c) Warnings. The labeling of the (MAOI) (certain drugs for depression, product contains the following warn- psychiatric, or emotional conditions, ings under the heading ‘‘Warnings’’: or Parkinson’s disease), or for 2 weeks (1) For oral and topical antitussives. ‘‘A after stopping the MAOI drug. If you do persistent cough may be a sign of a se- not know if your prescription drug con- rious condition. If cough persists for tains an MAOI, ask a doctor or phar- more than 1 week, tends to recur, or is macist before taking this product.’’ accompanied by fever, rash, or per- (vi) For products containing sistent headache, consult a doctor.’’ dextromethorphan or dextromethorphan (2) For oral and topical antitussives la- hydrobromide as identified in § 341.14 beled for adults or for adults and children (a)(3) and (a)(4) when labeled only for under 12 years of age. ‘‘Do not take this children under 12 years of age. Drug

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interaction precaution. ‘‘Do not use in a motor vehicle or operating machin- child who is taking a prescription mon- ery.’’ oamine oxidase inhibitor (MAOI) (cer- (C) ‘‘Do not use [bullet] with any tain drugs for depression, psychiatric, other product containing or emotional conditions, or Parkin- diphenhydramine, even one used on son’s disease), or for 2 weeks after stop- skin’’. ping the MAOI drug. If you do not (5) Topical antitussives—(i) For prod- know if your child’s prescription drug ucts containing camphor or menthol iden- contains an MAOI, ask a doctor or tified in § 341.14 (b) (1) and (2) in a suit- pharmacist before giving this product.’’ able ointment vehicle. ‘‘For external use (vii) For products containing only. Do not take by mouth or place in diphenhydramine citrate or nostrils.’’ diphenhydramine hydrochloride identified (ii) For products containing camphor or in § 341.14 (a)(5) and (a)(6). ‘‘May cause menthol identified in § 341.14(b) (1) and (2) excitability especially in children.’’ for steam inhalation use. ‘‘For steam in- (viii) For products containing halation only. Do not take by mouth.’’ diphenhydramine citrate or (iii) For any product containing cam- diphenhydramine hydrochloride identified phor or menthol in a suitable ointment ve- in § 341.14 (a)(5) and (a)(6) when labeled hicle or for steam inhalation use and only for children under 12 years of age— meets the definition of one of the signal (A) ‘‘Do not give this product to chil- words (‘‘extremely flammable,’’ ‘‘flam- dren who have a breathing problem mable,’’ ‘‘combustible’’) as described in 16 such as chronic bronchitis, or who have CFR 1500.3(b)(10). The labeling contains glaucoma, without first consulting the the appropriate flammability signal child’s doctor.’’ word(s) followed by a colon and the statement ‘‘Keep away from fire or (B) ‘‘May cause marked drowsiness. flame.’’ Sedatives and tranquilizers may in- (iv) For any product containing cam- crease the drowsiness effect. Do not phor or menthol in a suitable ointment ve- give this product to children who are hicle and that does not contain a flamma- taking sedatives or tranquilizers, with- bility signal word as described in 16 CFR out first consulting the child’s doctor.’’ 1500.3(b)(10). ‘‘When using this product, 1 (C) ‘‘Do not use [bullet] with any do not [bullet] 1 heat [bullet] micro- other product containing wave [bullet] add to hot water or any diphenhydramine, even one used on container where heating water. May skin’’. cause splattering and result in burns.’’ (ix) For products containing [Information highlighted in bold type.] diphenhydramine citrate or (v) For any product containing cam- diphenhydramine hydrochloride identified phor or menthol in a suitable ointment ve- in § 341.14 (a)(5) and (a)(6) when labeled hicle and that contains a flammability for use in adults and children under 12 signal word as described in 16 CFR years of age—(A) ‘‘Do not take this 1500.3(b)(10). ‘‘When using this product, product, unless directed by a doctor, if do not [bullet] heat [bullet] microwave you have a breathing problem such as [bullet] use near an open flame [bullet] emphysema or chronic bronchitis, or if add to hot water or any container you have glaucoma or difficulty in uri- where heating water. May cause splat- nation due to enlargement of the pros- tering and result in burns.’’ [Informa- tate gland.’’ tion highlighted in bold type.] (B) ‘‘May cause marked drowsiness; (vi) For any product containing cam- alcohol, sedatives, and tranquilizers phor or menthol for steam inhalation use. may increase the drowsiness effect. ‘‘When using this product, do not [bul- Avoid alcoholic beverages while taking let] heat [bullet] microwave [bullet] this product. Do not take this product use near an open flame [bullet] add to if you are taking sedatives or tranquil- hot water or any container where heat- izers, without first consulting your ing water except when adding to cold doctor. Use caution when driving a water only in a hot steam vaporizer.

1 See § 201.66(b)(4) of this chapter for defini- 1 For a definition of the term ‘‘bullet,’’ see tion of bullet symbol. § 201.66(b)(4) of this chapter.

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May cause splattering and result in dren 2 to under 6 years of age: Oral dos- burns.’’ [Information highlighted in age is 2.5 to 5 milligrams every 4 hours bold type.] or 7.5 milligrams every 6 to 8 hours, not (vii) For any product formulated in a to exceed 30 milligrams in 24 hours, or volatile vehicle. The labeling contains as directed by a doctor. Children under the following statement under the 2 years of age: Consult a doctor. heading ‘‘Other information’’: ‘‘Close (iv) For products containing container tightly and store at room diphenhydramine citrate identified in temperature away from heat.’’ § 341.14(a)(5). Adults and children 12 (d) Directions. The labeling of the years of age and over: oral dosage is 38 product contains the following infor- milligrams every 4 hours, not to exceed mation under the heading ‘‘Direc- 228 milligrams in 24 hours, or as ditions’’: rected by a doctor. Children 6 to under (1) Oral antitussives—(i) For products 12 years of age: oral dosage is 19 milli- containing chlophedianol hydrochloride grams every 4 hours, not to exceed 114 identified in § 341.14(a)(1). Adults and milligrams in 24 hours, or as directed children 12 years of age and over: Oral by a doctor. Children under 6 years of dosage is 25 milligrams every 6 to 8 age: consult a doctor. hours, not to exceed 100 milligrams in (v) For products containing 24 hours, or as directed by a doctor. diphenhydramine hydrochloride identified Children 6 to under 12 years of age: in § 341.14(a)(6). Adults and children 12 Oral dosage is 12.5 milligrams every 6 years of age and over: oral dosage is 25 to 8 hours, not to exceed 50 milligrams milligrams every 4 hours, not to exceed in 24 hours, or as directed by a doctor. 150 milligrams in 24 hours, or as di- Children under 6 years of age: Consult rected by a doctor. Children 6 to under a doctor. 12 years of age: oral dosage is 12.5 milli- (ii) For products containing codeine in- grams every 4 hours, not to exceed 75 gredients identified in § 341.14(a)(2). milligrams in 24 hours, or as directed Adults and children 12 years of age and by a doctor. Children under 6 years of over: Oral dosage is 10 to 20 milligrams age: consult a doctor. every 4 to 6 hours, not to exceed 120 (2) Topical antitussives—(i) For prod- milligrams in 24 hours, or as directed ucts containing camphor identified in by a doctor. Children 6 to under 12 § 341.14(b)(1) in a suitable ointment vehi- years of age: Oral dosage is 5 to 10 mil- cle. The product contains 4.7 to 5.3 per- ligrams every 4 to 6 hours, not to ex- cent camphor. ‘‘[bullet] see important ceed 60 milligrams in 24 hours, or as di- warnings under ‘When using this prod- rected by a doctor. Children under 6 uct’ [appears as the first statement years of age: Consult a doctor. A spe- under the heading ‘‘Directions’’ and is cial measuring device should be used to highlighted in bold type] [bullet] give an accurate dose of this product to adults and children 2 years and older: children under 6 years of age. Giving a [bullet] rub on the throat and chest in higher dose than recommended by a a thick layer [bullet] cover with a doctor could result in serious side ef- warm, dry cloth if desired [bullet] fects for your child. clothing should be loose about throat (iii) For products containing and chest to help vapors reach the nose dextromethorphan or dextromethorphan and mouth [bullet] use up to three hydrobromide identified in § 341.14(a) (3) times daily or as directed by a doctor and (4). The dosage is equivalent to [bullet] children under 2 years of age: dextromethorphan hydrobromide. Ask a doctor. Adults and children 12 years of age and (ii) For products containing menthol over: Oral dosage is 10 to 20 milligrams identified in § 341.14(b)(2) in a suitable every 4 hours or 30 milligrams every 6 ointment vehicle. The product contains to 8 hours, not to exceed 120 milligrams 2.6 to 2.8 percent menthol. ‘‘[bullet] see in 24 hours, or as directed by a doctor. important warnings under ’When using Children 6 to under 12 years of age: this product’ ’’ [appears as the first Oral dosage is 5 to 10 milligrams every statement under the heading ‘‘Direc- 4 hours or 15 milligrams every 6 to 8 tions’’ and is highlighted in bold type] hours, not to exceed 60 milligrams in 24 [bullet] adults and children 2 years and hours, or as directed by a doctor. Chil- older: [bullet] rub on the throat and

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chest in a thick layer [bullet] cover steam vaporizer. [bullet] use 1 table- with a warm, dry cloth if desired [bul- spoonful of solution for each quart of let] clothing should be loose about water or 11⁄2 teaspoonsful of solution throat and chest to help vapors reach for each pint of water [bullet] add solu- the nose and mouth [bullet] use up to tion directly to cold water only in a three times daily or as directed by a hot steam vaporizer [bullet] follow doctor [bullet] children under 2 years manufacturer’s directions for using va- of age: Ask a doctor. porizer or For products formulated to be (iii) For products containing menthol placed in the medication chamber of a hot identified in § 341.14(b)(2) in a lozenge. steam vaporizer. [bullet] place water in The product contains 5 to 10 milli- the vaporizer and follow manufactur- grams menthol. Adults and children 2 er’s directions for using vaporizer [bul- to under 12 years of age: Allow lozenge let] place solution in the medication to dissolve slowly in the mouth. May be repeated every hour as needed or as chamber only) [bullet] breathe in the directed by a doctor. Children under 2 medicated vapors [bullet] use up to years of age: Consult a doctor. three times daily or as directed by a (iv) For products containing camphor doctor [bullet] children under 2 years identified in § 341.14(b)(1) for steam inha- of age: Ask a doctor. lation use. The product contains 6.2 per- (e) The word ‘‘physician’’ may be sub- cent camphor. ‘‘[bullet] see important stituted for the word ‘‘doctor’’ in any warnings under ‘When using this prod- of the labeling statements in this sec- uct’ ’’ [appears as the first statement tion. under the heading ‘‘Directions’’ and is (f) Exemption from the general acci- highlighted in bold type] [bullet] dental overdose warning. The labeling adults and children 2 years and older: for antitussive drug products con- (select one of the following, as appro- taining the active ingredient identified priate: For products formulated to be in § 341.14(b)(2) marketed in accordance added directly to cold water inside a hot with § 341.74(d)(2)(iii) is exempt from steam vaporizer. [bullet] use 1 table- the requirement in § 330.1(g) of this spoonful of solution for each quart of chapter that the labeling bear the gen- 1 water or 1 ⁄2 teaspoonsful of solution eral warning statement ‘‘In case of ac- for each pint of water [bullet] add solu- cidental overdose, seek professional as- tion directly to cold water only in a sistance or contact a poison control hot steam vaporizer [bullet] follow center immediately.’’ The labeling manufacturer’s directions for using vaporizer or For products formulated to be must continue to bear the first part of placed in the medication chamber of a hot the general warning in § 330.1(g) of this steam vaporizer. [bullet] place water in chapter, which states, ‘‘Keep this and the vaporizer and follow manufactur- all drugs out of the reach of children.’’ er’s directions for using vaporizer [bul- [52 FR 30055, Aug. 12, 1987; 52 FR 35610, Sept. let] place solution in the medication 22, 1987; 53 FR 35809, Sept. 15, 1988; 55 FR chamber only) [bullet] breathe in the 27808, July 6, 1990; 55 FR 40383, Oct. 3, 1990; 58 medicated vapors [bullet] use up to FR 54236, Oct. 20, 1993; 59 FR 29174, June 3, three times daily or as directed by a 1994; 59 FR 36051, July 15, 1994; 64 FR 13295, doctor [bullet] children under 2 years Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 65 FR of age: Ask a doctor. 46867, Aug. 1, 2000; 67 FR 72559, Dec. 6, 2002] (v) For products containing menthol identified in § 341.14(b)(2) for steam inha- § 341.76 Labeling of bronchodilator lation use. The product contains 3.2 per- drug products. cent menthol. ‘‘[bullet] see important (a) Statement of identity. The labeling warnings under ‘When using this prod- of the product contains the established uct’ ’’[appears as the first statement name of the drug, if any, and identifies under the heading ‘‘Directions’’ and is the product as a ‘‘bronchodilator.’’ highlighted in bold type] [bullet] (b) Indication. The labeling of the adults and children 2 years and older: product states the following under the (select one of the following, as appro- heading ‘‘Use’’: ‘‘for temporary relief of priate: For products formulated to be added directly to cold water inside a hot

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mild symptoms of intermittent asth- (ii) ‘‘[Bullet] taking any drug that ma: [bullet] 1 wheezing [bullet] tight- contains phenylephrine, ness of chest [bullet] shortness of pseudoephedrine, ephedrine, or caffeine breath’’. Other truthful and nonmis- (such as for allergy, cough-cold, or leading statements, describing only the pain)’’. indication for use that has been estab- (4) The following information shall lished and listed in this paragraph (b) appear after the subheading ‘‘When may also be used, as provided in using this product’’ [in bold type]: § 330.1(c)(2) of this chapter, subject to (i) ‘‘[Bullet] your blood pressure or the provisions of section 502 of the Fed- heart rate may go up. This could in- eral Food, Drug, and Cosmetic Act re- crease your risk of heart attack or lating to misbranding and the prohibi- stroke, which may cause death.’’ [in tion in section 301(d) of the Federal bold type] Food, Drug, and Cosmetic Act against (ii) ‘‘[Bullet] your risk of heart at- the introduction or delivery for intro- tack or stroke increases if you: [Bullet] duction into interstate commerce of have a history of high blood pressure or unapproved new drugs in violation of heart disease [Bullet] take this product section 505(a) of the Federal Food, more frequently or take more than the Drug, and Cosmetic Act. recommended dose’’. [in bold type] (c) Warnings. The labeling of the (iii) ‘‘[Bullet] avoid foods or bev- product contains the following warn- erages that contain caffeine’’. ings under the heading ‘‘Warnings’’: (iv) ‘‘[Bullet] avoid dietary supple- (1) The following statements shall ap- ments containing ingredients reported pear after the subheading ‘‘Do not use’’ or claimed to have a stimulant effect’’. [in bold type]: (5) For products containing ephedrine, (i) ‘‘[Bullet] unless a doctor said you ephedrine hydrochloride, ephedrine sul- have asthma’’. fate, or racephedrine hydrochloride iden- (ii) ‘‘[Bullet] if you are now taking a tified in § 341.16(a), (b), (c), and (f). (i) prescription monoamine oxidase inhib- The following information shall appear itor (MAOI) (certain drugs taken for after the subheading ‘‘Asthma alert: depression, psychiatric or emotional Because asthma may be life threat- conditions, or Parkinson’s disease), or ening, see a doctor if you’’ [in bold for 2 weeks after stopping the MAOI type]: drug. If you do not know if your pre- (A) ‘‘[Bullet] are not better in 60 min- scription drug contains an MAOI, ask a utes’’. doctor or pharmacist before taking this (B) ‘‘[Bullet] get worse’’. product.’’ (2) The following information shall (C) ‘‘[Bullet] need more than [insert appear after the subheading ‘‘Ask a total number of dosage units that doctor before use if you have’’ [in bold equals 150 milligrams] in 24 hours’’. type]: ‘‘[bullet] ever been hospitalized (D) ‘‘[Bullet] use more than [insert for asthma [bullet] heart disease [bul- total number of dosage units that let] high blood pressure [bullet] diabe- equals 100 milligrams] in 24 hours for 3 tes [bullet] thyroid disease [bullet] sei- or more days a week’’. zures [bullet] narrow angle glaucoma (E) ‘‘[Bullet] have more than 2 asth- [bullet] a psychiatric or emotional con- ma attacks in a week’’. dition [bullet] trouble urinating due to (F) ‘‘These may be signs that your an enlarged prostate gland’’. asthma is getting worse.’’ (3) The following information shall (G) ‘‘[Bullet] This product will not appear after the subheading ‘‘Ask a give you asthma relief as quickly as an doctor or pharmacist before use if you inhaled bronchodilator.’’ are’’ [in bold type]: (ii) This ‘‘Asthma alert’’ shall appear (i) ‘‘[Bullet] taking prescription on any labeling that contains warnings drugs for asthma, obesity, weight con- and shall be the first warning state- trol, depression, or psychiatric or emo- ment under the heading ‘‘Warnings’’. tional conditions’’. (6) For products containing epinephrine, epinephrine bitartrate, or 1 See § 201.66(b)(4) of this chapter for the racepinephrine hydrochloride identified in definition of ‘‘bullet.’’ § 341.16(d), (e), and (g). (i) The following

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information shall appear after the sub- (2) For products containing epineph- heading ‘‘Asthma alert: Because asth- rine, epinephrine bitartrate, and ma may be life threatening, see a doc- racepinephrine hydrochloride identified in tor if you’’ [in bold type]: § 341.16(d), (e), and (g) for use in a hand- (A) ‘‘[Bullet] are not better in 20 min- held rubber bulb nebulizer. The ingre- utes’’. dient is used in an aqueous solution at (B) ‘‘[Bullet] get worse’’. a concentration equivalent to 1-percent (C) ‘‘[Bullet] need more than 12 epinephrine: inhalations in 24 hours’’. (i) ‘‘[Bullet] do not use more than di- (D) ‘‘[Bullet] use more than 9 rected’’ [appears as first bulleted state- inhalations in 24 hours for 3 or more ment under ‘‘Directions’’ and in bold days a week’’. type]. (E) ‘‘[Bullet] have more than 2 asth- (ii) ‘‘[Bullet] adults and children 4 ma attacks in a week’’. years of age and over: 1 to 3 inhalations (F) ‘‘These may be signs that your not more often than every 3 hours. Do asthma is getting worse.’’ not use more than 12 inhalations in 24 (ii) This ‘‘Asthma alert’’ shall appear hours. The use of this product by chil- on any labeling that contains warnings dren should be supervised by an adult.’’ and shall be the first warning state- (iii) ‘‘[Bullet] children under 4 years ment under the heading ‘‘Warnings.’’ of age: ask a doctor’’. (iii) For products intended for use in a hand-held rubber bulb nebulizer. The fol- (Collection of information requirement ap- lowing statement shall also appear proved by the Office of Management and after the subheading ‘‘Do not use’’ Budget under control number 0910–0237) along with the other information in [51 FR 35339, Oct. 2, 1986, as amended at 52 FR paragraph (c)(1) of this section: ‘‘[bul- 7126, Mar. 9, 1987; 52 FR 7830, Mar. 13, 1987; 53 let] if product is brown in color or FR 35810, Sept. 15, 1988; 58 FR 54242, Oct. 20, cloudy’’. 1993; 61 FR 25146, May 20, 1996; 62 FR 9684, (7) The following information shall Mar. 4, 1997; 64 FR 13295, Mar. 17, 1999; 76 FR appear after the subheading ‘‘Stop use 44487, July 26, 2011] and ask a doctor if’’ [in bold type]: § 341.78 Labeling of expectorant drug (i) ‘‘[Bullet] your asthma is getting products. worse (see Asthma alert)’’. (ii) ‘‘[Bullet] you have difficulty (a) Statement of identity. The labeling sleeping’’. of the product contains the established (iii) ‘‘[Bullet] you have a rapid heart name of the drug, if any, and identifies beat’’. the product as an ‘‘expectorant.’’ (iv) ‘‘[Bullet] you have tremors, nerv- (b) Indications. The labeling of the ousness, or seizure’’. product states, under the heading ‘‘In- (d) Directions. The labeling of the dications,’’ the following: ‘‘Helps loos- product contains the following infor- en phlegm (mucus) and thin bronchial mation under the heading ‘‘Direc- secretions to’’ (select one or more of tions’’: the following: ‘‘rid the bronchial pas- (1) For products containing ephedrine, sageways of bothersome mucus,’’ ephedrine hydrochloride, ephedrine sul- ‘‘drain bronchial tubes,’’ and ‘‘make fate, or racephedrine hydrochloride iden- coughs more productive’’). Other truth- tified in § 341.16(a), (b), (c), and (f): (i) ful and nonmisleading statements, de- ‘‘[Bullet] do not take more than di- scribing only the indications for use rected’’ [sentence appears as first that have been established and listed in bulleted statement under ‘‘Directions’’ this paragraph (b), may also be used, as and in bold type] provided in § 330.1(c)(2) of this chapter, (ii) ‘‘[Bullet] adults and children 12 subject to the provisions of section 502 years of age and over: oral dose is 12.5 of the act relating to misbranding and to 25 milligrams every 4 hours as need- the prohibition in section 301(d) of the ed. Do not take more than 150 milli- act against the introduction or deliv- grams in 24 hours’’. ery for introduction into interstate (iii) ‘‘[Bullet] children under 12 years commerce of unapproved new drugs in of age: ask a doctor’’. violation of section 505(a) of the act.

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(c) Warnings. The labeling of the this section. Other truthful and non- product contains the following warn- misleading statements, describing only ings, under the heading ‘‘Warnings’’: the indications for use that have been (1) ‘‘A persistent cough may be a sign established and listed in paragraphs of a serious condition. If cough persists (b)(1) and (b)(2) of this section, may for more than 1 week, tends to recur, also be used, as provided in § 330.1(c)(2) or is accompanied by a fever, rash, or of this chapter, subject to the provi- persistent headache, consult a doctor.’’ sions of section 502 of the Federal (2) For expectorant drug products la- Food, Drug, and Cosmetic Act (the act) beled for adults or for adults and children relating to misbranding and the prohi- under 12 years of age. ‘‘Do not take this bition in section 301(d) of the act product for persistent or chronic cough against the introduction or delivery for such as occurs with smoking, asthma, introduction into interstate commerce chronic bronchitis, or emphysema, or of unapproved new drugs in violation of where cough is accompanied by exces- section 505(a) of the act. sive phlegm (mucus) unless directed by (1) (Select one of the following: ‘‘For a doctor.’’ the temporary relief of nasal conges- (3) For expectorant drug products lation’’ or ‘‘Temporarily relieves nasal beled only for children under 12 years of congestion’’) (which may be followed age. ‘‘Do not give this product for per- by any of the following in paragraphs sistent or chronic cough such as occurs (b)(1) (i), (ii), and (iii) of this section): with asthma or if cough is accom- (i) ‘‘due to’’ (select one of the fol- panied by excessive phlegm (mucus) lowing: ‘‘the common cold’’ or ‘‘a unless directed by a doctor.’’ cold’’). (d) Directions. The labeling of the (ii) ‘‘due to’’ (select one of the fol- product contains the following infor- lowing: ‘‘hay fever,’’ ‘‘hay fever (aller- mation under the heading ‘‘Directions’’ gic rhinitis),’’ ‘‘hay fever or other for products containing guaifenesin upper respiratory allergies,’’ or ‘‘hay identified in § 341.18: Adults and chil- fever or other upper respiratory aller- dren 12 years of age and over: oral dos- gies (allergic rhinitis)’’). age is 200 to 400 milligrams every 4 (2) In addition to the information hours not to exceed 2,400 milligrams in identified in paragraph (b)(1) of this 24 hours. Children 6 to under 12 years of section, the labeling of the product age: oral dosage is 100 to 200 milligrams may contain any (one or more) of the every 4 hours not to exceed 1,200 milli- following statements: grams in 24 hours. Children 2 to under (i) (Select one of the following: ‘‘For 6 years of age: oral dosage is 50 to 100 the temporary relief of’’ or ‘‘Tempo- milligrams every 4 hours not to exceed rarily relieves’’) (select one of the fol- 600 milligrams in 24 hours. Children lowing: ‘‘stuffy nose,’’ ‘‘stopped up under 2 years of age: consult a doctor. nose,’’ ‘‘nasal stuffiness,’’ or ‘‘clogged (e) The word ‘‘physician’’ may be sub- up nose.’’) stituted for the word ‘‘doctor’’ in any (ii) (Select one of the following: ‘‘Re- of the labeling statements in this sec- duces swelling of,’’ ‘‘Decongests,’’ or tion. ‘‘Helps clear’’) ‘‘nasal passages; shrinks [54 FR 8509, Feb. 28, 1989, as amended at 57 swollen membranes.’’ FR 29177, June 30, 1992] (iii) ‘‘Temporarily restores freer breathing through the nose.’’ § 341.80 Labeling of nasal deconges- (iv) ‘‘Helps decongest sinus openings tant drug products. and passages; temporarily relieves (a) Statement of identity. The labeling sinus congestion and pressure.’’ of the product contains the established (v) ‘‘Promotes nasal and/or sinus name of the drug, if any, and identifies drainage; temporarily relieves sinus the product as a ‘‘nasal decongestant.’’ congestion and pressure.’’ (b) Indications. The labeling of the (c) Warnings. The labeling of the product states, under the heading ‘‘In- product contains the following warn- dications,’’ the phrase listed in para- ings under the heading ‘‘Warnings’’: graph (b)(1) of this section, as appro- (1) Oral nasal decongestants—(i) For priate, and may contain any additional products containing phenylephrine hydro- phrases listed in paragraph (b)(2) of chloride, pseudoephedrine hydrochloride,

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pseudoephedrine sulfate, or phenyl- identified in paragraph (c)(1)(i) of this ephrine bitartrate identified in § 341.20 section. (a)(1) through (a)(4) when labeled for (2) Topical nasal decongestants—(i) For adults. (A) ‘‘Do not exceed rec- products containing any topical nasal de- ommended dosage. [first sentence in congestant identified in § 341.20(b) when boldface type] If nervousness, dizziness, labeled for adults. (A) ‘‘Do not exceed or sleeplessness occur, discontinue use recommended dosage.’’ [sentence in and consult a doctor.’’ boldface type] (B) ‘‘If symptoms do not improve (B) ‘‘This product may cause tem- within 7 days or are accompanied by porary discomfort such as burning, fever, consult a doctor.’’ stinging, sneezing, or an increase in (C) ‘‘Do not take this product if you nasal discharge.’’ have heart disease, high blood pressure, (C) ‘‘The use of this container by thyroid disease, diabetes, or difficulty more than one person may spread in- in urination due to enlargement of the fection.’’ prostate gland unless directed by a doc- (ii) For products containing tor.’’ levmetamfetamine identified in (D) Drug interaction precaution. ‘‘Do § 341.20(b)(1) when used in an inhalant not use if you are now taking a pre- dosage form and when labeled for adults. scription monoamine oxidase inhibitor ‘‘Do not use this product for more than (MAOI) (certain drugs for depression, 7 days. Use only as directed. Frequent psychiatric, or emotional conditions, or prolonged use may cause nasal con- or Parkinson’s disease), or for 2 weeks gestion to recur or worsen. If symp- after stopping the MAOI drug. If you do toms persist, ask a doctor.’’ not know if your prescription drug con- (iii) For products containing ephedrine, tains an MAOI, ask a doctor or phar- ephedrine hydrochloride, ephedrine sul- macist before taking this product.’’ fate, naphazoline hydrochloride, (ii) For products containing phenyl- oxymetazoline hydrochloride, phenylephrine hydrochloride, pseudoephedrine ephrine hydrochloride, or xylometazoline hydrochloride, pseudoephedrine sulfate, hydrochloride identified in § 341.20 (b)(2), or phenylephrine bitartrate identified in (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and § 341.20 (a)(1) through (a)(4) when labeled (b)(10) when used as nasal sprays, drops, for children under 12 years of age. (A) or jellies and when labeled for adults. (A) ‘‘Do not exceed recommended dosage. ‘‘Do not use this product for more than [first sentence in boldface type] If 3 days. Use only as directed. Frequent nervousness, dizziness, or sleeplessness or prolonged use may cause nasal con- occur, discontinue use and consult a gestion to recur or worsen. If symp- doctor.’’ toms persist, consult a doctor.’’ (B) ‘‘If symptoms do not improve (B) ‘‘Do not use this product if you within 7 days or are accompanied by have heart disease, high blood pressure, fever, consult a doctor.’’ thyroid disease, diabetes, or difficulty (C) ‘‘Do not give this product to a in urination due to enlargement of the child who has heart disease, high blood prostate gland unless directed by a doc- pressure, thyroid disease, or diabetes tor.’’ unless directed by a doctor.’’ (iv) For products containing naphazo- (D) Drug interaction precaution. ‘‘Do line hydrochloride identified in not use in a child who is taking a pre- § 341.20(b)(6) at a concentration of 0.05 scription monoamine oxidase inhibitor percent. ‘‘Do not use this product in (MAOI) (certain drugs for depression, children under 12 years of age because psychiatric, or emotional conditions, it may cause sedation if swallowed.’’ or Parkinson’s disease), or for 2 weeks (v) For products containing after stopping the MAOI drug. If you do propylhexedrine identified in § 341.20(b)(9) not know if your child’s prescription when used in an inhalant dosage form drug contains an MAOI, ask a doctor or and when labeled for adults. ‘‘Do not use pharmacist before giving this product.’’ this product for more than 3 days. Use (iii) For oral nasal decongestant prod- only as directed. Frequent or prolonged ucts labeled for both adults and children use may cause nasal congestion to under 12 years of age. The labeling of recur or worsen. If symptoms persist, the product contains the warnings consult a doctor.’’

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(vi) For products containing any topical Adults and children 12 years of age and nasal decongestant identified in § 341.20(b) over: 10 milligrams every 4 hours not when labeled for children under 12 years to exceed 60 milligrams in 24 hours. of age. The labeling of the product con- Children 6 to under 12 years of age: 5 tains the warnings identified in para- milligrams every 4 hours not to exceed graph (c)(2)(i) of this section. 30 milligrams in 24 hours. Children 2 to (vii) For products containing under 6 years of age: 2.5 milligrams levmetamfetamine identified in every 4 hours not to exceed 15 milli- § 341.20(b)(1) when used in an inhalant grams in 24 hours. Children under 2 dosage form and when labeled for chil- years of age: consult a doctor. dren under 12 years of age. ‘‘Do not use (ii) For products containing this product for more than 7 days. Use pseudoephedrine hydrochloride or only as directed. Frequent or prolonged pseudoephedrine sulfate identified in use may cause nasal congestion to § 341.20 (a)(2) and (a)(3). Adults and chil- recur or worsen. If symptoms persist, dren 12 years of age and over: 60 milli- ask a doctor.’’ grams every 4 to 6 hours not to exceed (viii) For products containing ephed- 240 milligrams in 24 hours. Children 6 rine, ephedrine hydrochloride, ephedrine to under 12 years of age: 30 milligrams sulfate, naphazoline hydrochloride, every 4 to 6 hours not to exceed 120 oxymetazoline hydrochloride, phenyl- milligrams in 24 hours. Children 2 to ephrine hydrochloride, or xylometazoline under 6 years of age: 15 milligrams hydrochloride identified in § 341.20(b)(2), every 4 to 6 hours not to exceed 60 mil- (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and ligrams in 24 hours. Children under 2 (b)(10) when used as nasal sprays, drops, years of age: consult a doctor. or jellies and when labeled for children (iii) For products containing phenyl- under 12 years of age. (A) ‘‘Do not use ephrine bitartrate identified in this product for more than 3 days. Use § 341.20(a)(4). Include information on only as directed. Frequent or prolonged the number of dosage units and the use may cause nasal congestion to quantity of water the dosage units are recur or worsen. If symptoms persist, to be dissolved in prior to administra- consult a doctor.’’ tion as shown in the following table: (B) ‘‘Do not use this product in a Age 1 Dose 1 child who has heart disease, high blood pressure, thyroid disease, or diabetes Adults and children 15.6 milligrams every 4 hours not unless directed by a doctor.’’ 12 years of age to exceed 62.4 milligrams in 24 and over hours (ix) For products containing propylhexedrine identified in § 341.20(b)(9) Children 6 to under 7.8 milligrams every 4 hours not to when used in an inhalant dosage form 12 years of age exceed 31.2 milligrams in 24 hours and when labeled for children under 12 years of age. ‘‘Do not use this product Children under 6 Ask a doctor for more than 3 days. Use only as di- years of age rected. Frequent or prolonged use may 1Headings are not required to appear in the product’s cause nasal congestion to recur or labeling worsen. If symptoms persist, consult a (2) Topical nasal decongestants—(i) For doctor.’’ products containing levmetamfetamine (x) For topical nasal decongestant prod- identified in § 341.20(b)(1) when used in an ucts labeled for both adults and for chil- inhalant dosage form. The product deliv- dren under 12 years of age. The labeling ers in each 800 milliliters of air 0.04 to of the product contains the applicable 0.150 milligrams of levmetamfetamine. warnings identified in paragraphs Adults: 2 inhalations in each nostril (c)(2)(i), (c)(2)(ii), (c)(2)(iii), and (c)(2)(v) not more often than every 2 hours. of this section. Children 6 to under 12 years of age (d) Directions. The labeling of the (with adult supervision): 1 inhalation product contains the following infor- in each nostril not more often than mation under the heading ‘‘Direc- every 2 hours. Children under 6 years of tions’’: age: ask a doctor. (1) Oral nasal decongestants—(i) For (ii) For products containing ephedrine, products containing phenylephrine hydro- ephedrine hydrochloride, or ephedrine chloride identified in § 341.20(a)(1). sulfate identified in § 341.20(b) (2), (3),

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and (4)—(A) Nasal drops or sprays—For a (2) A 0.025-percent aqueous solution in 0.5-percent aqueous solution. Adults and a container having either a calibrated children 12 years of age and over: 2 or dropper or a metered-dose spray that de- 3 drops or sprays in each nostril not livers no more than 0.027 milligrams of more often than every 4 hours. Chil- oxymetazoline per three drops or three dren 6 to under 12 years of age (with sprays. Children 2 to under 6 years of adult supervision): 1 or 2 drops or age (with adult supervision): 2 or 3 sprays in each nostril not more often drops or sprays in each nostril not than every 4 hours. Children under 6 more often than every 10 to 12 hours. years of age: consult a doctor. Use only recommended amount. Do not (B) Nasal jelly—For a 0.5-percent exceed 2 doses in any 24-hour period. water-based jelly. Adults and children 6 [previous two sentences in boldface to under 12 years of age (with adult su- type] Children under 2 years of age: pervision): place a small amount in consult a doctor. each nostril and inhale well back into (B) Nasal jelly—For a 0.05-percent the nasal passages. Use not more often water-based jelly. Adults and children 6 than every 4 hours. to under 12 years of age (with adult su- (iii) For products containing naphazo- pervision): place a small amount in line hydrochloride identified in each nostril and inhale well back into § 341.20(b)(6)—(A) Nasal drops or sprays— the nasal passages. Use not more often (1) For a 0.05-percent aqueous solution. than every 10 to 12 hours. Do not ex- Adults and children 12 years of age and ceed 2 doses in any 24-hour period. Chil- over: 1 or 2 drops or sprays in each nos- dren under 6 years of age: consult a tril not more often than every 6 hours. doctor. Do not give to children under 12 years (v) For products containing phenyl- of age unless directed by a doctor. ephrine hydrochloride identified in (2) For a 0.025-percent aqueous solution. § 341.20(b)(8)—(A) Nasal drops or sprays— Children 6 to under 12 years of age (1) For a 1-percent aqueous solution. (with adult supervision): 1 or 2 drops or Adults and children 12 years of age and sprays in each nostril not more often over: 2 or 3 drops or sprays in each nos- than every 6 hours. Children under 6 tril not more often than every 4 hours. years of age: consult a doctor. Do not give to children under 12 years (B) Nasal jelly—(1) For a 0.05-percent of age unless directed by a doctor. water-based jelly. Adults and children 12 years of age and over: place a small (2) For a 0.5-percent aqueous solution. amount in each nostril and inhale well Adults and children 12 years of age and back into the nasal passages. Use not over: 2 or 3 drops or sprays in each nos- more often than every 6 hours. Do not tril not more often than every 4 hours. give to children under 12 years of age Do not give to children under 12 years unless directed by a doctor. of age unless directed by a doctor. (2) For a 0.025-percent water-based (3) For a 0.25-percent aqueous solution. jelly. Children 6 to under 12 years of age Adults and children 6 to under 12 years (with adult supervision): place a small of age (with adult supervision): 2 or 3 amount in each nostril and inhale well drops or sprays in each nostril not back into the nasal passages. Use not more often than every 4 hours. Chil- more often than every 6 hours. Chil- dren under 6 years of age: consult a dren under 6 years of age: consult a doctor. doctor. (4) A 0.125-percent aqueous solution in (iv) For products containing a container having either a calibrated oxymetazoline hydrochloride identified in dropper or a metered-dose spray that de- § 341.20(b)(7)—(A) Nasal drops or sprays— livers no more than 0.135 milligrams of (1) For a 0.05-percent aqueous solution. phenylephrine per three drops or three Adults and children 6 to under 12 years sprays. Children 2 to under 6 years of of age (with adult supervision): 2 or 3 age (with adult supervision): 2 or 3 drops or sprays in each nostril not drops or sprays in each nostril not more often than every 10 to 12 hours. more often than every 4 hours. Use Do not exceed 2 doses in any 24-hour only recommended amount. [previous period. Children under 6 years of age: sentence in boldface type] Children consult a doctor. under 2 years of age: consult a doctor.

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(B) Nasal jelly—(1) For a 1-percent doses in any 24-hour period. [previous water-based jelly. Adults and children 12 two sentences in boldface type] Chil- years of age and over: place a small dren under 2 years of age: consult a amount in each nostril and inhale well doctor. back into the nasal passages. Use not (B) Nasal jelly—(1) For a 0.1-percent more often than every 4 hours. Do not water-based jelly. Adults and children 12 give to children under 12 years of age years of age and over: place a small unless directed by a doctor. amount in each nostril and inhale well (2) For a 0.5-percent water-based jelly. back into the nasal passages. Use not Adults and children 12 years of age and more often than every 8 to 10 hours. Do over: place a small amount in each nos- not give to children under 12 years of tril and inhale well back into the nasal age unless directed by a doctor. passages. Use not more often than (2) For a 0.05-percent water-based jelly. every 4 hours. Do not give to children Children 6 to under 12 years of age under 12 years of age unless directed by (with adult supervision): place a small a doctor. amount in each nostril and inhale well (3) For a 0.25-percent water-based jelly. back into the nasal passages. Use not Adults and children 6 to under 12 years more often than every 8 to 10 hours. of age (with adult supervision): place a Children under 6 years of age: consult a small amount in each nostril and in- doctor. hale well back into the nasal passages. (viii) Other required statements—For Use not more often than every 4 hours. products containing levmetamfetamine or Children under 6 years of age: consult a propylhexedrine identified in § 341.20(b)(1) doctor. or (b)(9) when used in an inhalant dosage (vi) For products containing form. (A) ‘‘This inhaler is effective for a propylhexedrine identified in § 341.20(b)(9) minimum of 3 months after first use.’’ when used in an inhalant dosage form. (B) ‘‘Keep inhaler tightly closed.’’ The product delivers in each 800 milliliters of air 0.40 to 0.50 milligrams of [59 FR 43409, Aug. 23, 1994, as amended at 63 propylhexedrine. Adults and children 6 FR 40650, July 30, 1998; 64 FR 13295, Mar. 17, to under 12 years of age (with adult su- 1999; 65 FR 8, Jan. 3, 2000; 70 FR 58977, Oct. 11, pervision): 2 inhalations in each nostril 2005; 71 FR 43362, Aug. 1, 2006] not more often than every 2 hours. Children under 6 years of age: consult a § 341.85 Labeling of permitted combinations of active ingredients. doctor. (vii) For products containing The statements of identity, indica- xylometazoline hydrochloride identified in tions, warnings, and directions for use, § 341.20(b)(10)—(A) Nasal drops or respectively, applicable to each ingre- sprays—(1) For a 0.1-percent aqueous so- dient in the product may be combined lution. Adults and children 12 years of to eliminate duplicative words or age and over: 2 or 3 drops or sprays in phrases so that the resulting informa- each nostril not more often than every tion is clear and understandable. 8 to 10 hours. Do not give to children (a) Statement of identity. For a com- under 12 years of age unless directed by bination drug product that has an es- a doctor. tablished name, the labeling of the (2) A 0.05-percent aqueous solution in a product states the established name of container having either a calibrated drop- the combination drug product, followed per or a metered-dose spray that delivers by the statement of identity for each no more than 0.054 milligrams of ingredient in the combination, as es- xylometazoline per three drops or three tablished in the statement of identity sprays. Children 6 to under 12 years of sections of the applicable OTC drug age (with adult supervision): 2 or 3 monographs. If there is no established drops or sprays in each nostril not name, the labeling of the product more often than every 8 to 10 hours. states the statement of identity for Children 2 to under 6 years of age (with each ingredient in the combination, as adult supervision): 2 or 3 drops or established in the statement of iden- sprays in each nostril not more often tity sections of the applicable OTC than every 8 to 10 hours. Use only rec- drug monographs, unless otherwise ommended amount. Do not exceed 3 stated in this paragraph (a).

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(1) For permitted combinations identi- dients states ‘‘[bullet] temporarily re- fied in § 341.40(a), (c), (f), (g), (l), (m), (n), lieves [bullet] minor aches and pains (o), (q), and (r) containing an analgesic- [bullet] headache’’. antipyretic active ingredient. The analge- (ii) The indication(s) for the cough- sic-antipyretic component of the prod- cold ingredient(s) consists of the label- uct shall be identified as a ‘‘pain re- ing for antihistamines in § 341.72(b)(1) liever’’ or ‘‘analgesic (pain reliever).’’ or (b)(2) and/or nasal decongestants in If the product is also labeled to relieve § 341.80(b)(1)(ii), as appropriate, and the fever, then the analgesic-antipyretic labeling for any other cough-cold com- component is identified as a ‘‘pain re- bination. This labeling may follow a liever-fever reducer’’ or ‘‘analgesic separate bullet(s) or may be combined (pain reliever)-antipyretic (fever re- with the indication in paragraph ducer).’’ (b)(2)(i) of this section. (2) [Reserved] (3) For permitted combinations con- (b) Indications. The labeling of the taining an oral analgesic-antipyretic ac- product states, under the heading tive ingredient identified in § 341.40(a), ‘‘Uses,’’ the indication(s) for each in- (c), (f), (g), (m), (q), and (r) when labeled gredient in the combination, as estab- for relief of general cough-cold symptoms lished in the indications sections of the and/or the common cold and for relief of applicable OTC drug monographs, un- hay fever/allergic rhinitis and/or nasal less otherwise stated in this paragraph congestion symptoms. The labeling (b). Other truthful and nonmisleading states both indications in paragraphs statements, describing only the indica- (b)(1) and (b)(2) of this section. tions for use that have been established (4) For permitted combinations con- and listed in the applicable OTC drug taining an oral anesthetic-analgesic ac- monographs or listed in this paragraph tive ingredient identified in § 341.40(k), (s), (b), may also be used, as provided in (t), (z), (aa), and (bb). The labeling for § 330.1(c)(2) of this chapter, subject to the anesthetic-analgesic ingredients in the provisions of section 502 of the Fed- part 356 of this chapter should be used. eral Food, Drug, and Cosmetic Act (the act) relating to misbranding and the (5) For permitted combinations con- prohibition in section 301(d) of the act taining camphor, menthol, and euca- against the introduction or delivery for lyptus oil identified in § 341.40(u). The la- introduction into interstate commerce beling for antitussive ingredients in of unapproved new drugs in violation of § 341.74(b) should be used. section 505(a) of the act. (6) For permitted combinations con- (1) For permitted combinations containing levmetamfetamine with aromatics taining an analgesic-antipyretic active in- identified in § 341.40(v). The labeling for gredient identified in § 341.40(a), (c), (f). nasal decongestant ingredients in (g), (l), (m), (n), (o), (q), and (r) when la- § 341.80(b) should be used. beled for relief of general cough-cold (7) Other allowable statements. In addi- symptoms and/or the common cold. (i) The tion to the required information identi- labeling for the analgesic-antipyretic fied in paragraph (b) of this section, ingredients states ‘‘[bullet] tempo- the labeling of the combination drug rarily relieves [bullet] minor aches and product may contain any of the ‘‘other pains [bullet] headache’’ and ‘‘[bullet] allowable statements’’ (if any), that temporarily reduces fever’’. are identified in the applicable OTC (ii) The labeling for the cough-cold drug monographs, provided such state- ingredient(s) may follow a separate ments are neither placed in direct con- bullet(s) or may be combined with the junction with information required to relieves part of the indication in para- appear in the labeling nor occupy la- graph (b)(1)(i) of this section. beling space with greater prominence (2) For permitted combinations con- or conspicuousness than the required taining an analgesic-antipyretic active in- information. gredient identified in § 341.40(a), (c), (f), (c) Warnings. The labeling of the (g), (m), (q), and (r) when labeled for re- product states, under the heading lief of hay fever/allergic rhinitis and/or ‘‘Warnings,’’ the warning(s) for each in- nasal congestion symptoms. (i) The label- gredient in the combination, as estab- ing for the analgesic-antipyretic ingre- lished in the warnings sections of the

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applicable OTC drug monographs, un- (ii) For products labeled only for chil- less otherwise stated in paragraph (c) dren under 12 years of age. The warning of this section. in paragraph (c)(1)(ii) of this section (1) For permitted combinations con- should be used instead of the warnings taining an antitussive and an analgesic- in § 341.78(c)(3) and part 343 of this antipyretic identified in § 341.40(f), (g), (l), chapter. and (m). The labeling states the fol- (iii) For products labeled for both lowing warnings: adults and for children under 12 years of (i) For products labeled only for adults. age. The warning in paragraph The following warning should be used (c)(1)(iii) of this section should be used instead of the warnings in § 341.74(c)(1) instead of the warnings in § 341.78(c)(3) and part 343 of this chapter: ‘‘Stop use and part 343 of this chapter. and ask a doctor if [in bold type] [bul- (3) For permitted combinations con- let] pain or cough gets worse or lasts taining a nasal decongestant and an an- more than 7 days [bullet] fever gets algesic-antipyretic identified in § 341.40(c), worse or lasts more than 3 days [bullet] (g), (m), (n), (q), and (r). The labeling redness or swelling is present [bullet] states the following warnings: new symptoms occur [bullet] cough (i) For products labeled only for adults. comes back or occurs with rash or The following warning should be used headache that lasts. These could be instead of the warnings in signs of a serious condition.’’ § 341.80(c)(1)(i)(B) and part 343 of this (ii) For products labeled only for chil- chapter: ‘‘Stop use and ask a doctor if dren under 12 years of age. The following [in bold type] [bullet] pain or nasal warning should be used instead of the congestion gets worse or lasts more warnings in § 341.74(c)(3) and part 343 of than 7 days [bullet] fever gets worse or this chapter: ‘‘Stop use and ask a doc- lasts more than 3 days [bullet] redness tor if [in bold type] [bullet] pain or or swelling is present [bullet] new cough gets worse or lasts more than 5 symptoms occur’’. days [bullet] fever gets worse or lasts (ii) For products labeled for only chil- more than 3 days [bullet] redness or dren under 12 years of age. The following swelling is present [bullet] new symp- warning should be used instead of the toms occur [bullet] cough comes back warnings in § 341.80(c)(1)(ii)(B) and part or occurs with rash or headache that 343 of this chapter: ‘‘Stop use and ask a lasts. These could be signs of a serious doctor if [in bold type] [bullet] pain or condition.’’ nasal congestion gets worse or lasts (iii) For products labeled for both more than 5 days [bullet] fever gets adults and for children under 12 years of worse or lasts more than 3 days [bullet] age. The following warning should be redness or swelling is present [bullet] used instead of the warnings in new symptoms occur’’. § 341.74(c)(2) and part 343 of this chap- (iii) For products labeled for both ter: ‘‘Stop use and ask a doctor if [in adults and children under 12 years of age. bold type] [bullet] pain or cough gets The following warning should be used worse or lasts more than 5 days (chil- instead of the warnings in dren) or 7 days (adults) [bullet] fever § 341.80(c)(1)(iii) and part 343 of this gets worse or lasts more than 3 days chapter: ‘‘Stop use and ask a doctor if [bullet] redness or swelling is present [in bold type] [bullet] pain or nasal [bullet] new symptoms occur [bullet] congestion gets worse or lasts more cough comes back or occurs with rash than 5 days (children) or 7 days (adults) or headache that lasts. These could be [bullet] fever gets worse or lasts more signs of a serious condition.’’ than 3 days [bullet] redness or swelling (2) For permitted combinations con- is present [bullet] new symptoms taining an expectorant and an analgesic- occur’’. antipyretic identified in § 341.40(o). The (4) For permitted combinations con- labeling states the following warnings: taining an antihistamine combined with (i) For products labeled only for adults. an oral antitussive. The labeling states The warning in paragraph (c)(1)(i) of the warning ‘‘When using this product this section should be used instead of [in bold type] [bullet] may cause the warnings in § 341.78(c)(3) and part marked drowsiness.’’ The word 343 of this chapter. ‘‘marked’’ may be deleted from the

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warning upon petition under the provi- decongestant ingredients in sions of § 10.30 of this chapter provided § 341.80(d)(2)(i) and (d)(2)(viii). adequate data are submitted to dem- [67 FR 78170, Dec. 23, 2002, as amended at 70 onstrate that the combination product FR 58977, Oct. 11, 2005; 71 FR 43362, Aug. 1, does not cause a significant increase in 2006] drowsiness as compared with each active ingredient when tested alone. The § 341.90 Professional labeling. petition and the data it contains will The labeling of the product provided be maintained in a permanent file for to health professionals (but not to the public review in the Division of Dock- general public) may contain the fol- ets Management (HFA–305), Food and lowing additional dosage information Drug Administration, 5630 Fishers for products containing the active in- Lane, rm. 1061, Rockville, MD 20852. gredients identified below: (5) For permitted combinations con- (a) For products containing ephedrine, taining camphor, menthol, and euca- ephedrine hydrochloride, ephedrine sul- lyptus oil identified in § 341.40(u). The la- fate, or racephedrine hydrochloride iden- beling states the warnings for topical tified in § 341.16 (a), (b), (c), and (f). Chil- antitussive ingredients in § 341.74(c). dren 6 to under 12 years of age: oral (6) For permitted combinations con- dosage is 6.25 to 12.5 milligrams every 4 taining levmetamfetamine with aromatics hours, not to exceed 75 milligrams in 24 identified in § 341.40(v). The labeling hours. Children 2 to under 6 years of states the warnings for topical nasal age: oral dosage is 0.3 to 0.5 milligram decongestant ingredients in per kilogram of body weight every 4 § 341.80(c)(2). hours, not to exceed 2 milligrams per (d) Directions. The labeling of the kilogram of body weight in 24 hours. product states, under the heading ‘‘Di- (b) For products containing rections,’’ directions that conform to chlophedianol hydrochloride identified in the directions established for each in- 341.14(a)(1). Children 2 to under 6 years of age: oral dosage is 12.5 milligrams gredient in the directions sections of every 6 to 8 hours, not to exceed 50 mil- the applicable OTC drug monographs, ligrams in 24 hours. unless otherwise stated in paragraph (c) For products containing codeine in- (d) of this section. When the time ingredients identified in § 341.14(a)(2). (1) tervals or age limitations for adminis- Children 2 to under 6 years of age: Oral tration of the individual ingredients dosage is 1 milligram per kilogram differ, the directions for the combina- body weight per day administered in tion product may not exceed any max- four equal divided doses. The average imum dosage limits established for the body weight for each age may also be individual ingredients in the applicable used to determine dosage as follows: OTC drug monograph. For children 2 years of age (average (1) For permitted combinations con- body weight, 12 kilograms), the oral taining an anesthetic/analgesic and/or a dosage is 3 milligrams every 4 to 6 demulcent in a liquid dosage form identi- hours, not to exceed 12 milligrams in 24 fied in § 341.40(k), (s), (t), (w), (x), (y), (z), hours; for children 3 years of age (aver- (aa), and (bb). The labeling states ‘‘[op- age body weight, 14 kilograms), the tional, bullet] gargle, swish around, or oral dosage is 3.5 milligrams every 4 to keep in the mouth for at least 1 minute 6 hours, not to exceed 14 milligrams in and then swallow. Do not spit out.’’ 24 hours; for children 4 years of age (av- (2) For permitted combinations con- erage body weight, 16 kilograms), the taining camphor, menthol, and euca- oral dosage is 4 milligrams every 4 to 6 lyptus oil identified in § 341.40(u). The la- hours, not to exceed 16 milligrams in 24 beling states the directions for topical hours: for children 5 years of age (average body weight, 18 kilograms), the antitussive ingredients in § 341.74(d). oral dosage is 4.5 milligrams every 4 to (3) For permitted combinations con- 6 hours, not to exceed 18 milligrams in taining levmetamfetamine with aromatics 24 hours. The manufacturer must re- identified in § 341.40(v). The labeling late these dosages for its specific prod- states the directions for topical nasal uct dosages for its specific product to

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the use of the calibrated measuring de- (i) For products containing vice discussed in paragraph (c)(3) of dexchlorpheniramine maleate identified in this section. If age is used to determine § 341.12(e). Children 2 to under 6 years: the dose, the directions must include oral dosage is 0.5 milligram every 4 to instructions to reduce the dose for low- 6 hours, not to exceed 3 milligrams in weight children. 24 hours. (2) Parents should be instructed to (j) For products containing obtain and use a calibrated measuring diphenhydramine citrate identified in device for administering the drug to § 341.12(f). Children 2 to under 6 years of the child, to use extreme care in meas- age: oral dosage is 9.5 milligrams every uring the dosage, and not exceed the 4 to 6 hours, not to exceed 57 milli- recommended daily dosage. grams in 24 hours. (3) A dispensing device (such as a (k) For products containing dropper calibrated for age or weight) diphenhydramine hydrochloride identified should be dispensed along with the in § 341.12(g). Children 2 to under 6 years product when it is intended for use in of age: oral dosage is 6.25 milligrams children 2 to under 6 years of age to every 4 to 6 hours, not to exceed 37.5 prevent possible overdose due to im- mg in 24 hours. proper measuring of the dose. (l) For products containing doxylamine (4) Codeine is not recommended for succinate identified in § 341.12(h). Chil- use in children under 2 years of age. dren 2 to under 6 years of age: oral dos- Children under 2 years may be more age is 1.9 to 3.125 milligrams every 4 to susceptible to the respiratory depres- 6 hours, not to exceed 18.75 milligrams sant effects of codeine, including resin 24 hours. piratory arrest, coma, and death. (m) For products containing (d) The following labeling indication phenindamine tartrate identified in may be used for products containing § 341.12(i). Children 2 to under 6 years of guaifenesin identified in § 341.18 when age: oral dosage is 6.25 milligrams used as a single ingredient product. every 4 to 6 hours, not to exceed 37.5 ‘‘Helps loosen phlegm and thin bron- milligrams in 24 hours. chial secretions in patients with stable (n) For products containing chronic bronchitis.’’ pheniramine maleate identified in (e) For products containing § 341.12(j). Children 2 to under 6 years of brompheniramine maleate identified in age: oral dosage is 3.125 to 6.25 milli- § 341.12(a). Children 2 to under 6 years grams every 4 to 6 hours, not to exceed of age: oral dosage is 1 milligram every 37.5 milligrams in 24 hours. 4 to 6 hours, not to exceed 6 milligrams (o) For products containing pyrilamine in 24 hours. maleate identified in § 341.12(k). Children (f) For products containing 2 to under 6 years of age: oral dosage is chlorcyclizine hydrochloride identified in 6.25 to 12.5 milligrams every 6 to 8 § 341.12(b). Children 6 to under 12 years hours, not to exceed 50 milligrams in 24 of age: oral dosage is 12.5 milligrams hours. every 6 to 8 hours, not to exceed 37.5 (p) For products containing thonzyl- milligrams in 24 hours. Children 2 to amine hydrochloride identified in under 6 years of age: oral dosage is 6.25 § 341.12(l). Children 2 to under 6 years of milligrams every 6 to 8 hours, not to age: oral dosage is 12.5 to 25 milligrams exceed 18.75 milligrams in 24 hours. every 4 to 6 hours, not to exceed 150 (g) For products containing milligrams in 24 hours. chlorpheniramine maleate identified in (q) For products containing triprolidine § 341.12(c). Children 2 to under 6 years of hydrochloride identified in § 341.12(m). age: oral dosage is 1 milligram every 4 Children 4 to under 6 years of age: oral to 6 hours, not to exceed 6 milligrams dosage is 0.938 milligram every 4 to 6 in 24 hours. hours, not to exceed 3.744 milligrams in (h) For products containing 24 hours. Children 2 to under 4 years of dexbrompheniramine maleate identified in age: oral dosage is 0.625 milligram § 341.12(d). Children 2 to under 6 years every 4 to 6 hours, not to exceed 2.5 of age: oral dosage is 0.5 milligram milligrams in 24 hours. Infants 4 every 4 to 6 hours, not to exceed 3 mil- months to under 2 years of age: oral ligrams in 24 hours. dosage is 0.313 milligram every 4 to 6

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hours, not to exceed 1.252 milligrams in erally recognized as safe and effective 24 hours. and is not misbranded if it meets each (r) For products containing of the conditions in this part in addi- diphenhydramine citrate identified in tion to each of the general conditions § 341.14(a)(5). Children 2 to under 6 established in § 330.1 of this chapter. years of age: oral dosage is 9.5 milli- (b) References in this part to regu- grams every 4 hours, not to exceed 57 latory sections of the Code of Federal milligrams in 24 hours. Regulations are to chapter I of title 21 (s) For products containing unless otherwise noted. diphenhydramine hydrochloride identified in § 341.14(a)(6). Children 2 to under 6 § 343.3 Definitions. years of age: oral dosage is 6.25 milligrams every 4 hours, not to exceed 37.5 As used in this part: milligrams in 24 hours. Analgesic—antipyretic drug. An agent used to alleviate pain and to reduce [51 FR 35339, Oct. 2, 1986, as amended at 52 FR fever. 30057, Aug. 12, 1987; 54 FR 8509, Feb. 28, 1989; 57 FR 58376, Dec. 9, 1992; 59 FR 4218, Jan. 28, Cardiovascular drug. An agent used to 1994; 59 FR 29174, June 3, 1994; 59 FR 36051, prevent ischemic events. July 15, 1994] Rheumatologic drug. An agent used for the treatment of rheumatologic dis- PART 343—INTERNAL ANALGESIC, orders. ANTIPYRETIC, AND ANTIRHEU- MATIC DRUG PRODUCTS FOR Subpart B—Active Ingredients OVER-THE-COUNTER HUMAN USE § 343.10 [Reserved]

Subpart A—General Provisions § 343.12 Cardiovascular active ingredients. Sec. (a) Aspirin. 343.1 Scope. 343.3 Definitions. (b) Buffered aspirin. Aspirin identified in paragraph (a) of this section Subpart B—Active Ingredients may be buffered with any antacid ingredient(s) identified in § 331.11 of this 343.10 [Reserved] 343.12 Cardiovascular active ingredients. chapter provided that the finished 343.13 Rheumatologic active ingredients. product contains at least 1.9 milli- 343.20 [Reserved] equivalents of acid-neutralizing capac- 343.22 Permitted combinations of active in- ity per 325 milligrams of aspirin as gredients for cardiovascular- measured by the procedure provided in rheumatologic use. the United States Pharmacopeia 23/Na- Subpart C—Labeling tional Formulary 18. 343.50–343.60 [Reserved] § 343.13 Rheumatologic active ingredi- 343.80 Professional labeling. ents. Subpart D—Testing Procedures (a) Aspirin. (b) Buffered aspirin. Aspirin identi- 343.90 Dissolution and drug release testing. fied in paragraph (a) of this section AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, may be buffered with any antacid in- 360, 371. gredient(s) identified in § 331.11 of this SOURCE: 63 FR 56814, Oct. 23, 1998, unless chapter provided that the finished otherwise noted. product contains at least 1.9 milli- equivalents of acid-neutralizing capac- Subpart A—General Provisions ity per 325 milligrams of aspirin as measured by the procedure provided in § 343.1 Scope. the United States Pharmacopeia 23/Na- (a) An over-the-counter analgesic- tional Formulary 18. antipyretic drug product in a form suitable for oral administration is gen-

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§ 343.20 [Reserved] total sodium content in milligrams per dosage unit if the sodium content of a single rec- § 343.22 Permitted combinations of ac- ommended dose is 5 milligrams or more, the es- tive ingredients for cardiovascular- tablished name(s) (in alphabetical order) of any rheumatologic use. inactive ingredient(s) which may cause an allergic hypersensitivity reaction, the pharma- Combinations containing aspirin cological or therapeutic class of the drug, and must meet the standards of an accept- the chemical name(s) and structural formula(s) able dissolution test, as set forth in of the drug.) Aspirin is an odorless white, § 343.90. The following combinations are needle-like crystalline or powdery substance. permitted: Aspirin identified in §§ 343.12 When exposed to moisture, aspirin and 343.13 may be combined with any hydrolyzes into salicylic and acetic acids, antacid ingredient identified in § 331.11 and gives off a vinegary-odor. It is highly of this chapter or any combination of lipid soluble and slightly soluble in water. antacids permitted in accordance with CLINICAL PHARMACOLOGY § 331.10(a) of this chapter provided that the finished product meets the require- Mechanism of Action: Aspirin is a more po- ments of § 331.10 of this chapter and is tent inhibitor of both prostaglandin synthesis and platelet aggregation than other marketed in a form intended for inges- salicylic acid derivatives. The differences in tion as a solution. activity between aspirin and salicylic acid are thought to be due to the acetyl group on Subpart C—Labeling the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo- §§ 343.50–343.60 [Reserved] oxygenase via acetylation. § 343.80 Professional labeling. PHARMACOKINETICS The labeling of an over-the-counter Absorption: In general, immediate release drug product written for health profes- aspirin is well and completely absorbed from sionals (but not for the general public) the gastrointestinal (GI) tract. Following absorption, aspirin is hydrolyzed to salicylic shall consist of the following: acid with peak plasma levels of salicylic acid (a) For products containing aspirin occurring within 1–2 hours of dosing (see identified in §§ 343.12 and 343.13 or per- PHARMACOKINETICS—Metabolism). The rate of mitted combinations identified in § 343.22. absorption from the GI tract is dependent (These products must meet United upon the dosage form, the presence or ab- States Pharmacopeia (USP) standards sence of food, gastric pH (the presence or ab- for dissolution or drug release in sence of GI antacids or buffering agents), and § 343.90.) other physiologic factors. Enteric coated aspirin products are erratically absorbed from (1) The labeling contains the fol- the GI tract. lowing prescribing information under Distribution: Salicylic acid is widely dis- the heading ‘‘Comprehensive Pre- tributed to all tissues and fluids in the body scribing Information’’ and the sub- including the central nervous system (CNS), headings ‘‘Description,’’ ‘‘Clinical breast milk, and fetal tissues. The highest Pharmacology,’’ ‘‘Clinical Studies,’’ concentrations are found in the plasma, ‘‘Animal Toxicology,’’ ‘‘Indications and liver, renal cortex, heart, and lungs. The pro- Usage,’’ ‘‘Contraindications,’’ ‘‘Warn- tein binding of salicylate is concentration- ings,’’ ‘‘Precautions,’’ ‘‘Adverse Reac- dependent, i.e., nonlinear. At low concentrations (<100 micrograms/milliliter (μg/mL)), tions,’’ ‘‘Drug Abuse and Dependence,’’ approximately 90 percent of plasma salicy- ‘‘Overdosage,’’ ‘‘Dosage and Adminis- late is bound to albumin while at higher con- tration,’’ and ‘‘How Supplied’’ in the centrations (>400 μg/mL), only about 75 per- exact language and the exact order pro- cent is bound. The early signs of salicylic vided as follows: overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma con- COMPREHENSIVE PRESCRIBING centrations approximating 200 μg/mL. Severe INFORMATION toxic effects are associated with levels >400 μg/mL. (See ADVERSE REACTIONS and OVER- DESCRIPTION DOSAGE.) (Insert the proprietary name and the estab- Metabolism: Aspirin is rapidly hydrolyzed lished name (if any) of the drug, type of dosage in the plasma to salicylic acid such that form (followed by the phrase ‘‘for oral adminis- plasma levels of aspirin are essentially tration’’), the established name(s) and quantity undetectable 1–2 hours after dosing. Salicylic of the active ingredient(s) per dosage unit, the acid is primarily conjugated in the liver to

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form salicyluric acid, a phenolic glu- duced a 23-percent reduction in the risk of curonide, an acyl glucuronide, and a number vascular mortality. Aspirin was also shown of minor metabolites. Salicylic acid has a to have an additional benefit in patients plasma half-life of approximately 6 hours. given a thrombolytic agent. Salicylate metabolism is saturable and total Prevention of Recurrent MI and Unstable An- body clearance decreases at higher serum gina Pectoris: These indications are supported concentrations due to the limited ability of by the results of six large, randomized, the liver to form both salicyluric acid and multi-center, placebo-controlled trials of phenolic glucuronide. Following toxic doses predominantly male post-MI subjects and (10–20 grams (g)), the plasma half-life may be one randomized placebo-controlled study of increased to over 20 hours. men with unstable angina pectoris. Aspirin Elimination: The elimination of salicylic therapy in MI subjects was associated with a acid follows zero order pharmacokinetics; significant reduction (about 20 percent) in (i.e., the rate of drug elimination is constant the risk of the combined endpoint of subse- in relation to plasma concentration). Renal quent death and/or nonfatal reinfarction in excretion of unchanged drug depends upon these patients. In aspirin-treated unstable urine pH. As urinary pH rises above 6.5, the angina patients the event rate was reduced renal clearance of free salicylate increases to 5 percent from the 10 percent rate in the from <5 percent to >80 percent. placebo group. Alkalinization of the urine is a key concept Chronic Stable Angina Pectoris: In a random- in the management of salicylate overdose. ized, multi-center, double-blind trial de- (See OVERDOSAGE.) Following therapeutic signed to assess the role of aspirin for pre- doses, approximately 10 percent is found ex- vention of MI in patients with chronic stable creted in the urine as salicylic acid, 75 per- angina pectoris, aspirin significantly recent as salicyluric acid, and 10 percent phe- duced the primary combined endpoint of nolic and 5 percent acyl glucuronides of sali- nonfatal MI, fatal MI, and sudden death by 34 cylic acid. percent. The secondary endpoint for vascular Pharmacodynamics Aspirin affects platelet events (first occurrence of MI, stroke, or vas- aggregation by irreversibly inhibiting cular death) was also significantly reduced prostaglandin cyclo-oxygenase. This effect (32 percent). lasts for the life of the platelet and prevents Revascularization Procedures: Most patients the formation of the platelet aggregating who undergo coronary artery factor thromboxane A2. Nonacetylated revascularization procedures have already salicylates do not inhibit this enzyme and had symptomatic coronary artery disease for have no effect on platelet aggregation. At which aspirin is indicated. Similarly, pa- somewhat higher doses, aspirin reversibly in- tients with lesions of the carotid bifurcation hibits the formation of prostaglandin I2 sufficient to require carotid endarterectomy (prostacyclin), which is an arterial vaso- are likely to have had a precedent event. As- dilator and inhibits platelet aggregation. pirin is recommended for patients who un- At higher doses aspirin is an effective anti- dergo revascularization procedures if there is inflammatory agent, partially due to inhibi- a preexisting condition for which aspirin is tion of inflammatory mediators via cyclo- already indicated. oxygenase inhibition in peripheral tissues. In Rheumatologic Diseases: In clinical studies vitro studies suggest that other mediators of in patients with rheumatoid arthritis, juve- inflammation may also be suppressed by as- nile rheumatoid arthritis, ankylosing spon- pirin administration, although the precise dylitis and osteoarthritis, aspirin has been mechanism of action has not been eluci- shown to be effective in controlling various dated. It is this nonspecific suppression of cyclo-oxygenase activity in peripheral tis- indices of clinical disease activity. sues following large doses that leads to its ANIMAL TOXICOLOGY primary side effect of gastric irritation. (See ADVERSE REACTIONS.) The acute oral 50 percent lethal dose in rats is about 1.5 g/kilogram (kg) and in mice CLINICAL STUDIES 1.1 g/kg. Renal papillary necrosis and de- Ischemic Stroke and Transient Ischemic At- creased urinary concentrating ability occur tack (TIA): In clinical trials of subjects with in rodents chronically administered high TIA’s due to fibrin platelet emboli or doses. Dose-dependent gastric mucosal in- ischemic stroke, aspirin has been shown to jury occurs in rats and humans. Mammals significantly reduce the risk of the combined may develop aspirin toxicosis associated endpoint of stroke or death and the com- with GI symptoms, circulatory effects, and bined endpoint of TIA, stroke, or death by central nervous system depression. (See about 13–18 percent. OVERDOSAGE.) Suspected Acute Myocardial Infarction (MI): INDICATIONS AND USAGE In a large, multi-center study of aspirin, streptokinase, and the combination of aspi- Vascular Indications (Ischemic Stroke, TIA, rin and streptokinase in 17,187 patients with Acute MI, Prevention of Recurrent MI, Unstable suspected acute MI, aspirin treatment pro- Angina Pectoris, and Chronic Stable Angina

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Pectoris): Aspirin is indicated to: (1) Reduce inform patients about the signs and symp- the combined risk of death and nonfatal toms of GI side effects and what steps to stroke in patients who have had ischemic take if they occur. stroke or transient ischemia of the brain due Peptic Ulcer Disease: Patients with a his- to fibrin platelet emboli, (2) reduce the risk tory of active peptic ulcer disease should of vascular mortality in patients with a sus- avoid using aspirin, which can cause gastric pected acute MI, (3) reduce the combined mucosal irritation and bleeding. risk of death and nonfatal MI in patients with a previous MI or unstable angina pec- PRECAUTIONS toris, and (4) reduce the combined risk of MI General and sudden death in patients with chronic stable angina pectoris. Renal Failure: Avoid aspirin in patients Revascularization Procedures (Coronary Ar- with severe renal failure (glomerular filtra- tery Bypass Graft (CABG), Percutaneous tion rate less than 10 mL/minute). Transluminal Coronary Angioplasty (PTCA), Hepatic Insufficiency: Avoid aspirin in pa- and Carotid Endarterectomy): Aspirin is indi- tients with severe hepatic insufficiency. cated in patients who have undergone Sodium Restricted Diets: Patients with so- revascularization procedures (i.e., CABG, dium-retaining states, such as congestive PTCA, or carotid endarterectomy) when heart failure or renal failure, should avoid there is a preexisting condition for which as- sodium-containing buffered aspirin prepara- pirin is already indicated. tions because of their high sodium content. Rheumatologic Disease Indications (Rheu- matoid Arthritis, Juvenile Rheumatoid Arthritis, Laboratory Tests Spondyloarthropathies, Osteoarthritis, and the Aspirin has been associated with elevated Arthritis and Pleurisy of Systemic Lupus hepatic enzymes, blood urea nitrogen and Erythematosus (SLE)): Aspirin is indicated for serum creatinine, hyperkalemia, protein- the relief of the signs and symptoms of rheu- uria, and prolonged bleeding time. matoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondyloarthropathies, Drug Interactions and arthritis and pleurisy associated with Angiotensin Converting Enzyme (ACE) Inhibi- SLE. tors: The hyponatremic and hypotensive ef- CONTRAINDICATIONS fects of ACE inhibitors may be diminished by the concomitant administration of aspirin Allergy: Aspirin is contraindicated in pa- due to its indirect effect on the renin- tients with known allergy to nonsteroidal angiotensin conversion pathway. anti-inflammatory drug products and in pa- Acetazolamide: Concurrent use of aspirin tients with the syndrome of asthma, rhinitis, and acetazolamide can lead to high serum and nasal polyps. Aspirin may cause severe concentrations of acetazolamide (and tox- urticaria, angioedema, or bronchospasm icity) due to competition at the renal tubule (asthma). for secretion. Reye’s Syndrome: Aspirin should not be used Anticoagulant Therapy (Heparin and War- in children or teenagers for viral infections, farin): Patients on anticoagulation therapy with or without fever, because of the risk of are at increased risk for bleeding because of Reye’s syndrome with concomitant use of as- drug-drug interactions and the effect on pirin in certain viral illnesses. platelets. Aspirin can displace warfarin from protein binding sites, leading to prolonga- WARNINGS tion of both the prothrombin time and the Alcohol Warning: Patients who consume bleeding time. Aspirin can increase the anti- three or more alcoholic drinks every day coagulant activity of heparin, increasing should be counseled about the bleeding risks bleeding risk. involved with chronic, heavy alcohol use Anticonvulsants: Salicylate can displace while taking aspirin. protein-bound phenytoin and valproic acid, Coagulation Abnormalities: Even low doses leading to a decrease in the total concentra- of aspirin can inhibit platelet function lead- tion of phenytoin and an increase in serum ing to an increase in bleeding time. This can valproic acid levels. adversely affect patients with inherited (he- Beta Blockers: The hypotensive effects of mophilia) or acquired (liver disease or vita- beta blockers may be diminished by the con- min K deficiency) bleeding disorders. comitant administration of aspirin due to in- GI Side Effects: GI side effects include hibition of renal prostaglandins, leading to stomach pain, heartburn, nausea, vomiting, decreased renal blood flow, and salt and fluid and gross GI bleeding. Although minor upper retention. GI symptoms, such as dyspepsia, are com- Diuretics: The effectiveness of diuretics in mon and can occur anytime during therapy, patients with underlying renal or cardio- physicians should remain alert for signs of vascular disease may be diminished by the ulceration and bleeding, even in the absence concomitant administration of aspirin due to of previous GI symptoms. Physicians should inhibition of renal prostaglandins, leading to

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decreased renal blood flow and salt and fluid Central Nervous System: Agitation, cerebral retention. edema, coma, confusion, dizziness, headache, Methotrexate: Salicylate can inhibit renal subdural or intracranial hemorrhage, leth- clearance of methotrexate, leading to bone argy, seizures. marrow toxicity, especially in the elderly or Fluid and Electrolyte: Dehydration, hyper- renal impaired. kalemia, metabolic acidosis, respiratory Nonsteroidal Anti-inflammatory Drugs alkalosis. (NSAID’s): The concurrent use of aspirin with Gastrointestinal: Dyspepsia, GI bleeding, ul- other NSAID’s should be avoided because ceration and perforation, nausea, vomiting, this may increase bleeding or lead to de- transient elevations of hepatic enzymes, hep- creased renal function. atitis, Reye’s Syndrome, pancreatitis. Oral Hypoglycemics: Moderate doses of aspi- Hematologic: Prolongation of the pro- rin may increase the effectiveness of oral thrombin time, disseminated intravascular hypoglycemic drugs, leading to hypo- coagulation, coagulopathy, glycemia. thrombocytopenia. Uricosuric Agents (Probenecid and Hypersensitivity: Acute anaphylaxis, Sulfinpyrazone): Salicylates antagonize the angioedema, asthma, bronchospasm, laryn- uricosuric action of uricosuric agents. geal edema, urticaria. Carcinogenesis, Mutagenesis, Impairment of Musculoskeletal: Rhabdomyolysis. Fertility: Administration of aspirin for 68 Metabolism: Hypoglycemia (in children), weeks at 0.5 percent in the feed of rats was hyperglycemia. not carcinogenic. In the Ames Salmonella Reproductive: Prolonged pregnancy and assay, aspirin was not mutagenic; however, labor, stillbirths, lower birth weight infants, aspirin did induce chromosome aberrations antepartum and postpartum bleeding. in cultured human fibroblasts. Aspirin inhib- Respiratory: Hyperpnea, pulmonary edema, its ovulation in rats. (See Pregnancy.) tachypnea. Pregnancy: Pregnant women should only Special Senses: Hearing loss, tinnitus. Pa- take aspirin if clearly needed. Because of the tients with high frequency hearing loss may known effects of NSAID’s on the fetal cardio- have difficulty perceiving tinnitus. In these vascular system (closure of the ductus patients, tinnitus cannot be used as a clin- arteriosus), use during the third trimester of ical indicator of salicylism. pregnancy should be avoided. Salicylate Urogenital: Interstitial nephritis, papillary products have also been associated with al- necrosis, proteinuria, renal insufficiency and terations in maternal and neonatal hemo- failure. stasis mechanisms, decreased birth weight, and with perinatal mortality. DRUG ABUSE AND DEPENDENCE Labor and Delivery: Aspirin should be avoided 1 week prior to and during labor and Aspirin is nonnarcotic. There is no known delivery because it can result in excessive potential for addiction associated with the blood loss at delivery. Prolonged gestation use of aspirin. and prolonged labor due to prostaglandin in- OVERDOSAGE hibition have been reported. Nursing Mothers: Nursing mothers should Salicylate toxicity may result from acute avoid using aspirin because salicylate is ex- ingestion (overdose) or chronic intoxication. creted in breast milk. Use of high doses may The early signs of salicylic overdose lead to rashes, platelet abnormalities, and (salicylism), including tinnitus (ringing in bleeding in nursing infants. the ears), occur at plasma concentrations ap- Pediatric Use: Pediatric dosing rec- proaching 200 μg/mL. Plasma concentrations ommendations for juvenile rheumatoid ar- of aspirin above 300 μg/mL are clearly toxic. thritis are based on well-controlled clinical Severe toxic effects are associated with lev- studies. An initial dose of 90–130 mg/kg/day els above 400 μg/mL. (See CLINICAL PHARMA- in divided doses, with an increase as needed COLOGY.) A single lethal dose of aspirin in for anti-inflammatory efficacy (target plas- adults is not known with certainty but death ma salicylate levels of 150–300 μg/mL) are ef- may be expected at 30 g. For real or sus- fective. At high doses (i.e., plasma levels of pected overdose, a Poison Control Center greater than 200 μg/mL), the incidence of tox- should be contacted immediately. Careful icity increases. medical management is essential. Signs and Symptoms: In acute overdose, se- ADVERSE REACTIONS vere acid-base and electrolyte disturbances Many adverse reactions due to aspirin in- may occur and are complicated by gestion are dose-related. The following is a hyperthermia and dehydration. Respiratory list of adverse reactions that have been re- alkalosis occurs early while ported in the literature. (See WARNINGS.) hyperventilation is present, but is quickly Body as a Whole: Fever, hypothermia, followed by metabolic acidosis. thirst. Treatment: Treatment consists primarily of Cardiovascular: Dysrhythmias, hypo- supporting vital functions, increasing salicy- tension, tachycardia. late elimination, and correcting the acid-

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base disturbance. Gastric emptying and/or CABG: 325 mg daily starting 6 hours post- lavage is recommended as soon as possible procedure. Continue therapy for 1 year post- after ingestion, even if the patient has vom- procedure. ited spontaneously. After lavage and/or PTCA: The initial dose of 325 mg should be emesis, administration of activated char- given 2 hours pre-surgery. Maintenance dose coal, as a slurry, is beneficial, if less than 3 is 160–325 mg daily. Continue therapy indefi- hours have passed since ingestion. Charcoal nitely. adsorption should not be employed prior to Carotid Endarterectomy: Doses of 80 mg once emesis and lavage. daily to 650 mg twice daily, started Severity of aspirin intoxication is deter- presurgery, are recommended. Continue mined by measuring the blood salicylate therapy indefinitely. level. Acid-base status should be closely fol- Rheumatoid Arthritis: The initial dose is 3 g lowed with serial blood gas and serum pH a day in divided doses. Increase as needed for measurements. Fluid and electrolyte balance anti-inflammatory efficacy with target plas- should also be maintained. ma salicylate levels of 150–300 μg/mL. At high In severe cases, hyperthermia and doses (i.e., plasma levels of greater than 200 hypovolemia are the major immediate μg/mL), the incidence of toxicity increases. threats to life. Children should be sponged Juvenile Rheumatoid Arthritis: Initial dose is with tepid water. Replacement fluid should 90–130 mg/kg/day in divided doses. Increase as be administered intravenously and aug- needed for anti-inflammatory efficacy with mented with correction of acidosis. Plasma target plasma salicylate levels of 150–300 μg/ electrolytes and pH should be monitored to mL. At high doses (i.e., plasma levels of promote alkaline diuresis of salicylate if greater than 200 μg/mL), the incidence of tox- renal function is normal. Infusion of glucose icity increases. may be required to control hypoglycemia. Spondyloarthropathies: Up to 4 g per day in Hemodialysis and peritoneal dialysis can divided doses. be performed to reduce the body drug con- Osteoarthritis: Up to 3 g per day in divided tent. In patients with renal insufficiency or doses. in cases of life-threatening intoxication, di- Arthritis and Pleurisy of SLE: The initial alysis is usually required. Exchange trans- dose is 3 g a day in divided doses. Increase as fusion may be indicated in infants and young needed for anti-inflammatory efficacy with children. target plasma salicylate levels of 150–300 μg/ mL. At high doses (i.e., plasma levels of DOSAGE AND ADMINISTRATION greater than 200 mμ/mL), the incidence of Each dose of aspirin should be taken with toxicity increases. a full glass of water unless patient is fluid restricted. Anti-inflammatory and analgesic HOW SUPPLIED dosages should be individualized. When aspi- (Insert specific information regarding, rin is used in high doses, the development of strength of dosage form, units in which the dos- tinnitus may be used as a clinical sign of ele- age form is generally available, and information vated plasma salicylate levels except in pa- to facilitate identification of the dosage form as tients with high frequency hearing loss. required under § 201.57(k)(1), (k)(2), and (k)(3).) Ischemic Stroke and TIA: 50–325 mg once a Store in a tight container at 25 °C (77 °F); ex- day. Continue therapy indefinitely. cursions permitted to 15–30 °C (59–86 °F). Suspected Acute MI: The initial dose of 160– 162.5 mg is administered as soon as an MI is REV: October 23, 1998. suspected. The maintenance dose of 160–162.5 (2) In addition to, and immediately mg a day is continued for 30 days post-infarc- preceding, the labeling required under tion. After 30 days, consider further therapy paragraph (a)(1) of this section, the based on dosage and administration for pre- professional labeling may contain the vention of recurrent MI. following highlights of prescribing in- Prevention of Recurrent MI: 75–325 mg once formation in the exact language and a day. Continue therapy indefinitely. Unstable Angina Pectoris: 75–325 mg once a exact format provided, but only when day. Continue therapy indefinitely. accompanied by the comprehensive Chronic Stable Angina Pectoris: 75–325 mg prescribing information required in once a day. Continue therapy indefinitely. paragraph (a)(1) of this section.

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(b) [Reserved] [63 FR 56814, Oct. 23, 1998; 63 FR 66015, 66016, Dec. 1, 1998, as amended at 64 FR 49653, Sept. 14, 1999]

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Subpart D—Testing Procedures Subpart B—Active Ingredients 344.10 Earwax removal aid active ingre- § 343.90 Dissolution and drug release testing. dient. 344.12 Ear drying aid active ingredient. (a) [Reserved] (b) Aspirin capsules. Aspirin capsules Subpart C—Labeling must meet the dissolution standard for 344.50 Labeling of earwax removal aid drug aspirin capsules as contained in the products. United States Pharmacopeia (USP) 23 344.52 Labeling of ear drying aid drug prod- at page 132. ucts. (c) Aspirin delayed-release capsules and aspirin delayed-release tablets. Aspirin AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, delayed-release capsules and aspirin 360, 371. delayed-release tablets must meet the SOURCE: 51 FR 28660, Aug. 8, 1986, unless drug release standard for aspirin de- otherwise noted. layed-release capsules and aspirin delayed-release tablets as contained in Subpart A—General Provisions USP 23 at pages 133 and 136 respectively. § 344.1 Scope. (d) Aspirin tablets. Aspirin tablets (a) An over-the-counter topical otic must meet the dissolution standard for drug product in a form suitable for top- aspirin tablets as contained in USP 23 ical administration is generally recog- at page 134. nized as safe and effective and is not (e) Aspirin, alumina, and magnesia tab- misbranded if it meets each of the con- lets. Aspirin in combination with alu- ditions in this part in addition to each mina and magnesia in a tablet dosage of the general conditions established in form must meet the dissolution stand- § 330.1. ard for aspirin, alumina, and magnesia (b) References in this part to regu- tablets as contained in USP 23 at page latory sections of the Code of Federal 138. Regulations are to chapter I of title 21 (f) Aspirin, alumina, and magnesium unless otherwise noted. oxide tablets. Aspirin in combination with alumina, and magnesium oxide in § 344.3 Definitions. a tablet dosage form must meet the dissolution standard for aspirin, alu- As used in this part: mina, and magnesium tablets as con- (a) Anhydrous glycerin. An ingredient tained in USP 23 at page 139. that may be prepared by heating glyc- ° (g) Aspirin effervescent tablets for oral erin U.S.P. at 150 C for 2 hours to drive solution. Aspirin effervescent tablets off the moisture content. for oral solution must meet the dis- (b) Earwax removal aid. A drug used in solution standard for aspirin effer- the external ear canal that aids in the vescent tablets for oral solution as con- removal of excessive earwax. tained in USP 23 at page 137. (c) Water-clogged ears. The retention (h) Buffered aspirin tablets. Buffered of water in the external ear canal, aspirin tablets must meet the dissolu- thereby causing discomfort and a sen- tion standard for buffered aspirin tab- sation of fullness or hearing impair- lets as contained in USP 23 at page 135. ment. (d) Ear drying aid. A drug used in the PART 344—TOPICAL OTIC DRUG external ear canal to help dry water- PRODUCTS FOR OVER-THE- clogged ears. COUNTER HUMAN USE [51 FR 28660, Aug. 8, 1986, as amended at 65 FR 48905, Aug. 10, 2000] Subpart A—General Provisions

Sec. 344.1 Scope. 344.3 Definitions.

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Subpart B—Active Ingredients (3) ‘‘Do not use for more than 4 days; if excessive earwax remains after use of § 344.10 Earwax removal aid active in- this product, consult a doctor.’’ gredient. (4) ‘‘Avoid contact with the eyes.’’ The active ingredient of the product (d) Directions. The labeling of the consists of carbamide peroxide 6.5 per- product contains the following state- cent formulated in an anhydrous glyc- ment under the heading ‘‘Directions’’: erin vehicle. FOR USE IN THE EAR ONLY. Adults and children over 12 years of age: tilt [51 FR 28660, Aug. 8, 1986, as amended at 65 head sideways and place 5 to 10 drops FR 48905, Aug. 10, 2000] into ear. Tip of applicator should not enter ear canal. Keep drops in ear for § 344.12 Ear drying aid active ingredient. several minutes by keeping head tilted or placing cotton in the ear. Use twice The active ingredient of the product daily for up to 4 days if needed, or as consists of isopropyl alcohol 95 percent directed by a doctor. Any wax remain- in an anhydrous glycerin 5 percent ing after treatment may be removed by base. gently flushing the ear with warm [65 FR 48905, Aug. 10, 2000] water, using a soft rubber bulb ear syringe. Children under 12 years of age: Subpart C—Labeling consult a doctor. [51 FR 28660, Aug. 8, 1986; 52 FR 7830, Mar. 13, § 344.50 Labeling of earwax removal 1987; 65 FR 48905, Aug. 10, 2000] aid drug products. (a) Statement of identity. The labeling § 344.52 Labeling of ear drying aid drug products. of the product contains the established name of the drug, if any, and identifies (a) Statement of identity. The labeling the product as an ‘‘earwax removal of the product contains the established aid.’’ name of the drug, if any, and identifies (b) Indication. The labeling of the the product as an ‘‘ear drying aid.’’ product states, under the heading ‘‘In- (b) Indications. The labeling of the dication,’’ the following: ‘‘For occa- product states, under the heading sional use as an aid to’’ (which may be ‘‘Use,’’ the following: ‘‘dries water in followed by: ‘‘soften, loosen, and’’) the ears’’ (optional, which may be fol- ‘‘remove excessive earwax.’’ Other lowed by: ‘‘and relieves water-clogged truthful and nonmisleading state- ears’’) (which may be followed by any ments, describing only the indications or all of the following: ‘‘after: [bullet] 1 for use that have been established and swimming [bullet] showering [bullet] listed in this paragraph (b), may also bathing [bullet] washing the hair’’). be used, as provided in § 330.1(c)(2), sub- Other truthful and nonmisleading ject to the provisions of section 502 of statements, describing only the indica- the act relating to misbranding and the tions for use that have been established prohibition in section 301(d) of the act and listed in paragraph (b) of this sec- against the introduction or delivery for tion, may also be used, as provided in introduction into interstate commerce § 330.1(c)(2) of this chapter, subject to of unapproved new drugs in violation of the provisions of section 502 of the Fed- section 505(a) of the act. eral Food, Drug, and Cosmetic Act (the (c) Warnings. The labeling of the act) relating to misbranding and the product contains the following warn- prohibition in section 301(d) of the act ings under the heading ‘‘Warnings’’: against the introduction or delivery for (1) ‘‘Do not use if you have ear drain- introduction into interstate commerce age or discharge, ear pain, irritation, of unapproved new drugs in violation of or rash in the ear or are dizzy; consult section 505(a) of the act. a doctor.’’ (c) Warnings. The labeling of the (2) ‘‘Do not use if you have an injury product contains the following warn- or perforation (hole) of the ear drum or ings under the heading ‘‘Warnings’’: after ear surgery unless directed by a doctor.’’ 1 See § 201.66(b)(4) of this chapter.

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(1) ‘‘Flammable [in bold type]: Keep this part and each general condition es- away from fire or flame.’’ tablished in § 330.1 of this chapter. (2) ‘‘Do not use [in bold type] in the (b) References in this part to regu- eyes.’’ latory sections of the Code of Federal (3) ‘‘Ask a doctor before use if you Regulations are to chapter I of title 212 have [in bold type] [bullet] ear drain- unless otherwise noted. age or discharge [bullet] pain, irritation, or rash in the ear [bullet] had ear § 346.3 Definitions. surgery [bullet] dizziness.’’ As used in this part: (4) ‘‘Stop use and ask a doctor if [in (a) Analgesic, anesthetic drug. A topi- bold type] irritation (too much burn- cally (externally) applied drug that re- ing) or pain occurs.’’ lieves pain by depressing cutaneous (d) Directions. The labeling of the sensory receptors. product contains the following state- (b) Anorectal drug. A drug that is used ment under the heading ‘‘Directions’’: to relieve symptoms caused by [optional, bullet] ‘‘apply 4 to 5 drops in anorectal disorders in the anal canal, each affected ear.’’ perianal area, and/or the lower rectal [65 FR 48905, Aug. 10, 2000] areas. (c) Antipruritic drug. A topically (ex- PART 346—ANORECTAL DRUG ternally) applied drug that relieves itching by depressing cutaneous sen- PRODUCTS FOR OVER-THE- sory receptors. COUNTER HUMAN USE (d) Astringent drug. A drug that is applied topically (externally) to the skin Subpart A—General Provisions or mucous membranes for a local and Sec. limited protein coagulant effect. 346.1 Scope. (e) External use. Topical application 346.3 Definitions. of an anorectal drug product to the skin of the perianal area and/or the Subpart B—Active Ingredients skin of the anal canal. 346.10 Local anesthetic active ingredients. (f) Intrarectal use. Topical application 346.12 Vasoconstrictor active ingredients. of an anorectal drug product to the 346.14 Protectant active ingredients. mucous membrane of the rectum. 346.16 Analgesic, anesthetic, and anti- (g) Keratolytic drug. A drug that pruritic active ingredients. causes desquamation (loosening) and 346.18 Astringent active ingredients. debridement or sloughing of the sur- 346.20 Keratolytic active ingredients. face cells of the epidermis. 346.22 Permitted combinations of anorectal (h) Local anesthetic drug. A drug that active ingredients. produces local disappearance of pain, Subpart C—Labeling burning, itching, irritation, and/or discomfort by reversibly blocking nerve 346.50 Labeling of anorectal drug products. conduction when applied to nerve tis- 346.52 Labeling of permitted combinations sue in appropriate concentrations. of anorectal active ingredients. (i) Protectant drug. A drug that pro- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, vides a physical barrier, forming a pro- 360, 371. tective coating over skin or mucous SOURCE: 55 FR 31779, Aug. 3, 1990, unless membranes. otherwise noted. (j) Vasoconstrictor. A drug that causes temporary constriction of blood ves- Subpart A—General Provisions sels. § 346.1 Scope. Subpart B—Active Ingredients (a) An over-the-counter anorectal drug product in a form suitable for ex- § 346.10 Local anesthetic active ingre- ternal (topical) or intrarectal (rectal) dients. administration is generally recognized The active ingredient of the product as safe and effective and is not mis- consists of any of the following when branded if it meets each condition in used in the concentration or within the

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concentration range established for (10) White petrolatum. each ingredient: (b) The following active ingredients (a) Benzocaine 5 to 20 percent. may not be used as a sole protectant (b) Benzyl alcohol 1 to 4 percent. ingredient but may be used in combina- (c) Dibucaine 0.25 to 1 percent. tion with one, two, or three other pro- (d) Dibucaine hydrochloride 0.25 to 1 tectant active ingredients in accord- percent. ance with § 346.22 (a), (b), (n), and (o) (e) Dyclonine hydrochloride 0.5 to 1 and with the following limitations: percent. (1) Calamine not to exceed 25 percent (f) Lidocaine 2 to 5 percent. by weight per dosage unit (based on the (g) Pramoxine hydrochloride 1 per- zinc oxide content of calamine). cent. (2) Cod liver oil, provided that the (h) Tetracaine 0.5 to 1 percent. product is labeled so that the amount (i) Tetracaine hydrochloride 0.5 to 1 of the product that is used in a 24-hour percent. period represents a quantity that provides 10,000 U.S.P. units of vitamin A § 346.12 Vasoconstrictor active ingre- and 400 U.S.P. units of cholecalciferol. dients. (3) Shark liver oil, provided that the The active ingredient of the product product is labeled so that the amount consists of any of the following when of the product that is used in a 24-hour used in the concentration or within the period represents a quantity that pro- concentration range established for vides 10,000 U.S.P. units of vitamin A each ingredient. and 400 U.S.P. units of cholecalciferol. (a) Ephedrine sulfate 0.1 to 1.25 per- (4) Zinc oxide not to exceed 25 percent. cent by weight per dosage unit. (b) Epinephrine 0.005 to 0.01 percent. (c) Epinephrine hydrochloride 0.005 to § 346.16 Analgesic, anesthetic, and 0.01 percent. antipruritic active ingredients. (d) Phenylephrine hydrochloride 0.25 The active ingredient of the product percent. consists of any of the following when used within the concentration range § 346.14 Protectant active ingredients. established for each ingredient: (a) The following active ingredients (a) Camphor 0.1 to 3 percent. may be used as the sole protectant ac- (b) Juniper tar 1 to 5 percent. tive ingredient in a product if the in- (c) Menthol 0.1 to 1 percent. gredient as identified constitutes 50 § 346.18 Astringent active ingredients. percent or more by weight of the final product. In addition, the following ac- The active ingredient of the product tive ingredients may be used in con- consists of any of the following when centrations of less than 50 percent by used within the concentration range weight only when used in combinations established for each ingredient: in accordance with § 346.22 (a), (b), or (a) Calamine, within a concentration (n). range of 5 to 25 percent by weight per (1) Aluminum hydroxide gel. dosage unit (based on the zinc oxide (2) Cocoa butter. content of calamine). (3) Glycerin in a 20- to 45-percent (b) Witch hazel, 10 to 50 percent. (weight/weight) aqueous solution so (c) Zinc oxide, within a concentration that the final product contains not less range of 5 to 25 percent by weight per than 10 and not more than 45 percent dosage unit. glycerin (weight/weight). Any combina- [55 FR 31779, Aug. 3, 1990, as amended at 59 tion product containing glycerin must FR 28767, June 3, 1994] contain at least this minimum amount of glycerin. § 346.20 Keratolytic active ingredients. (4) Hard fat. The active ingredient of the product (5) Kaolin. consists of any of the following when (6) Lanolin. used within the concentration range (7) Mineral oil. established for each ingredient: (8) Petrolatum. (a) Alcloxa 0.2 to 2 percent. (9) Topical starch. (b) Resorcinol 1 to 3 percent.

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§ 346.22 Permitted combinations of § 346.12 and with any single astringent anorectal active ingredients. identified in § 346.18. (a) Any two, three, or four (k) Any single local anesthetic iden- protectants identified in § 346.14(a) may tified in § 346.10 may be combined with be combined, except aluminum hydrox- any single astringent identified in ide gel in § 346.14(a)(1) and kaolin in § 346.18 and with any single keratolytic § 346.14(a)(5) may not be combined with identified in § 346.20. any ingredient in § 346.14(a) (2), (4), (6), (l) Any single vasoconstrictor identi- (7), (8) and (10), and (b) (2) and (3), pro- fied in § 346.12 may be combined with vided that the combined percentage by any single analgesic, anesthetic, and weight of all protectants in the com- antipruritic identified in § 346.16 and bination is at least 50 percent of the with any single astringent identified in final product (e.g., 1 gram of a 2-gram § 346.18. dosage unit). Any protectant ingre- (m) Any single analgesic, anesthetic, dient included in the combination must and antipruritic identified in § 346.16 be present at a level that contributes may be combined with any single as- at least 12.5 percent by weight (e.g., tringent identified in § 346.18 and with 0.25 gram of a 2-gram dosage unit), ex- any single keratolytic identified in cept cod liver oil and shark liver oil. If § 346.20. an ingredient in § 346.14(b) is included (n) Any combination of ingredients in the combination, it must not exceed listed in paragraphs (c) through (m) of the concentration limit specified in this section may be combined with up § 346.14(b). to four protectants in accordance with (b) Any single anorectal ingredient paragraph (a) of this section. identified in § 346.10, 346.12, 346.16, (o) Any product containing calamine 346.18, or 346.20 may be combined with for use as a protectant and/or as an as- up to four protectants in accordance tringent and/or containing zinc oxide with paragraph (a) of this section. for use as a protectant and/or as an as- (c) Any single local anesthetic identi- tringent may not have a total weight fied in § 346.10 may be combined with of zinc oxide exceeding 25 percent by any single vasoconstrictor identified in weight per dosage unit. § 346.12. (d) Any single local anesthetic iden- Subpart C—Labeling tified in § 346.10 may be combined with any single astringent identified in § 346.50 Labeling of anorectal drug § 346.18. products. (e) Any single local anesthetic identi- The labeling of the product contains fied in § 346.10 may be combined with the following information for anorectal any single keratolytic identified in ingredients identified in §§ 346.10, 346.12, § 346.20. 346.14, 346.16, 346.18, and 346.20, and for (f) Any single vasoconstrictor identi- combinations of anorectal ingredients fied in § 346.12 may be combined with identified in § 346.22. Unless otherwise any single astringent identified in specified, the labeling in this subpart is § 346.18. applicable to anorectal drug products (g) Any single analgesic, anesthetic, for both external and intrarectal use. and antipruritic identified in § 346.16 (a) Statement of identity. The labeling may be combined with any single as- of the product contains the established tringent identified in § 346.18. name of the drug, if any, and identifies (h) Any single analgesic, anesthetic, the product as ‘‘anorectal (hemor- and antipruritic identified in § 346.16 rhoidal),’’ ‘‘hemorrhoidal,’’ ‘‘hemor- may be combined with any single rhoidal (anorectal) (insert dosage form, keratolytic identified in § 346.20. e.g., cream, lotion, or ointment).’’ (i) Any single astringent identified in (b) Indications. The labeling of the § 346.18 may be combined with any sin- product states, under the heading ‘‘In- gle keratolytic identified in § 346.20. dications,’’ any of the phrases listed in (j) Any single local anesthetic identi- paragraph (b) of this section, as appro- fied in § 346.10 may be combined with priate. Other truthful and nonmis- any single vasoconstrictor identified in leading statements, describing only the

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indications for use that have been es- and/or intrarectal use containing any pro- tablished and listed in this paragraph, tectant identified in § 346.14(a) (2), (4), (6) may also be used, as provided in through (10), and (b) (1) through (4). § 330.1(c)(2) of this chapter, subject to (A) ‘‘Temporarily forms a protective the provisions of section 502 of the Fed- coating over inflamed tissues to help eral Food, Drug, and Cosmetic Act (the prevent drying of tissues.’’ act) relating to misbranding and the (B) ‘‘Temporarily protects irritated prohibition in section 301(d) of the act areas.’’ against the introduction or delivery for (C) ‘‘Temporarily relieves burning.’’ introduction into interstate commerce (D) ‘‘Provides temporary relief from of unapproved new drugs in violation of skin irritations.’’ section 505(a) of the act. (E) ‘‘Temporarily provides a coating (1) (‘‘For the temporary relief of,’’ for relief of anorectal discomforts.’’ ‘‘Gives temporary relief of,’’ or ‘‘Helps (F) ‘‘Temporarily protects the in- relieve the’’) (As an option, select one flamed, irritated anorectal surface’’ or both of the following: ‘‘local’’ or (select one of the following: ‘‘to help ‘‘anorectal’’) [select one or more of the make bowel movements less painful’’ following: ‘‘discomfort,’’ ‘‘itching,’’ or or ‘‘from irritation and abrasion during ‘‘itching and discomfort,’’ followed by: bowel movement’’). ‘‘in the perianal area’’ or ‘‘associated (G) ‘‘Temporarily protects inflamed with’’ (select one or more of the fol- perianal skin.’’ lowing: ‘‘hemorrhoids,’’ ‘‘anorectal dis- (H) ‘‘Temporarily relieves the symp- orders,’’ ‘‘inflamed hemorrhoidal tis- toms of perianal skin irritation.’’ sues,’’ ‘‘anorectal inflammation,’’ (iv) For products containing aluminum ‘‘hemorrhoidal tissues,’’ or ‘‘piles hydroxide gel identified in § 346.14(a)(1) (hemorrhoids).’’)] and for products containing kaolin identi- (2) Additional indications. Indications fied in § 346.14(a)(5). ‘‘For the temporary applicable to each active ingredient of relief of itching associated with moist the product may be combined to elimi- anorectal conditions.’’ nate duplicative words or phrases so (v) For products for external use only that the resulting indication is clear containing any analgesic, anesthetic, and and understandable. In addition to the antipruritic identified in § 346.16. (A) indication identified in paragraph (b)(1) ‘‘For the temporary relief of’’ (select of this section, the labeling of the prod- one or both of the following: ‘‘pain’’ or uct intended for external or intrarectal ‘‘burning’’). use may also contain the following in- (B) ‘‘Can help distract from pain.’’ dications, as appropriate. (C) ‘‘May provide a cooling sensa- (i) For products for external use only tion.’’ containing any ingredient identified in (vi) For products for external use only § 346.10. ‘‘For the temporary relief of’’ containing witch hazel identified in (select one or more of the following: § 346.18(b), and for products for external ‘‘pain,’’ ‘‘soreness,’’ or ‘‘burning’’). use and/or intrarectal use containing cal- (ii) For products containing epineph- amine or zinc oxide identified in § 346.18 rine or epinephrine hydrochloride identi- (a) and (c). fied in § 346.12 (b) and (c) for external use (A) ‘‘Aids in protecting irritated only, and for products containing ephed- anorectal areas.’’ rine sulfate or phenylephrine hydro- (B) ‘‘Temporary relief of’’ (select one chloride identified in § 346.12 (a) and (d). or both of the following: ‘‘irritation’’ (A) ‘‘Temporarily reduces the swell- or ‘‘burning’’). ing associated with’’ (select one of the (vii) For products for external use only following: ‘‘irritated hemorrhoidal tis- containing any ingredient identified in sue and other anorectal disorders’’ or § 346.20. The indication in paragraph ‘‘irritation in hemorrhoids and other (b)(1) of this section applies. anorectal disorders’’). (c) Warnings. Warnings applicable to (B) ‘‘Temporarily shrinks hemor- each active ingredient of the product rhoidal tissue.’’ may be combined to eliminate duplica- (iii) For products for external use only tive words or phrases so that the re- containing glycerin identified in sulting warning is clear and under- § 346.14(a)(3) and for products for external standable. The labeling of the product

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contains the following warnings under with the ability of this product to ad- the heading ‘‘Warnings’’: here properly to the skin area.’’ (1) ‘‘If condition worsens or does not (9) For products for external use only improve within 7 days, consult a doc- containing resorcinol identified in tor.’’ § 346.20(b). ‘‘Do not use on open wounds (2) ‘‘Do not exceed the recommended near the anus.’’ daily dosage unless directed by a doc- (d) Directions. Directions applicable tor.’’ to each active ingredient of the prod- (3) ‘‘In case of bleeding, consult a uct may be combined to eliminate du- doctor promptly.’’ plicative words or phrases so that the (4) For products for external use only. resulting information is clear and un- ‘‘Do not put this product into the rec- derstandable. The labeling of the prod- tum by using fingers or any mechan- uct contains the following information ical device or applicator.’’ under the heading ‘‘Directions’’: (5) For products for intrarectal use to be (1) ‘‘Adults: When practical, cleanse used with a special applicator such as a the affected area’’ (select one or both pile pipe or other mechanical device. ‘‘Do of the following: ‘‘with mild soap and not use this product with an applicator warm water and rinse thoroughly’’ or if the introduction of the applicator ‘‘by patting or blotting with an appro- into the rectum causes additional pain. priate cleansing pad’’). ‘‘Gently dry by Consult a doctor promptly.’’ patting or blotting with toilet tissue or (6) For products for external use only a soft cloth before application of this containing any local anesthetic identified product.’’ [Other appropriate directions in § 346.10, menthol identified in in this section may be inserted here.] § 346.16(c), or resorcinol identified in ‘‘Children under 12 years of age: con- § 346.20(b). ‘‘Certain persons can develop sult a doctor.’’ allergic reactions to ingredients in this (2) For products for external use only. product. If the symptom being treated ‘‘Apply externally to the affected area’’ does not subside or if redness, irrita- (insert appropriate time interval of ad- tion, swelling, pain, or other symptoms ministration as identified in para- develop or increase, discontinue use graphs (d)(6), (7), (8), or (9) of this sec- and consult a doctor.’’ tion). (3) For products for external use that (7) For products containing any vaso- are pads containing anorectal ingredients. constrictor identified in § 346.12. (i) ‘‘Do ‘‘Gently apply to the affected area by not use this product if you have heart patting and then discard.’’ disease, high blood pressure, thyroid (4) For products for intrarectal use that disease, diabetes, or difficulty in urina- are wrapped suppositories. ‘‘Remove tion due to enlargement of the prostate wrapper before inserting into the rec- gland unless directed by a doctor.’’ tum.’’ (ii) ‘‘Ask a doctor or pharmacist be- (5) For products for intrarectal use that fore use if you are [bullet] 1 presently are to be used with a special applicator taking a prescription drug for high such as a pile pipe or other mechanical blood pressure or depression.’’ device. ‘‘FOR INTRARECTAL USE: At- (iii) For products containing ephedrine tach applicator to tube. Lubricate ap- sulfate identified in § 346.12(a). ‘‘Some plicator well, then gently insert appli- users of this product may experience cator into the rectum.’’ nervousness, tremor, sleeplessness, (6) For products for external use only nausea, and loss of appetite. If these containing any of the local anesthetics symptoms persist or become worse, identified in § 346.10; analgesics, anes- consult your doctor.’’ thetics, and antipruritics identified in (8) For products containing aluminum § 346.16; or alcloxa or resorcinol identified hydroxide gel identified in § 346.14(a)(1) in § 346.20. Apply to the affected area up and for products containing kaolin identi- to 6 times daily. fied in § 346.14(a)(5). ‘‘Remove petro- (i) For products for external use only latum or greasy ointment before using containing dibucaine or dibucaine hydro- this product because they interfere chloride identified in § 346.10 (c) and (d). Apply to the affected area up to 3 or 4 1 See § 201.66(b)(4) of this chapter. times daily.

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(ii) For products for external use only gredient in the combination, as estab- containing pramoxine hydrochloride iden- lished in the warnings sections of this tified in § 346.10(g). Apply to the affected subpart. area up to 5 times daily. (d) Directions. The labeling of the (7) For products containing vaso- product states, under the heading ‘‘Di- constrictors identified in § 346.12. Apply rections,’’ directions that conform to to the affected area up to 4 times daily. the directions established for each in- (8) For products for external use only gredient in the directions sections of containing glycerin identified in this subpart. When the time intervals § 346.14(a)(3) or witch hazel identified in or age limitations for administration § 346.18(b), and for products for external of the individual ingredients differ, the and/or intrarectal use containing any pro- directions for the combination product tectant identified in § 346.14(a)(1), (2), (4), may not exceed any maximum dosage (5), (6), (7), and (9), and (b)(1), (2), (3), limits established for the individual in- and (4), or any astringent identified in gredients in the applicable OTC drug § 346.18(a) and (c). Apply to the affected monograph. area up to 6 times daily or after each bowel movement. PART 347—SKIN PROTECTANT (9) For products containing petrolatum DRUG PRODUCTS FOR OVER-THE- or white petrolatum identified in § 346.14(a)(8) and (10). Apply liberally to COUNTER HUMAN USE the affected area as often as necessary. (e) The word ‘‘physician’’ may be sub- Subpart A—General Provisions stituted for the word ‘‘doctor’’ in any Sec. of the labeling statements in this sec- 347.1 Scope. tion. 347.3 Definitions.

[55 FR 31779, Aug. 3, 1990, as amended at 59 Subpart B—Active Ingredients FR 28767, June 3, 1994; 64 FR 13295, Mar. 17, 1999] 347.10 Skin protectant active ingredients. 347.12 Astringent active ingredients. § 346.52 Labeling of permitted com- 347.20 Permitted combinations of active in- binations of anorectal active ingre- gredients. dients. Indications, warnings, and directions Subpart C—Labeling for use, respectively, applicable to each 347.50 Labeling of skin protectant drug ingredient in the product may be com- products. bined to eliminate duplicative words or 347.52 Labeling of astringent drug products. phrases so that the resulting informa- 347.60 Labeling of permitted combinations tion is clear and understandable. of active ingredients. (a) Statement of identity. For a com- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, bination drug product that has an es- 360, 371. tablished name, the labeling of the product states the established name of SOURCE: 58 FR 54462, Oct. 21, 1993, unless the combination drug product, followed otherwise noted. by the statement of identity established in § 346.50(a). For a combination Subpart A—General Provisions drug product that does not have an established name, the labeling of the § 347.1 Scope. product states the statement of iden- (a) An over-the-counter skin protect- tity established in § 346.50(a). ant drug product in a form suitable for (b) Indications. The labeling of the topical administration is generally rec- product states, under the heading ‘‘In- ognized as safe and effective and is not dications,’’ the indication(s) for each misbranded if it meets each condition ingredient in the combination, as es- in this part and each general condition tablished in the indications sections of established in § 330.1 of this chapter. this subpart. (b) References in this part to regu- (c) Warnings. The labeling of the latory sections of the Code of Federal product states, under the heading Regulations are to chapter I of title 21 ‘‘Warnings,’’ the warning(s) for each in- unless otherwise noted.

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§ 347.3 Definitions. (l) Mineral oil, 50 to 100 percent; 30 to 35 percent in combination with col- As used in this part: loidal oatmeal in accordance with Astringent drug product. A drug prod- § 347.20(a)(4). uct applied to the skin or mucous (m) Petrolatum, 30 to 100 percent. membranes for a local and limited pro- (n) [Reserved] tein coagulant effect. (o) Sodium bicarbonate. Lip protectant drug product. A drug (p) [Reserved] product that temporarily prevents dry- (q) Topical starch, 10 to 98 percent. ness and helps relieve chapping of the (r) White petrolatum, 30 to 100 per- exposed surfaces of the lips; tradition- cent. ally called ‘‘lip balm.’’ (s) Zinc acetate, 0.1 to 2 percent. Poison ivy, oak, sumac dermatitis. An (t) Zinc carbonate, 0.2 to 2 percent. allergic contact dermatitis due to ex- (u) Zinc oxide, 1 to 25 percent. posure to plants of the genus Rhus (poison ivy, poison oak, poison sumac), § 347.12 Astringent active ingredients. which contain urushiol, a potent skin- The active ingredient of the product sensitizer. consists of any one of the following Skin protectant drug product. A drug within the specified concentration es- product that temporarily protects in- tablished for each ingredient: jured or exposed skin or mucous mem- (a) Aluminum acetate, 0.13 to 0.5 per- brane surfaces from harmful or annoy- cent (depending on the formulation and ing stimuli, and may help provide re- concentration of the marketed product, lief to such surfaces. the manufacturer must provide ade- [68 FR 33376, June 4, 2003] quate directions so that the resulting solution to be used by the consumer Subpart B—Active Ingredients contains 0.13 to 0.5 percent aluminum acetate). (b) Aluminum sulfate, 46 to 63 per- SOURCE: 68 FR 33377, June 4, 2003, unless cent (the concentration is based on the otherwise noted. anhydrous equivalent). § 347.10 Skin protectant active ingredi- (c) Witch hazel. ents. § 347.20 Permitted combinations of ac- The active ingredients of the product tive ingredients. consist of any of the following, within (a) Combinations of skin protectant ac- the concentration specified for each in- tive ingredients. (1) Any two or more of gredient: the ingredients identified in § 347.10(a), (a) Allantoin, 0.5 to 2 percent. (d), (e), (i), (k), (l), (m), and (r) may be (b) Aluminum hydroxide gel, 0.15 to 5 combined provided the combination is percent. labeled according to § 347.50(b)(1) and (c) Calamine, 1 to 25 percent. provided each ingredient in the com- (d) Cocoa butter, 50 to 100 percent. bination is within the concentration (e) Cod liver oil, 5 to 13.56 percent, in specified in § 347.10. accordance with § 347.20(a)(1) or (a)(2), (2) Any two or more of the ingredi- provided the product is labeled so that ents identified in § 347.10(a), (d), (e), (g), the quantity used in a 24-hour period (h), (i), (k), (l), (m), and (r) may be does not exceed 10,000 U.S.P. Units vi- combined provided the combination is tamin A and 400 U.S.P. Units cholecal- labeled according to § 347.50(b)(2) and ciferol. provided each ingredient in the com- (f) Colloidal oatmeal, 0.007 percent bination is within the concentration minimum; 0.003 percent minimum in specified in § 347.10. combination with mineral oil in ac- (3) Any two or more of the ingredi- cordance with § 347.20(a)(4). ents identified in § 347.10(b), (c), (j), (s), (g) Dimethicone, 1 to 30 percent. (t), and (u) may be combined provided (h) Glycerin, 20 to 45 percent. the combination is labeled according to (i) Hard fat, 50 to 100 percent. § 347.50(b)(3) and provided each ingre- (j) Kaolin, 4 to 20 percent. dient in the combination is within the (k) Lanolin, 12.5 to 50 percent. concentration specified in § 347.10.

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(4) The ingredients identified in §§ 347.60(b)(3) and 352.60(b) of this chap- § 347.10(f) and (l) may be combined pro- ter. vided the combination is labeled ac- [68 FR 33377, June 4, 2003, as amended at 74 cording to § 347.50(b)(7) and provided FR 9765, Mar. 6, 2009] each ingredient in the combination is EFFECTIVE DATE NOTE: At 68 FR 33377, June within the concentration specified in 4, 2003, in § 347.20 paragraph (d) was stayed § 347.10. until further notice, effective June 4, 2004. At (b) Combination of ingredients to pre- 74 FR 9765, Mar. 6, 2009, in § 347.20, paragraph pare an aluminum acetate solution. Alu- (d) was redesignated as paragraph (e). minum sulfate tetradecahydrate may be combined with calcium acetate Subpart C—Labeling monohydrate in powder or tablet form to provide a 0.13 to 0.5 percent alu- SOURCE: 68 FR 33377, June 4, 2003, unless minum acetate solution when the pow- otherwise noted. der or tablet is dissolved in the volume § 347.50 Labeling of skin protectant of water specified in ‘‘Directions.’’ drug products. (c) Combinations of skin protectant and A skin protectant drug product may external analgesic active ingredients. Any have more than one labeled use and la- one (two when required to be in com- beling appropriate to different uses bination) or more of the active ingredi- may be combined to eliminate duplica- ents identified in § 347.10(a), (d), (e), (i), tive words or phrases as long as the la- (k), (l), (m), and (r) may be combined beling is clear and understandable. with any of the following generally rec- When the labeling of the product con- ognized as safe and effective external tains more than one labeled use, the analgesic active ingredients: Single appropriate statement(s) of identity, amine and ‘‘caine’’-type local anes- indications, warnings, and directions thetics, alcohols and ketones, antihis- must be stated in the labeling. tamines, or any permitted combination (a) Statement of identity. The labeling of these ingredients, but not with hy- of the product contains the established drocortisone, provided the product is name of the drug, if any, and identifies labeled according to § 347.60(b)(l). the product with one or more of the (d) Combinations of skin protectant and following: first aid antiseptic active ingredients. Any (1) For any product. ‘‘Skin protectant’’ (optional, may add dosage form, one (two when required to be in com- e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or bination) or more of the active ingredi- ‘‘ointment’’). ents identified in § 347.10(a), (d), (e), (i), (2) For any product formulated as a lip (k), (l), (m), and (r) may be combined protectant. ‘‘Skin protectant,’’ ‘‘lip pro- with any generally recognized as safe tectant,’’ or ‘‘lip balm’’ (optional, may and effective single first aid antiseptic add dosage form, e.g., ‘‘cream,’’ ‘‘gel,’’ active ingredient, or any permitted ‘‘lotion,’’ or ‘‘ointment’’). combination of these ingredients, pro- (3) For products containing any ingre- vided the product is labeled according dient in § 347.10(b), (c), (j), (s), (t), and to § 347.60(b)(2). (u). ‘‘Poison ivy, oak, sumac drying’’ (e) Combinations of skin protectant and (optional, may add dosage form, e.g., sunscreen active ingredients. Any one ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or ‘‘oint- (two when required to be in combina- ment’’). tion) or more of the skin protectant ac- (4) For products containing any ingre- tive ingredients identified in § 347.10(a), dient in § 347.10(b), (c), (f), (j), (o), (s), (t), (d), (e), (g), (h), (i), (k), (l), (m), and (r) and (u). ‘‘Poison ivy, oak, sumac pro- may be combined with any generally tectant.’’ recognized as safe and effective single (b) Indications. The labeling of the sunscreen active ingredient, or any product states, under the heading ‘‘Uses,’’ one or more of the phrases list- permitted combination of these ingre- ed in this paragraph (b), as appropriate. dients, provided the product meets the Other truthful and nonmisleading conditions in § 352.20(b) of this chapter statements, describing only the uses and is labeled according to that have been established and listed in

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this paragraph (b), may also be used, as (5) For products containing sodium bi- provided in § 330.1(c)(2) of this chapter, carbonate identified in § 347.10(o). The la- subject to the provisions of section 502 beling states ‘‘temporarily protects of the Federal Food, Drug, and Cos- and helps relieve minor skin irritation metic Act (the act) relating to mis- and itching due to: [bullet] poison ivy, branding and the prohibition in section oak, or sumac [bullet] insect bites’’. 301(d) of the act against the introduc- (6) For products containing topical tion or delivery for introduction into starch identified in § 347.10(q). The label- interstate commerce of unapproved ing states ‘‘temporarily protects and new drugs in violation of section 505(a) helps relieve minor skin irritation’’. of the act. (7) For products containing the com- (1) For products containing any ingre- bination of ingredients in § 347.20(a)(4). dient in § 347.10(a), (d), (e), (i), (k), (l), The labeling states ‘‘temporarily pro- (m), and (r). The labeling states ‘‘tem- tects and helps relieve minor skin irri- porarily protects minor: [bullet] 1 cuts tation and itching due to: [select one [bullet] scrapes [bullet] burns’’. or more of the following: ‘rashes’ or (2) For products containing any ingre- ‘eczema’].’’ [If both conditions are dient in § 347.10(a), (d), (e), (g), (h), (i), used, each is preceded by a bullet.] (k), (l), (m), and (r)—(i) The labeling (c) Warnings. The labeling of the states (optional: ‘‘helps prevent and’’) product contains the following warn- ‘‘temporarily protects’’ (optional: ‘‘and ings under the heading ‘‘Warnings’’: helps relieve’’) (optional: ‘‘chafed,’’) (1) ‘‘For external use only’’ in accord ‘‘chapped or cracked skin’’ (optional: with § 201.66(c)(5)(i) of this chapter. For ‘‘and lips’’). This statement may be fol- products containing only mineral oil in lowed by the optional statement: § 347.10(l) or sodium bicarbonate in ‘‘helps’’ (optional: ‘‘prevent and’’) § 347.10(o), this warning may be omitted ‘‘protect from the drying effects of if labeling for oral use of the product is also provided. wind and cold weather’’. [If both state- (2) ‘‘When using this product [bullet] ments are used, each is preceded by a do not get into eyes’’. bullet.] (3) ‘‘Stop use and ask a doctor if [bul- (ii) For products formulated as a lip let] condition worsens [bullet] symp- protectant. The labeling states (op- toms last more than 7 days or clear up tional: ‘‘helps prevent and’’) ‘‘tempo- and occur again within a few days’’. rarily protects’’ (optional: ‘‘and helps (4) For products labeled according to relieve’’) (optional: ‘‘chafed,’’) § 347.50(b)(1) or (b)(2): ‘‘Do not use on ‘‘chapped or cracked lips’’. This state- [bullet] deep or puncture wounds [bul- ment may be followed by the optional let] animal bites [bullet] serious statement: ‘‘helps’’ (optional: ‘‘prevent burns’’. and’’) ‘‘protect from the drying effects (5) For products containing colloidal of wind and cold weather’’. [If both oatmeal identified in § 347.10(f) when la- statements are used, each is preceded beled for use as a soak in a tub. ‘‘When by a bullet.] using this product [bullet] to avoid (3) For products containing any ingre- slipping, use mat in tub or shower’’. dient in § 347.10(b), (c), (j), (s), (t), and (6) For powder products containing (u). The labeling states ‘‘dries the ooz- kaolin identified in § 347.10(j) or topical ing and weeping of poison: [bullet] ivy starch identified in § 347.10(q)—(i) ‘‘Do [bullet] oak [bullet] sumac’’. not use on [bullet] broken skin’’. (4) For products containing colloidal (ii) ‘‘When using this product [bullet] oatmeal identified in § 347.10(f). The la- keep away from face and mouth to beling states ‘‘temporarily protects avoid breathing it’’. and helps relieve minor skin irritation (7) For products containing colloidal and itching due to: [select one or more oatmeal identified in § 347.10(f) or so- of the following: ‘[bullet] rashes’ ‘[bul- dium bicarbonate identified in let] eczema’ ‘[bullet] poison ivy, oak, § 347.10(o) when labeled for use as a or sumac’ ‘[bullet] insect bites’].’’ soak, compress, or wet dressing. ‘‘When using this product [bullet] in some skin 1 See § 201.66(b)(4) of this chapter for defini- conditions, soaking too long may tion of bullet symbol. overdry’’.

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(d) Directions. The labeling of the (ii) The labeling states ‘‘For use as a product contains the following state- soak in a bath: [bullet] dissolve 1 to 2 ments, as appropriate, under the head- cupfuls in a tub of warm water [bullet] ing ‘‘Directions’’: soak for 10 to 30 minutes as needed, or (1) For products labeled according to as directed by a doctor [bullet] pat dry § 347.50(b)(1), (b)(2), (b)(3), (b)(5), or (do not rub) to keep a thin layer on the (b)(6). The labeling states ‘‘apply as skin’’. needed’’. (iii) The labeling states ‘‘For use as a (2) For products containing colloidal compress or wet dressing: [bullet] add oatmeal identified in § 347.10(f)—(i) For sodium bicarbonate to water to make a products requiring dispersal in water. The mixture in a container [bullet] soak a labeling states ‘‘[bullet] turn warm clean, soft cloth in the mixture [bullet] water faucet on to full force [bullet] apply cloth loosely to affected area for slowly sprinkle’’ (manufacturer to in- 15 to 30 minutes [bullet] repeat as need- sert quantity to be used) ‘‘of colloidal ed or as directed by a doctor [bullet] oatmeal directly under the faucet into discard mixture after each use’’. the tub or container [bullet] stir any (iv) Any of the directions in para- colloidal oatmeal settled on the bot- graphs (d)(3)(i), (d)(3)(ii), or (d)(3)(iii) of tom’’. this section shall be followed by the statement: ‘‘[bullet] children under 2 (A) For products used as a soak in a years: ask a doctor’’. bath. The manufacturer must provide (4) For products containing aluminum adequate directions to obtain a solu- hydroxide gel identified in § 347.10(b). The tion containing a minimum of 0.007 labeling states ‘‘[bullet] children under percent colloidal oatmeal or 0.003 per- 6 months: ask a doctor’’. cent colloidal oatmeal in the oilated (5) For products containing glycerin form for a tub bath, sitz bath, or infant identified in § 347.10(h). The labeling bath, or a minimum of 0.25 percent col- states ‘‘[bullet] children under 6 loidal oatmeal for a foot bath. ‘‘For use months: ask a doctor’’. as a soak in a bath: [bullet] soak af- (6) For products containing zinc acetate fected area for 15 to 30 minutes as need- identified in § 347.10(s). The labeling ed, or as directed by a doctor [bullet] states ‘‘[bullet] children under 2 years: pat dry (do not rub) to keep a thin ask a doctor’’. layer on the skin’’. (e) Products formulated and labeled as (B) For products used as a compress or a lip protectant and that meet the criteria wet dressing. The manufacturer must established in § 201.66(d)(10) of this chap- provide adequate directions to obtain a ter. The title, headings, subheadings, solution containing a minimum of 0.25 and information described in § 201.66(c) percent colloidal oatmeal. ‘‘For use as of this chapter shall be printed in ac- a compress or wet dressing: [bullet] cordance with the following specifica- soak a clean, soft cloth in the mixture tions: [bullet] apply cloth loosely to affected (1) The labeling shall meet the re- area for 15 to 30 minutes [bullet] repeat quirements of § 201.66(c) of this chapter as needed or as directed by a doctor except that the title, headings, and in- [bullet] discard mixture after each formation described in § 201.66(c)(1), use’’. (c)(3), (c)(6), and (c)(7) may be omitted, (ii) For topical products intended for di- and the headings, subheadings, and in- rect application. The labeling states formation described in § 201.66(c)(2), ‘‘apply as needed’’. (c)(4), and (c)(5) may be presented as (3) For products containing sodium bi- follows: carbonate identified in § 347.10(o). The la- (i) The active ingredients beling states ‘‘[bullet] adults and chil- (§ 201.66(c)(2) of this chapter) shall be dren 2 years of age and over:’’ listed in alphabetical order. (i) The labeling states ‘‘For use as a (ii) The heading and the indication paste: [bullet] add enough water to the required by § 201.66(c)(4) of this chapter sodium bicarbonate to form a paste may be limited to: ‘‘Use [in bold type] [bullet] apply to the affected area of helps’’ (optional: ‘‘prevent and’’) ‘‘pro- the skin as needed, or as directed by a tect’’ (optional: ‘‘and relieve’’) doctor’’. ‘‘chapped lips’’. If both optional terms

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are used, the indication may be limited (2) The labeling shall be printed in to: ‘‘Use [in bold type] helps prevent, accordance with the requirements of protect, and relieve chapped lips’’. § 201.66(d) of this chapter except that (iii) The ‘‘external use only’’ warning any requirements related to in § 347.50(c)(1) and in § 201.66(c)(5)(i) of § 201.66(c)(3) and (c)(7) may be omitted. this chapter may be omitted. The [68 FR 33377, June 4, 2003, as amended at 68 warnings in § 347.50(c)(2), (c)(3), and FR 68511, Dec. 9, 2003; 73 FR 6017, Feb. 1, 2008] (c)(4) are not required. (iv) The subheadings in § 347.52 Labeling of astringent drug § 201.66(c)(5)(iii) through (c)(5)(vi) of products. this chapter may be omitted, provided (a) Statement of identity. The labeling the information after the heading of the product contains the established ‘‘Warning’’ contains the warning in name of the drug, if any, and identifies § 347.50(e)(1)(iii). the product as an ‘‘astringent.’’ For (v) The warnings in § 201.66(c)(5)(x) of products containing the combination of this chapter may be omitted. aluminum sulfate tetradecahydrate and (2) The labeling shall be printed in calcium acetate monohydrate identified in accordance with the requirements of § 347.20(b), under the ‘‘Purpose’’ heading § 201.66(d) of this chapter except that identified in § 201.66(c)(3) of this chap- any requirements related to ter, the labeling of each active ingre- § 201.66(c)(1), (c)(3), (c)(6), and (c)(7), and dient in the product states the horizontal barlines and hairlines ‘‘Astringent*’’, which is followed by described in § 201.66(d)(8), may be omit- the statements ‘‘* When combined to- ted. gether in water, these ingredients form (f) Products containing only cocoa but- the active ingredient aluminum ace- ter, petrolatum, or white petrolatum iden- tate. See [the following in bold italic tified in § 347.10(d), (m), and (r), singly or type] Directions.’’ in combination with each other, and mar- (b) Indications. The labeling of the keted other than as a lip protectant. (1) product states, under the heading The labeling shall meet the require- ‘‘Uses’’ any of the phrases listed in this ments of § 201.66(c) of this chapter ex- paragraph (b), as appropriate. Other cept that the headings and information truthful and nonmisleading statements described in § 201.66(c)(3) and (c)(7) may describing only the indications for use be omitted, and the headings, sub- that have been established and listed in headings, and information described in this paragraph (b) may also be used, as § 201.66(c)(2), (c)(4), and (c)(5) may be provided in § 330.1(c)(2) of this chapter, presented as follows: subject to the provisions of section 502 (i) The active ingredients of the Federal Food, Drug, and Cos- (§ 201.66(c)(2) of this chapter) shall be metic Act (the act) relating to mis- listed in alphabetical order. branding and the prohibition of section (ii) The heading and the indication 301(d) of the act against the introduc- required by § 201.66(c)(4) of this chapter tion or delivery for introduction into may be limited to ‘‘Use [in bold type] interstate commerce of unapproved helps protect minor cuts and burns’’ or new drugs in violation of section 505(a) ‘‘Use [in bold type] helps’’ (optional: of the act. ‘‘prevent and’’) ‘‘protect chapped skin’’ (1) For products containing aluminum or ‘‘Use [in bold type] helps protect acetate identified in § 347.12(a) or the com- minor cuts and burns and’’ (optional: bination of aluminum sulfate ‘‘prevent and protect’’) ‘‘chapped tetradecahydrate and calcium acetate skin’’. monohydrate identified in § 347.20(b). (iii) The warning in § 347.50(c)(3) may ‘‘For temporary relief of minor skin ir- be revised to read ‘‘See a doctor if con- ritations due to: [select one or more of dition lasts more than 7 days.’’ the following: ‘poison ivy,’ ‘poison (iv) The subheadings in oak,’ ‘poison sumac,’ ‘insect bites,’ § 201.66(c)(5)(iv) through (c)(5)(vii) of ‘athlete’s foot,’ or ‘rashes caused by this chapter may be omitted, provided soaps, detergents, cosmetics, or jew- the information after the heading elry’].’’ ‘‘Warnings’’ contains the warnings in (2) For products containing aluminum § 347.50(c)(2), (c)(4), and (f)(1)(iii). sulfate identified in § 347.12(b) for use as a

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styptic pencil. ‘‘Stops bleeding caused [bullet] soak affected area for 15 to 30 by minor surface cuts and abrasions as minutes as needed, or as directed by a may occur during shaving.’’ doctor [bullet] repeat 3 times a day or (3) For products containing witch hazel as directed by a doctor [bullet] discard identified in § 347.12(c). ‘‘Relieves minor solution after each use’’ . skin irritations due to: [select one or (ii) For products used as a compress or more of the following: ’insect bites,’ wet dressing. ‘‘For use as a compress or ’minor cuts,’ or ’minor scrapes’].’’ [If wet dressing: [preceding words in bold more than one condition is used, each type] [bullet] soak a clean, soft cloth in is preceded by a bullet.] the solution [bullet] apply cloth loose- (c) Warnings. The labeling of the ly to affected area for 15 to 30 minutes product contains the following warn- [bullet] repeat as needed or as directed ings under the heading ‘‘Warnings’’: by a doctor [bullet] discard solution (1) For all products—(i) The labeling after each use’’. states ‘‘For external use only’’. (2) For products containing aluminum (ii) The labeling states ‘‘When using sulfate identified in § 347.12(b) for use as a this product [bullet] avoid contact with styptic pencil. ‘‘Moisten tip of pencil eyes. If contact occurs, rinse thor- with water and apply to the affected oughly with water.’’ area. Dry pencil after use.’’ (2) For products containing aluminum (3) For products containing witch hazel acetate identified in § 347.12(a), witch identified in § 347.12(c). ‘‘Apply as often hazel identified in § 347.12(c), or the com- as needed’’. bination of aluminum sulfate (4) tetradecahydrate and calcium acetate For products containing the com- monohydrate identified in § 347.20(b). The bination of aluminum sulfate labeling states ‘‘Stop use and ask a tetradecahydrate and calcium acetate doctor if [bullet] condition worsens or monohydrate identified in § 347.20(b)—(i) symptoms last more than 7 days’’. For powder dosage form. The labeling (3) For products containing aluminum states ‘‘[bullet] dissolve 1 to 3 packets acetate identified in § 347.12(a) or the com- in [insert volume] of cool or warm bination of aluminum sulfate water [bullet] stir until fully dissolved; tetradecahydrate and calcium acetate do not strain or filter. The resulting monohydrate identified in § 347.20(b) mixture contains [insert percent] (1 when labeled for use as a compress or wet packet), [insert percent] (2 packets), or dressing. The labeling states ‘‘When [insert percent] (3 packets) aluminum using this product [bullet] do not cover acetate and is ready for use.’’ These compress or wet dressing with plastic statements shall be the first state- to prevent evaporation’’. ments under the heading ‘‘Directions’’. (4) For products containing aluminum (ii) For tablet dosage form. The label- acetate identified in § 347.12(a) or the coming states ‘‘[bullet] dissolve 1 to 3 tab- bination of aluminum sulfate lets in [insert volume] of cool or warm tetradecahydrate and calcium acetate water [bullet] stir until fully dissolved; monohydrate identified in § 347.20(b) do not strain or filter. The resulting when labeled for use as a soak, compress, mixture contains [insert percent] (1 or wet dressing. The labeling states tablet), [insert percent] (2 tablets), or ‘‘When using this product [bullet] in [insert percent] (3 tablets) aluminum some skin conditions, soaking too long acetate and is ready for use.’’ These may overdry’’. statements shall be the first state- (d) Directions. The labeling of the ments under the heading ‘‘Directions’’. product contains the following infor- (e) Products formulated and labeled as mation under the heading ‘‘Direc- a styptic pencil and that meet the criteria tions’’: established in § 201.66(d)(10) of this chap- (1) For products containing aluminum ter. The title, headings, subheadings, acetate identified in § 347.12(a) or the com- and information described in § 201.66(c) bination of aluminum sulfate of this chapter shall be printed in ac- tetradecahydrate and calcium acetate cordance with the following specifica- monohydrate identified in § 347.20(b)—(i) tions: For products used as a soak. ‘‘For use as (1) The labeling shall meet the re- a soak: [preceding words in bold type] quirements of § 201.66(c) of this chapter

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except that the headings and informa- tity sections of the applicable OTC tion described in § 201.66(c)(3) and (c)(7) drug monographs. may be omitted, and the headings, sub- (b) Indications. The labeling of the headings, and information described in product states, under the heading § 201.66(c)(4) and (c)(5) may be presented ‘‘Uses,’’ the indication(s) for each in- as follows: gredient in the combination as estab- (i) The heading and indication re- lished in the indications sections of the quired by § 201.66(c)(4) of this chapter applicable OTC drug monographs, un- may be limited to: ‘‘Use [in bold type] less otherwise stated in this paragraph stops bleeding of minor cuts from shav- (b). Other truthful and nonmisleading ing’’. statements, describing only the indica- (ii) The ‘‘external use only’’ warning tions for use that have been established in § 347.52(c)(1) and in § 201.66(c)(5)(i) of in the applicable OTC drug monographs this chapter may be omitted. The sec- or listed in this paragraph (b) may also ond warning in § 347.52(c)(1) may state: be used, as provided in § 330.1(c)(2) of ‘‘avoid contact with eyes’’. The warn- this chapter, subject to the provisions ing in § 201.66(c)(5)(x) may be limited to of section 502 of the Federal Food, the following: ‘‘Keep out of reach of Drug, and Cosmetic Act (the act) relat- children.’’ The subheadings in ing to misbranding and the prohibition § 201.66(c)(5)(iii) through (c)(5)(vii) may in section 301(d) of the act against the be omitted, provided the information introduction or delivery for introduc- after the heading ‘‘Warning’’ contains tion into interstate commerce of unap- the warnings in this paragraph. proved new drugs in violation of sec- (2) The labeling shall be printed in tion 505(a) of the act. In addition to the accordance with the requirements of required information identified in this § 201.66(d) of this chapter except that paragraph (b), the labeling of the prod- any requirements related to uct may contain any of the ‘‘other al- § 201.66(c)(3) and (c)(7), and the hori- lowable statements’’ that are identified zontal barlines and hairlines described in § 201.66(d)(8), may be omitted. in the applicable monographs, provided such statements are neither placed in [68 FR 33377, June 4, 2003, as amended at 68 direct conjunction with information re- FR 35293, June 13, 2003; 69 FR 3005, Jan. 22, quired to appear in the labeling nor oc- 2004; 74 FR 9765, Mar. 6, 2009] cupy labeling space with greater prominence or conspicuousness than the re- § 347.60 Labeling of permitted combinations of active ingredients. quired information. (1) Combinations of skin protectant and The statement of identity, indica- external analgesic active ingredients in tions, warnings, and directions for use, § 347.20(b). In addition to any or all of respectively, applicable to each ingre- the indications for skin protectant dient in the product may be combined drug products in § 347.50(b)(1), any or all to eliminate duplicative words or of the allowable indications for exter- phrases so that the resulting information is clear and understandable. nal analgesic drug products may be used if the product is labeled for con- (a) Statement of identity. For a com- current symptoms. bination drug product that has an established name, the labeling of the (2) Combinations of skin protectant and product states the established name of first aid antiseptic active ingredients in the combination drug product, followed § 347.20(c). In addition to any or all of by the statement of identity for each the indications for skin protectant ingredient in the combination, as es- drug products in § 347.50(b)(1), the re- tablished in the statement of identity quired indications for first aid anti- sections of the applicable OTC drug septic drug products should be used. monographs. For a combination drug (3) Combinations of skin protectant and product that does not have an estab- sunscreen active ingredients in § 347.20(d). lished name, the labeling of the prod- In addition to any or all of the indica- uct states the statement of identity for tions for skin protectant drug products each ingredient in the combination, as in § 347.50(b)(2)(i), the required indica- established in the statement of iden- tions for sunscreen drug products

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should be used and any or all of the ad- Subpart C—Labeling ditional indications for sunscreen drug 348.50 Labeling of external analgesic drug products may be used. products. (c) Warnings. The labeling of the AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, product states, under the heading 360, 371. ‘‘Warnings,’’ the warning(s) for each ingredient in the combination, as estab- SOURCE: 57 FR 27656, June 19, 1992, unless otherwise noted. lished in the warnings section of the applicable OTC drug monographs unless otherwise stated in this paragraph Subpart A—General Provisions (c). § 348.1 Scope. (1) For combinations containing a skin (a) An over-the-counter external an- protectant and a sunscreen identified in algesic drug product in a form suitable §§ 347.20(d) and 352.20(b). The warnings for topical administration is generally for sunscreen drug products in recognized as safe and effective and is § 352.60(c) of this chapter are used. not misbranded if it meets each condi- (2) [Reserved] tion in this part and each general con- (d) Directions. The labeling of the dition established in § 330.1 of this product states, under the heading ‘‘Di- chapter. rections,’’ directions that conform to (b) References in this part to regu- the directions established for each in- latory sections of the Code of Federal gredient in the directions sections of Regulations are to chapter I of title 21 the applicable OTC drug monographs, unless otherwise noted. unless otherwise stated in this para- § 348.3 Definitions. graph (d). When the time intervals or age limitations for administration of As used in this part: the individual ingredients differ, the (a) Male genital desensitizing drug directions for the combination product product. A drug product applied to the penis to help in temporarily slowing may not contain any dosage that ex- the onset of ejaculation. ceeds those established for any indi- (b) [Reserved] vidual ingredient in the applicable OTC drug monograph(s), and may not provide for use by any age group lower Subpart B—Active Ingredients than the highest minimum age limit § 348.10 Analgesic, anesthetic, and established for any individual ingre- antipruritic active ingredients. dient. The active ingredient of the product (1) For combinations containing a skin consists of any of the following within protectant and a sunscreen identified in the specified concentration established §§ 347.20(d) and 352.20(b). The directions for each ingredient: for sunscreen drug products in (a) Male genital desensitizers. (1) Ben- § 352.60(d) of this chapter are used. zocaine, 3 to 7.5 percent in a water- (2) [Reserved] soluble base. (2) Lidocaine in a metered spray with PART 348—EXTERNAL ANALGESIC approximately 10 milligrams per spray. (b) [Reserved] DRUG PRODUCTS FOR OVER-THE- COUNTER HUMAN USE Subpart C—Labeling Subpart A—General Provisions § 348.50 Labeling of external analgesic drug products. Sec. 348.1 Scope. (a) Statement of identity. The labeling 348.3 Definitions. of the product contains the established name of the drug, if any, and identifies Subpart B—Active Ingredients the product as follows: (1) For products containing any ingre- 348.10 Analgesic, anesthetic, and anti- dient identified in § 348.10(a). ‘‘Male gen- pruritic active ingredients. ital desensitizer.’’

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(2) [Reserved] course, or use as directed by a doctor. (b) Indications. The labeling of the Wash product off after intercourse.’’ product states, under the heading ‘‘In- (ii) For products containing lidocaine dications,’’ any of the phrases listed in identified in § 348.10(a)(2). ‘‘Apply 3 or paragraph (b) of this section. Other more sprays, not to exceed 10, to head truthful and nonmisleading state- and shaft of penis before intercourse, ments, describing only the indications or use as directed by a doctor. Wash for use that have been established and product off after intercourse.’’ listed in paragraph (b) of this section, (2) [Reserved] may also be used, as provided in (e) The word ‘‘physician’’ may be sub- § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Fed- stituted for the word ‘‘doctor’’ in any eral Food, Drug, and Cosmetic Act (the of the labeling statements in this sec- act) relating to misbranding and the tion. prohibition in section 301(d) of the act against the introduction or delivery for PART 349—OPHTHALMIC DRUG introduction into interstate commerce PRODUCTS FOR OVER-THE- of unapproved new drugs in violation of COUNTER HUMAN USE section 505(a) of the act. (1) For products containing any ingre- Subpart A—General Provisions dient identified in § 348.10(a). (i) ‘‘Helps in the prevention of premature ejacula- Sec. tion.’’ 349.1 Scope. (ii) ‘‘For temporary male genital de- 349.3 Definitions. sensitization, helping to slow the onset of ejaculation.’’ Subpart B—Active Ingredients (iii) ‘‘Helps in temporarily’’ (select 349.10 Ophthalmic astringent. one of the following: ‘‘retarding the 349.12 Ophthalmic demulcents. onset of,’’ ‘‘slowing the onset of,’’ or 349.14 Ophthalmic emollients. ‘‘prolonging the time until’’) followed 349.16 Ophthalmic hypertonicity agent. by ‘‘ejaculation.’’ 349.18 Ophthalmic vasoconstrictors. (iv) ‘‘For reducing oversensitivity in 349.20 Eyewashes. the male in advance of intercourse.’’ 349.30 Permitted combinations of active in- (2) [Reserved] gredients. (c) Warnings. The labeling of the product contains the following warn- Subpart C—Labeling ings under the heading ‘‘Warnings’’: (1) For products containing any ingre- 349.50 Labeling of ophthalmic drug prod- dient identified in § 348.10(a). (i) ‘‘Pre- ucts. mature ejaculation may be due to a 349.55 Labeling of ophthalmic astringent condition requiring medical super- drug products. vision. If this product, used as directed, 349.60 Labeling of ophthalmic demulcent does not provide relief, discontinue use drug products. and consult a doctor.’’ 349.65 Labeling of ophthalmic emollient drug products. (ii) ‘‘Avoid contact with the eyes.’’ 349.70 Labeling of ophthalmic hypertonicity (iii) ‘‘If you or your partner develop a drug products. rash or irritation, such as burning or 349.75 Labeling of ophthalmic vasocon- itching, discontinue use. If symptoms strictor drug products. persist, consult a doctor.’’ 349.78 Labeling of eyewash drug products. (2) [Reserved] 349.79 Labeling of permitted combinations (d) Directions. The labeling of the of active ingredients. product contains the following infor- 349.80 Professional labeling. mation under the heading ‘‘Direc- tions’’: AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. (1) For products containing any ingredient identified in § 348.10(a)—(i) For SOURCE: 53 FR 7090, Mar. 4, 1988, unless oth- products containing benzocaine identified erwise noted. in § 348.10(a)(1). ‘‘Apply a small amount to head and shaft of penis before inter-

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Subpart A—General Provisions causes transient constriction of con- junctival blood vessels. § 349.1 Scope. (a) An over-the-counter ophthalmic Subpart B—Active Ingredients drug product in a form suitable for topical administration is generally recog- § 349.10 Ophthalmic astringent. nized as safe and effective and is not The active ingredient and its con- misbranded if it meets each of the concentration in the product is as follows: ditions in this part and each of the gen- Zinc sulfate, 0.25 percent. eral conditions established in § 330.1. (b) References in this part to regu- § 349.12 Ophthalmic demulcents. latory sections of the Code of Federal The active ingredients of the product Regulations are to chapter I of title 21 consist of any of the following, within unless otherwise noted. the established concentrations for each ingredient: § 349.3 Definitions. (a) Cellulose derivatives: As used in this part: (1) Carboxymethylcellulose sodium, (a) Ophthalmic drug product. A drug 0.2 to 2.5 percent. product, which should be sterile in ac- (2) Hydroxyethyl cellulose, 0.2 to 2.5 cordance with § 200.50, to be applied to percent. the eyelid or instilled in the eye. (3) Hypromellose, 0.2 to 2.5 percent. (b) Astringent. A locally acting phar- (4) Methylcellulose, 0.2 to 2.5 percent. macologic agent which, by precipi- (b) Dextran 70, 0.1 percent when used tating protein, helps to clear mucus with another polymeric demulcent from the outer surface of the eye. agent in this section. (c) Buffering agent. A substance which (c) Gelatin, 0.01 percent. stabilizes the pH of solutions against (d) Polyols, liquid: changes produced by introduction of (1) Glycerin, 0.2 to 1 percent. acids or bases from such sources as (2) Polyethylene glycol 300, 0.2 to 1 drugs, body fluids, tears, etc. percent. (d) An agent, usually a Demulcent. (3) Polyethylene glycol 400, 0.2 to 1 water-soluble polymer, which is ap- percent. plied topically to the eye to protect (4) Polysorbate 80, 0.2 to 1 percent. and lubricate mucous membrane sur- (5) Propylene glycol, 0.2 to 1 percent. faces and relieve dryness and irrita- (e) Polyvinyl alcohol, 0.1 to 4 percent. tion. (f) Povidone, 0.1 to 2 percent. (e) Emollient. An agent, usually a fat or oil, which is applied locally to eye- [53 FR 7090, Mar. 4, 1988, as amended at 68 FR lids to protect or soften tissues and to 32982, June 3, 2003] prevent drying and cracking. (f) Eyewash, eye lotion, irrigating solu- § 349.14 Ophthalmic emollients. tion. A sterile aqueous solution in- The active ingredients of the product tended for washing, bathing, or flush- consist of any of the following: ing the eye. (a) Lanolin preparations: (g) Hypertonicity agent. An agent (1) Anhydrous lanolin, 1 to 10 percent which exerts an osmotic gradient in combination with one or more ole- greater than that present in body tis- aginous emollient agents included in sues and fluids, so that water is drawn the monograph. from the body tissues and fluids across (2) Lanolin, 1 to 10 percent in com- semipermeable membranes. Applied bination with one or more oleaginous topically to the eye, a hypertonicity emollient agents included in the mono- agent creates an osmotic gradient graph. which draws water out of the cornea. (b) Oleaginous ingredients: (h) Isotonicity. A state or quality in (1) Light mineral oil, up to 50 percent which the osmotic pressure in two in combination with one or more other fluids is equal. emollient agents included in the mono- (i) Vasoconstrictor. A pharmacologic graph. agent which, when applied topically to (2) Mineral oil, up to 50 percent in the mucous membranes of the eye, combination with one or more other

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emollient agents included in the mono- may be combined with any single oph- graph. thalmic vasoconstrictor active ingre- (3) Paraffin, up to 5 percent in com- dient identified in § 349.18. bination with one or more other emol- (b) Any two or three ophthalmic de- lient agents included in the mono- mulcent active ingredients identified graph. in § 349.12 may be combined. (4) Petrolatum, up to 100 percent. (c) Any single ophthalmic demulcent (5) White ointment, up to 100 percent. active ingredient identified in § 349.12 (6) White petrolatum, up to 100 per- or any ophthalmic demulcent combina- cent. tion identified in paragraph (b) of this (7) White wax, up to 5 percent in com- section may be combined with any sin- bination with one or more other emol- gle ophthalmic vasoconstrictor identi- lient agents included in the mono- fied in § 349.18. graph. (d) Any single ophthalmic astringent (8) Yellow wax, up to 5 percent in active ingredient identified in § 349.10 combination with one or more other may be combined with any single oph- emollient agents included in the mono- thalmic vasoconstrictor active ingre- graph. dient identified in § 349.18 and any single ophthalmic demulcent identified in § 349.16 Ophthalmic hypertonicity § 349.12 or ophthalmic demulcent com- agent. bination identified in paragraph (b) of The active ingredient and its con- this section. centration in the product is as follows: (e) Any two or more emollient active Sodium chloride, 2 to 5 percent. ingredients identified in § 349.14 may be combined as necessary to give the § 349.18 Ophthalmic vasoconstrictors. product proper consistency for applica- The active ingredient of the product tion to the eye. consists of one of the following, within the established concentration for each Subpart C—Labeling ingredient: (a) Ephedrine hydrochloride, 0.123 § 349.50 Labeling of ophthalmic drug percent. products. (b) Naphazoline hydrochloride, 0.01 to (a) The word ‘‘physician’’ may be 0.03 percent. substituted for the word ‘‘doctor’’ in (c) Phenylephrine hydrochloride, 0.08 any of the labeling statements in this to 0.2 percent. part. (d) Tetrahydrozoline hydrochloride, (b) Where applicable, indications in 0.01 to 0.05 percent. this part applicable to each ingredient § 349.20 Eyewashes. in the product may be combined to eliminate duplicative words or phrases The active ingredient of the product so that the resulting information is is purified water. The product also con- clear and understandable. Other truth- tains suitable tonicity agents to estab- ful and nonmisleading statements, de- lish isotonicity with tears, suitable scribing only the indications for use agents for establishing pH and that have been established and listed in buffering to achieve the same pH as this part, may also be used, as provided tears, and a suitable preservative in § 330.1(c)(2), subject to the provisions agent. of section 502 of the act relating to [68 FR 7921, Feb. 19, 2003] misbranding and the prohibition in section 301(d) of the act against the intro- § 349.30 Permitted combinations of ac- duction or delivery for introduction tive ingredients. into interstate commerce of unap- The following combinations are per- proved new drugs in violation of sec- mitted provided each active ingredient tion 505(a) of the act. is present within the established con- (c) The labeling of the product concentration, and the product is labeled tains the following warnings, under the in accordance with § 349.79. heading ‘‘Warnings’’: (a) Any single ophthalmic astringent (1) For ophthalmic drug products pack- active ingredient identified in § 349.10 aged in multi-use containers. ‘‘To avoid

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contamination, do not touch tip of con- ‘‘demulcent (lubricant)’’ (select one of tainer to any surface. Replace cap after the following: ‘‘eye’’ or ‘‘ophthalmic’’) using.’’ ‘‘(insert dosage form, e.g., drops).’’ (2) For ophthalmic drug products pack- (b) Indications. The labeling of the aged in single-use containers. ‘‘To avoid product states, under the heading ‘‘In- contamination, do not touch tip of con- dications,’’ one or more of the fol- tainer to any surface. Do not reuse. lowing phrases: Once opened, discard.’’ (1) ‘‘For the temporary relief of burn- (3) For ophthalmic drug products con- ing and irritation due to dryness of the taining mercury compounds used as a pre- eye.’’ servative. ‘‘This product contains (name (2) ‘‘For the temporary relief of dis- and quantity of mercury-containing in- comfort due to minor irritations of the gredient) as a preservative. Do not use eye or to exposure to wind or sun.’’ this product if you are sensitive to’’ (3) ‘‘For use as a protectant against (select one of the following: ‘‘mercury’’ further irritation or to relieve dryness or ‘‘(insert name of mercury-con- of the eye.’’ taining ingredient) or any other ingre- (4) ‘‘For use as a lubricant to prevent dient containing mercury).’’ further irritation or to relieve dryness § 349.55 Labeling of ophthalmic astrin- of the eye.’’ gent drug products. (c) Warnings. In addition to the warnings in § 349.50, the labeling of the prod- (a) Statement of identity. The labeling uct contains the following warnings of the product contains the established under the heading ‘‘Warnings’’ for name of the drug, if any, and identifies products containing any ingredient the product as an ‘‘astringent’’ (select identified in § 349.12: one of the following: ‘‘eye’’ or ‘‘oph- (1) ‘‘If you experience eye pain, thalmic’’) ‘‘(insert dosage form, e.g., changes in vision, continued redness or drops).’’ irritation of the eye, or if the condition (b) Indications. The labeling of the worsens or persists for more than 72 product states, under the heading ‘‘In- hours, discontinue use and consult a dications,’’ the following phrase: ‘‘For doctor.’’ the temporary relief of discomfort from minor eye irritations.’’ (2) ‘‘If solution changes color or be- (c) Warnings. In addition to the warn- comes cloudy, do not use.’’ ings in § 349.50, the labeling of the prod- (d) Directions. The labeling of the uct contains the following warnings product contains the following infor- under the heading ‘‘Warnings’’ for mation under the heading ‘‘Direc- products containing any ingredient tions’’: Instill 1 or 2 drops in the af- identified in § 349.10: fected eye(s) as needed. (1) ‘‘If you experience eye pain, changes in vision, continued redness or § 349.65 Labeling of ophthalmic emollient drug products. irritation of the eye, or if the condition worsens or persists for more than 72 (a) Statement of identity. The labeling hours, discontinue use and consult a of the product contains the established doctor.’’ name of the drug(s), if any, and identi- (2) ‘‘If solution changes color or be- fies the product as a ‘‘lubricant’’ or comes cloudy, do not use.’’ ‘‘emollient (lubricant)’’ (select one of (d) Directions. The labeling of the the following: ‘‘eye’’ or ‘‘ophthalmic’’) product contains the following infor- ‘‘(insert dosage form, e.g., ointment).’’ mation under the heading ‘‘Direc- (b) Indications. The labeling of the tions’’: Instill 1 to 2 drops in the af- product states, under the heading ‘‘In- fected eye(s) up to four times daily. dications,’’ one or more of the following phrases: § 349.60 Labeling of ophthalmic demul- (1) ‘‘For the temporary relief of burn- cent drug products. ing and irritation due to dryness of the (a) Statement of identity. The labeling eye.’’ of the product contains the established (2) ‘‘For the temporary relief of dis- name of the drug(s), if any, and identi- comfort due to minor irritations of the fies the product as a ‘‘lubricant’’ or eye or to exposure to wind or sun.’’

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(3) ‘‘For use as a protectant against tions’’: Instill 1 or 2 drops in the af- further irritation or to relieve dryness fected eye(s) every 3 or 4 hours, or as of the eye.’’ directed by a doctor. (4) ‘‘For use as a lubricant to prevent further irritation or to relieve dryness § 349.75 Labeling of ophthalmic vaso- of the eye.’’ constrictor drug products. (c) Warnings. In addition to the warn- (a) Statement of identity. The labeling ings in § 349.50, the labeling of the prod- of the product contains the established uct contains the following warnings name of the drug(s), if any, and identi- under the heading ‘‘Warnings’’ for fies the product as a ‘‘redness reliever’’ products containing any ingredient or ‘‘vasoconstrictor (redness reliever)’’ identified in § 349.14: ‘‘If you experience (select one of the following: ‘‘eye’’ or eye pain, changes in vision, continued redness or irritation of the eye, or if ‘‘ophthalmic’’) ‘‘(insert dosage form, the condition worsens or persists for e.g., drops).’’ more than 72 hours, discontinue use (b) Indications. The labeling of the and consult a doctor.’’ product states, under the heading ‘‘In- (d) Directions. The labeling of the dications,’’ the following phrase: ‘‘Re- product contains the following infor- lieves redness of the eye due to minor mation under the heading ‘‘Direc- eye irritations.’’ tions’’: Pull down the lower lid of the (c) Warnings. In addition to the warn- affected eye and apply a small amount ings in § 349.50, the labeling of the prod- (one-fourth inch) of ointment to the in- uct contains the following warnings side of the eyelid. under the heading ‘‘Warnings’’ for products containing any ingredient § 349.70 Labeling of ophthalmic identified in § 349.18: hypertonicity drug products. (1) ‘‘If you experience eye pain, (a) Statement of identity. The labeling changes in vision, continued redness or of the product contains the established irritation of the eye, or if the condition name of the drug, if any, and identifies worsens or persists for more than 72 the product as a ‘‘hypertonicity’’ (se- hours, discontinue use and consult a lect one of the following: ‘‘eye’’ or doctor.’’ ‘‘ophthalmic’’) ‘‘(insert dosage form, (2) ‘‘Ask a doctor before use if you e.g., drops).’’ have [in bold type] narrow angle glau- (b) Indications. The labeling of the product states, under the heading ‘‘In- coma.’’ dications,’’ the following phrase: ‘‘For (3) ‘‘Overuse of this product may the temporary relief of corneal produce increased redness of the eye.’’ edema.’’ (4) ‘‘If solution changes color or be- (c) Warnings. In addition to the warn- comes cloudy, do not use.’’ ings in § 349.50, the labeling of the prod- (5) ‘‘When using this product [in bold uct contains the following warnings type] pupils may become enlarged tem- under the heading ‘‘Warnings’’ for porarily.’’ products containing any ingredient (d) Directions. The labeling of the identified in § 349.16: product contains the following infor- (1) ‘‘Do not use this product except mation under the heading ‘‘Direc- under the advice and supervision of a tions’’: Instill 1 to 2 drops in the af- doctor. If you experience eye pain, fected eye(s) up to four times daily. changes in vision, continued redness or irritation of the eye, or if the condition [53 FR 7090, Mar. 4, 1988, as amended at 65 FR worsens or persists, consult a doctor.’’ 38428, June 21, 2000] (2) ‘‘This product may cause temporary burning and irritation on being § 349.78 Labeling of eyewash drug products. instilled into the eye.’’ (3) ‘‘If solution changes color or be- (a) Statement of identity. The labeling comes cloudy, do not use.’’ of the product identifies the product (d) Directions. The labeling of the with one or more of the following product contains the following infor- terms: ‘‘eyewash,’’ ‘‘eye irrigation,’’ or mation under the heading ‘‘Direc- ‘‘eye irrigating solution.’’

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(b) Indications. The labeling of the § 349.79 Labeling of permitted com- product states, under the heading ‘‘In- binations of active ingredients. dications,’’ one of the following Statements of identity, indications, phrases: warnings, and directions for use, re- (1) ‘‘For’’ (select one of the following: spectively, applicable to each ingre- ‘‘flushing,’’ ‘‘irrigating,’’ ‘‘cleansing,’’ dient in the product may be combined ‘‘washing,’’ or ‘‘bathing’’) ‘‘the eye to to eliminate duplicative words or remove’’ (select one or more of the fol- phrases so that the resulting informa- lowing: ‘‘loose foreign material,’’ ‘‘air tion is clear and understandable. pollutants (smog or pollen),’’ or (a) Statement of identity. For a com- ‘‘chlorinated water’’). bination drug product that has an es- (2) ‘‘For’’ (select one of the following: tablished name, the labeling of the ‘‘flushing,’’ ‘‘irrigating,’’ ‘‘cleansing,’’ product states the established name of ‘‘washing,’’ or ‘‘bathing’’) ‘‘the eye to the combination drug product, followed help relieve’’ (select one or more of the by the statement of identity for each following: ‘‘irritation,’’ ‘‘discomfort,’’ ingredient in the combination, as es- ‘‘burning,’’ ‘‘stinging,’’ ‘‘smarting,’’ or tablished in the statement of identity ‘‘itching’’) ‘‘by removing’’ (select one sections of this part. For a combina- or more of the following: ‘‘loose foreign tion drug product that does not have material,’’ ‘‘air pollutants (smog or an established name, the labeling of pollen),’’ or ‘‘chlorinated water’’). the product states the statement of (c) Warnings. In addition to the warn- identity for each ingredient in the ings in § 349.50, the labeling of the prod- combination, as established in the uct contains the following warnings statement of identity sections of this under the heading ‘‘Warnings’’ for all part. eyewash products: (b) Indications. The labeling of the (1) ‘‘If you experience eye pain, product states, under the heading ‘‘In- changes in vision, continued redness or dications,’’ the indication(s) for each irritation of the eye, or if the condition ingredient in the combination, as es- worsens or persists, consult a doctor.’’ tablished in the indications sections of (2) ‘‘Obtain immediate medical treat- this part. ment for all open wounds in or near the (c) Warnings. The labeling of the eyes.’’ product states, under the heading ‘‘Warnings,’’ the warning(s) for each in- (3) ‘‘If solution changes color or be- gredient in the combination, as estab- comes cloudy, do not use.’’ lished in the warnings sections of this (d) Directions. The labeling of the part. product contains the following infor- (d) Directions. The labeling of the mation under the heading ‘‘Direc- product states, under the heading ‘‘Di- tions’’: rections,’’ directions that conform to (1) For eyewash products intended for the directions established for each in- use with an eyecup. Rinse cup with gredient in the directions sections of clean water immediately before each this part. When the time intervals or use. Avoid contamination of rim and age limitations for administration of inside surfaces of cup. Fill cup half full the individual ingredients differ, the and apply the cup to the affected eye, directions for the combination product pressing tightly to prevent the escape may not exceed any maximum dosage of the liquid, and tilt the head back- limits established for the individual in- ward. Open eyelids wide and rotate eye- gredients in the applicable OTC drug ball to ensure thorough bathing with monograph. the wash or lotion. Rinse cup with clean water after each use. § 349.80 Professional labeling. (2) For eyewash products intended for The labeling of any OTC ophthalmic use with a nozzle applicator. Flush the demulcent drug product provided to affected eye as needed, controlling the health professionals (but not to the rate of flow of solution by pressure on general public) may contain instruc- the bottle. tions for the use of these products in [53 FR 7090, Mar. 4, 1988, as amended at 68 FR professional eye examinations (i.e., 7921, Feb. 19, 2003] gonioscopy, electroretinography).

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PART 350—ANTIPERSPIRANT DRUG chloride, aluminum to zirconium, and PRODUCTS FOR OVER-THE- aluminum plus zirconium to chloride COUNTER HUMAN USE atomic ratios described in the U.S. Pharmacopeia-National Formulary. Subpart A—General Provisions The concentration of ingredients in paragraphs (b) through (j) of this sec- Sec. tion is calculated on an anhydrous 350.1 Scope. basis, omitting from the calculation 350.3 Definition. any buffer component present in the compound, in an aerosol or nonaerosol Subpart B—Active Ingredients dosage form. The concentration of in- 350.10 Antiperspirant active ingredients. gredients in paragraphs (k) through (r) of this section is calculated on an an- Subpart C—Labeling hydrous basis, omitting from the cal- 350.50 Labeling of antiperspirant drug prod- culation any buffer component present ucts. in the compound, in a nonaerosol dosage form. The labeled declaration of Subpart D—Guidelines for Effectiveness the percentage of the active ingredient Testing should exclude any water, buffer components, or propellant. 350.60 Guidelines for effectiveness testing of antiperspirant drug products. (a) Aluminum chloride up to 15 percent, calculated on the hexahydrate AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, form, in an aqueous solution nonaer- 360, 371. osol dosage form. SOURCE: 68 FR 34291, June 9, 2003, unless (b) Aluminum chlorohydrate up to 25 otherwise noted. percent. (c) Aluminum chlorohydrex poly- Subpart A—General Provisions ethylene glycol up to 25 percent. (d) Aluminum chlorohydrex pro- § 350.1 Scope. pylene glycol up to 25 percent. (a) An over-the-counter anti- (e) Aluminum dichlorohydrate up to perspirant drug product in a form suit- 25 percent. able for topical administration is gen- (f) Aluminum dichlorohydrex poly- erally recognized as safe and effective ethylene glycol up to 25 percent. and is not misbranded if it meets each (g) Aluminum dichlorohydrex pro- condition in this part and each general pylene glycol up to 25 percent. condition established in § 330.1 of this chapter. (h) Aluminum sesquichlorohydrate (b) References in this part to regu- up to 25 percent. latory sections of the Code of Federal (i) Aluminum sesquichlorohydrex Regulations are to chapter I of title 21 polyethylene glycol up to 25 percent. unless otherwise noted. (j) Aluminum sesquichlorohydrex propylene glycol up to 25 percent. § 350.3 Definition. (k) Aluminum zirconium As used in this part: octachlorohydrate up to 20 percent. Antiperspirant. A drug product ap- (l) Aluminum zirconium plied topically that reduces the produc- octachlorohydrex gly up to 20 percent. tion of perspiration (sweat) at that (m) Aluminum zirconium site. pentachlorohydrate up to 20 percent. (n) Aluminum zirconium Subpart B—Active Ingredients pentachlorohydrex gly up to 20 percent. (o) Aluminum zirconium § 350.10 Antiperspirant active ingredi- tetrachlorohydrate up to 20 percent. ents. (p) Aluminum zirconium The active ingredient of the product tetrachlorohydrex gly up to 20 percent. consists of any of the following within (q) Aluminum zirconium the established concentration and dos- trichlorohydrate up to 20 percent. age formulation. Where applicable, the (r) Aluminum zirconium ingredient must meet the aluminum to trichlorohydrex gly up to 20 percent.

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Subpart C—Labeling extra effective protection,’’ ‘‘extra effective protection lasts 24 hours,’’ or § 350.50 Labeling of antiperspirant ‘‘extra effective protection lasts all drug products. day’’. (a) Statement of identity. The labeling (c) Warnings. The labeling of the of the product contains the established product contains the following state- name of the drug, if any, and identifies ments under the heading ‘‘Warnings’’: the product as an ‘‘antiperspirant.’’ (1) ‘‘Do not use on broken skin’’. (b) Indications. The labeling of the (2) ‘‘Stop use if rash or irritation oc- product states, under the heading curs’’. ‘‘Uses,’’ the phrase listed in paragraph (3) ‘‘Ask a doctor before use if you (b)(1) of this section and may contain have kidney disease’’. any additional phrases listed in paragraphs (b)(2) through (b)(5) of this sec- (4) For products in an aerosolized dos- tion, as appropriate. Other truthful and age form. (i) ‘‘When using this product nonmisleading statements, describing [bullet] 1 keep away from face and only the uses that have been estab- mouth to avoid breathing it’’. lished and listed in paragraphs (b)(1) (ii) The warning required by § 369.21 through (b)(5) of this section, may also of this chapter for drugs in dispensers be used, as provided in § 330.1(c)(2) of pressurized by gaseous propellants. this chapter, subject to the provisions (d) Directions. The labeling of the of section 502 of the Federal Food, product contains the following state- Drug, and Cosmetic Act (the act) relat- ment under the heading ‘‘Directions’’: ing to misbranding and the prohibition ‘‘apply to underarms only’’. in section 301(d) of the act against the introduction or delivery for introduc- EFFECTIVE DATE NOTE: At 69 FR 61149, Oct. tion into interstate commerce of unap- 15, 2004, the limitation of the enhanced dura- proved new drugs in violation of section claim to 24 hours (21 CFR 350.50 (b)(3) and (b) (5)) was stayed until further notice. tion 505(a) of the act. (1) For any product, the labeling states [select one of the following: Subpart D—Guidelines for ‘‘decreases,’’ ‘‘lessens,’’ or ‘‘reduces’’] Effectiveness Testing ‘‘underarm’’ [select one of the following: ‘‘dampness,’’ ‘‘perspiration,’’ § 350.60 Guidelines for effectiveness ‘‘sweat,’’ ‘‘sweating,’’ or ‘‘wetness’’]. testing of antiperspirant drug prod- (2) The labeling may state ‘‘also [se- ucts. lect one of the following: ‘decreases,’ An antiperspirant in finished dosage ‘lessens,’ or ‘reduces’] underarm [select form may vary in degree of effective- one of the following: ‘dampness,’ ‘per- ness because of minor variations in for- spiration,’ ‘sweat,’ ‘sweating,’ or ‘wet- mulation. To assure the effectiveness ness’] due to stress’’. of an antiperspirant, the Food and (3) For products that demonstrate Drug Administration is providing standard effectiveness (20 percent guidelines that manufacturers may use sweat reduction) over a 24-hour period, in testing for effectiveness. These the labeling may state [select one of guidelines are on file in the Dockets the following: ‘‘all day protection,’’ Management Branch (HFA–305), Food ‘‘lasts all day,’’ ‘‘lasts 24 hours,’’ or ‘‘24 and Drug Administration, 5630 Fishers hour protection’’]. Lane, rm. 1061, Rockville, MD 20852. (4) For products that demonstrate extra effectiveness (30 percent sweat These guidelines are available on the reduction), the labeling may state FDA’s web site at http://www.fda.gov/ ‘‘extra effective’’. cder/otc/index.htm or on request for a (5) Products that demonstrate extra nominal charge by submitting a Free- effectiveness (30 percent sweat reduc- dom of Information (FOI) request in tion) sustained over a 24-hour period writing to FDA’s Division of Freedom may state the claims in paragraphs of Information (address is located on (b)(3) and (b)(4) of this section either individually or combined, e.g., ‘‘24 hour 1 See § 201.66(b)(4) of this chapter for defini- extra effective protection’’, ‘‘all day tion of bullet.

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the agency’s web site at http:// § 352.3 Definitions. www.fda.gov. As used in this part: [68 FR 34291, June 9, 2003, as amended at 76 (a) Minimal erythema dose (MED). The FR 31470, June 1, 2011; 79 FR 68115, Nov. 14, quantity of erythema-effective energy 2014] (expressed as Joules per square meter) required to produce the first percep- PART 352—SUNSCREEN DRUG tible, redness reaction with clearly de- PRODUCTS FOR OVER-THE- fined borders. COUNTER HUMAN USE [STAYED (b) Product category designation (PCD). INDEFINITELY] A labeling designation for sunscreen drug products to aid in selecting the Subpart A—General Provisions type of product best suited to an individual’s complexion (pigmentation) Sec. and desired response to ultraviolet 352.1 Scope. 352.3 Definitions. (UV) radiation. (1) Minimal sun protection product. A Subpart B—Active Ingredients sunscreen product that provides a sun protection factor (SPF) value of 2 to 352.10 Sunscreen active ingredients. under 12. 352.20 Permitted combinations of active ingredients. (2) Moderate sun protection product. A sunscreen product that provides an Subpart C—Labeling SPF value of 12 to under 30. (3) High sun protection product. A sun- 352.50 Principal display panel of all sunscreen product that provides an SPF screen drug products. value of 30 or above. 352.52 Labeling of sunscreen drug products. 352.60 Labeling of permitted combinations (c) Sunscreen active ingredient. An ac- of active ingredients. tive ingredient listed in § 352.10 that ab- sorbs, reflects, or scatters radiation in Subpart D—Testing Procedures the UV range at wavelengths from 290 to 400 nanometers. 352.70 Standard sunscreen. 352.71 Light source (solar simulator). (d) Sun protection factor (SPF) value. 352.72 General testing procedures. The UV energy required to produce an 352.73 Determination of SPF value. MED on protected skin divided by the 352.76 Determination if a product is water UV energy required to produce an MED resistant or very water resistant. on unprotected skin, which may also be 352.77 Test modifications. defined by the following ratio: SPF AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, value = MED (protected skin (PS))/ 360, 371. MED (unprotected skin (US)), where SOURCE: 64 FR 27687, May 21, 1999, unless MED (PS) is the minimal erythema otherwise noted. dose for protected skin after application of 2 milligrams per square centi- EFFECTIVE DATE NOTE: At 68 FR 33381, June 4, 2003, part 352 was stayed until further no- meter of the final formulation of the tice, effective June 4, 2004. sunscreen product, and MED (US) is the minimal erythema dose for unpro- Subpart A—General Provisions tected skin, i.e., skin to which no sunscreen product has been applied. In ef- § 352.1 Scope. fect, the SPF value is the reciprocal of (a) An over-the-counter sunscreen the effective transmission of the prod- drug product in a form suitable for top- uct viewed as a UV radiation filter. ical administration is generally recognized as safe and effective and is not Subpart B—Active Ingredients misbranded if it meets each condition in this part and each general condition § 352.10 Sunscreen active ingredients. established in § 330.1 of this chapter. The active ingredient of the product (b) References in this part to regu- consists of any of the following, within latory sections of the Code of Federal the concentration specified for each in- Regulations are to Chapter I of Title 21 gredient, and the finished product pro- unless otherwise noted. vides a minimum SPF value of not less

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than 2 as measured by the testing pro- combined with each other in a single cedures established in subpart D of this product when used in the concentra- part: tions established for each ingredient in (a) Aminobenzoic acid (PABA) up to § 352.10. The concentration of each ac- 15 percent. tive ingredient must be sufficient to (b) Avobenzone up to 3 percent. contribute a minimum SPF of not less (c) Cinoxate up to 3 percent. than 2 to the finished product. The fin- (d) [Reserved] ished product must have a minimum (e) Dioxybenzone up to 3 percent. SPF of not less than the number of (f) Homosalate up to 15 percent. sunscreen active ingredients used in (g) [Reserved] (h) Menthyl anthranilate up to 5 per- the combination multiplied by 2. cent. (2) Two or more sunscreen active in- (i) Octocrylene up to 10 percent. gredients identified in § 352.10(b), (c), (j) Octyl methoxycinnamate up to 7.5 (e), (f), (i) through (l), (o), and (q) may percent. be combined with each other in a single (k) Octyl salicylate up to 5 percent. product when used in the concentra- (l) Oxybenzone up to 6 percent. tions established for each ingredient in (m) Padimate O up to 8 percent. § 352.10. The concentration of each ac- (n) Phenylbenzimidazole sulfonic tive ingredient must be sufficient to acid up to 4 percent. contribute a minimum SPF of not less (o) Sulisobenzone up to 10 percent. than 2 to the finished product. The fin- (p) Titanium dioxide up to 25 percent. ished product must have a minimum (q) Trolamine salicylate up to 12 per- SPF of not less than the number of cent. sunscreen active ingredients used in (r) Zinc oxide up to 25 percent. the combination multiplied by 2. [64 FR 27687, May 21, 1999] (b) Combinations of sunscreen and skin EFFECTIVE DATE NOTE: At 67 FR 41823, June protectant active ingredients. Any single 20, 2002, § 352.10 was amended by revising sunscreen active ingredient or any per- paragraphs (f) through (n), effective Sept. 1, mitted combination of sunscreen ac- 2002. This amendment could not be incor- tive ingredients when used in the con- porated because at 66 FR 67485, Dec. 31, 2001, centrations established for each ingre- the effective date was stayed until further notice. For the convenience of the user, the dient in § 352.10 may be combined with revised text is set forth as follows: one or more skin protectant active ingredients identified in § 347.10(a), (d), § 352.10 Sunscreen active ingredients. (e), (g), (h), (i), (k), (l), (m), and (r) of this chapter. The concentration of each * * * * * sunscreen active ingredient must be (f) Ensulizole up to 4 percent. sufficient to contribute a minimum (g) Homosalate up to 15 percent. SPF of not less that 2 to the finished (h) [Reserved] product. The finished product must (i) Meradimate up to 5 percent. have a minimum SPF of not less than (j) Octinoxate up to 7.5 percent. (k) Octisalate up to 5 percent. the number of sunscreen active ingredi- (l) Octocrylene up to 10 percent. ents used in the combination multi- (m) Oxybenzone up to 6 percent. plied by 2, and the product must be la- (n) Padimate O up to 8 percent. beled according to § 352.60. (c) [Reserved] * * * * * [64 FR 27687, May 21, 1999, as amended at 68 § 352.20 Permitted combinations of ac- FR 33380, June 4, 2003] tive ingredients. EFFECTIVE DATE NOTE: At 67 FR 41823, June The SPF of any combination product 20, 2002, § 352.20 was amended by revising is measured by the testing procedures paragraphs (a)(1) through (a)(2), effective established in subpart D of this part. Sept. 1, 2002. This amendment could not be (a) Combinations of sunscreen active in- incorporated because at 66 FR 67485, Dec. 31, gredients. (1) Two or more sunscreen ac- 2001 the effective date was stayed until fur- tive ingredients identified in § 352.10(a), ther notice. For the convenience of the user, (c), (e), (f), and (h) through (r) may be the text is set forth as follows:

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§ 352.20 Permitted combinations of active (b) For products that satisfy the water ingredients. resistant sunscreen product testing procedures in § 352.76. (1) (Select one of the * * * * * following: ‘‘Water,’’ ‘‘Water/Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Resistant.’’ (a) Combinations of sunscreen active ingredients. (1) Two or more sunscreen active ingre- (2) ‘‘SPF (insert SPF value of the dients identified in § 352.10(a), (c), (e), (f), (g), product, as stated in paragraph (a)(1) and (i) through (r) may be combined with or (a)(2) of this section, after it has each other in a single product when used in been tested using the water resistant the concentrations established for each in- sunscreen product testing procedures gredient in § 352.10. The concentration of in § 352.76).’’ each active ingredient must be sufficient to (c) For products that satisfy the very contribute a minimum SPF of not less than water resistant sunscreen product testing 2 to the finished product. The finished prod- procedures in § 352.76. (1) ‘‘Very’’ (select uct must have a minimum SPF of not less than the number of sunscreen active ingredi- one of the following: ‘‘Water,’’ ‘‘Water/ ents used in the combination multiplied by 2. Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Re- (2) Two or more sunscreen active ingredi- sistant.’’ ents identified in § 352.10(b), (c), (e), (g), (j) (2) ‘‘SPF (insert SPF value of the through (m), (o), and (q) may be combined product, as stated in paragraph (a)(1) with each other in a single product when or (a)(2) of this section, after it has used in the concentrations established for been tested using the very water resist- each ingredient in § 352.10. The concentration ant sunscreen product testing proce- of each active ingredient must be sufficient dures in § 352.76).’’ to contribute a minimum SPF of not less than 2 to the finished product. The finished § 352.52 Labeling of sunscreen drug product must have a minimum SPF of not products. less than the number of sunscreen active ingredients used in the combination multiplied (a) Statement of identity. The labeling by 2. of the product contains the established name of the drug, if any, and identifies * * * * * the product as a ‘‘sunscreen.’’ (b) Indications. The labeling of the product states, under the heading Subpart C—Labeling ‘‘Uses,’’ all of the phrases listed in paragraph (b)(1) of this section that are § 352.50 Principal display panel of all applicable to the product and may con- sunscreen drug products. tain any of the additional phrases list- In addition to the statement of iden- ed in paragraph (b)(2) of this section, as tity required in § 352.52, the following appropriate. Other truthful and non- labeling statements shall be promi- misleading statements, describing only nently placed on the principal display the uses that have been established and panel: listed in this paragraph (b), may also (a) For products that do not satisfy the be used, as provided in § 330.1(c)(2) of water resistant or very water resistant this chapter, subject to the provisions sunscreen product testing procedures in of section 502 of the act relating to § 352.76—(1) For products with SPF values misbranding and the prohibition in sec- up to 30. ‘‘SPF (insert tested SPF value tion 301(d) of the act against the intro- of the product up to 30).’’ duction or delivery for introduction (2) For products with SPF values over into interstate commerce of unap- 30. ‘‘SPF 30’’ (select one of the fol- proved new drugs in violation of sec- lowing: ‘‘plus’’ or ‘‘ + ’’). Any state- tion 505(a) of the act. ment accompanying the marketed (1) For products containing any ingre- product that states a specific SPF dient in § 352.10. (i) ‘‘[bullet] 1 helps pre- value above 30 or similar language in- vent sunburn [bullet] higher SPF gives dicating a person can stay in the sun more sunburn protection’’. more than 30 times longer than with- (ii) For products that satisfy the water out sunscreen will cause the product to resistant testing procedures identified in be misbranded under section 502 of the § 352.76. ‘‘[bullet] retains SPF after 40 Federal Food, Drug, and Cosmetic Act (the act). 1 See § 201.66(b)(4) of this chapter.

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minutes of’’ (select one or more of the ing ‘‘Directions.’’ More detailed direc- following: ‘‘activity in the water,’’ tions applicable to a particular product ‘‘sweating,’’ or ‘‘perspiring’’). formulation (e.g., cream, gel, lotion, (iii) For products that satisfy the very oil, spray, etc.) may also be included. water resistant testing procedures identi- (1) For products containing any ingre- fied in § 352.76. ‘‘[bullet] retains SPF dient in § 352.10. (i) ‘‘[bullet] apply’’ (se- after 80 minutes of’’ (select one or more lect one or more of the following, as of the following: ‘‘activity in the applicable: ‘‘liberally,’’ ‘‘generously,’’ water,’’ ‘‘sweating,’’ or ‘‘perspiring’’). ‘‘smoothly,’’ or ‘‘evenly’’) ‘‘(insert ap- (2) Additional indications. In addition propriate time interval, if a waiting pe- to the indications provided in para- riod is needed) before sun exposure and graph (b)(1) of this section, the fol- as needed’’. lowing may be used for products con- (ii) ‘‘[bullet] children under 6 months taining any ingredient in § 352.10: of age: ask a doctor’’. (i) For products that provide an SPF of (2) In addition to the directions pro- 2 to under 12. Select one or both of the vided in § 352.52(d)(1), the following may following: [‘‘[bullet]’’ (select one of the be used for products containing any in- following: ‘‘provides minimal,’’ ‘‘pro- gredient in § 352.10. ‘‘[bullet] reapply as vides minimum,’’ ‘‘minimal,’’ or ‘‘min- needed or after towel drying, swim- imum’’) ‘‘protection against’’ (select ming, or’’ (select one of the following: one of the following: ‘‘sunburn’’ or ‘‘sweating’’ or ‘‘perspiring’’). ‘‘sunburn and tanning’’)], or ‘‘[bullet] (3) If the additional directions provided for skin that sunburns minimally’’. in § 352.52(d)(2) are used, the phrase ‘‘and (ii) For products that provide an SPF of as needed’’ in § 352.52(d)(1) is not re- 12 to under 30. Select one or both of the quired. following: [‘‘[bullet]’’ (select one of the (4) For products marketed as a lip pro- following: ‘‘provides moderate’’ or tectant or lipstick. The directions in ‘‘moderate’’) ‘‘protection against’’ (se- paragraphs (d)(1) and (d)(2) of this sec- lect one of the following: ‘‘sunburn’’ or tion are not required. ‘‘sunburn and tanning’’)], or ‘‘[bullet] (e) Statement on product performance— for skin that sunburns easily’’. (1) For products containing any ingre- (iii) For products that provide an SPF dient identified in § 352.10, the following of 30 or above. Select one or both of the PCD labeling claims may be used under following: [‘‘[bullet]’’ (select one of the the heading ‘‘Other information’’ or any- following: ‘‘provides high’’ or ‘‘high’’) where outside of the ‘‘Drug Facts’’ box or ‘‘protection against’’ (select one of the enclosure. following: ‘‘sunburn’’ or ‘‘sunburn and (i) For products containing active ingre- tanning’’)], or ‘‘[bullet] for skin highly dient(s) that provide an SPF value of 2 to sensitive to sunburn’’. under 12. (Select one of the following: (c) Warnings. The labeling of the ‘‘minimal’’ or ‘‘minimum’’) ‘‘sun pro- product contains the following warn- tection product.’’ ings under the heading ‘‘Warnings:’’ (ii) For products containing active in- (1) For products containing any ingre- gredient(s) that provide an SPF value of dient in § 352.10. (i) ‘‘When using this 12 to under 30. ‘‘moderate sun protec- product [bullet] keep out of eyes. Rinse tion product.’’ with water to remove.’’ (iii) For products containing active in- (ii) ‘‘Stop use and ask a doctor if gredient(s) that provide an SPF value of [bullet] rash or irritation develops and 30 or above. ‘‘high sun protection prod- lasts’’. uct.’’ (2) For products containing any ingre- (2) For products containing any ingredient identified in § 352.10 marketed as a dient identified in § 352.10, the following lip protectant or lipstick. The external labeling statement may be used under the use only warning in § 201.66(c)(5)(i) of heading ‘‘Other information’’ or any- this chapter and the warning in para- where outside of the ‘‘Drug Facts’’ box or graph (c)(1)(i) of this section are not re- enclosure. ‘‘Sun alert: Limiting sun ex- quired. posure, wearing protective clothing, (d) Directions. The labeling of the and using sunscreens may reduce the product contains the following state- risks of skin aging, skin cancer, and ments, as appropriate, under the head- other harmful effects of the sun.’’ Any

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variation of this statement will cause horizontal barlines and hairlines de- the product to be misbranded under scribed in § 201.66(d)(8), may be omitted. section 502 of the act. [64 FR 27687, May 21, 1999, as amended at 68 (f) Products labeled for use only on spe- FR 33380, June 4, 2003] cific small areas of the face (e.g., lips, nose, ears, and/or around eyes) and that § 352.60 Labeling of permitted com- meet the criteria established in binations of active ingredients. § 201.66(d)(10) of this chapter. The title, Statements of identity, indications, headings, subheadings, and information warnings, and directions for use, re- described in § 201.66(c) of this chapter spectively, applicable to each ingre- shall be printed in accordance with the dient in the product may be combined following specifications: to eliminate duplicative words or (1) The labeling shall meet the re- phrases so that the resulting informa- quirements of § 201.66(c) of this chapter tion is clear and understandable. except that the title, headings, and in- (a) Statement of identity. For a com- formation described in § 201.66(c)(1), bination drug product that has an es- (c)(3), and (c)(7) may be omitted, and tablished name, the labeling of the the headings, subheadings, and infor- product states the established name of mation described in § 201.66(c)(2), (c)(4), the combination drug product, followed (c)(5), and (c)(6) may be presented as by the statement of identity for each follows: ingredient in the combination, as es- (i) The active ingredients tablished in the statement of identity (§ 201.66(c)(2) of this chapter) shall be sections of the applicable OTC drug listed in alphabetical order. monographs. For a combination drug (ii) The heading and the indication product that does not have an estab- required by § 201.66(c)(4) of this chapter lished name, the labeling of the prod- may be limited to: ‘‘Use [in bold type] uct states the statement of identity for helps protect against sunburn.’’ For a each ingredient in the combination, as lip protectant product, the heading and established in the statement of iden- the indication required by § 201.66(c)(4) tity sections of the applicable OTC may be limited to: ‘‘Use [in bold type] drug monographs. helps protect against sunburn and (b) Indications. The labeling of the chapped lips.’’ product states, under the heading (iii) The ‘‘external use only’’ warning ‘‘Uses,’’ the indication(s) for each in- in § 201.66(c)(5)(i) of this chapter may be gredient in the combination as estab- omitted. lished in the indications sections of the (iv) The subheadings in applicable OTC drug monographs, un- § 201.66(c)(5)(iii) through (c)(5)(vii) of less otherwise stated in this paragraph. this chapter may be omitted, provided Other truthful and nonmisleading the information after the heading statements, describing only the indica- ‘‘Warnings’’ states: ‘‘Keep out of eyes.’’ tions for use that have been established and ‘‘Stop use if skin rash occurs.’’ in the applicable OTC drug monographs (v) The warning in § 201.66(c)(5)(x) of or listed in this paragraph (b), may this chapter may be limited to the fol- also be used, as provided by § 330.1(c)(2) lowing: ‘‘Keep out of reach of chil- of this chapter, subject to the provi- dren.’’ sions of section 502 of the Federal (vi) For a lip protectant product or Food, Drug, and Cosmetic Act (the act) lipstick, the warnings ‘‘Keep out of relating to misbranding and the prohi- eyes’’ in § 352.52(f)(1)(iv) and ‘‘Keep out bition in section 301(d) of the act of reach of children’’ in § 352.52(f)(1)(v) against the introduction or delivery for and the directions in § 352.52(d) may be introduction into interstate commerce omitted. of unapproved new drugs in violation of (2) The labeling shall be printed in section 505(a) of the act. accordance with the requirements of (1) In addition, the labeling of the § 201.66(d) of this chapter except that product may contain any of the ‘‘other any requirements related to allowable statements’’ that are identi- § 201.66(c)(1), (c)(3), and (c)(7), and the fied in the applicable monographs.

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(2) For permitted combinations con- mining the SPF value of a sunscreen taining a sunscreen and a skin protect- drug product to ensure the uniform ant identified in § 352.20(b), any or all of evaluation of sunscreen drug products. the applicable indications for sun- The standard sunscreen shall be an 8- screens in § 352.52(b) and the indication percent homosalate preparation with a for skin protectants in § 347.50(b)(2)(i) of mean SPF value of 4.47 (standard devi- this chapter should be used. For prod- ation = 1.279). In order for the SPF de- ucts marketed as a lip protectant, the termination of a test product to be indication in § 352.52(f)(1)(ii) should be considered valid, the SPF of the stand- used. ard sunscreen must fall within the (c) Warnings. The labeling of the standard deviation range of the ex- product states, under the heading pected SPF (i.e., 4.47 ±1.279) and the 95- ‘‘Warnings,’’ the warning(s) for each in- percent confidence interval for the gredient in the combination, as estab- mean SPF must contain the value 4. lished in the warnings section of the (b) Preparation of the standard applicable OTC drug monographs, ex- homosalate sunscreen. (1) The standard cept that the warning for skin homosalate sunscreen is prepared from protectants in § 347.50(c)(3) of this chap- two different preparations (preparation ter is not required for permitted com- A and preparation B) with the fol- binations containing a sunscreen and a lowing compositions: skin protectant identified in § 352.20(b). For products marketed as a lip protect- COMPOSITION OF PREPARATION A AND ant or lipstick, § 352.52(f)(1)(iii), PREPARATION B OF THE STANDARD SUNSCREEN (f)(1)(iv) (except ‘‘Keep out of eyes,’’ which may be omitted), and (f)(1)(vi) Ingredients Percent by weight apply. Preparation A (d) Directions. The labeling of the Lanolin ...... 5.00 Homosalate ...... 8.00 product states, under the heading ‘‘di- White petrolatum ...... 2.50 rections,’’ directions that conform to Stearic acid ...... 4.00 the directions established for each in- Propylparaben ...... 0.05 gredient in the directions sections of Preparation B Methylparaben ...... 0.10 the applicable OTC drug monographs, Edetate disodium ...... 0.05 unless otherwise stated in this para- Propylene glycol ...... 5.00 graph. When the time intervals or age Triethanolamine ...... 1.00 limitations for administration of the Purified water U.S.P ...... 74.30 individual ingredients differ, the direc- (2) Preparation A and preparation B tions for the combination product may are heated separately to 77 to 82 °C, not contain any dosage that exceeds with constant stirring, until the con- those established for any individual in- tents of each part are solubilized. Add gredient in the applicable OTC drug preparation A slowly to preparation B monograph(s), and may not provide for while stirring. Continue stirring until use by any age group lower than the the emulsion formed is cooled to room highest minimum age limit established temperature (15 to 30 °C). Add suffi- for any individual ingredient. For per- cient purified water to obtain 100 mitted combinations containing a sun- grams of standard sunscreen prepara- screen and a skin protectant identified tion. in § 352.20(b), the directions for sun- (c) Assay of the standard homosalate screens in § 352.52(d) should be used. For sunscreen. Assay the standard products marketed as a lip protectant or lipstick, § 352.52(d)(4) applies. homosalate sunscreen preparation by the following method to ensure proper [64 FR 27687, May 21, 1999, as amended at 68 concentration: FR 33380, June 4, 2003] (1) Preparation of the assay solvent. The solvent consists of 1 percent gla- Subpart D—Testing Procedures cial acetic acid (V/V) in denatured ethanol. The denatured ethanol should not § 352.70 Standard sunscreen. contain a UV radiation absorbing dena- (a) Laboratory validation. A standard turant. sunscreen shall be used concomitantly (2) Preparation of a 1-percent solution in the testing procedures for deter- of the standard homosalate sunscreen

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preparation. Accurately weigh 1 gram of its total energy output contributed by the standard homosalate sunscreen wavelengths longer than 400 nano- preparation into a 100-milliliter volu- meters. In addition, a solar simulator metric flask. Add 50 milliliters of the should have no significant time-related assay solvent. Heat on a steam bath fluctuations in radiation emissions and mix well. Cool the solution to after an appropriate warmup time, and room temperature (15 to 30 °C). Then it should have good beam uniformity dilute the solution to volume with the (within 10 percent) in the exposure assay solvent and mix well to make a plane. To ensure that the solar simu- 1-percent solution. lator delivers the appropriate spectrum (3) Preparation of the test solution (1:50 of UV radiation, it must be measured dilution of the 1-percent solution). Filter periodically with an accurately-cali- a portion of the 1-percent solution brated spectroradiometer system or through number 1 filter paper. Discard equivalent instrument. the first 10 to 15 milliliters of the filtrate. Collect the next 20 milliliters of § 352.72 General testing procedures. the filtrate (second collection). Add 1 (a) Selection of test subjects (male and milliliter of the second collection of female). (1) Only fair-skin subjects with the filtrate to a 50-milliliter volu- skin types I, II, and III using the fol- metric flask. Dilute this solution to lowing guidelines shall be selected: volume with assay solvent and mix well. This is the test solution (1:50 dilu- Selection of Fair-skin Subjects tion of the 1-percent solution). Skin Type and Sunburn and Tanning History (4) Spectrophotometric determination. (Based on first 30 to 45 minutes sun exposure The absorbance of the test solution is after a winter season of no sun exposure.) measured in a suitable double beam I—Always burns easily; never tans (sen- spectrophotometer with the assay sol- sitive). vent and reference beam at a wave- II—Always burns easily; tans minimally (sensitive). length near 306 nanometers. III—Burns moderately; tans gradually (light (5) Calculation of the concentration of brown) (normal). homosalate. The concentration of IV—Burns minimally; always tans well homosalate is determined by the fol- (moderate brown) (normal). lowing formula which takes into con- V—Rarely burns; tans profusely (dark sideration the absorbance of the sam- brown) (insensitive). ple of the test solution, the dilution of VI—Never burns; deeply pigmented (insensi- the 1-percent solution (1:50), the weight tive). of the sample of the standard (2) A medical history shall be ob- homosalate sunscreen preparation (1 tained from all subjects with emphasis gram), and the standard absorbance on the effects of sunlight on their skin. value (172) of homosalate as deter- Ascertain the general health of the in- mined by averaging the absorbance of a dividual, the individual’s skin type (I, large number of batches of raw II, or III), whether the individual is homosalate: taking medication (topical or sys- Concentration of homosalate = absorb- temic) that is known to produce abnor- ance × 50 × 100 × 172 = percent con- mal sunlight responses, and whether centration by weight. the individual is subject to any abnor- mal responses to sunlight, such as a § 352.71 Light source (solar simulator). phototoxic or photoallergic response. A solar simulator used for deter- (b) Test site inspection. The physical mining the SPF of a sunscreen drug examination shall determine the pres- product should be filtered so that it ence of sunburn, suntan, scars, active provides a continuous emission spec- dermal lesions, and uneven skin tones trum from 290 to 400 nanometers simi- on the areas of the back to be tested. lar to sunlight at sea level from the The presence of nevi, blemishes, or sun at a zenith angle of 10° it has less moles will be acceptable if in the phy- than 1 percent of its total energy out- sician’s judgment they will not inter- put contributed by nonsolar wave- fere with the study results. Excess hair lengths shorter than 290 nanometers; on the back is acceptable if the hair is and it has not more than 5 percent of clipped or shaved.

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(c) Informed consent. Legally effective being evaluated at the same time, the written informed consent must be ob- test products and the standard sun- tained from all individuals. screen, as specified in § 352.70, should be (d) Test site delineation—(1) Test site applied in a blinded, randomized man- area. A test site area serves as an area ner. If only one sunscreen drug product for determining the subject’s MED is being tested, the testing subsites after application of either the sun- should be exposed to the varying doses screen standard or the test sunscreen of UV radiation in a randomized man- product, or for determining the sub- ner. ject’s MED when the skin is unpro- (f) Waiting period. Before exposing the tected (control site). The area to be test site areas after applying a product, tested shall be the back between the a waiting period of at least 15 minutes beltline and the shoulder blade is required. (scapulae) and lateral to the midline. (g) Number of subjects. A test panel Each test site area for applying a prod- shall consist of not more than 25 sub- uct or the standard sunscreen shall be jects with the number fixed in advance a minimum of 50-square centimeters, by the investigator. From this panel, e.g., 5 × 10 centimeters. The test site at least 20 subjects must produce valid areas are outlined with ink. If the per- data for analysis. son is to be tested in an upright position, the lines shall be drawn on the (h) Response criteria. In order that the skin with the subject upright. If the person who evaluates the MED re- subject is to be tested while prone, the sponses does not know which sunscreen markings shall be made with the sub- formulation was applied to which site ject prone. or what doses of UV radiation were ad- (2) Test subsite area. Each test site ministered, he/she must not be the area shall be divided into at least three same person who applied the sunscreen test subsite areas that are at least 1 drug product to the test site or admin- square centimeter. Usually four or five istered the doses of UV radiation. After subsites are employed. Each test UV radiation exposure from the solar subsite within a test site area is sub- simulator is completed, all immediate jected to a specified dosage of UV radi- responses shall be recorded. These ination, in a series of UV radiation expo- clude several types of typical responses sures, in which the test site area is ex- such as the following: An immediate posed for the determination of the darkening or tanning, typically greyish MED. or purplish in color, fading in 30 to 60 (e) Application of test materials. To en- minutes, and attributed to photo-oxi- sure standardized reporting and to de- dation of existing melanin granules; fine a product’s SPF value, the applica- immediate reddening, fading rapidly, tion of the product shall be expressed and viewed as a normal response of on a weight basis per unit area which capillaries and venules to heat, visible establishes a standard film. Both the and infrared radiation; and an imme- test sunscreen product and the stand- diate generalized heat response, resem- ard sunscreen application shall be 2 bling prickly heat rash, fading in 30 to milligrams per square centimeter. For 60 minutes, and apparently caused by oils and most lotions, the viscosity is heat and moisture generally irritating such that the material can be applied to the skin’s surface. After the imme- with a volumetric syringe. For creams, diate responses are noted, each subject heavy gels, and butters, the product shall shield the exposed area from fur- shall be warmed slightly so that it can ther UV radiation for the remainder of be applied volumetrically. On heating, the test day. The MED is determined 22 care shall be taken not to alter the to 24 hours after exposure. The ery- product’s physical characteristics, es- thema responses of the test subject pecially separation of the formula- should be evaluated under the fol- tions. Pastes and ointments shall be lowing conditions: The source of illu- weighed, then applied by spreading on mination should be either a tungsten the test site area. A product shall be light bulb or a warm white fluorescent spread by using a finger cot. If two or light bulb that provides a level of illu- more sunscreen drug products are mination at the test site within the

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range of 450 to 550 lux, and the test sub- cates the product was not spread even- ject should be in the same position ly), or if the subject was noncompliant used when the test site was irradiated. (e.g., subject withdraws from the test Testing depends upon determining the due to illness or work conflicts, subject smallest dose of energy that produces does not shield the exposed testing redness reaching the borders of the ex- sites from further UV radiation until posure site at 22 to 24 hours the MED is read, etc.). postexposure for each series of exposures. To determine the MED, some- § 352.73 Determination of SPF value. what more intense erythemas must also be produced. The goal is to have (a)(1) The following erythema action some exposures that produce abso- spectrum shall be used to calculate the lutely no effect, and of those exposures erythema effective exposure of a solar that produce an effect, the maximal ex- simulator: posure should be no more than twice Vi (λ) = 1.0 (250 <λ <298 nm) the total energy of the minimal expo- 0.094 (298 - λ Vi (λ) = 1.0 ) (298 <λ <328 nanometers) sure. V (λ) = 1.00.015 (139 - λ) (328 <λ <400 nanometers) (i) Rejection of test data. Test data i shall be rejected if the exposure series (2) The data contained in this action fails to elicit an MED response on ei- spectrum are to be used as spectral ther the treated or unprotected skin weighting factors to calculate the ery- sites, or if the responses on the treated thema effective exposure of a solar sites are randomly absent (which indi- simulator as follows:

(b) Determination of MED of the unpro- inherent MED. The doses selected shall tected skin. A series of UV radiation ex- be a geometric series represented by posures expressed as Joules per square (1.25n), wherein each exposure time in- meter (adjusted to the erythema action terval is 25 percent greater than the spectrum calculated according to previous time to maintain the same § 352.73(a)) is administered to the relative uncertainty (expressed as a subsite areas on each subject with an constant percentage), independent of accurately calibrated solar simulator. the subject’s sensitivity to UV radi- A series of five exposures shall be ad- ation, regardless of whether the subject ministered to the untreated, unpro- has a high or low MED. Usually, the tected skin to determine the subject’s MED of a person’s unprotected skin is

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determined the day prior to testing a SPF value = the ratio of erythema ef- product. This MED(US) shall be used in fective exposure (Joules per square the determination of the series of UV meter) (MED(PS)) to the erythema ef- radiation exposures to be administered fective exposure (Joules per square to the protected site in subsequent meter) (MED(US)). testing. The MED(US) should be deter- (d) Determination of the test product’s mined again on the same day as the SPF value and PCD. Use data from at standard and test sunscreens and this least 20 test subjects with n rep- MED(US) should be used in calculating resenting the number of subjects used. the SPF. First, for each subject, compute the (c) Determination of individual SPF SPF value as stated in § 352.73(b) and values. A series of UV radiation expo- (c). Second, compute the mean SPF sures expressed as Joules per square value, x¯ , and the standard deviation, s, meter (adjusted to the erythema action for these subjects. Third, obtain the spectrum calculated according to upper 5-percent point from the t dis- § 352.73(a)) is administered to the tribution table with n-1 degrees of free- subsite areas on each subject with an dom. Denote this value by t. Fourth, accurately-calibrated solar simulator. compute ts/ √n. Denote this quantity A series of seven exposures shall be ad- by A (i.e., A = ts/ √n). Fifth, calculate ministered to the protected test sites the SPF value to be used in labeling as to determine the MED of the protected follows: the label SPF equals the larg- skin (MED(PS)). The doses selected est whole number less than x¯ . - A. shall consist of a geometric series of Sixth and last, the drug product is five exposures, where the middle expo- classified into a PCD as follows: if 30 + sure is placed to yield the expected A

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(3) 20-minute rest period (do not PART 355—ANTICARIES DRUG towel test sites). PRODUCTS FOR OVER-THE- (4) 20 minutes moderate activity in COUNTER HUMAN USE water. (5) Conclude water test (air dry test Subpart A—General Provisions sites without toweling). (6) Begin solar simulator exposure to Sec. test site areas as described in § 352.73. 355.1 Scope. (b) Procedure for testing a very water 355.3 Definitions. resistant sunscreen product. For sun- Subpart B—Active Ingredients screen products making the claim of ‘‘very water resistant,’’ the label SPF 355.10 Anticaries active ingredients. shall be the label SPF value deter- 355.20 Packaging conditions. mined after 80 minutes of water immer- sion using the following procedure for Subpart C—Labeling the very water resistant test: 355.50 Labeling of anticaries drug products. (1) Apply sunscreen product (followed 355.55 Principal display panel of all fluoride by the waiting period after application rinse drug products. of the sunscreen product indicated on 335.60 Professional labeling. the product labeling). (2) 20 minutes moderate activity in Subpart D—Testing Procedures water. 355.70 Testing procedures for fluoride den- (3) 20-minute rest period (do not tifrice drug products. towel test sites). AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (4) 20 minutes moderate activity in 360, 371. water. (5) 20-minute rest period (do not SOURCE: 60 FR 52507, Oct. 6, 1995, unless towel test sites). otherwise noted. (6) 20 minutes moderate activity in EDITORIAL NOTE: Nomenclature changes to water. part 355 appear at 69 FR 13717, Mar. 24, 2004. (7) 20-minute rest period (do not towel test sites). Subpart A—General Provisions (8) 20 minutes moderate activity in water. § 355.1 Scope. (9) Conclude water test (air dry test (a) An over-the-counter anticaries sites without toweling). drug product in a form suitable for top- (10) Begin solar simulator exposure ical administration to the teeth is gen- to test site areas as described in erally recognized as safe and effective § 352.73. and is not misbranded if it meets each condition in this part and each general § 352.77 Test modifications. condition established in § 330.1 of this The formulation or mode of adminis- chapter. tration of certain products may require (b) References in this part to regu- modification of the testing procedures latory sections of the Code of Federal in this subpart. In addition, alternative Regulations are to chapter I of title 21 methods (including automated or in unless otherwise noted. vitro procedures) employing the same basic procedures as those described in § 355.3 Definitions. this subpart may be used. Any proposed As used in this part: modification or alternative procedure (a) Abrasive. Solid materials that are shall be submitted as a petition in ac- added to dentifrices to facilitate me- cord with § 10.30 of this chapter. The pe- chanical removal of dental plaque, de- tition should contain data to support bris, and stain from tooth surfaces. the modification or data dem- (b) Anhydrous glycerin. An ingredient onstrating that an alternative proce- that may be prepared by heating glyc- dure provides results of equivalent ac- erin U.S.P. at 150 °C for 2 hours to drive curacy. All information submitted will off the moisture content. be subject to the disclosure rules in (c) Anticaries drug. A drug that aids part 20 of this chapter. in the prevention and prophylactic

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treatment of dental cavities (decay, Subpart B—Active Ingredients caries). (d) Dental caries. A disease of calcified § 355.10 Anticaries active ingredients. tissues of teeth characterized by The active ingredient of the product demineralization of the inorganic por- consists of any of the following when tion and destruction of the organic ma- used in the concentration and dosage trix. form established for each ingredient: (e) Dentifrice. An abrasive-containing (a) Sodium fluoride—(1) Dentifrices con- dosage form (gel, paste, or powder) for taining 850 to 1,150 ppm theoretical total delivering an anticaries drug to the fluorine in a gel or paste dosage form. So- teeth. dium fluoride 0.188 to 0.254 percent with (f) Fluoride. The inorganic form of the an available fluoride ion concentration ≥650 parts per million (ppm). chemical element fluorine in combina- (2) Dentifrices containing 850 to 1,150 tion with other elements. ppm theoretical total fluorine in a pow- (g) Fluoride ion. The negatively dered dosage form. Sodium fluoride 0.188 charged atom of the chemical element to 0.254 percent with an available fluo- fluorine. ride ion concentration of ≥850 ppm for (h) Fluoride supplement. A special products containing the abrasive so- treatment rinse dosage form that is indium bicarbonate and a poured-bulk tended to be swallowed, and is pro- density of 1.0 to 1.2 grams per milli- moted to health professionals for use in liter. areas where the water supply contains (3) Treatment rinses. (i) An aqueous so- 0 to 0.7 parts per million (ppm) fluoride lution of acidulated phosphate fluoride ion. derived from sodium fluoride (i) Preventive treatment gel. A dosage acidulated with a mixture of sodium form for delivering an anticaries drug phosphate, monobasic, and phosphoric to the teeth. Preventive treatment gels acid to a level of 0.1 molar phosphate are formulated in an anhydrous glyc- ion and a pH of 3.0 to 4.5 and which erin base with suitable thickening yields an effective fluoride ion con- agents included to adjust viscosity. centration of 0.02 percent. Preventive treatment gels do not con- (ii) An aqueous solution of acidulated phosphate fluoride derived from so- tain abrasives. dium fluoride acidulated with a mix- (j) Treatment rinse. A liquid dosage ture of sodium phosphate, dibasic, and form for delivering an anticaries drug phosphoric acid to a pH of 3.5 and to the teeth. which yields an effective fluoride ion (k) Treatment rinse concentrated solu- concentration of 0.01 percent. tion. A fluoride treatment rinse in a (iii) Sodium fluoride 0.02 percent concentrated form to be mixed with aqueous solution with a pH of approxi- water before using to result in the ap- mately 7. propriate fluoride concentration speci- (iv) Sodium fluoride 0.05 percent fied in the monograph. aqueous solution with a pH of approxi- (l) Treatment rinse effervescent tablets. mately 7. A fluoride treatment rinse prepared by (v) Sodium fluoride concentrate con- adding an effervescent tablet (a containing adequate directions for mixing centrated solid dosage form) to water with water before using to result in a before using to result in the appro- 0.02-percent or 0.05-percent aqueous so- priate fluoride concentration specified lution with a pH of approximately 7. in the monograph. (b) Sodium monofluorophosphate—(1) (m) Treatment rinse powder. A fluoride Dentifrices containing 850 to 1,150 ppm treatment rinse prepared by adding the theoretical total fluorine in a gel or paste powder (a concentrated solid dosage dosage form. Sodium monofluorophosphate 0.654 to 0.884 percent with an form) to water before using to result in available fluoride ion concentration the appropriate fluoride concentration (consisting of PO F= and F¥ combined) specified in the monograph. 3 ≥800 ppm. [60 FR 52507, Oct. 6, 1995, as amended at 61 FR (2) Dentifrices containing 1,500 ppm the- 52286, Oct. 7, 1996] oretical total fluorine in a gel or paste

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dosage form. Sodium monofluoro- article, and from efflorescence, deli- phosphate 1.153 percent with an avail- quescence, or evaporation under the or- able fluoride ion concentration (con- dinary or customary conditions of han- = ¥ sisting of PO3 F and F combined) dling, shipment, storage, and distribu- ≥1,275 ppm. tion, and is capable of tight reclosure. (c) Stannous fluoride—(1) Dentifrices containing 850 to 1,150 ppm theoretical Subpart C—Labeling total fluorine in a gel or paste dosage form. (i) Stannous fluoride 0.351 to 0.474 § 355.50 Labeling of anticaries drug percent with an available fluoride ion products. concentration ≥700 ppm for products (a) Statement of identity. The labeling containing abrasives other than cal- of the product contains the established cium pyrophosphate. name of the drug, if any, and identifies (ii) Stannous fluoride 0.351 to 0.474 the product as: (select one or both of percent with an available fluoride ion the following: ‘anticavity’ or ‘fluoride’) concentration ≥290 ppm for products (select one of the following as appro- containing the abrasive calcium priate: ‘‘dentifrice,’’ ‘‘toothpaste,’’ pyrophosphate. ‘‘tooth polish,’’ ‘‘tooth powder;’’ (op- (2) Preventive treatment gel. Stannous tional: ‘‘dental’’) ‘‘preventive treat- fluoride 0.4 percent in an anhydrous ment gel;’’ or (optional: ‘‘treatment’’ glycerin gel, made from anhydrous or ‘‘dental’’)) (select one of the fol- glycerin and the addition of suitable lowing: ‘‘rinse,’’ ‘‘concentrated solu- thickening agents to adjust viscosity. tion,’’ ‘‘rinse powder,’’ or ‘‘rinse effer- (3) Treatment rinse. Stannous fluoride vescent tablets’’). The word ‘‘mouth- concentrate marketed in a stable form wash’’ may be substituted for the word and containing adequate directions for ‘‘rinse’’ in this statement of identity if mixing with water immediately before the product also has a cosmetic use, as using to result in a 0.1-percent aqueous defined in section 201(i) of the Federal solution. Food, Drug, and Cosmetic Act (the act) [60 FR 52507, Oct. 6, 1995, as amended at 61 FR (21 U.S.C. 321(i)). 52286, Oct. 7, 1996] (b) Indication. The labeling of the product states, under the heading ‘‘In- § 355.20 Packaging conditions. dication,’’ the following: ‘‘Aids in the (a) Package size limitation. Due to the prevention of dental (select one of the toxicity associated with fluoride active following: ‘‘cavities,’’ ‘‘decay,’’ ‘‘caries ingredients, the following package size (decay),’’ or ‘‘caries (cavities)’’). Other limitations are required for anticaries truthful and nonmisleading state- drug products: ments, describing only the indication (1) Dentifrices. Dentifrice (toothpastes for use that has been established and and tooth powders) packages shall not listed in this paragraph (b), may also contain more than 276 milligrams (mg) be used, as provided in § 330.1(c)(2) of total fluorine per package. this chapter, subject to the provisions (2) Preventive treatment gels and treat- of section 502 of the Federal Food, ment rinses. Preventive treatment gel Drug, and Cosmetic Act (the act) relat- and treatment rinse packages shall not ing to misbranding and the prohibition contain more than 120 mg total fluo- in section 301(d) of the act against the rine per package. introduction or delivery for introduc- (3) Exception. Package size limitation into interstate commerce of unap- tions do not apply to anticaries drug proved new drugs in violation of sec- products marketed for professional of- tion 505(a) of the act. fice use only and labeled in accord with (c) Warning. The labeling of the prod- § 355.60. uct contains the following warning (b) Tight container packaging. To min- under the heading ‘‘Warning’’: imize moisture contamination, all fluo- (1) For all fluoride dentifrice (gel, paste, ride powdered dentifrices shall be pack- and powder) products. ‘‘Keep out of aged in a tight container as defined as reach of children under 6 years of age. a container that protects the contents [highlighted in bold type] If more than from contamination by extraneous liq- used for brushing is accidentally swal- uids, solids, or vapors, from loss of the lowed, get medical help or contact a

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Poison Control Center right away.’’ least twice a day, or as directed by a These warnings shall be used in place dentist or doctor. Instruct children of the general warning statements re- under 12 years of age in good brushing quired by § 330.1(g) of this chapter. and rinsing habits (to minimize swal- (2) For all fluoride rinse and preventive lowing). Supervise children as nec- treatment gel products. ‘‘Keep out of essary until capable of using without reach of children. [highlighted in bold supervision. Children under 6 years of type] If more than used for’’ (select ap- age: Do not use unless directed by a propriate word: ‘‘brushing’’ or ‘‘rins- dentist or doctor. ing’’) ‘‘is accidentally swallowed, get (2) For anticaries treatment rinse prod- medical help or contact a Poison Con- ucts—(i) For acidulated phosphate fluo- trol Center right away.’’ These warn- ride solution containing 0.02 percent fluo- ings shall be used in place of the gen- ride ion, sodium fluoride 0.05 percent, so- eral warning statements required by dium fluoride concentrate, and stannous § 330.1(g) of this chapter. fluoride concentrate identified in (d) Directions. The labeling of the § 355.10(a)(3)(i), (a)(3)(iv), (a)(3)(v), and product contains the following state- (c)(3). Adults and children 6 years of ments under the heading ‘‘Directions’’: age and older: Use once a day after (1) For anticaries dentifrice products— brushing your teeth with a toothpaste. (i) Gel or paste dosage form with a theo- Vigorously swish 10 milliliters of rinse retical total fluorine concentration of 850 between your teeth for 1 minute and to 1,150 ppm identified in § 355.10(a)(1), then spit out. Do not swallow the rinse. (b)(1), and (c)(1). Adults and children 2 Do not eat or drink for 30 minutes after years of age and older: Brush teeth rinsing. Instruct children under 12 thoroughly, preferably after each meal years of age in good rinsing habits (to or at least twice a day, or as directed minimize swallowing). Supervise chil- by a dentist or doctor. Instruct children as necessary until capable of dren under 6 years of age in good using without supervision. Children brushing and rinsing habits (to mini- under 6 years of age: Consult a dentist mize swallowing). Supervise children or doctor. as necessary until capable of using (ii) For acidulated phosphate fluoride without supervision. Children under 2 solution containing 0.01 percent fluoride years of age: Consult a dentist or doc- ion and sodium fluoride 0.02 percent aque- tor. ous solution identified in § 355.10(a)(3)(ii) (ii) Gel or paste dosage form with a the- and (a)(3)(iii). Adults and children 6 oretical total fluorine concentration of years of age and older: Use twice a day 1,500 ppm identified in § 355.10(b)(2). after brushing your teeth with a tooth- Adults and children 6 years of age and paste. Vigorously swish 10 milliliters of older: Brush teeth thoroughly, pref- rinse between your teeth for 1 minute erably after each meal or at least twice and then spit out. Do not swallow the a day, or as directed by a dentist or rinse. Do not eat or drink for 30 min- doctor. Instruct children under 12 years utes after rinsing. Instruct children of age in good brushing and rinsing under 12 years of age in good rinsing habits (to minimize swallowing). Su- habits (to minimize swallowing). Su- pervise children as necessary until ca- pervise children as necessary until capable of using without supervision. pable of using without supervision. Children under 6 years of age: Do not Children under 6 years of age: consult a use unless directed by a dentist or doc- dentist or doctor. tor. (3) For stannous fluoride treatment (iii) Powdered dosage form with a theo- rinse products. (i) ‘‘Use immediately retical total fluorine concentration of 850 after preparing the rinse.’’ to 1,150 ppm identified in § 355.10(a)(2). (ii) For powder or effervescent tablets Adults and children 6 years of age and used to prepare treatment rinses. ‘‘Do not older: Apply powder to a wet tooth- use as a rinse until all the’’ (select one brush; completely cover all bristles. of the following: ‘‘powder’’ or ‘‘tablet’’) Brush for at least 30 seconds. Reapply ‘‘has dissolved.’’ powder as before and brush again. (4) For anticaries preventive treatment Rinse and spit out thoroughly. Brush gel products. Adults and children 6 teeth, preferably after each meal or at years of age and older: Use once a day

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after brushing your teeth with a tooth- have a greater tendency to develop cav- paste. Apply the gel to your teeth and ities.’’ brush thoroughly. Allow the gel to re- [60 FR 52507, Oct. 6, 1995; 60 FR 57927, Nov. 24, main on your teeth for 1 minute and 1995; 61 FR 51187, Oct. 7, 1996; 64 FR 13296, then spit out. Do not swallow the gel. Mar. 17, 1999] Do not eat or drink for 30 minutes after brushing. Instruct children under 12 § 355.55 Principal display panel of all fluoride rinse drug products. years of age in the use of this product (to minimize swallowing). Supervise In addition to the statement of iden- children as necessary until capable of tity required in § 355.50, the following using without supervision. Children statement shall be prominently placed under 6 years of age: consult a dentist on the principal display panel: ‘‘IM- PORTANT: Read directions for proper or doctor. use.’’ (5) For all concentrated treatment rinse solutions, powders, and effervescent tab- § 355.60 Professional labeling. lets. The following statement shall ap- (a) The labeling for anticaries fluo- pear as the first statement under direc- ride treatment rinses identified in tions: ‘‘Do not use before mixing with § 355.10(a)(3) and (c)(3) that are spe- water.’’ cially formulated so they may be swal- (e) Additional labeling statements for lowed (fluoride supplements) and are anticaries drug products. The following provided to health professionals (but statements need not appear under not to the general public) may contain warnings, but are required to appear on the following additional dosage infor- the label of anticaries drugs products mation: Children 3 to under 14 years of as applicable. age: As a supplement in areas where (1) For all preventive treatment gels. the water supply is nonfluoridated (less ‘‘This is a(n)’’ (select one or both of the than 0.3 parts per million (ppm)), clean following: ‘‘anticavity’’ or ‘‘fluoride’’) the teeth with a toothpaste and rinse ‘‘preventive treatment gel, not a tooth- with 5 milliliters (mL) of 0.02 percent or 10 mL of 0.01 percent fluoride ion paste. Read directions carefully before rinse daily, then swallow. When the using.’’ water supply contains 0.3 to 0.7 ppm (2) For all stannous fluoride treatment fluoride ion, reduce the dose to 2.5 mL rinse, preventive treatment gel, and den- of 0.02 percent or 5 mL of 0.01 percent tifrice products. ‘‘This product may fluoride ion rinse daily. produce surface staining of the teeth. (b) The labeling for products mar- Adequate toothbrushing may prevent keted to health to health professionals these stains which are not harmful or in package sizes larger than those spec- permanent and may be removed by ified in § 355.20 shall include the state- your dentist.’’ ments: ‘‘For Professional Office Use (f) Optional additional labeling state- Only’’ and ‘‘This product is not in- ments—(1) For fluoride treatment rinses tended for home or unsupervised con- and preventive treatment gels. The fol- sumer use.’’ lowing labeling statement may appear in the required boxed area designated Subpart D—Testing Procedures ‘‘APPROVED USES’’: ‘‘The combined daily use of a fluoride preventive treat- § 355.70 Testing procedures for fluoride dentifrice drug products. ment’’ (select one of the following: ‘‘rinse’’ or ‘‘gel’’) ‘‘and a fluoride tooth- (a) A fluoride dentifrice drug product paste can help reduce the incidence of shall meet the biological test require- dental cavities.’’ ments for animal caries reduction and one of the following tests: Enamel solu- (2) For dentifrice products containing bility reduction or fluoride enamel up- 1,500 ppm theoretical total fluorine. take. The testing procedures for these ‘‘Adults and children over 6 years of biological tests are labeled Biological age may wish to use this extra- Testing Procedures for Fluoride strength fluoride dentifrice if they re- Dentifrices; these testing procedures are side in a nonfluoridated area or if they on file under Docket No. 80N–0042 in

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the Division of Dockets Management Subpart I—Deodorant Drug Products for (HFA–305), Food and Drug Administra- Internal Use tion, 5630 Fishers Lane, rm. 1061, Rock- ville, MD 20852, and are available on re- 357.801 Scope. 357.803 Definitions. quest to that office. 357.810 Active ingredients for deodorant (b) The United States Pharmacopeia drug products for internal use. fluoride dentifrice reference standards 357.850 Labeling of deodorant drug products along with reference standard stability for internal use. profiles (total fluoride, available fluo- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, ride ion, pH, and specific gravity) re- 360, 371. quired to be used in the biological tests are available to any purchaser upon written request to the United States Subpart A [Reserved] Pharmacopeial Convention, Inc., 1260 Twinbrook Parkway, Rockville, MD Subpart B—Anthelmintic Drug 20852. Products (c) Alternative testing procedures may be used. Any proposed modifica- SOURCE: 51 FR 27759, Aug. 1, 1986, unless tion or alternative testing procedures otherwise noted. shall be submitted as a petition in accord with § 10.30 of this chapter. The pe- § 357.101 Scope. tition should contain data to support (a) An over-the-counter anthelmintic the modification or data dem- drug product in a form suitable for oral onstrating that an alternative testing administration is generally recognized procedure provides results of equiva- as safe and effective and is not mis- lent accuracy. All information sub- branded if it meets each condition in mitted will be subjected to the disclo- this subpart and each general condition sure rules in part 20 of this chapter. established in § 330.1. [60 FR 52507, Oct. 6, 1995, as amended at 68 FR (b) References in this subpart to reg- 24879, May 9, 2003] ulatory sections of the Code of Federal Regulations are to chapter I of title 21 PART 357—MISCELLANEOUS INTER- unless otherwise noted. NAL DRUG PRODUCTS FOR § 357.103 Definition. OVER-THE-COUNTER HUMAN USE As used in this subpart: Anthelmintic. An agent that is destructive to worms. Subpart A [Reserved] Subpart B—Anthelmintic Drug Products § 357.110 Anthelmintic active ingredient. Sec. The active ingredient of the product 357.101 Scope. is pyrantel pamoate when used within 357.103 Definition. 357.110 Anthelmintic active ingredient. the dosage limits established in 357.150 Labeling of anthelmintic drug prod- § 357.150(d)(1). ucts. 357.152 Package inserts for anthelmintic § 357.150 Labeling of anthelmintic drug products. drug products. 357.180 Professional labeling. (a) Statement of identity. The labeling of the product contains the established Subpart C—Cholecystokinetic Drug name of the drug, if any, and identifies Products the product as a ‘‘pinworm treatment.’’ 357.201 Scope. (b) Indication. The labeling of the 357.203 Definition. product states, under the heading ‘‘In- 357.210 Cholecystokinetic active ingredi- dication,’’ the following: ‘‘For the ents. treatment of pinworms.’’ Other truth- 357.250 Labeling of cholecystokinetic drug products. ful and nonmisleading statements, de- 357.280 Professional labeling. scribing only the indications for use that have been established and listed in Subparts D–H [Reserved] this paragraph (b), may also be used, as 332

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provided in § 330.1(c)(2), subject to the the entire household should be treated provisions of section 502 of the act re- unless otherwise advised. See Warn- lating to misbranding and the prohibi- ings. If any worms other than tion in section 301(d) of the act against pinworms are present before or after the introduction or delivery for intro- treatment, consult a doctor. If any duction into interstate commerce of symptoms or pinworms are still unapproved new drugs in violation of present after treatment, consult a doc- section 505(a) of the act. tor. (c) Warnings. The labeling of the (3) ‘‘This product can be taken any product contains the following warnings under the heading ‘‘Warnings’’: time of day, with or without meals. It (1) ‘‘Abdominal cramps, nausea, vom- may be taken alone or with milk or iting, diarrhea, headache, or dizziness fruit juice. Use of a laxative is not nec- sometimes occur after taking this essary prior to, during, or after medi- drug. If any of these conditions persist cation.’’ consult a doctor.’’ (e) Optional wording. The word ‘‘phy- (2) ‘‘If you are pregnant or have liver sician’’ may be substituted for the disease, do not take this product unless word ‘‘doctor’’ in any of the labeling directed by a doctor.’’ statements in this section. (d) Directions. The labeling of the product contains the following infor- [51 FR 27759, Aug. 1, 1986; 52 FR 7831, Mar. 13, mation under the heading ‘‘Direc- 1987, as amended at 53 FR 35810, Sept. 15, tions’’: 1988] (1) Adults, children 12 years of age § 357.152 Package inserts for anthel- and over, and children 2 years to under mintic drug products. 12 years of age: Oral dosage is a single dose of 5 milligrams of pyrantel base The labeling of the product contains per pound, or 11 milligrams per kilo- a consumer package insert which in- gram, of body weight not to exceed 1 cludes the following information: gram. Dosing information should be (a) A discussion of the symptoms sug- converted to easily understood direc- gestive of pinworm infestation, includ- tions for the consumer using the fol- ing a statement that pinworms must be lowing dosage schedule: visually identified before taking this medication. Weight Dosage (taken as a single dose) 1 (b) A detailed description of how to

Less than 25 pounds or Do not use unless directed find and identify the pinworm. under 2 years old. by a doctor. (c) A commentary on the life cycle of 25 to 37 pounds ...... 125 milligrams. the pinworm. 38 to 62 pounds ...... 250 milligrams. 63 to 87 pounds ...... 375 milligrams. (d) A commentary on the ways in 88 to 112 pounds ...... 500 milligrams. which pinworms may be spread from 113 to 137 pounds ...... 625 milligrams. 138 to 162 pounds ...... 750 milligrams. person to person and hygienic proce- 163 to 187 pounds ...... 875 milligrams. dures to follow to avoid such spreading. 188 pounds and over ...... 1,000 milligrams. (e) The appropriate labeling informa- 1 Depending on the product, the label should state the tion contained in § 357.150 quantity of drug as a liquid measurement (e.g., teaspoonsful) or as the number of dosage units (e.g., tablets) to be taken for the varying body weights. (If appropriate, it is rec- (Collection of information requirement ap- ommended that a measuring cup graduated by body weight proved by the Office of Management and and/or liquid measurement be provided with the product.) Budget under control number 0910–0232) Manufacturers should present this information as appropriate for their product and may vary the format of this chart as [51 FR 27759, Aug. 1, 1986, as amended at 52 necessary. FR 2515, Jan. 23, 1987] (2) ‘‘Read package insert carefully before taking this medication. Take § 357.180 Professional labeling. only according to directions and do not The labeling provided to health pro- exceed the recommended dosage unless fessionals (but not to the general pub- directed by a doctor. Medication should only be taken on time as a single dose; lic) may contain an additional indica- do not repeat treatment unless dition: ‘‘For the treatment of common rected by a doctor. When one indi- roundworm infestation.’’ vidual in a household has pinworms,

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Subpart C—Cholecystokinetic § 357.250 Labeling of cholecystokinetic Drug Products drug products. (a) Statement of identity. The labeling § 357.201 Scope. of the product contains the established (a) An over-the-counter name of the drug, if any, and identifies cholecystokinetic drug product in a the product as a ‘‘gallbladder diag- form suitable for oral administration is nostic agent.’’ generally recognized as safe and effec- (b) Indications. The labeling of the tive and is not misbranded if it meets product states, under the heading ‘‘In- each of the conditions in this subpart dications,’’ the following: ‘‘For the in addition to each of the general con- contraction of the gallbladder during ditions established in § 330.1. diagnostic gallbladder studies.’’ Other (b) References in this subpart to reg- truthful and nonmisleading state- ulatory sections of the Code of Federal ments, describing only the indications Regulations are to chapter I of title 21 for use that have been established and unless otherwise noted. listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2), sub- [48 FR 27005, June 10, 1983] ject to the provisions of section 502 of the act relating to misbranding and the § 357.203 Definition. prohibition in section 301(d) of the act As used in this subpart: against the introduction or delivery for Cholecystokinetic drug product. A drug introduction into interstate commerce product that causes contraction of the of unapproved new drugs in violation of gallbladder and is used during the section 505(a) of the act. course of diagnostic gallbladder studies (c) Warnings. [Reserved] (cholecystography). (d) Directions. The labeling of the product contains the following state- [48 FR 27005, June 10, 1983] ments under the heading ‘‘Directions’’: (1) ‘‘Take only when instructed by a § 357.210 Cholecystokinetic active ingredients. doctor:’’ (2) For products containing 50-percent The active ingredient of the product aqueous emulsion of corn oil. consists of any of the following when (i) ‘‘Shake well before using.’’ used within the specified concentration (ii) Oral dosage is 60 milliliters 20 and dosage form established for each minutes before diagnostic gallbladder ingredient: x-ray or as directed by a doctor. (a) 50-percent aqueous emulsion of (3) For products containing corn oil. hydrogeneated soybean oil. Oral dosage (b) Hydrogenated soybean oil in a is 12.4 grams in a suitable, water-dis- suitable, water-dispersible powder. The persible powder in 2 to 3 ounces of hydrogenated soybean oil is food-grade, water. Stir briskly to prepare a suspen- partially hydrogenated with a melting sion before using. Drink 20 minutes be- point of 41 to 43.5 °C, an iodine value of fore diagnostic gallbladder x-ray or as 65 to 69, and a fatty acid composition directed by a doctor. as follows: (e) The word ‘‘physician’’ may be substituted for the word ‘‘doctor’’ in any Percent Fatty acid com- of the labeling statements in this sec- position tion. Myristic acid ...... 0.1 [48 FR 27005, June 10, 1983, as amended at 51 Palmitic acid ...... 10.0 FR 16267, May 1, 1986; 52 FR 7830, Mar. 13, Palmitoleic acid ...... 0.1 1987; 54 FR 8321, Feb. 28, 1989] Stearic acid ...... 13.5 Oleic acid ...... 72.0 § 357.280 Professional labeling. Linoleic acid ...... 3.8 Linolenic acid ...... 0.1 The labeling provided to health pro- Arachidic acid ...... 0.5 fessionals (but not to the general pub- Behenic acid ...... 0.2 lic) may contain the following information for ingredients identified in [54 FR 8321, Feb. 28, 1989] § 357.210: Indication. ‘‘For visualization

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of biliary ducts during cholecys- (b) Indications. The labeling of the tography.’’ product states, under the heading ‘‘In- dications,’’ any of the phrases listed in [54 FR 8321, Feb. 28, 1989] paragraph (b) of this section as appropriate. Other truthful and nonmis- Subparts D–H [Reserved] leading statements, describing only the indications for use that have been es- Subpart I—Deodorant Drug tablished and listed in paragraph (b) of Products for Internal Use this section may also be used, as provided in § 330.1(c)(2) of this chapter, SOURCE: 55 FR 19865, May 11, 1990, unless subject to the provisions of section 502 otherwise noted. of the Federal Food, Drug, and Cos- metic Act (the act) relating to mis- § 357.801 Scope. branding and the prohibition in section (a) An over-the-counter deodorant 301(d) of the act against the introduc- drug product for internal use in a form tion or delivery for introduction into suitable for oral administration is gen- interstate commerce of unapproved erally recognized as safe and effective new drugs in violation of section 505(a) and is not misbranded if it meets each of the act. condition in this subpart and each gen- (1) For products containing bismuth eral condition established in § 330.1 of subgallate identified in § 357.810(a). ‘‘An this chapter. aid to reduce odor from a colostomy or (b) References in this subpart to reg- ileostomy.’’ ulatory sections of the Code of Federal (2) For products containing Regulations are to chapter I of title 21 chlorophyllin copper complex identified in unless otherwise noted. § 357.810(b). (i) ‘‘An aid to reduce odor from a colostomy or ileostomy.’’ § 357.803 Definitions. (ii) ‘‘An aid to reduce fecal odor due As used in this subpart: to incontinence.’’ (a) Colostomy. An external operative (c) Warnings. The labeling of the opening of the colon. product contains the following warn- (b) Deodorant for internal use. An in- ings under the heading ‘‘Warnings’’: (1) gredient taken internally to reduce For products containing chlorophyllin odors arising from conditions such as copper complex identified in § 357.810(b). colostomies, ileostomies, or fecal in- (i) ‘‘If cramps or diarrhea occurs, re- continence. duce the dosage. If symptoms persist, (c) Ileostomy. An external operative consult your doctor.’’ opening from the ileum. (ii) The warning required by § 330.1(g) (d) Incontinence. An inability to re- of this chapter concerning overdose is tain urine or feces. not required on products containing chlorophyllin copper complex identi- § 357.810 Active ingredients for deo- fied in § 357.810(b). dorant drug products for internal (2) [Reserved] use. (d) Directions. The labeling of the The active ingredient of the product product contains the following infor- consists of either of the following when mation under the heading ‘‘Direc- used within the dosage limits estab- tions.’’ lished for each ingredient in § 357.850(d): (1) For products containing bismuth (a) Bismuth subgallate. subgallate identified in § 357.810(a). (b) Chlorophyllin copper complex. Adults and children 12 years of age and over: Oral dosage is 200 to 400 milli- § 357.850 Labeling of deodorant drug grams up to 4 times daily. Children products for internal use. under 12 years of age: consult a doctor. (a) Statement of identity. The labeling (2) For products containing of the product contains the established chlorophyllin copper complex identified in name of the drug, if any, and identifies § 357.810(b). Adults and children 12 years the product as a ‘‘deodorant for inter- of age and over: Oral dosage is 100 to nal use’’ or as a ‘‘colostomy or ileos- 200 milligrams daily in divided doses as tomy deodorant.’’ required. If odor is not controlled, take

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up to an additional 100 milligrams 358.720 Permitted combinations of active in- daily in divided doses as required. The gredients. smallest effective dose should be used. 358.750 Labeling of drug products for the Do not exceed 300 milligrams daily. control of dandruff, seborrheic dermatitis, or psoriasis. Children under 12 years of age: consult 358.760 Labeling of permitted combinations a doctor. of active ingredients for the control of dandruff.

PART 358—MISCELLANEOUS EXTER- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, NAL DRUG PRODUCTS FOR 360, 371.

OVER-THE-COUNTER HUMAN SOURCE: 55 FR 33255, Aug. 14, 1990, unless USE otherwise noted.

Subpart A [Reserved] Subpart A [Reserved] Subpart B—Wart Remover Drug Products Subpart B—Wart Remover Drug Sec. Products 358.101 Scope. 358.103 Definitions. § 358.101 Scope. 358.110 Wart remover active ingredients. 358.150 Labeling of wart remover drug prod- (a) An over-the-counter wart remover ucts. drug product in a form suitable for topical application is generally recognized Subpart C [Reserved] as safe and effective and is not misbranded if it meets each of the condi- Subpart D—Ingrown Toenail Relief Drug tions in this subpart and each of the Products general conditions established in § 330.1 358.301 Scope. of this chapter. 358.303 Definitions. (b) References in this subpart to reg- 358.310 Ingrown toenail relief active ingre- ulatory sections of the Code of Federal dient. Regulations are to chapter I of title 21 358.350 Labeling of ingrown toenail relief unless otherwise noted. drug products. § 358.103 Definitions. Subpart E [Reserved] As used in this subpart: Subpart F—Corn and Callus Remover Drug (a) Wart remover drug product. A top- Products ical agent used for the removal of common or plantar warts. 358.501 Scope. (b) Collodion-like vehicle. A solution 358.503 Definitions. containing pyroxylin (nitrocellulose) 358.510 Corn and callus remover active ingredients. in an appropriate nonaqueous solvent 358.550 Labeling of corn and callus remover that leaves a transparent cohesive film drug products. when applied to the skin in a thin layer. Subpart G—Pediculicide Drug Products (c) Plaster vehicle. A fabric, plastic, or other suitable backing material in 358.601 Scope. which medication is usually incor- 358.603 Definition. 358.610 Pediculicide active ingredients. porated for topical application to the 358.650 Labeling of pediculicide drug prod- skin. ucts. § 358.110 Wart remover active ingredi- Subpart H—Drug Products for the Control ents. of Dandruff, Seborrheic Dermatitis, and The product consists of any of the Psoriasis following active ingredients within the specified concentration and in the dos- 358.701 Scope. 358.703 Definitions. age form established for each ingre- 358.710 Active ingredients for the control of dient. dandruff, seborrheic dermatitis, or psori- (a) Salicylic acid 12 to 40 percent in a asis. plaster vehicle.

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(b) Salicylic acid 5 to 17 percent in a flammable,’’ ‘‘flammable,’’ ‘‘combus- collodion-like vehicle. tible,’’ consistent with 16 CFR (c) Salicylic acid 15 percent in a 1500.3(b)(10). karaya gum, glycol plaster vehicle. (ii) ‘‘Keep away from fire or flame.’’ (3) For any product formulated in a § 358.150 Labeling of wart remover volatile vehicle. ‘‘Cap bottle tightly and drug products. store at room temperature away from (a) Statement of identity. The labeling heat.’’ of the product contains the established (4) For any product formulated in a col- name of the drug, if any, and identifies lodion-like vehicle. (i) ‘‘If product gets the product as a ‘‘wart remover.’’ into the eye, flush with water for 15 (b) Indications. The labeling of the minutes.’’ product states, under the heading ‘‘In- (ii) ‘‘Avoid inhaling vapors.’’ dications,’’ any of the phrases listed in (d) Directions. The labeling of the paragraph (b) of this section. Other product contains the following infor- truthful and nonmisleading statements, describing only the indications mation under the heading ‘‘Direc- for use that have been established in tions’’: paragraph (b) of this section, may also (1) For products containing salicylic be used, as provided in § 330.1(c)(2) of acid identified in § 358.110(a). ‘‘Wash af- this chapter, subject to the provisions fected area.’’ (Optional: ‘‘May soak of section 502 of the Federal Food, wart in warm water for 5 minutes.’’) Drug, and Cosmetic Act (the act) relat- ‘‘Dry area thoroughly.’’ (If appropriate: ing to misbranding and the prohibition ‘‘Cut plaster to fit wart.’’) ‘‘Apply in section 301(d) of the act against the medicated plaster. Repeat procedure introduction or delivery for introduc- every 48 hours as needed (until wart is tion into interstate commerce of unap- removed) for up to 12 weeks.’’ proved new drugs in violation of sec- (2) For products containing salicylic tion 505(a) of the act. acid identified in § 358.110(b). ‘‘Wash af- (1) ‘‘For the removal of common fected area.’’ (Optional: ‘‘May soak warts. The common wart is easily rec- wart in warm water for 5 minutes.’’) ognized by the rough ‘cauliflower-like’ ‘‘Dry area thoroughly. Apply’’ (select appearance of the surface.’’ one of the following, as appropriate: (2) ‘‘For the removal of plantar warts ‘‘one drop’’ or ‘‘small amount’’) ‘‘at a on the bottom of the foot. The plantar time with’’ (select one of the following, wart is recognized by its location only as appropriate: ‘‘applicator’’ or on the bottom of the foot, its tender- ‘‘brush’’) ‘‘to sufficiently cover each ness, and the interruption of the foot- wart. Let dry. Repeat this procedure print pattern.’’ once or twice daily as needed (until (c) Warnings. The labeling of the wart is removed) for up to 12 weeks.’’ product contains the following warn- (3) For products containing salicylic ings under the heading ‘‘Warnings’’: acid identified in § 358.110(c). ‘‘Wash af- (1) For products containing any ingre- fected area.’’ (Optional: ‘‘May soak dient identified in § 358.110. (i) ‘‘For ex- wart in warm water for 5 minutes.’’) ternal use only.’’ ‘‘Dry area thoroughly. Gently smooth (ii) ‘‘Do not use this product on irri- wart surface with emery file supplied.’’ tated skin, on any area that is infected (If appropriate: ‘‘Cut plaster to fit or reddened, if you are a diabetic, or if wart.’’) ‘‘Apply a drop of warm water to you have poor blood circulation.’’ the wart, keeping the surrounding skin (iii) ‘‘If discomfort persists, see your dry. Apply medicated plaster at bed- doctor.’’ time and leave in place for at least 8 (iv) ‘‘Do not use on moles, birth- hours. In the morning, remove plaster marks, warts with hair growing from and discard. Repeat procedure every 24 them, genital warts, or warts on the hours as needed (until wart is removed) face or mucous membranes.’’ for up to 12 weeks.’’ (2) For any product formulated in a (e) The word ‘‘physician’’ may be sub- flammable vehicle. (i) The labeling stituted for the word ‘‘doctor’’ in any should contain an appropriate flamma- of the labeling statements in this sec- bility signal word, e.g. ‘‘extremely tion.

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(f) The phrase ‘‘or podiatrist’’ may be molecules interpenetrated with a liq- used in addition to the word ‘‘doctor’’ uid. in any of the labeling statements in this section when a product is labeled § 358.350 Labeling of ingrown toenail with the indication identified in relief drug products. § 358.150(b)(2). (a) Statement of identity. The labeling of the product contains the established [55 FR 33255, Aug. 14, 1990; 55 FR 37403, Sept. 11, 1990, as amended at 57 FR 44495, Sept. 28, name of the product, if any, and identi- 1992; 59 FR 60317, Nov. 23, 1994] fies the product as an ‘‘ingrown toenail relief product’’ or as an ‘‘ingrown toe- Subpart C [Reserved] nail discomfort reliever.’’ (b) Indications. The labeling of the product states, under the heading Subpart D—Ingrown Toenail Relief ‘‘Use,’’ the following: ‘‘for temporary Drug Products relief of’’ [select one or both of the following: ‘pain’ or ‘discomfort’] ‘‘from in- SOURCE: 68 FR 24348, May 7, 2003, unless grown toenails’’. Other truthful and otherwise noted. nonmisleading statements, describing only the use that has been established § 358.301 Scope. and listed in this paragraph (b), may (a) An over-the-counter ingrown toe- also be used, as provided in § 330.1(c)(2) nail relief drug product in a form suit- of this chapter, subject to the provi- able for topical administration is gen- sions of section 502 of the Federal erally recognized as safe and effective Food, Drug, and Cosmetic Act (the act) and is not misbranded if it meets each relating to misbranding and the prohi- condition in this subpart and each gen- bition in section 301(d) of the act eral condition established in § 330.1 of against the introduction or delivery for this chapter. introduction into interstate commerce (b) References in this subpart to reg- of unapproved new drugs in violation of ulatory sections of the Code of Federal section 505(a) of the act. Regulations are to chapter 1 of title 21 (c) Warnings. The labeling of the unless otherwise noted. product contains the following warnings under the heading ‘‘Warnings’’: § 358.303 Definitions. (1) ‘‘For external use only’’ in accord As used in this subpart: with § 201.66(c)(5)(i) of this chapter. (a) Ingrown toenail relief drug product. (2) ‘‘Do not use [bullet] 1 on open A drug product applied to an ingrown sores’’. toenail that relieves pain or discomfort (3) ‘‘Ask a doctor before use if you either by softening the nail or by hard- have [bullet] diabetes [bullet] poor cir- ening the nail bed. culation [bullet] gout’’. (b) Retainer ring. A die cut poly- (4) ‘‘When using this product [bullet] ethylene foam pad coated on one side use with a retainer ring’’. with medical grade acrylic pressure- (5) ‘‘Stop use and ask a doctor if [bul- sensitive adhesive. The retainer ring let] redness or swelling of your toe in- has slots, center-cut completely creases [bullet] discharge is present through the foam with the cut of suffi- around the nail [bullet] symptoms last cient size to allow for localization of an more than 7 days or clear up and occur active ingredient in a gel vehicle to a again within a few days’’. specific target area. The retainer ring (d) Directions. The labeling of the is used with adhesive bandage strips to product contains the following state- place over the retainer ring to hold it ments under the heading ‘‘Directions’’: in place. (1) ‘‘[Bullet] adults and children 12 years and over:’’ § 358.310 Ingrown toenail relief active (i) ‘‘[Bullet] wash the affected area ingredient. and dry thoroughly [bullet] place re- The active ingredient of the product tainer ring on toe with slot over the is sodium sulfide 1 percent in a gel vehicle. The gel vehicle is an aqueous, 1 See § 201.66(b)(4) of this chapter for defini- semisolid system with large organic tion of bullet.

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area where the ingrown nail and the § 358.510 Corn and callus remover ac- skin meet. Smooth ring down firmly. tive ingredients. [bullet] apply enough gel product to fill The product consists of any of the the slot in the ring [bullet] place round following active ingredients within the center section of bandage strip directly specified concentrations and in the dos- over the gel-filled ring to seal the gel age form established for each ingre- in place. Smooth ends of bandage strip dient. around toes.’’ (a) Salicylic acid 12 to 40 percent in a (ii) ‘‘[Bullet] repeat twice daily plaster vehicle. (morning and night) for up to 7 days (b) Salicylic acid 12 to 17.6 percent in until discomfort is relieved or until the a collodion-like vehicle. nail can be lifted out of the nail groove § 358.550 Labeling of corn and callus and easily trimmed’’. remover drug products. (2) ‘‘[Bullet] children under 12 years: (a) Statement of identity. The labeling ask a doctor’’. of the product contains the established name of the drug, if any, and identifies Subpart E [Reserved] the product as a ‘‘corn and callus remover.’’ Subpart F—Corn and Callus (b) Indications. The labeling of the Remover Drug Products product states, under the heading ‘‘In- dications,’’ the phrase listed in paragraph (b)(1) of this section and may SOURCE: 55 FR 33261, Aug. 14, 1990, unless contain the additional phrase listed in otherwise noted. paragraph (b)(2) of this section. Other truthful and nonmisleading state- § 358.501 Scope. ments, describing only the indications (a) An over-the-counter corn and cal- for use that have been established in lus remover drug product in a form paragraph (b) of this section, may also suitable for topical application is gen- be used, as provided in § 330.1(c)(2) of erally recognized as safe and effective this chapter, subject to the provisions and is not misbranded if it meets each of section 502 of the Federal Food, of the conditions in this subpart and Drug, and Cosmetic Act (the act) relat- each of the general conditions estab- ing to misbranding and the prohibition lished in § 330.1 of this chapter. in section 301(d) of the act against the (b) References in this subpart to reg- introduction or delivery for introduc- ulatory sections of the Code of Federal tion into interstate commerce of unap- Regulations are to chapter I of title 21 proved new drugs in violation of sec- unless otherwise noted. tion 505(a) of the act. (1) ‘‘For the removal of corns and cal- § 358.503 Definitions. luses.’’ (2) In addition to the information As used in this subpart: identified in paragraph (b)(1) of this (a) Corn and callus remover drug prod- section, the labeling of the product uct. A topical agent used for the re- may contain the following statement: moval of corns and calluses. ‘‘Relieves pain by removing corns and (b) Collodion-like vehicle. A solution calluses.’’ containing pyroxylin (nitrocellulose) (c) Warnings. The labeling of the in an appropriate nonaqueous solvent product contains the following warn- that leaves a transparent cohesive film ings under the heading ‘‘Warnings’’: when applied to the skin in a thin (1) For products containing any ingre- layer. dient identified in § 358.510. (i) ‘‘For ex- (c) Plaster vehicle. A fabric, plastic, or ternal use only.’’ other suitable backing material in (ii) ‘‘Do not use this product on irritated skin, on any area that is infected which medication is usually incor- or reddened, if you are a diabetic, or if porated for topical application to the you have poor blood circulation.’’ skin. (iii) ‘‘If discomfort persists, see your doctor or podiatrist.’’

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(2) For any product formulated in a § 358.601 Scope. flammable vehicle. (i) The labeling (a) An over-the-counter pediculicide should contain an appropriate flamma- drug product in a form suitable for top- bility signal word, e.g., ‘‘extremely ical application is generally recognized flammable,’’ ‘‘flammable,’’ ‘‘combus- as safe and effective and is not mis- tible,’’ consistent with 16 CFR branded if it meets each condition in 1500.3(b)(10). this subpart and each general condition (ii) ‘‘Keep away from fire or flame.’’ established in § 330.1 of this chapter. (3) For any product formulated in a volatile vehicle. ‘‘Cap bottle tightly and (b) References in this subpart to reg- store at room temperature away from ulatory sections of the Code of Federal heat.’’ Regulations are to chapter I of title 21 unless otherwise noted. (4) For any product formulated in a collodion-like vehicle. (i) ‘‘If product gets § 358.603 Definition. into the eye, flush with water for 15 minutes.’’ As used in this subpart: (ii) ‘‘Avoid inhaling vapors.’’ Pediculicide drug product. A drug (d) Directions. The labeling of the product for the treatment of head, product contains the following infor- pubic (crab), and body lice. mation under the heading ‘‘Direc- tions’’: § 358.610 Pediculicide active ingredi- (1) For products containing salicylic ents. acid identified in § 358.510(a). ‘‘Wash af- The active ingredients of the product fected area and dry thoroughly.’’ (If ap- consist of the combination of pyre- propriate: ‘‘Cut plaster to fit corn/cal- thrum extract (providing a concentra- lus.’’) ‘‘Apply medicated plaster. After tion of pyrethrins of 0.17 to 0.33 per- 48 hours remove the medicated plaster. cent) with piperonyl butoxide (2 to 4 Repeat this procedure every 48 hours as percent) in a nonaerosol dosage formu- needed for up to 14 days (until corn/cal- lation. lus is removed).’’ (Optional: ‘‘May soak corn/callus in warm water for 5 min- [63 FR 43303, Aug. 13, 1998] utes to assist in removal.’’) § 358.650 Labeling of pediculicide drug (2) For products containing salicylic products. acid identified in § 358.510(b). ‘‘Wash affected area and dry thoroughly. Apply’’ (a) Statement of identity. The labeling (select one of the following, as appro- of the product contains the established priate: ‘‘one drop’’ or ‘‘small amount’’) name of the drug, if any, and identifies ‘‘at a time with’’ (select one of the fol- the product as a ‘‘lice treatment.’’ lowing, as appropriate: ‘‘applicator’’ or (b) Indications. The labeling of the ‘‘brush’’) ‘‘to sufficiently cover each product states, under the heading corn/callus. Let dry. Repeat this proce- ‘‘Uses,’’ the following: ‘‘treats head, dure once or twice daily as needed for pubic (crab), and body lice.’’ Other up to 14 days (until corn/callus is re- truthful and nonmisleading state- moved).’’ (Optional: ‘‘May soak corn/ ments, describing only the uses that callus in warm water for 5 minutes to have been established and listed in this assist in removal.’’) paragraph (b), may also be used, as pro- (e) The word ‘‘physician’’ may be sub- vided in § 330.1(c)(2) of this chapter, stituted for the word ‘‘doctor’’ in any subject to the provisions of section 502 of the labeling statements in this sec- of the Federal Food, Drug, and Cos- tion. metic Act (the act) relating to misbranding and the prohibition in section [55 FR 33261, Aug. 14, 1990, as amended at 57 301(d) of the act against the introduc- FR 44494, Sept. 28, 1992] tion or delivery for introduction into interstate commerce of unapproved Subpart G—Pediculicide Drug new drugs in violation of section 505(a) Products of the act. (c) Warnings. The labeling of the SOURCE: 58 FR 65455, Dec. 14, 1993, unless product contains the following warn- otherwise noted. ings under the heading ‘‘Warnings’’:

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(1) ‘‘For external use only’’ in accord (ii) For nonshampoo products ‘‘Treat with § 201.66(c)(5)(i) of this chapter. [in bold type] [bullet] apply thoroughly (2) ‘‘Do not use [bullet] 1 near eyes to (optional, may add ‘‘dry’’) hair or [bullet] inside nose, mouth, or vagina other affected area. For head lice, first [bullet] on lice in eyebrows or eye- apply behind ears and to back of neck. lashes. See a doctor if lice are present [bullet] allow product to remain for 10 in these areas.’’ minutes, but no longer [bullet] wash (3) ‘‘Ask a doctor before use if you area thoroughly with warm water and are [bullet] allergic to ragweed. May soap or shampoo [bullet] for head lice, cause breathing difficulty or an asth- towel dry hair and comb out tangles’’. matic attack.’’ (5) ‘‘Remove lice and their eggs (nits) (4) ‘‘When using this product [bullet] [in bold type] [bullet] use a fine-tooth keep eyes tightly closed and protect or special lice/nit comb. Remove any eyes with a washcloth or towel [bullet] remaining nits by hand (using a throw- if product gets in eyes, flush with away glove). [bullet] hair should re- water right away [bullet] scalp itching main slightly damp while removing or redness may occur’’. nits [bullet] if hair dries during comb- (5) ‘‘Stop use and ask a doctor if [bul- ing, dampen slightly with water [bullet] breathing difficulty occurs [bullet] let] for head lice, part hair into sec- eye irritation occurs [bullet] skin or tions. Do one section at a time starting scalp irritation continues or infection on top of head. Longer hair may take 1 occurs’’. to 2 hours. [bullet] lift a 1- to 2-inch (d) Directions. The labeling of the wide strand of hair. Place comb as product contains the following infor- close to scalp as possible and comb mation under the heading ‘‘Direc- with a firm, even motion away from tions’’: scalp. [bullet] pin back each strand of (1) The labeling states ‘‘[bullet] Im- hair after combing [bullet] clean comb portant: Read warnings before use’’ often. Wipe nits away with tissue and [statement shall appear first and in discard in a plastic bag. Seal bag and bold type]. discard to prevent lice from coming (2) The labeling states ‘‘adults and back. [bullet] after combing, thor- children 2 years and over:’’ [in bold oughly recheck for lice/nits. Repeat type]. combing if necessary. [bullet] check (3) For head lice treatment products daily for any lice/nits that you ‘‘Inspect [in bold type] [bullet] check missed’’. each household member with a magni- (6) The labeling states ‘‘[bullet] a sec- fying glass in bright light for lice/nits ond treatment must be done in 7 to 10 (eggs) [bullet] look for tiny nits near days to kill any newly hatched lice’’. scalp, beginning at back of neck and (7) The labeling states ‘‘[bullet] if in- behind ears [bullet] examine small sec- festation continues, see a doctor for tions of hair at a time [bullet] unlike other treatments’’. dandruff which moves when touched, (8) The labeling states ‘‘children nits stick to the hair [bullet] if either under 2 years:’’ [in bold type] ‘‘ask a lice or nits are found, treat with this doctor’’. product’’. (e) Other information. The labeling of (4) Select one of the following: the product contains the following (i) For shampoo products ‘‘Treat [in statements, as appropriate, under the bold type] [bullet] apply thoroughly to heading ‘‘Other information.’’ This in- (optional, may add ‘‘dry’’) hair or other formation may appear in a package in- affected area. For head lice, first apply sert. If a package insert is used, the behind ears and to back of neck. [bul- ‘‘Other information’’ section on the let] allow product to remain for 10 min- outer carton or container label shall utes, but no longer [bullet] use warm include a statement referring to the water to form a lather, shampoo, then package insert for additional informa- thoroughly rinse [bullet] for head lice, tion. towel dry hair and comb out tangles’’. (1) ‘‘Head lice [highlighted in bold type] [bullet] lay small white eggs 1 See § 201.66(b)(4) of this chapter for defini- (nits) on hair shaft close to scalp [bul- tion of bullet symbol. let] nits are most easily found on back

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of neck or behind ears [bullet] disinfect Subpart H—Drug Products for the hats, hair ribbons, scarves, coats, tow- Control of Dandruff, els, and bed linens by machine washing Seborrheic Dermatitis, and in hot water (above 54 °C (130 °F)), then Psoriasis using hottest dryer cycle for at least 20 minutes [bullet] items that cannot be washed (bedspreads, blankets, pillows, SOURCE: 56 FR 63568, Dec. 4, 1991, unless otherwise noted. stuffed toys, etc.) should be dry- cleaned or sealed in a plastic bag for 4 § 358.701 Scope. weeks, then removed outdoors and (a) An over-the-counter dandruff, shaken out very hard before using seborrheic dermatitis, or psoriasis drug again [bullet] items that cannot be product in a form suitable for topical washed, dry-cleaned, or stored may be application is generally recognized as sprayed with a product designed for safe and effective and is not mis- this purpose [bullet] soak all combs branded if it meets each of the condi- ° and brushes in hot water (above 54 C tions in this subpart and each general (130 °F)) for at least 10 minutes [bullet] condition established in § 330.1 of this vacuum all carpets, mattresses, uphol- chapter. stered furniture, and car seats that (b) References in this subpart to reg- may have been used by affected peo- ulatory sections of the Code of Federal ple’’. Regulations are to chapter I of title 21 (2) ‘‘Pubic (crab) lice [highlighted in unless otherwise noted. bold type] [bullet] may be transmitted by sexual contact. Sexual partners § 358.703 Definitions. should be treated simultaneously to As used in this subpart: avoid reinfestation [bullet] lice are (a) Coal tar. The tar used for medic- very small and look like brown or grey inal purposes that is obtained as a by- dots on skin [bullet] usually cause in- product during the destructive distilla- tense itching and lay small white eggs tion of bituminous coal at tempera- (nits) on the hair shaft generally close tures in the range of 900 °C to 1,100 °C. to the skin surface [bullet] may be It may be further processed using ei- present on the short hairs of groin, ther extraction with alcohol and suit- thighs, trunk, and underarms, and oc- able dispersing agents and maceration casionally on the beard and mustache times or fractional distillation with or [bullet] disinfect underwear by ma- without the use of suitable organic sol- chine washing in hot water (above 54 °C vents. (130 °F)), then using hottest dryer cycle (b) Dandruff. A condition involving for at least 20 minutes’’. an increased rate of shedding of dead (3) ‘‘Body lice [highlighted in bold epidermal cells of the scalp. type] [bullet] body lice and their eggs (c) Psoriasis. A condition of the scalp (nits) are generally found in the seams or body characterized by irritation, of clothing particularly in waistline itching, redness, and extreme excess shedding of dead epidermal cells. and armpit area [bullet] body lice feed on skin then return to clothing to lay (d) Seborrheic dermatitis. A condition of the scalp or body characterized by their eggs [bullet] disinfect clothing by irritation, itching, redness, and excess machine washing in hot water (above shedding of dead epidermal cells. 54 °C (130 °F)), then using hottest dryer (e) Selenium sulfide, micronized. Se- cycle for at least 20 minutes [bullet] do lenium sulfide that has been finely not seal clothing in a plastic bag be- ground and that has a median particle cause nits can remain dormant for up size of approximately 5 micrometers to 30 days’’. (μm), with not more than 0.1 percent of [68 FR 75417, Dec. 31, 2003] the particles greater than 15 μm and not more than 0.1 percent of the particles less than 0.5 μm. [56 FR 63568, Dec. 4, 1991, as amended at 59 FR 4001, Jan. 28, 1994]

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§ 358.710 Active ingredients for the § 358.720 Permitted combinations of control of dandruff, seborrheic der- active ingredients. matitis, or psoriasis. (a) Combination of active ingredients The active ingredient of the product for the control of dandruff. Salicylic consists of any of the following within acid identified in § 358.710(a)(4) may be the specified concentration established combined with sulfur identified in for each ingredient: § 358.710(a)(7) provided each ingredient (a) Active ingredients for the control of is present within the established con- dandruff. (1) Coal tar, 0.5 to 5 percent. centration and the product is labeled When a coal tar solution, derivative, or according to § 358.750. fraction is used as the source of the (b) Combination of control of dandruff coal tar, the labeling shall specify the and external analgesic active ingredients. identity and concentration of the coal Coal tar identified in § 358.710(a)(1) may tar source used and the concentration be used at a concentration of 1.8 per- of the coal tar present in the final cent coal tar solution, on a weight to product. volume basis, in combination with (2) Pyrithione zinc, 0.3 to 2 percent menthol, 1.5 percent, in a shampoo for- when formulated to be applied and then mulation provided the product is la- washed off after brief exposure. beled according to § 358.760. (3) Pyrithione zinc, 0.1 to 0.25 percent [72 FR 9852, Mar. 6, 2007] when formulated to be applied and left on the skin or scalp. § 358.750 Labeling of drug products for (4) Salicylic acid, 1.8 to 3 percent. the control of dandruff, seborrheic (5) Selenium sulfide, 1 percent. dermatitis, or psoriasis. (6) Selenium sulfide, micronized, 0.6 (a) Statement of identity. The labeling percent. of the product contains the established (7) Sulfur, 2 to 5 percent. name of the drug, if any, and identifies (b) Active ingredients for the control of the product with one or more of the seborrheic dermatitis. (1) Coal tar, 0.5 to following, as appropriate: 5 percent. When a coal tar solution, de- (1) ‘‘Dandruff (insert product form)’’ rivative, or fraction is used as the or ‘‘antidandruff (insert product source of the coal tar, the labeling form)’’. shall specify the identity and con- (2) ‘‘Seborrheic dermatitis (insert centration of the coal tar source used product form)’’. and the concentration of the coal tar (3) ‘‘Psoriasis (insert product form)’’. present in the final product. (b) Indications. The labeling of the (2) Pyrithione zinc, 0.95 to 2 percent product states, under the heading ‘‘In- when formulated to be applied and then dications,’’ the phrase listed in para- washed off after brief exposure. graph (b)(1) of this section and may (3) Pyrithione zinc, 0.1 to 0.25 percent contain any of the terms listed in para- when formulated to be applied and left graph (b)(2) or (b)(3) of this section. on the skin or scalp. Other truthful and nonmisleading (4) Salicylic acid, 1.8 to 3 percent. statements, describing only the indica- (5) Selenium sulfide, 1 percent. tions for use that have been established and listed in paragraph (b) of this sec- (c) Active ingredients for the control of tion, may also be used, as provided in psoriasis. (1) Coal tar, 0.5 to 5 percent. § 330.1(c)(2) of this chapter, subject to When a coal tar solution, derivative, or the provisions of section 502 of the Fed- fraction is used as the source of the eral Food, Drug, and Cosmetic Act (the coal tar, the labeling shall specify the act) relating to misbranding and the identity and concentration of the coal prohibition in section 301(d) of the act tar source used and the concentration against the introduction or delivery for of the coal tar present in the final introduction into interstate commerce product. of unapproved new drugs in violation of (2) Salicylic acid, 1.8 to 3 percent. section 505(a) of the act. [56 FR 63568, Dec. 4, 1991, as amended at 59 (1) (‘‘For relief of’’ or ‘‘Controls’’) FR 4001, Jan. 28, 1994] ‘‘the symptoms of’’ (select one or more

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of the following, as appropriate: ‘‘dan- of the body, consult your doctor before druff,’’ ‘‘seborrheic dermatitis,’’ and/or using this product.’’ ‘‘psoriasis.’’) (d) Directions. The labeling of the (2) The following terms or phrases product contains the following infor- may be used in place of or in addition mation under the heading ‘‘Direc- to the words ‘‘For the relief of’’ or tions.’’ More detailed directions appli- ‘‘Controls’’ in the indications in para- cable to a particular product formula- graph (b)(1) of this section: ‘‘fights,’’ tion may also be included. ‘‘reduces,’’ ‘‘helps eliminate,’’ ‘‘helps (1) For products containing active in- stop,’’ ‘‘controls recurrence of,’’ ‘‘fights gredients for the control of dandruff, recurrence of,’’ ‘‘helps prevent recur- seborrheic dermatitis, or psoriasis when rence of,’’ ‘‘reduces recurrence of,’’ formulated to be applied and then washed ‘‘helps eliminate recurrence of,’’ ‘‘helps off after brief (a few minutes) exposure stop recurrence of.’’ (e.g, shampoos, preshampoo rinses, (3) The following terms may be used in place of the words ‘‘the symptoms postshampoo rinses). ‘‘For best results of’’ in the indications in paragraph use at least twice a week or as directed (b)(1) of this section: (‘‘skin’’ and/or by a doctor.’’ ‘‘scalp,’’ as appropriate) (select one or (2) For products containing active in- more of the following: ‘‘itching,’’ ‘‘irri- gredients for the control of dandruff, tation,’’ ‘‘redness,’’ ‘‘flaking,’’ ‘‘scal- seborrheic dermatitis, or psoriasis when ing,’’) ‘‘associated with.’’ formulated so as to be applied and left on (c) Warnings. The labeling of the the skin or scalp (e.g., creams, ointments, product contains the following warn- lotions, hairgrooms). ‘‘Apply to affected ings under the heading ‘‘Warnings’’: areas one to four times daily or as di- (1) For products containing any ingre- rected by a doctor.’’ dient identified in § 358.710. (i) ‘‘For ex- (3) For products containing active internal use only.’’ gredients for the control of seborrheic der- (ii) ‘‘Avoid contact with the eyes. If matitis or psoriasis of the skin when for- contact occurs, rinse eyes thoroughly mulated as soaps. ‘‘Use on affected areas with water.’’ in place of your regular soap.’’ (iii) ‘‘If condition worsens or does not (e) The word ‘‘physician’’ may be sub- improve after regular use of this prod- stituted for the word ‘‘doctor’’ in any uct as directed, consult a doctor.’’ of the labeling statements in this sec- (2) For any product containing coal tar tion. identified in § 358.710(a), (b), or (c). (i) ‘‘Use caution in exposing skin to sun- § 358.760 Labeling of permitted com- light after applying this product. It binations of active ingredients for may increase your tendency to sunburn the control of dandruff. for up to 24 hours after application.’’ The statement of identity, indica- (ii) ‘‘Do not use for prolonged periods tions, warnings, and directions for use, without consulting a doctor.’’ respectively, applicable to each ingre- (3) For products containing coal tar dient in the product may be combined when formulated to be applied and left on to eliminate duplicative words or the skin (e.g., creams, ointments, lotions). ‘‘Do not use this product in or around phrases so that the resulting informa- the rectum or in the genital area or tion is clear and understandable. groin except on the advice of a doctor.’’ (a) Statement of identity. For a com- (4) For products containing coal tar bination drug product that has an es- identified in § 358.710(c) for the control of tablished name, the labeling of the psoriasis. ‘‘Do not use this product with product states the established name of other forms of psoriasis therapy such the combination drug product, followed as ultraviolet radiation or prescription by the statement of identity for each drugs unless directed to do so by a doc- ingredient in the combination, as es- tor.’’ tablished in the statement of identity (5) For products containing any ingre- sections of the applicable OTC drug dient identified in § 358.710(b) or (c) for monographs. the control of seborrheic dermatitis or pso- (1) Combinations of control of dandruff riasis. ‘‘If condition covers a large area and external analgesic active ingredients

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in § 358.720(b). The label states ‘‘dan- graph (d). When the time intervals or druff/anti-itch shampoo’’ or ‘‘anti- age limitations for administration of dandruff/anti-itch shampoo’’. the individual ingredients differ, the (2) [Reserved] directions for the combination product (b) Indications. The labeling of the may not contain any dosage that ex- product states, under the heading ceeds those established for any indi- ‘‘Uses,’’ one or more of the phrases list- vidual ingredient in the applicable OTC ed in this paragraph (b), as appropriate. drug monograph(s), and may not pro- Other truthful and nonmisleading vide for use by any age group lower statements, describing only the uses than the highest minimum age limit that have been established and listed in established for any individual ingre- this paragraph (b), may also be used, as dient. provided in § 330.1(c)(2) of this chapter, (1) Combinations of control of dandruff subject to the provisions of section 502 and external analgesic active ingredients of the Federal Food, Drug, and Cos- in § 358.720(b). The labeling states metic Act (the act) relating to mis- ‘‘[bullet] wet hair [bullet] apply sham- branding and the prohibition in section poo and work into a lather [bullet] 301(d) of the act against the introduc- rinse thoroughly [bullet] for best re- tion or delivery for introduction into sults, use at least twice a week or as interstate commerce of unapproved directed by a doctor’’. new drugs in violation of section 505(a) (2) [Reserved] of the act. [72 FR 9852, Mar. 6, 2007] (1) Combinations of control of dandruff and external analgesic active ingredients PART 361—PRESCRIPTION DRUGS in § 358.720(b). The labeling states FOR HUMAN USE GENERALLY ‘‘[bullet] [select one of the following: ‘for relief of’ or ‘controls’] the symp- RECOGNIZED AS SAFE AND EF- toms of dandruff [bullet] [select one of FECTIVE AND NOT MISBRANDED: the following: ‘additional’ or ‘extra’] DRUGS USED IN RESEARCH relief of itching due to dandruff’’. (2) The following terms or phrases AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, may be used in place of or in addition 371; 42 U.S.C. 262. to the words ‘‘for the relief of’’ or ‘‘controls’’ in the indications in para- § 361.1 Radioactive drugs for certain graph (b)(1) of this section: ‘‘fights,’’ research uses. ‘‘reduces,’’ ‘‘helps eliminate,’’ ‘‘helps (a) Radioactive drugs (as defined in stop,’’ ‘‘controls recurrence of,’’ ‘‘fights § 310.3(n) of this chapter) are generally recurrence of,’’ ‘‘helps prevent recur- recognized as safe and effective when rence of,’’ ‘‘reduces recurrence of,’’ administered, under the conditions set ‘‘helps eliminate recurrence of,’’ ‘‘helps forth in paragraph (b) of this section, stop recurrence of.’’ to human research subjects during the (3) The following terms may be used course of a research project intended to in place of the words ‘‘the symptoms obtain basic information regarding the of’’ in the indication in paragraph (b)(1) metabolism (including kinetics, dis- of this section: ‘‘scalp’’ (select one or tribution, and localization) of a radio- more of the following: ‘‘itching,’’ ‘‘irri- actively labeled drug or regarding tation,’’ ‘‘redness,’’ ‘‘flaking,’’ ‘‘scal- human physiology, pathophysiology, or ing’’) ‘‘associated with’’. biochemistry, but not intended for im- (c) Warnings. The labeling of the mediate therapeutic, diagnostic, or product states, under the heading similar purposes or to determine the ‘‘Warnings,’’ the warning(s) listed in safety and effectiveness of the drug in § 358.750(c)(1) and (c)(2). humans for such purposes (i.e., to carry (d) Directions. The labeling of the out a clinical trial). Certain basic re- product states, under the heading ‘‘Di- search studies, e.g., studies to deter- rections,’’ directions that conform to mine whether a drug localizes in a par- the directions established for each in- ticular organ or fluid space and to de- gredient in the directions sections of scribe the kinetics of that localization, the applicable OTC drug monographs, may have eventual therapeutic or diag- unless otherwise stated in this para- nostic implications, but the initial

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studies are considered to be basic re- (3) Limit on radiation dose. The search within the meaning of this sec- amount of radioactive material to be tion. administered shall be such that the (b) The conditions under which use of subject receives the smallest radiation radioactive drugs for research are con- dose with which it is practical to per- sidered safe and effective are: form the study without jeopardizing (1) Approval by Radioactive Drug Re- the benefits to be obtained from the search Committee. A Radioactive Drug study. Research Committee, composed and ap- (i) Under no circumstances may the proved by the Food and Drug Adminis- radiation dose to an adult research tration in accordance with paragraph subject from a single study or cumula- (c) of this section, has determined, in tively from a number of studies con- accordance with the standards set ducted within 1 year be generally rec- forth in paragraph (d) of this section, ognized as safe if such dose exceeds the that: following: (i) The pharmacological dose is with- Whole body, active blood-forming or- in the limits set forth in paragraph gans, lens of the eye, and gonads: (b)(2) of this section; Rems (ii) The radiation dose is within the limits set forth in paragraph (b)(3) of Single dose ...... 3 Annual and total dose commitment ...... 5 this section; Other organs: (iii) The radiation exposure is justi- Single dose ...... 5 fied by the quality of the study being Annual and total dose commitment ...... 15 undertaken and the importance of the (ii) For a research subject under 18 information it seeks to obtain; years of age at his last birthday, the (iv) The study meets the other re- radiation dose shall not exceed 10 per- quirements set forth in paragraph (d) cent of that set forth in paragraph of this section regarding qualifications (b)(3)(i) of this section. of the investigator, proper licensure for (iii) All radioactive material included handling radioactive materials, selec- in the drug either as essential material tion and consent of research subjects, or as a significant contaminant or im- quality of radioactive drugs used, re- purity shall be included when deter- search protocol design, reporting of ad- mining the total radiation doses and verse reactions, and approval by an ap- dose commitments. Radiation doses propriate Institutional Review Com- from x-ray procedures that are part of mittee; and the research study (i.e., would not have (v) The use of the radioactive drug in occurred but for the study) shall also human subjects has the approval of the be included. The possibility of followup Radioactive Drug Research Committee. studies shall be considered for inclu- (2) Limit on pharmacological dose. The sion in the dose calculations. amount of active ingredient or com- (iv) Numerical definitions of dose bination of active ingredients to be ad- shall be based on an absorbed fraction ministered shall be known not to cause method of radiation absorbed dose cal- any clinically detectable pharma- culation, such as the system set forth cological effect in human beings. If the by the Medical Internal Radiation Dose same active ingredients (exclusive of Committee of the Society of Nuclear the radionuclide) are to be adminis- Medicine, or the system set forth by tered simultaneously, e.g., under a the International Commission on Radi- ‘‘Investigational New Drug Applica- ological Protection. tion’’ or for a therapeutic use in ac- (c) A Radioactive Drug Research cordance with labeling for a drug ap- Committee, in order to comply with proved under part 314 of this chapter, paragraph (b)(1) of this section, shall be the total amount of active ingredients composed, shall function, and shall ob- including the radionuclide shall be tain and maintain approval of the Food known not to exceed the dose limita- and Drug Administration in con- tions applicable to the separate admin- formity with the following: istration of the active ingredients ex- (1) Membership. A Radioactive Drug cluding the radionuclide. Research Committee shall consist of at

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least five individuals. Each committee (3) Reports. Each Radioactive Drug shall include the following three indi- Research Committee shall submit an viduals: (i) A physician recognized as a annual report on or before January 31 specialist in nuclear medicine, (ii) a of each year to the Food and Drug Ad- person qualified by training and experi- ministration, Center for Drug Evalua- ence to formulate radioactive drugs, tion and Research, HFD–160, 5600 Fish- and (iii) a person with special com- ers Lane, Rockville, MD 20857. The an- petence in radiation safety and radi- nual report shall include the names ation dosimetry. The remainder of the and qualifications of the members of, committee shall consist of individuals and of any consultants used by, the Ra- qualified in various disciplines perti- dioactive Drug Research Committee, nent to the field of nuclear medicine and, for each study conducted during (e.g., radiology, internal medicine, the preceding year, a summary of in- clinical pathology, hematology, endo- formation presented in the following crinology, radiation therapy, radiation format: physics, radiation biophysics, health physics, and radiopharmacy). Member- REPORT ON RESEARCH USE OF RADIOACTIVE ship shall be sufficiently diverse to per- DRUG mit expert review of the technical and 1. Title of the research project. scientific aspects of proposals sub- 2. Brief description of the purpose of the mitted to the committee. The addition research project. of consultants in other pertinent med- 3. Name of the investigator responsible. ical disciplines is encouraged. A Radio- 4. Pharmacological dose: a. Active ingredients. active Drug Research Committee shall b. Maximum amount administered per sub- be either associated with a medical in- ject. stitution operated for care of patients 5. Name of the radionuclide(s) used, includ- and with sufficient scientific expertise ing any present, as significant contaminants to allow for selection of committee or impurities. members from its faculty, or with a 6. Radiation absorbed dose. Provide the committee established by a State au- maximum dose commitement to the whole thority to provide advice on radiation body and each organ specified in 21 CFR 361.1(b)(3)(i) that was received by a rep- health matters. Joint committees in- resentative subject and the calculations or volving more than one medical institu- references that were used to estimate these tion which have been established in maximum dose commitments. The report order to achieve a high level and diver- shall include the dose contribution of both sity of experience will be acceptable. the administered radionuclide(s) and any X- The Director of the Center for Drug ray procedures associated with the study. If Evaluation and Research may modify the study elicits data on the uptake or excre- any of the foregoing requirements in a tion of the radioactive drug pertinent to the estimation of dose commitment, report the particular situation where alternative mean value and range of values. For each factors provide substantially the same subject provide: composition and association. (a) Age, sex, and approximate weight. (2) Function. Each Radioactive Drug (b) Total activity of each radionuclide ad- Research Committee shall select a ministered for each radioactive drug used in chairman, who shall sign all applica- the study. Report each X-ray procedure used tions, minutes, and reports of the com- in conjunction with the study. mittee. Each committee shall meet at (c) If the subject has participated in other radioactive drug research studies, report the least once each quarter in which re- name of the radioactive drug used in these search activity has been authorized or other studies, the date of administration, conducted. A quorum consisting of and the total activity of each radionuclide more than 50 percent of the member- administered. If any X-ray procedures were ship must be present with appropriate used, identify the X-ray procedure(s) and in- representation of the required fields of clude an estimate of the absorbed radiation specialization. Minutes shall be kept doses. and shall include the numerical results (d) If more than one administration of a radioactive drug per subject, cumulative radi- of votes on protocols involving use in ation dose and dose commitment, expressed human subjects. No member shall vote as whole body, active blood-forming organs, on a protocol in which he is an investi- lens of the eye, gonads, and other organ gator. doses from the administered radionuclides.

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7. A claim of confidentiality, if any. (5) Monitoring. The Food and Drug NOTE: Contents of this report are available Administration shall conduct periodic for public disclosure unless confidentiality is reviews of approved committees. Moni- requested by the investigator and it is ade- toring of the activities of the com- quately shown by the investigator that the mittee shall be conducted through re- report constitutes a trade secret or confiden- view of its annual report, through re- tial commercial information as defined in 21 view of minutes and full protocols for CFR 20.61. certain studies, and through on-site in- llllllllllll spections. Investigator (d) In making the determination re- llllllllllll quired in paragraph (b)(1) of this sec- Chairman, Radioactive Drug tion, a Radioactive Drug Research Research Committee Committee shall consider the following At any time a proposal is approved requirements and assure that each is which involves exposure either of more met: than 30 research subjects, or of any re- (1) Radiation dose to subjects. To as- search subject under 18 years of age, sure that the radiation dose to re- the committee shall immediately sub- search subjects is as low as practicable mit to the Food and Drug Administra- to perform the study and meet the cri- tion a special summary of information teria of § 361.1(b)(3), the Radioactive in the format shown in this paragraph. Drug Research Committee shall require Contents of these reports are available that: for public disclosure, unless confiden- (i) The investigator provide absorbed tiality is requested by the investigator dose calculations based on biologic dis- and it is adequately shown by the in- tribution data available from published vestigator that the report constitutes a literature or from other valid studies. trade secret or confidential commer- (ii) The investigator provide for an cial information as defined in § 20.61 of acceptable method of radioassay of the this chapter. radioactive drug prior to its use to as- (4) Approval. Each Radioactive Drug sure that the dose calculations actu- Research Committee shall be specifi- ally reflect the administered dose. cally approved by the Center for Drug (iii) The radioactive drug chosen for Evaluation and Research of the Food the study has that combination of half- and Drug Administration. Applications life, types of radiations, radiation en- shall be submitted to the Food and ergy, metabolism, chemical properties, Drug Administration, Center for Drug etc., which results in the lowest dose to Evaluation and Research, HFD–160, 5600 the whole body or specific organs with Fishers Lane, Rockville, MD 20857, and which it is possible to obtain the nec- shall contain the names and qualifica- essary information. tions of the members of the committee, (iv) The investigator utilize adequate and a statement that the committee and appropriate instrumentation for agrees to comply with the require- the detection and measurement of the ments set forth in this section. Ap- specific radionuclide. proval shall be based upon an assess- (2) Pharmacological dosage. To deter- ment of the qualifications of the mem- mine that the amount of active ingre- bers of the committee, and the assur- dients to be administered does not ex- ance that all necessary fields of exper- ceed the limitations set forth in para- tise are covered. Approval of a com- graph (b)(2) of this section, the committee may be withdrawn at any time mittee shall require that the investi- for failure of the committee to comply gator provide pharmacological dose with any of the requirements of this calculations based on data available section. Approval of a committee shall from published literature or from other remain effective unless and until the valid human studies. FDA withdraws such approval. Changes (3) Qualifications of investigators. Each in membership and applications for investigator shall be qualified by train- new members shall be submitted to the ing and experience to conduct the pro- Food and Drug Administration as soon posed research studies. as, or before, vacancies occur on the (4) License to handle radioactive mate- committee. rials. The responsible investigator or

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institutions shall, in the case of reac- this chapter, to research subjects under tor-produced isotopes, be licensed by this section, shall be permitted unless the Nuclear Regulatory Commission or the Radioactive Drug Research Com- Agreement State to possess and use the mittee concludes, in its judgment, that specific radionuclides for research use scientific knowledge and benefit is or be a listed investigator under a likely to result from that study. There- broad license, or in the case of non-re- fore, the protocol shall be based upon a actor-produced isotopes, be licensed by sound rationale derived from appro- other appropriate State or local au- priate animal studies or published lit- thorities, when required by State or erature and shall be of sound design local law, to possess and use the spe- such that information of scientific cific radionuclides for research use. value may result. The radiation dose (5) Human research subjects. Each in- shall be both sufficient and no greater vestigator shall select appropriate than necessary to obtain valid meas- human subjects and shall obtain the re- urement. The projected number of sub- view and approval of an institutional jects shall be sufficient but no greater review committee that conforms to the than necessary for the purpose of the requirements of part 56 of this chapter, study. The number of subjects shall and shall obtain the consent of the sub- also reflect the fact that the study is jects or their legal representatives in intended to obtain basic research infor- accordance with part 50 of this chapter. mation referred to in paragraph (a) of The research subjects shall be at least this section and not intended for imme- 18 years of age and legally competent. diate therapeutic, diagnostic or similar Exceptions are permitted only in those purposes or to determine the safety special situations when it can be dem- and effectiveness of the drug in humans onstrated to the committee that the for such purposes (i.e., to carry out a study presents a unique opportunity to clinical trial). gain information not currently avail- (8) Adverse reactions. The investigator able, requires the use of research sub- shall immediately report to the Radio- jects less than 18 years of age, and is active Drug Research Committee all without significant risk to the subject. adverse effects associated with the use Studies involving minors shall be sup- of the radioactive drug in the research ported with review by qualified pedi- study. All adverse reactions probably atric consultants to the Radioactive attributable to the use of the radio- Drug Research Committee. Each fe- active drug in the research study shall male research subject of childbearing be immediately reported by the Radio- potential shall state in writing that active Drug Research Committee to she is not pregnant, or, on the basis of the Food and Drug Administration, a pregnancy test be confirmed as not Center for Drug Evaluation and Re- pregnant, before she may participate in search, HFD–160, 5600 Fishers Lane, any study. Rockville, MD 20857. (6) Quality of radioactive drug. The ra- (9) Approval by an institutional review dioactive drug used in the research board. The investigator shall obtain the study shall meet appropriate chemical, review and approval of an institutional pharmaceutical, radiochemical, and review board that conforms to the re- radionuclidic standards of identity, quirements of part 56 of this chapter. strength, quality, and purity as needed (e) The results of any research con- for safety and be of such uniform and ducted pursuant to this section as part reproducible quality as to give signifi- of the evaluation of a drug pursuant to cance to the research study conducted. part 312 of this chapter shall be in- The Radioactive Drug Research Com- cluded in the submissions required mittee shall determine that radio- under part 312 of this chapter. active materials for parenteral use are (f) A radioactive drug prepared, pack- prepared in sterile and pyrogen-free aged, distributed, and primarily inform. tended for use in accordance with the (7) Research protocol. No matter how requirements of this section shall be small the amount of radioactivity, no exempt from section 502(f)(1) of the act study involving administration of a ra- and §§ 201.5 and 201.100 of this chapter if dioactive drug, as defined in § 310.3(n) of the packaging, label, and labeling are

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in compliance with Federal, State, and (1) and (12) of this section may be local law regarding radioactive mate- placed on the shielded container only. rials and if the label of the immediate container and shielded container, if [40 FR 31308, July 25, 1975, as amended at 40 FR 44543, Sept. 29, 1975; 42 FR 15674, Mar. 22, any, either separate from or as part of 1977; 43 FR 14646, Apr. 7, 1978; 46 FR 8955, Jan. any label and labeling required for ra- 27, 1981; 49 FR 44460, Nov. 7, 1984; 50 FR 8996, dioactive materials by the Nuclear Mar. 6, 1985; 55 FR 11582, Mar. 29, 1990; 56 FR Regulatory Commission or by State or 10806, Mar. 14, 1991; 67 FR 4907, Feb. 1, 2002] local radiological health authorities bear the following: PART 369—INTERPRETATIVE STATE- (1) The statement ‘‘Rx only’’; MENTS RE WARNINGS ON DRUGS (2) The statement ‘‘To be administered in compliance with the require- AND DEVICES FOR OVER-THE- ments of Federal regulations regarding COUNTER SALE radioactive drugs for research use (21 CFR 361.1)’’; Subpart A—Definitions and Interpretations (3) The established name of the drug, Sec. if any; 369.1 Purpose of issuance. (4) The established name and quan- 369.2 Definitions. tity of each active ingredient; 369.3 Warnings required on drugs exempted (5) The name and half-life of the from prescription-dispensing require- radionuclide, total quantity of radioac- ments of section 503(b)(1)(C). tivity in the drug product’s immediate 369.4 Warnings suggested for drugs by for- container, and amount of radioactivity mal or informal statements of policy. per unit volume or unit mass at a des- 369.6 [Reserved] ignated referenced time; 369.7 Warnings required by official com- (6) The route of administration, if it pendia. is for the other than oral use; 369.8 Warning statements in relation to (7) The net quantity of contents; conditions for use. 369.9 General warnings re accidental inges- (8) An identifying lot or control num- tion by children. ber from which it is possible to deter- 369.10 Conspicuousness of warning state- mine the complete manufacturing his- ments. tory of the package of the drug; (9) The name and address of the man- Subpart B—Warning and Caution ufacturer, packer, or distributor; Statements for Drugs (10) The expiration date, if any; (11) If the drug is intended for paren- 369.20 Drugs; recommended warning and teral use, a statement as to whether caution statements. the contents are sterile; 369.21 Drugs; warning and caution statements required by regulations. (12) If the drug is for other than oral use, the names of all inactive ingredi- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, ents, except that: 355, 371. (i) Trace amounts of harmless sub- SOURCE: 39 FR 11745, Mar. 29, 1974, unless stances added solely for individual otherwise noted. product identification need not be EDITORIAL NOTE: Nomenclature changes to named. part 369 appear at 69 FR 13717, Mar. 24, 2004. (ii) If the drug is intended for parenteral use, the quantity or proportion of all inactive ingredients, except that in- Subpart A—Definitions and gredients added to adjust pH or to Interpretations make the drug isotonic may be de- clared by name and a statement of § 369.1 Purpose of issuance. their effect; if the vehicle is water for The warning and caution statements injection, it need not be named. Pro- suggested in subparts B and C of this vided, however, That in the case of con- part, for inclusion in the label or label- tainers too small or otherwise unable ing of drugs and devices subject to sec- to accommodate a label with sufficient tion 502(d) and (f)(2) and other relevant space to bear all such information, the provisions of the Federal Food, Drug, information required by paragraphs (f) and Cosmetic Act are issued for the

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purpose of assisting industry in pre- § 369.4 Warnings suggested for drugs paring proper labeling for these arti- by formal or informal statements of cles for over-the-counter sale and in policy. meeting the legal requirements of the The warning and caution statements act that the label or labeling of drugs included in subpart B of this part in no and devices bear adequate warnings, in way affect any warning statement sug- such manner and form as are necessary gested for such drugs or devices by any for the protection of users. Only sec- statement of policy or interpretation tion 502(d) of the act requires use of the in subchapter C of this chapter. specific language included in these suggested warning and caution state- [39 FR 11745, Mar. 29, 1974, as amended at 40 ments. These suggested warning or FR 13496, Mar. 27, 1975] caution statements are illustrative of § 369.6 [Reserved] those that may be necessary or desirable. It is the responsibility of the § 369.7 Warnings required by official manufacturer, packer, shipper, or dis- compendia. tributor in interstate commerce to see Any drug included in the official that such statements are adequate for compendia defined by the act shall compliance with the provisions of the bear such warning or caution state- law. Omission of any article from this ment as may be required by such com- suggested list does not relieve drugs pendia, and no statement in subpart B and devices subject to provisions of the or subpart C of this part is intended to act from bearing adequate warning or alter, modify, or permit the omission caution statements where such state- of any such statement required by such ments are necessary or desirable for compendia. the protection of the user. § 369.8 Warning statements in relation § 369.2 Definitions. to conditions for use. (a) As used in this part, the term act The mention in any warning or cau- means the Federal Food, Drug, and tion statement included in subparts A, Cosmetic Act. B, and C of this part, of a disease condi- (b) The terms drugs and devices are tion does not imply a finding on the defined in section 201(g) and (k) of the part of the Food and Drug Administra- act. tion that any drug or device is effica- (c) Official compendia are defined in cious in such condition; nor is any drug section 201(j) of the act. or device bearing labeling referring to such disease condition precluded from § 369.3 Warnings required on drugs ex- regulatory action under the applicable empted from prescription-dispensing requirements of section provisions of the act if such claim is 503(b)(1)(C). considered to be misbranding. Drugs exempted from prescription- § 369.9 General warnings re accidental dispensing requirements under section ingestion by children. 503(b)(1)(C) of the act are subject to the Section 369.20 includes under certain labeling requirements prescribed in items, but not all medicines, the state- § 310.201(a) of this chapter. Although, ment: ‘‘Keep this and all medicines out for convenience, warning and caution of children’s reach. In case of overdose, statements for a number of the drugs get medical help or contact a Poison named in § 310.201 of this chapter Control Center right away,’’ or ‘‘Keep (cross-referenced in the text of this out of reach of children.’’ However, in part) are included in subpart B of this view of the possibility of accidental in- part, the inclusion of such drugs in gestion of drugs, it is not only sug- §§ 369.20, 369.21, 369.22 in no way affects gested but is recommended that one of the requirements for compliance with these statements be used on the label § 310.201(a) of this chapter, or the provi- of all drug products. sions of an effective application pursuant to section 505(b) of the act. [64 FR 13296, Mar. 17, 1999]

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§ 369.10 Conspicuousness of warning ANTIHISTAMINICS, ORAL. (See also statements. § 310.201(a)(4) and (a)(24) of this chapter.) Necessary warning statements should appear in the labeling prominently and Caution—This preparation may cause conspicuously as compared to other drowsiness. Do not drive or operate words, statements, designs, and de- machinery while taking this medica- vices, and in bold type on clearly con- tion. Do not give to children under 6 trasting background, in order to com- years of age or exceed the rec- ply with the provisions of section 502(c) ommended dosage unless directed by and (f)(2) of the act. The warning state- physician. ments should be placed in the labeling The reference to drowsiness is not required on preparations for the pro- in juxtaposition with the directions for motion of sleep or on preparations that use and, in any case, should appear on are shown not to produce drowsiness. the label when there is sufficient label space in addition to mandatory label ANTIPYRINE. information. Warning—Do not exceed recommended dosage. If skin rash appears, Subpart B—Warning and Caution discontinue use and consult physician. Statements for Drugs ANTISEPTICS FOR EXTERNAL USE. Caution—In case of deep or puncture § 369.20 Drugs; recommended warning wounds or serious burns, consult physi- and caution statements. cian. If redness, irritation, swelling, or ACETANILID. pain persists or increases or if infection occurs discontinue use and consult Warning—Do not exceed rec- physician. ommended dosage. Overdosage or con- The reference to wounds and burns is tinued use may result in serious blood not required on preparations intended disturbances. solely for diaper rash. ACETOPHENETIDIN CONTAINING ARSENIC PREPARATIONS. PREPARATIONS. (See § 201.309 of this Warning—Frequent or prolonged use chapter.) may cause serious injury. Do not ex- Warning—This medication may dam- ceed recommended dosage. Keep out of age the kidneys when used in large the reach of children. amounts or for a long period of time. BELLADONNA PREPARATIONS AND Do not take more than the rec- PREPARATIONS OF ITS ALKALOIDS ommended dosage, nor take regularly (ATROPINE, HYOSCYAMINE, AND for longer than 10 days without con- SCOPOLAMINE (HYOSCINE); sulting your physician. HYOSCYAMUS, STRAMONIUM, THEIR DERIVATIVES, AND RE- ANESTHETICS FOR EXTERNAL USE LATED DRUG PREPARATIONS. (LOCAL ANESTHETICS). (See also § 310.201(a)(19) and (23) of this chapter.) Warning—Not to be used by persons having glaucoma or excessive pressure Caution—Do not use in the eyes. Not within the eye, by elderly persons for prolonged use. If the condition for (where undiagnosed glaucoma or exces- which this preparation is used persists sive pressure within the eye occurs or if a rash or irritation develops, dis- most frequently), or by children under continue use and consult physician. 6 years of age, unless directed by a phy- ANTIHISTAMINICS FOR EXTERNAL sician. Discontinue use if blurring of USE (EXCEPT PREPARATIONS FOR vision, rapid pulse, or dizziness occurs. OPHTHALMIC USE). Do not exceed recommended dosage. Not for frequent or prolonged use. If Caution—Do not use in the eyes. If dryness of the mouth occurs, decrease the condition for which this prepara- dosage. If eye pain occurs, discontinue tion is used persists or if a rash or irri- use and see your physician imme- tation develops, discontinue use and diately as this may indicate consult physician. undiagnosed glaucoma.

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In the case of scopolamine or scopol- more than 2 months unless directed by amine aminoxide preparations indi- physician. cated for insomnia, the portion of the This warning is not required on arti- above warning that reads ‘‘children cles containing not more than 0.5 milli- under 6 years of age’’ should read in- gram of cobalt as a cobalt salt per dos- stead ‘‘children under 12 years of age’’. age unit and which recommend admin- BORIC ACID (POWDERED, CRYS- istration of not more than 0.5 milli- TALLINE, OR GRANULAR). gram per dose and not more than 2 milligrams per 24-hour period. Warning—Do not use as a dusting ‘‘COUGH-DUE-TO-COLD’’ PREPARA- powder, especially on infants, or take TIONS. (See also § 310.201(a)(20) of this internally. Use only as a solution. Do chapter.) not apply to badly broken or raw skin, or to large areas of the body. Warning—Persons with a high fever BROMIDES. or persistent cough should not use this preparation unless directed by physi- Caution—Use only as directed. Do not cian. give to children or use in the presence COUNTERIRRITANTS AND of kidney disease. If skin rash appears RUBEFACIENTS. or if nervous symptoms persist, recur frequently, or are unusual, discontinue Caution—Do not apply to irritated use and consult physician. skin or if excessive irritation develops. CARBOLIC ACID (PHENOL) PREP- Avoid getting into the eyes or on mu- ARATIONS (MORE THAN 0.5 PER- cous membranes. CENT) FOR EXTERNAL USE. If offered for use in arthritis or rheumatism, in juxtaposition therewith, Warning—Use according to direc- the statement: tions. Do not apply to large areas of Caution—If pain persists for more the body. If applied to fingers or toes, than 10 days, or redness is present, or do not bandage. in conditions affecting children under CATHARTICS AND LAXATIVES—IR- 12 years of age consult a physician im- RITANTS AND OTHER PERISTALTIC mediately. STIMULANTS. See also ‘‘Salicylates’’ in this section for additional warnings for prepara- Warning—Do not use when abdominal tions containing methyl salicylate. pain, nausea, or vomiting are present. Frequent or prolonged use of this prep- CREOSOTE, CRESOLS, GUAIACOL, aration may result in dependence on AND SIMILAR SUBSTANCES IN laxatives. PREPARATIONS FOR EXTERNAL Mercury preparations should have USE. added to the ‘‘frequent use’’ statement, Caution—Do not apply to large areas the words ‘‘and serious mercury poi- of the body. soning’’. CREOSOTE, CRESOLS, GUAIACOL, Phenolphthalein preparations should AND SIMILAR SUBSTANCES IN bear, in addition to the general warn- DOUCHE PREPARATIONS. ing, the following statement: Caution—If skin rash appears, do not Warning—The use of solutions use this or any other preparation con- stronger than those recommended may taining phenolphthalein. result in severe local irritation, burns, See also Mineral Oil Laxatives. or serious poisoning. Mix as directed before pouring into douche bag. Do not CHLORATES: MOUTH WASH OR GAR- use more often than twice weekly un- GLE. less directed by physician. Avoid swallowing. DENTURE RELINERS, PADS, AND COBALT PREPARATIONS (See also CUSHIONS. § 250.106 of this chapter.) Warning—For temporary use only. Warning—Do not exceed the rec- Long-term use of this product may lead ommended dosage. Do not administer to faster bone loss, continuing irrita- to children under 12 years of age unless tion, sores, and tumors. For Use Only directed by physician. Do not use for Until a Dentist Can Be Seen.

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DENTURE REPAIR KITS. children. In case of overdose, get med- Warning—For emergency repairs only. ical help or contact a Poison Control Long-term use of home-repaired den- Center right away.’’ tures may cause faster bone loss, con- OPHTHALMIC PREPARATIONS. (See tinuing irritation, sores, and tumors. also § 200.50 of this chapter.) This kit for emergency use only. See Boric acid offered for use in the prep- Dentist Without Delay. aration of ophthalmic solutions should DOUCHE PREPARATIONS. bear the statement: Prepare solution Warning—Do not use more often than by boiling in water. Store in a sterile twice weekly unless directed by physi- container. Prepare sufficient for one cian. day’s use and discard unused portion. See also Creosote * * * Douche for PHENACETIN-CONTAINING PREPA- additional warning. RATION. (See acetophenetidin.) DRESSINGS, PROTECTIVE SPRAY- PHENYLPROPANOLAMINE HY- ON TYPE. (See also § 310.201(a) (11) and DROCHLORIDE PREPARATIONS, (18) of this chapter.) ORAL. Warning—In case of deep or puncture Caution—Individuals with high blood wounds or serious burns consult physi- pressure, heart disease, diabetes, or cian. If redness, irritation, swelling or thyroid disease should use only as di- pain persists or increases or if infection rected by physician. occurs consult physician. Keep away POTASSIUM PERMANGANATE from eyes or other mucous membranes. AQUEOUS SOLUTIONS (CONTAINING Avoid inhaling. NOT MORE THAN 0.04 PERCENT PO- See also Dispensers Pressurized by TASSIUM PERMANGANATE). (See Gaseous Propellants * * * for addi- § 250.108 of this chapter.) tional warnings to be included for products under pressure. Warning—For external use on the IODINE AND IODIDES (ORAL). skin only. Severe injury may result from use internally or as a douche. Caution—If a skin rash appears, dis- Avoid contact with mucous mem- continue use and consult physician. branes. MERCURY PREPARATIONS FOR EX- QUININE AND OTHER CINCHONA DE- TERNAL USE. RIVATIVES (EXCEPT FOR USE IN Warning—Discontinue use if rash or MALARIA). irritation develops or if condition for Caution—Discontinue use if ringing which used persists. Frequent or pro- in the ears, deafness, skin rash, or vis- longed use, or application to large ual disturbances occur. areas may cause serious mercury poi- RESINS, OLEORESINS, AND VOLA- soning. TILE OILS. MINERAL OIL LAXATIVES. (See also § 201.302 of this chapter.) Caution—If nausea, vomiting, abdominal discomfort, diarrhea, or skin rash Caution—Take only at bedtime. occurs, discontinue use and consult Avoid prolonged use. Do not administer physician. to infants or young children, in pregnancy, or to bedridden or aged patients RESORCINOL (NOT THE unless directed by physician. MONOACETATE) HAIR PREPARA- TIONS. NASAL PREPARATIONS: VASO- CONSTRICTORS (PHENYL- Caution—Excessive use of this prepa- PROPANOLAMINE). ration may temporarily discolor blond, white, or red hair. Caution—Do not exceed recommended dosage. SALICYLATES, INCLUDING ASPIRIN AND SALICYLAMIDE (EXCEPT NUX VOMICA AND STRYCHNINE METHYL SALICYLATE, EFFER- PREPARATIONS. VESCENT SALICYLATE PREPARA- ‘‘Do not use more than the rec- TIONS, AND PREPARATIONS OF ommended dosage. Keep out of reach of AMINOSALICYLIC ACID AND ITS

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SALTS). (See also § 201.314 of this chap- SODIUM PERBORATE MOUTHWASH ter.) AND GARGLE AND TOOTHPASTE. ‘‘Keep out of reach of children. In Caution—Discontinue use if irritation case of overdose, get medical help or or inflammation develops, or increases. contact a Poison Control Center right Avoid swallowing. away;’’ or ‘‘Keep out of reach of children.’’ SULFONAMIDE NOSE DROPS. If the article is an aspirin prepara- Caution—Do not use if a known al- tion, it should bear the first of the lergy to sulfonamide drugs exists. above two warning statements. In either case, the above information SULFUR PREPARATION FOR EX- should appear on the label. TERNAL USE. Caution—For children under 3 years Caution—If undue skin irritation de- of age, consult your physician; or velops or increases, discontinue use Caution—For younger children, con- and consult physician. sult your physician. THROAT PREPARATIONS FOR TEM- One of the two immediately pre- PORARY RELIEF OF MINOR SORE ceding caution statements is required THROAT: LOZENGES, TROCHES, on the label of all aspirin tablets, but WASHES, GARGLES, ETC. (See also such a statement is not required on the § 201.315 of this chapter.) labels of other salicylates clearly offered for administration to adults only. Warning—Severe or persistent sore If offered for use in arthritis or rheu- throat or sore throat accompanied by matism, in juxtaposition therewith, high fever, headache, nausea, and vom- the statement: iting may be serious. Consult physician Caution—If pain persists for more promptly. Do not use more than 2 days than 10 days, or redness is present, or or administer to children under 3 years in conditions affecting children under of age unless directed by physician. 12 years of age, consult a physician im- TOOTHACHE PREPARATIONS. mediately. For temporary use only until a den- SALICYLATES: METHYL SALICY- tist can be consulted. LATE (WINTERGREEN OIL). (See also §§ 201.303 and 201.314 of this chapter.) ZINC STEARATE DUSTING POW- DERS. ‘‘Do not use otherwise than as directed. Keep out of reach of children to ‘‘Keep out of reach of children; avoid avoid accidental poisoning. If swal- inhaling. If swallowed, get medical lowed, get medical help or contact a help or contact a Poison Control Cen- Poison Control Center right away.’’ ter right away.’’ If the preparation is a counter-irri- [39 FR 11745, Mar. 29, 1974, as amended at 40 tant or rubefacient the statement: FR 8917, Mar. 3, 1975; 40 FR 13496, Mar. 27, Caution—Discontinue use if excessive 1975; 41 FR 10885, Mar. 15, 1976; 51 FR 27760, irritation of the skin develops. Avoid Aug. 1, 1986; 51 FR 35340, Oct. 2, 1986; 52 FR getting into the eyes or on mucous 15893, Apr. 30, 1987; 52 FR 30057, Aug. 12, 1987; membranes. 52 FR 47324, Dec. 11, 1987; 53 FR 7093, Mar. 4, 1988; 55 FR 31783, Aug. 3, 1990; 57 FR 58376, If offered for use in arthritis or rheu- Dec. 9, 1992; 59 FR 43412, Aug. 23, 1994; 64 FR matism, in juxtaposition therewith, 13296, Mar. 17, 1999; 68 FR 18882, Apr. 17, 2003; the statement: 68 FR 34293, June 9, 2003] Caution—If pain persists for more than 10 days, or redness is present, or § 369.21 Drugs; warning and caution in conditions affecting children under statements required by regulations. 12 years of age consult a physician im- ACETAMINOPHEN (N-ACETYL-p- mediately. AMINOPHENOL) (See § 310.201(a)(1) of SILVER. this chapter.) Caution—Frequent or prolonged use Warning—Do not give to children of this preparation may result in per- under 3 years of age or use for more manent discoloration of skin and mu- than 10 days unless directed by a physi- cous membranes. cian.

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If offered for use in arthritis, or rheu- If the label of any package is too matism, in juxtaposition therewith, small to accommodate the warnings, the statement: the Commissioner may establish by Caution—If pain persists for more regulation an acceptable alternative than 10 days, or redness is present, or method, e.g., a type size smaller than in conditions affecting children under 1⁄16 inch in height. A petition request- 12 years of age consult a physician im- ing such a regulation, as an amend- mediately. ment to this paragraph, shall be sub- ALCOHOL RUBBING COMPOUND. mitted to the Division of Dockets Man- (See 26 CFR 182.855(a)(5); The National agement in the form established in Formulary, Tenth Edition 1955, pp. 27– part 10 of this chapter. 28; and section 502(g) of the act). Warning—Avoid spraying in eyes. Contents under pressure. Do not punc- Warning—For external use only. If ture or incinerate. Do not store at tem- taken internally serious gastric perature above 120 °F. Keep out of distrubances will result. reach of children. ANTIHISTAMINICS, ORAL (PHENYL- In the case of products packaged in TOLOXAMINE DIHYDROGEN CIT- glass containers, the word ‘‘break’’ RATE AND CHLOROTHEN CITRATE may be substituted for the word PREPARATIONS). (See § 310.201(a)(4) ‘‘puncture.’’ and (a)(24) of this chapter.) The words ‘‘Avoid spraying in eyes’’ may be deleted from the warning in the Caution—This preparation may cause case of a product not expelled as a drowsiness. Do not drive or operate spray, or that is intended to be used in machinery while taking this medica- the eyes. tion. Do not give to children under 6 In addition to the above warning, the years of age or exceed the rec- label of a drug packaged in a self-pres- ommended dosage unless directed by surized container in which the propel- physician. lant consists in whole or in part of a If offered for symptoms of colds, the halocarbon or hydrocarbon shall bear statement: the following warning: Caution—If relief does not occur Warning—Use only as directed. Inten- within 3 days, discontinue use and con- tional misuse by deliberately concen- sult physician. trating and inhaling the contents can DICYCLOMINE HYDROCHLORIDE be harmful or fatal. WITH AN ANTACID. (See § 310.201(a)(8) The warning is not required for the of this chapter.) following products: Warning—Do not exceed the rec- (a) Products expelled in the form of a ommended dosage. Do not administer foam or cream, which contain less than to children under 12 years of age or use ten percent propellant in the con- for a prolonged period unless directed tainer; by physician, since persistent or recur- (b) Products in a container with a ring symptoms may indicate a serious physical barrier that prevents escape of disease requiring medical attention. the propellant at the time of use; (c) Products of a net quantity of con- DIPHEMANIL METHYLSULFATE tents of less than 2 ozs. that are de- FOR EXTERNAL USE. (See signed to release a measured amount of § 310.201(a)(22) of this chapter.) product with each valve actuation; Caution—If redness, irritation, swell- (d) Products of a net quantity of con- ing, or pain persists or increases, dis- tents of less than 1⁄2 oz. continue use and consult physician. DYCLONINE HYDROCHLORIDE. (See DRUGS IN DISPENSERS PRESSUR- § 310.201(a)(23) of this chapter.) IZED BY GASEOUS PROPELLANTS. Caution—Do not use in the eyes. Not (See also § 310.201(a) (11) and (18) of this for prolonged use. Do not apply to chapter.) large areas of the body. If redness, irri- The warnings herein shall appear tation, swelling, or pain persists or in- prominently and conspicuously, but in creases, discontinue use unless directed no case may the letters be less than 1⁄16 by physician. Do not use, but consult inch in height. physician for deep or puncture wounds

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or serious burns. Do not use in case of apply to large areas of the body. If red- rectal bleeding, as this may indicate ness, irritation, swelling, or pain per- serious disease. sists or increases, discontinue use un- HEXADENOL. (See § 310.201(a)(11) of less directed by a physician. this chapter.) SODIUM GENTISATE. (See §§ 201.314 Caution—Do not use for treatment of and 310.301(a)(2) of this chapter.) serious burns or skin conditions or for Warning—Do not use in children conditions which persist for prolonged under 6 years of age or use for pro- periods. In such cases, consult your longed period unless directed by physi- physician. Do not spray in vicinity of cian. eyes, mouth, nose, or ears. Do not store ‘‘Keep out of reach of children. In above 120 °F. case of overdose, get medical help or IPECAC SYRUP IN ONE-FLUID contact a Poison Control Center right OUNCE CONTAINERS FOR EMER- away.’’ GENCY TREATMENT OF POISONING, If offered for use in arthritis or rheu- TO INDUCE VOMITING. (See § 201.308 matism, in juxtaposition therewith, of this chapter.) the statement: Ipecac syrup packaged for over-the- Caution—If pain persists for more counter sale must bear statements to than 10 days, or redness is present, or the following effect, in a prominent in conditions affecting children under and conspicuous manner: 12 years of age, consult a physician im- The following statement (boxed and mediately. in red letters): TUAMINOHEPTANE SULFATE ‘‘For emergency use to cause vom- NASAL PREPARATIONS. (See iting in poisoning. Before using, call § 310.201(a)(16) of this chapter.) physician, the Poison Control Center, or hospital emergency room imme- Caution—Do not exceed recommended diately for advice.’’ dosage. Overdosage may cause nervous- The following warning: Warning— ness, restlessness, or sleeplessness. In- Keep out of reach of children. Do not dividuals with high blood pressure, use in unconscious persons. Ordinarily, heart disease, diabetes, or thyroid dis- this drug should not be used if strych- ease should use only as directed by nine, corrosives such as alkalies (lye) physician. Do not use for more than 3 and strong acids, or petroleum dis- or 4 consecutive days unless directed tillates such as kerosene, gasoline, coal by physician. oil, fuel oil, paint thinner, or cleaning VIBESATE PREPARATIONS. (See fluid have been ingested. § 310.201(a)(18) of this chapter.) ISOAMYLHYRDOCUPREINE AND ZO- LAMINE HYDROCHLORIDE RECTAL Caution—Do not use but consult phy- PREPARATIONS FOR EXTERNAL sician for deep or puncture wounds or USE (See § 310.201(a)(3) of this chapter.) serious burns. If redness, irritation, swelling, or pain persists or increases, Warning—Do not use this preparation discontinue use and consult physician. in case of rectal bleeding, as this may Warning—Contents under pressure. indicate serious disease. Do not puncture. Do not use or store NEOMYCIN SULFATE WITH A VASO- near heat or open flame. Exposure to CONSTRICTOR, IN NASAL PREPARA- temperatures above 130 °Fahrenheit TIONS (SPRAY OR DROPS). may cause bursting. Never throw con- Caution—Do not exceed recommended tainer into fire or incinerator. dosage. Do not administer to children [39 FR 11745, Mar. 29, 1974] under 3 years of age unless directed by physician. EDITORIAL NOTE: For FEDERAL REGISTER citations affecting § 369.21, see the List of CFR PRAMOXINE HYDROCHLORIDE FOR Sections Affected, which appears in the EXTERNAL USE. (See § 310.201(a)(19) of Finding Aids section of the printed volume this chapter.) and at www.fdsys.gov. Caution—Do not use in the eyes or nose. Not for prolonged use. Do not PARTS 370–499 [RESERVED] 357

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A list of CFR titles, subtitles, chapters, subchapters and parts and an alphabetical list of agencies publishing in the CFR are included in the CFR Index and Finding Aids volume to the Code of Federal Regulations which is published separately and revised annually. Table of CFR Titles and Chapters Alphabetical List of Agencies Appearing in the CFR List of CFR Sections Affected

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Title 1—General Provisions

I Administrative Committee of the Federal Register (Parts 1—49) II Office of the Federal Register (Parts 50—299) III Administrative Conference of the United States (Parts 300—399) IV Miscellaneous Agencies (Parts 400—599) VI National Capital Planning Commission (Parts 600—699)

Title 2—Grants and Agreements

SUBTITLE A—OFFICE OF MANAGEMENT AND BUDGET GUIDANCE FOR GRANTS AND AGREEMENTS I Office of Management and Budget Governmentwide Guidance for Grants and Agreements (Parts 2—199) II Office of Management and Budget Guidance (Parts 200—299) SUBTITLE B—FEDERAL AGENCY REGULATIONS FOR GRANTS AND AGREEMENTS III Department of Health and Human Services (Parts 300—399) IV Department of Agriculture (Parts 400—499) VI Department of State (Parts 600—699) VII Agency for International Development (Parts 700—799) VIII Department of Veterans Affairs (Parts 800—899) IX Department of Energy (Parts 900—999) X Department of the Treasury (Parts 1000—1099) XI Department of Defense (Parts 1100—1199) XII Department of Transportation (Parts 1200—1299) XIII Department of Commerce (Parts 1300—1399) XIV Department of the Interior (Parts 1400—1499) XV Environmental Protection Agency (Parts 1500—1599) XVIII National Aeronautics and Space Administration (Parts 1800— 1899) XX United States Nuclear Regulatory Commission (Parts 2000—2099) XXII Corporation for National and Community Service (Parts 2200— 2299) XXIII Social Security Administration (Parts 2300—2399) XXIV Department of Housing and Urban Development (Parts 2400— 2499) XXV National Science Foundation (Parts 2500—2599) XXVI National Archives and Records Administration (Parts 2600—2699)

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XXVII Small Business Administration (Parts 2700—2799) XXVIII Department of Justice (Parts 2800—2899) XXIX Department of Labor (Parts 2900—2999) XXX Department of Homeland Security (Parts 3000—3099) XXXI Institute of Museum and Library Services (Parts 3100—3199) XXXII National Endowment for the Arts (Parts 3200—3299) XXXIII National Endowment for the Humanities (Parts 3300—3399) XXXIV Department of Education (Parts 3400—3499) XXXV Export-Import Bank of the United States (Parts 3500—3599) XXXVI Office of National Drug Control Policy, Executive Office of the President (Parts 3600—3699) XXXVII Peace Corps (Parts 3700—3799) LVIII Election Assistance Commission (Parts 5800—5899) LIX Gulf Coast Ecosystem Restoration Council (Parts 5900—5999)

Title 3—The President

I Executive Office of the President (Parts 100—199)

Title 4—Accounts

I Government Accountability Office (Parts 1—199)

Title 5—Administrative Personnel

I Office of Personnel Management (Parts 1—1199) II Merit Systems Protection Board (Parts 1200—1299) III Office of Management and Budget (Parts 1300—1399) IV Office of Personnel Management and Office of the Director of National Intelligence (Parts 1400—1499) V The International Organizations Employees Loyalty Board (Parts 1500—1599) VI Federal Retirement Thrift Investment Board (Parts 1600—1699) VIII Office of Special Counsel (Parts 1800—1899) IX Appalachian Regional Commission (Parts 1900—1999) XI Armed Forces Retirement Home (Parts 2100—2199) XIV Federal Labor Relations Authority, General Counsel of the Fed- eral Labor Relations Authority and Federal Service Impasses Panel (Parts 2400—2499) XVI Office of Government Ethics (Parts 2600—2699) XXI Department of the Treasury (Parts 3100—3199) XXII Federal Deposit Insurance Corporation (Parts 3200—3299) XXIII Department of Energy (Parts 3300—3399) XXIV Federal Energy Regulatory Commission (Parts 3400—3499) XXV Department of the Interior (Parts 3500—3599) XXVI Department of Defense (Parts 3600—3699)

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XXVIII Department of Justice (Parts 3800—3899) XXIX Federal Communications Commission (Parts 3900—3999) XXX Farm Credit System Insurance Corporation (Parts 4000—4099) XXXI Farm Credit Administration (Parts 4100—4199) XXXIII Overseas Private Investment Corporation (Parts 4300—4399) XXXIV Securities and Exchange Commission (Parts 4400—4499) XXXV Office of Personnel Management (Parts 4500—4599) XXXVI Department of Homeland Security (Parts 4600—4699) XXXVII Federal Election Commission (Parts 4700—4799) XL Interstate Commerce Commission (Parts 5000—5099) XLI Commodity Futures Trading Commission (Parts 5100—5199) XLII Department of Labor (Parts 5200—5299) XLIII National Science Foundation (Parts 5300—5399) XLV Department of Health and Human Services (Parts 5500—5599) XLVI Postal Rate Commission (Parts 5600—5699) XLVII Federal Trade Commission (Parts 5700—5799) XLVIII Nuclear Regulatory Commission (Parts 5800—5899) XLIX Federal Labor Relations Authority (Parts 5900—5999) L Department of Transportation (Parts 6000—6099) LII Export-Import Bank of the United States (Parts 6200—6299) LIII Department of Education (Parts 6300—6399) LIV Environmental Protection Agency (Parts 6400—6499) LV National Endowment for the Arts (Parts 6500—6599) LVI National Endowment for the Humanities (Parts 6600—6699) LVII General Services Administration (Parts 6700—6799) LVIII Board of Governors of the Federal Reserve System (Parts 6800— 6899) LIX National Aeronautics and Space Administration (Parts 6900— 6999) LX United States Postal Service (Parts 7000—7099) LXI National Labor Relations Board (Parts 7100—7199) LXII Equal Employment Opportunity Commission (Parts 7200—7299) LXIII Inter-American Foundation (Parts 7300—7399) LXIV Merit Systems Protection Board (Parts 7400—7499) LXV Department of Housing and Urban Development (Parts 7500— 7599) LXVI National Archives and Records Administration (Parts 7600—7699) LXVII Institute of Museum and Library Services (Parts 7700—7799) LXVIII Commission on Civil Rights (Parts 7800—7899) LXIX Tennessee Valley Authority (Parts 7900—7999) LXX Court Services and Offender Supervision Agency for the District of Columbia (Parts 8000—8099) LXXI Consumer Product Safety Commission (Parts 8100—8199) LXXIII Department of Agriculture (Parts 8300—8399)

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LXXIV Federal Mine Safety and Health Review Commission (Parts 8400—8499) LXXVI Federal Retirement Thrift Investment Board (Parts 8600—8699) LXXVII Office of Management and Budget (Parts 8700—8799) LXXX Federal Housing Finance Agency (Parts 9000—9099) LXXXIII Special Inspector General for Afghanistan Reconstruction (Parts 9300—9399) LXXXIV Bureau of Consumer Financial Protection (Parts 9400—9499) LXXXVI National Credit Union Administration (Parts 9600—9699) XCVII Department of Homeland Security Human Resources Manage- ment System (Department of Homeland Security—Office of Personnel Management) (Parts 9700—9799) XCVIII Council of the Inspectors General on Integrity and Efficiency (Parts 9800—9899) XCIX Military Compensation and Retirement Modernization Commis- sion (Parts 9900—9999) C National Council on Disability (Parts 10000—10049)

Title 6—Domestic Security

I Department of Homeland Security, Office of the Secretary (Parts 1—199) X Privacy and Civil Liberties Oversight Board (Parts 1000—1099)

Title 7—Agriculture

SUBTITLE A—OFFICE OF THE SECRETARY OF AGRICULTURE (PARTS 0—26) SUBTITLE B—REGULATIONS OF THE DEPARTMENT OF AGRICULTURE I Agricultural Marketing Service (Standards, Inspections, Mar- keting Practices), Department of Agriculture (Parts 27—209) II Food and Nutrition Service, Department of Agriculture (Parts 210—299) III Animal and Plant Health Inspection Service, Department of Ag- riculture (Parts 300—399) IV Federal Crop Insurance Corporation, Department of Agriculture (Parts 400—499) V Agricultural Research Service, Department of Agriculture (Parts 500—599) VI Natural Resources Conservation Service, Department of Agri- culture (Parts 600—699) VII Farm Service Agency, Department of Agriculture (Parts 700— 799) VIII Grain Inspection, Packers and Stockyards Administration (Fed- eral Grain Inspection Service), Department of Agriculture (Parts 800—899) IX Agricultural Marketing Service (Marketing Agreements and Or- ders; Fruits, Vegetables, Nuts), Department of Agriculture (Parts 900—999)

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X Agricultural Marketing Service (Marketing Agreements and Or- ders; Milk), Department of Agriculture (Parts 1000—1199) XI Agricultural Marketing Service (Marketing Agreements and Or- ders; Miscellaneous Commodities), Department of Agriculture (Parts 1200—1299) XIV Commodity Credit Corporation, Department of Agriculture (Parts 1400—1499) XV Foreign Agricultural Service, Department of Agriculture (Parts 1500—1599) XVI Rural Telephone Bank, Department of Agriculture (Parts 1600— 1699) XVII Rural Utilities Service, Department of Agriculture (Parts 1700— 1799) XVIII Rural Housing Service, Rural Business-Cooperative Service, Rural Utilities Service, and Farm Service Agency, Depart- ment of Agriculture (Parts 1800—2099) XX Local Television Loan Guarantee Board (Parts 2200—2299) XXV Office of Advocacy and Outreach, Department of Agriculture (Parts 2500—2599) XXVI Office of Inspector General, Department of Agriculture (Parts 2600—2699) XXVII Office of Information Resources Management, Department of Agriculture (Parts 2700—2799) XXVIII Office of Operations, Department of Agriculture (Parts 2800— 2899) XXIX Office of Energy Policy and New Uses, Department of Agri- culture (Parts 2900—2999) XXX Office of the Chief Financial Officer, Department of Agriculture (Parts 3000—3099) XXXI Office of Environmental Quality, Department of Agriculture (Parts 3100—3199) XXXII Office of Procurement and Property Management, Department of Agriculture (Parts 3200—3299) XXXIII Office of Transportation, Department of Agriculture (Parts 3300—3399) XXXIV National Institute of Food and Agriculture (Parts 3400—3499) XXXV Rural Housing Service, Department of Agriculture (Parts 3500— 3599) XXXVI National Agricultural Statistics Service, Department of Agri- culture (Parts 3600—3699) XXXVII Economic Research Service, Department of Agriculture (Parts 3700—3799) XXXVIII World Agricultural Outlook Board, Department of Agriculture (Parts 3800—3899) XLI [Reserved] XLII Rural Business-Cooperative Service and Rural Utilities Service, Department of Agriculture (Parts 4200—4299)

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I Department of Homeland Security (Immigration and Naturaliza- tion) (Parts 1—499) V Executive Office for Immigration Review, Department of Justice (Parts 1000—1399)

Title 9—Animals and Animal Products

I Animal and Plant Health Inspection Service, Department of Ag- riculture (Parts 1—199) II Grain Inspection, Packers and Stockyards Administration (Packers and Stockyards Programs), Department of Agri- culture (Parts 200—299) III Food Safety and Inspection Service, Department of Agriculture (Parts 300—599)

Title 10—Energy

I Nuclear Regulatory Commission (Parts 0—199) II Department of Energy (Parts 200—699) III Department of Energy (Parts 700—999) X Department of Energy (General Provisions) (Parts 1000—1099) XIII Nuclear Waste Technical Review Board (Parts 1300—1399) XVII Defense Nuclear Facilities Safety Board (Parts 1700—1799) XVIII Northeast Interstate Low-Level Radioactive Waste Commission (Parts 1800—1899)

Title 11—Federal Elections

I Federal Election Commission (Parts 1—9099) II Election Assistance Commission (Parts 9400—9499)

Title 12—Banks and Banking

I Comptroller of the Currency, Department of the Treasury (Parts 1—199) II Federal Reserve System (Parts 200—299) III Federal Deposit Insurance Corporation (Parts 300—399) IV Export-Import Bank of the United States (Parts 400—499) V Office of Thrift Supervision, Department of the Treasury (Parts 500—599) VI Farm Credit Administration (Parts 600—699) VII National Credit Union Administration (Parts 700—799) VIII Federal Financing Bank (Parts 800—899) IX Federal Housing Finance Board (Parts 900—999) X Bureau of Consumer Financial Protection (Parts 1000—1099) XI Federal Financial Institutions Examination Council (Parts 1100—1199) XII Federal Housing Finance Agency (Parts 1200—1299)

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XIII Financial Stability Oversight Council (Parts 1300—1399) XIV Farm Credit System Insurance Corporation (Parts 1400—1499) XV Department of the Treasury (Parts 1500—1599) XVI Office of Financial Research (Parts 1600—1699) XVII Office of Federal Housing Enterprise Oversight, Department of Housing and Urban Development (Parts 1700—1799) XVIII Community Development Financial Institutions Fund, Depart- ment of the Treasury (Parts 1800—1899)

Title 13—Business Credit and Assistance

I Small Business Administration (Parts 1—199) III Economic Development Administration, Department of Com- merce (Parts 300—399) IV Emergency Steel Guarantee Loan Board (Parts 400—499) V Emergency Oil and Gas Guaranteed Loan Board (Parts 500—599)

Title 14—Aeronautics and Space

I Federal Aviation Administration, Department of Transportation (Parts 1—199) II Office of the Secretary, Department of Transportation (Aviation Proceedings) (Parts 200—399) III Commercial Space Transportation, Federal Aviation Adminis- tration, Department of Transportation (Parts 400—1199) V National Aeronautics and Space Administration (Parts 1200— 1299) VI Air Transportation System Stabilization (Parts 1300—1399)

Title 15—Commerce and Foreign Trade

SUBTITLE A—OFFICE OF THE SECRETARY OF COMMERCE (PARTS 0— 29) SUBTITLE B—REGULATIONS RELATING TO COMMERCE AND FOREIGN TRADE I Bureau of the Census, Department of Commerce (Parts 30—199) II National Institute of Standards and Technology, Department of Commerce (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) IV Foreign-Trade Zones Board, Department of Commerce (Parts 400—499) VII Bureau of Industry and Security, Department of Commerce (Parts 700—799) VIII Bureau of Economic Analysis, Department of Commerce (Parts 800—899) IX National Oceanic and Atmospheric Administration, Department of Commerce (Parts 900—999)

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XI National Technical Information Service, Department of Com- merce (Parts 1100—1199) XIII East-West Foreign Trade Board (Parts 1300—1399) XIV Minority Business Development Agency (Parts 1400—1499) SUBTITLE C—REGULATIONS RELATING TO FOREIGN TRADE AGREE- MENTS XX Office of the United States Trade Representative (Parts 2000— 2099) SUBTITLE D—REGULATIONS RELATING TO TELECOMMUNICATIONS AND INFORMATION XXIII National Telecommunications and Information Administration, Department of Commerce (Parts 2300—2399) [Reserved]

Title 16—Commercial Practices

I Federal Trade Commission (Parts 0—999) II Consumer Product Safety Commission (Parts 1000—1799)

Title 17—Commodity and Securities Exchanges

I Commodity Futures Trading Commission (Parts 1—199) II Securities and Exchange Commission (Parts 200—399) IV Department of the Treasury (Parts 400—499)

Title 18—Conservation of Power and Water Resources

I Federal Energy Regulatory Commission, Department of Energy (Parts 1—399) III Delaware River Basin Commission (Parts 400—499) VI Water Resources Council (Parts 700—799) VIII Susquehanna River Basin Commission (Parts 800—899) XIII Tennessee Valley Authority (Parts 1300—1399)

Title 19—Customs Duties

I U.S. Customs and Border Protection, Department of Homeland Security; Department of the Treasury (Parts 0—199) II United States International Trade Commission (Parts 200—299) III International Trade Administration, Department of Commerce (Parts 300—399) IV U.S. Immigration and Customs Enforcement, Department of Homeland Security (Parts 400—599) [Reserved]

Title 20—Employees’ Benefits

I Office of Workers’ Compensation Programs, Department of Labor (Parts 1—199) II Railroad Retirement Board (Parts 200—399)

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III Social Security Administration (Parts 400—499) IV Employees’ Compensation Appeals Board, Department of Labor (Parts 500—599) V Employment and Training Administration, Department of Labor (Parts 600—699) VI Office of Workers’ Compensation Programs, Department of Labor (Parts 700—799) VII Benefits Review Board, Department of Labor (Parts 800—899) VIII Joint Board for the Enrollment of Actuaries (Parts 900—999) IX Office of the Assistant Secretary for Veterans’ Employment and Training Service, Department of Labor (Parts 1000—1099)

Title 21—Food and Drugs

I Food and Drug Administration, Department of Health and Human Services (Parts 1—1299) II Drug Enforcement Administration, Department of Justice (Parts 1300—1399) III Office of National Drug Control Policy (Parts 1400—1499)

Title 22—Foreign Relations

I Department of State (Parts 1—199) II Agency for International Development (Parts 200—299) III Peace Corps (Parts 300—399) IV International Joint Commission, United States and Canada (Parts 400—499) V Broadcasting Board of Governors (Parts 500—599) VII Overseas Private Investment Corporation (Parts 700—799) IX Foreign Service Grievance Board (Parts 900—999) X Inter-American Foundation (Parts 1000—1099) XI International Boundary and Water Commission, United States and Mexico, United States Section (Parts 1100—1199) XII United States International Development Cooperation Agency (Parts 1200—1299) XIII Millennium Challenge Corporation (Parts 1300—1399) XIV Foreign Service Labor Relations Board; Federal Labor Relations Authority; General Counsel of the Federal Labor Relations Authority; and the Foreign Service Impasse Disputes Panel (Parts 1400—1499) XV African Development Foundation (Parts 1500—1599) XVI Japan-United States Friendship Commission (Parts 1600—1699) XVII United States Institute of Peace (Parts 1700—1799)

Title 23—Highways

I Federal Highway Administration, Department of Transportation (Parts 1—999)

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II National Highway Traffic Safety Administration and Federal Highway Administration, Department of Transportation (Parts 1200—1299) III National Highway Traffic Safety Administration, Department of Transportation (Parts 1300—1399)

Title 24—Housing and Urban Development

SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF HOUSING AND URBAN DEVELOPMENT (PARTS 0—99) SUBTITLE B—REGULATIONS RELATING TO HOUSING AND URBAN DE- VELOPMENT I Office of Assistant Secretary for Equal Opportunity, Department of Housing and Urban Development (Parts 100—199) II Office of Assistant Secretary for Housing-Federal Housing Com- missioner, Department of Housing and Urban Development (Parts 200—299) III Government National Mortgage Association, Department of Housing and Urban Development (Parts 300—399) IV Office of Housing and Office of Multifamily Housing Assistance Restructuring, Department of Housing and Urban Develop- ment (Parts 400—499) V Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 500—599) VI Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 600—699) [Reserved] VII Office of the Secretary, Department of Housing and Urban Devel- opment (Housing Assistance Programs and Public and Indian Housing Programs) (Parts 700—799) VIII Office of the Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Section 8 Housing Assistance Programs, Section 202 Di- rect Loan Program, Section 202 Supportive Housing for the El- derly Program and Section 811 Supportive Housing for Persons With Disabilities Program) (Parts 800—899) IX Office of Assistant Secretary for Public and Indian Housing, De- partment of Housing and Urban Development (Parts 900—1699) X Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Interstate Land Sales Registration Program) (Parts 1700—1799) XII Office of Inspector General, Department of Housing and Urban Development (Parts 2000—2099) XV Emergency Mortgage Insurance and Loan Programs, Depart- ment of Housing and Urban Development (Parts 2700—2799) [Reserved] XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Parts 3200—3899)

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XXIV Board of Directors of the HOPE for Homeowners Program (Parts 4000—4099) [Reserved] XXV Neighborhood Reinvestment Corporation (Parts 4100—4199)

Title 25—Indians

I Bureau of Indian Affairs, Department of the Interior (Parts 1— 299) II Indian Arts and Crafts Board, Department of the Interior (Parts 300—399) III National Indian Gaming Commission, Department of the Inte- rior (Parts 500—599) IV Office of Navajo and Hopi Indian Relocation (Parts 700—899) V Bureau of Indian Affairs, Department of the Interior, and Indian Health Service, Department of Health and Human Services (Parts 900—999) VI Office of the Assistant Secretary, Indian Affairs, Department of the Interior (Parts 1000—1199) VII Office of the Special Trustee for American Indians, Department of the Interior (Parts 1200—1299)

Title 26—Internal Revenue

I Internal Revenue Service, Department of the Treasury (Parts 1— End)

Title 27—Alcohol, Tobacco Products and Firearms

I Alcohol and Tobacco Tax and Trade Bureau, Department of the Treasury (Parts 1—399) II Bureau of Alcohol, Tobacco, Firearms, and Explosives, Depart- ment of Justice (Parts 400—699)

Title 28—Judicial Administration

I Department of Justice (Parts 0—299) III Federal Prison Industries, Inc., Department of Justice (Parts 300—399) V Bureau of Prisons, Department of Justice (Parts 500—599) VI Offices of Independent Counsel, Department of Justice (Parts 600—699) VII Office of Independent Counsel (Parts 700—799) VIII Court Services and Offender Supervision Agency for the District of Columbia (Parts 800—899) IX National Crime Prevention and Privacy Compact Council (Parts 900—999) XI Department of Justice and Department of State (Parts 1100— 1199)

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SUBTITLE A—OFFICE OF THE SECRETARY OF LABOR (PARTS 0—99) SUBTITLE B—REGULATIONS RELATING TO LABOR I National Labor Relations Board (Parts 100—199) II Office of Labor-Management Standards, Department of Labor (Parts 200—299) III National Railroad Adjustment Board (Parts 300—399) IV Office of Labor-Management Standards, Department of Labor (Parts 400—499) V Wage and Hour Division, Department of Labor (Parts 500—899) IX Construction Industry Collective Bargaining Commission (Parts 900—999) X National Mediation Board (Parts 1200—1299) XII Federal Mediation and Conciliation Service (Parts 1400—1499) XIV Equal Employment Opportunity Commission (Parts 1600—1699) XVII Occupational Safety and Health Administration, Department of Labor (Parts 1900—1999) XX Occupational Safety and Health Review Commission (Parts 2200—2499) XXV Employee Benefits Security Administration, Department of Labor (Parts 2500—2599) XXVII Federal Mine Safety and Health Review Commission (Parts 2700—2799) XL Pension Benefit Guaranty Corporation (Parts 4000—4999)

Title 30—Mineral Resources

I Mine Safety and Health Administration, Department of Labor (Parts 1—199) II Bureau of Safety and Environmental Enforcement, Department of the Interior (Parts 200—299) IV Geological Survey, Department of the Interior (Parts 400—499) V Bureau of Ocean Energy Management, Department of the Inte- rior (Parts 500—599) VII Office of Surface Mining Reclamation and Enforcement, Depart- ment of the Interior (Parts 700—999) XII Office of Natural Resources Revenue, Department of the Interior (Parts 1200—1299)

Title 31—Money and Finance: Treasury

SUBTITLE A—OFFICE OF THE SECRETARY OF THE TREASURY (PARTS 0—50) SUBTITLE B—REGULATIONS RELATING TO MONEY AND FINANCE I Monetary Offices, Department of the Treasury (Parts 51—199) II Fiscal Service, Department of the Treasury (Parts 200—399) IV Secret Service, Department of the Treasury (Parts 400—499) V Office of Foreign Assets Control, Department of the Treasury (Parts 500—599)

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VI Bureau of Engraving and Printing, Department of the Treasury (Parts 600—699) VII Federal Law Enforcement Training Center, Department of the Treasury (Parts 700—799) VIII Office of Investment Security, Department of the Treasury (Parts 800—899) IX Federal Claims Collection Standards (Department of the Treas- ury—Department of Justice) (Parts 900—999) X Financial Crimes Enforcement Network, Department of the Treasury (Parts 1000—1099)

Title 32—National Defense

SUBTITLE A—DEPARTMENT OF DEFENSE I Office of the Secretary of Defense (Parts 1—399) V Department of the Army (Parts 400—699) VI Department of the Navy (Parts 700—799) VII Department of the Air Force (Parts 800—1099) SUBTITLE B—OTHER REGULATIONS RELATING TO NATIONAL DE- FENSE XII Defense Logistics Agency (Parts 1200—1299) XVI Selective Service System (Parts 1600—1699) XVII Office of the Director of National Intelligence (Parts 1700—1799) XVIII National Counterintelligence Center (Parts 1800—1899) XIX Central Intelligence Agency (Parts 1900—1999) XX Information Security Oversight Office, National Archives and Records Administration (Parts 2000—2099) XXI National Security Council (Parts 2100—2199) XXIV Office of Science and Technology Policy (Parts 2400—2499) XXVII Office for Micronesian Status Negotiations (Parts 2700—2799) XXVIII Office of the Vice President of the United States (Parts 2800— 2899)

Title 33—Navigation and Navigable Waters

I Coast Guard, Department of Homeland Security (Parts 1—199) II Corps of Engineers, Department of the Army, Department of De- fense (Parts 200—399) IV Saint Lawrence Seaway Development Corporation, Department of Transportation (Parts 400—499)

Title 34—Education

SUBTITLE A—OFFICE OF THE SECRETARY, DEPARTMENT OF EDU- CATION (PARTS 1—99) SUBTITLE B—REGULATIONS OF THE OFFICES OF THE DEPARTMENT OF EDUCATION I Office for Civil Rights, Department of Education (Parts 100—199)

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II Office of Elementary and Secondary Education, Department of Education (Parts 200—299) III Office of Special Education and Rehabilitative Services, Depart- ment of Education (Parts 300—399) IV Office of Career, Technical and Adult Education, Department of Education (Parts 400—499) V Office of Bilingual Education and Minority Languages Affairs, Department of Education (Parts 500—599) [Reserved] VI Office of Postsecondary Education, Department of Education (Parts 600—699) VII Office of Educational Research and Improvement, Department of Education (Parts 700—799) [Reserved] SUBTITLE C—REGULATIONS RELATING TO EDUCATION XI (Parts 1100—1199) [Reserved] XII National Council on Disability (Parts 1200—1299)

Title 35 [Reserved]

Title 36—Parks, Forests, and Public Property

I National Park Service, Department of the Interior (Parts 1—199) II Forest Service, Department of Agriculture (Parts 200—299) III Corps of Engineers, Department of the Army (Parts 300—399) IV American Battle Monuments Commission (Parts 400—499) V Smithsonian Institution (Parts 500—599) VI [Reserved] VII Library of Congress (Parts 700—799) VIII Advisory Council on Historic Preservation (Parts 800—899) IX Pennsylvania Avenue Development Corporation (Parts 900—999) X Presidio Trust (Parts 1000—1099) XI Architectural and Transportation Barriers Compliance Board (Parts 1100—1199) XII National Archives and Records Administration (Parts 1200—1299) XV Oklahoma City National Memorial Trust (Parts 1500—1599) XVI Morris K. Udall Scholarship and Excellence in National Environ- mental Policy Foundation (Parts 1600—1699)

Title 37—Patents, Trademarks, and Copyrights

I United States Patent and Trademark Office, Department of Commerce (Parts 1—199) II U.S. Copyright Office, Library of Congress (Parts 200—299) III Copyright Royalty Board, Library of Congress (Parts 300—399) IV National Institute of Standards and Technology, Department of Commerce (Parts 400—599)

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I Department of Veterans Affairs (Parts 0—199) II Armed Forces Retirement Home (Parts 200—299)

Title 39—Postal Service

I United States Postal Service (Parts 1—999) III Postal Regulatory Commission (Parts 3000—3099)

Title 40—Protection of Environment

I Environmental Protection Agency (Parts 1—1099) IV Environmental Protection Agency and Department of Justice (Parts 1400—1499) V Council on Environmental Quality (Parts 1500—1599) VI Chemical Safety and Hazard Investigation Board (Parts 1600— 1699) VII Environmental Protection Agency and Department of Defense; Uniform National Discharge Standards for Vessels of the Armed Forces (Parts 1700—1799) VIII Gulf Coast Ecosystem Restoration Council (Parts 1800—1899)

Title 41—Public Contracts and Property Management

SUBTITLE A—FEDERAL PROCUREMENT REGULATIONS SYSTEM [NOTE] SUBTITLE B—OTHER PROVISIONS RELATING TO PUBLIC CONTRACTS 50 Public Contracts, Department of Labor (Parts 50–1—50–999) 51 Committee for Purchase From People Who Are Blind or Severely Disabled (Parts 51–1—51–99) 60 Office of Federal Contract Compliance Programs, Equal Employ- ment Opportunity, Department of Labor (Parts 60–1—60–999) 61 Office of the Assistant Secretary for Veterans’ Employment and Training Service, Department of Labor (Parts 61–1—61–999) 62—100 [Reserved] SUBTITLE C—FEDERAL PROPERTY MANAGEMENT REGULATIONS SYSTEM 101 Federal Property Management Regulations (Parts 101–1—101–99) 102 Federal Management Regulation (Parts 102–1—102–299) 103—104 [Reserved] 105 General Services Administration (Parts 105–1—105–999) 109 Department of Energy Property Management Regulations (Parts 109–1—109–99) 114 Department of the Interior (Parts 114–1—114–99) 115 Environmental Protection Agency (Parts 115–1—115–99) 128 Department of Justice (Parts 128–1—128–99) 129—200 [Reserved] SUBTITLE D—OTHER PROVISIONS RELATING TO PROPERTY MANAGE- MENT [RESERVED]

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SUBTITLE E—FEDERAL INFORMATION RESOURCES MANAGEMENT REGULATIONS SYSTEM [RESERVED] SUBTITLE F—FEDERAL TRAVEL REGULATION SYSTEM 300 General (Parts 300–1—300–99) 301 Temporary Duty (TDY) Travel Allowances (Parts 301–1—301–99) 302 Relocation Allowances (Parts 302–1—302–99) 303 Payment of Expenses Connected with the Death of Certain Em- ployees (Part 303–1—303–99) 304 Payment of Travel Expenses from a Non-Federal Source (Parts 304–1—304–99)

Title 42—Public Health

I Public Health Service, Department of Health and Human Serv- ices (Parts 1—199) ii—III [Reserved] IV Centers for Medicare & Medicaid Services, Department of Health and Human Services (Parts 400—699) V Office of Inspector General-Health Care, Department of Health and Human Services (Parts 1000—1099)

Title 43—Public Lands: Interior

SUBTITLE A—OFFICE OF THE SECRETARY OF THE INTERIOR (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC LANDS I Bureau of Reclamation, Department of the Interior (Parts 400— 999) II Bureau of Land Management, Department of the Interior (Parts 1000—9999) III Utah Reclamation Mitigation and Conservation Commission (Parts 10000—10099)

Title 44—Emergency Management and Assistance

I Federal Emergency Management Agency, Department of Home- land Security (Parts 0—399) IV Department of Commerce and Department of Transportation (Parts 400—499)

Title 45—Public Welfare

SUBTITLE A—DEPARTMENT OF HEALTH AND HUMAN SERVICES (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC WELFARE II Office of Family Assistance (Assistance Programs), Administra- tion for Children and Families, Department of Health and Human Services (Parts 200—299)

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III Office of Child Support Enforcement (Child Support Enforce- ment Program), Administration for Children and Families, Department of Health and Human Services (Parts 300—399) IV Office of Refugee Resettlement, Administration for Children and Families, Department of Health and Human Services (Parts 400—499) V Foreign Claims Settlement Commission of the United States, Department of Justice (Parts 500—599) VI National Science Foundation (Parts 600—699) VII Commission on Civil Rights (Parts 700—799) VIII Office of Personnel Management (Parts 800—899) IX Denali Commission (Parts 900—999) X Office of Community Services, Administration for Children and Families, Department of Health and Human Services (Parts 1000—1099) XI National Foundation on the Arts and the Humanities (Parts 1100—1199) XII Corporation for National and Community Service (Parts 1200— 1299) XIII Administration for Children and Families, Department of Health and Human Services (Parts 1300—1399) XVI Legal Services Corporation (Parts 1600—1699) XVII National Commission on Libraries and Information Science (Parts 1700—1799) XVIII Harry S. Truman Scholarship Foundation (Parts 1800—1899) XXI Commission of Fine Arts (Parts 2100—2199) XXIII Arctic Research Commission (Parts 2300—2399) XXIV James Madison Memorial Fellowship Foundation (Parts 2400— 2499) XXV Corporation for National and Community Service (Parts 2500— 2599)

Title 46—Shipping

I Coast Guard, Department of Homeland Security (Parts 1—199) II Maritime Administration, Department of Transportation (Parts 200—399) III Coast Guard (Great Lakes Pilotage), Department of Homeland Security (Parts 400—499) IV Federal Maritime Commission (Parts 500—599)

Title 47—Telecommunication

I Federal Communications Commission (Parts 0—199) II Office of Science and Technology Policy and National Security Council (Parts 200—299) III National Telecommunications and Information Administration, Department of Commerce (Parts 300—399)

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IV National Telecommunications and Information Administration, Department of Commerce, and National Highway Traffic Safe- ty Administration, Department of Transportation (Parts 400— 499) V The First Responder Network Authority (Parts 500—599)

Title 48—Federal Acquisition Regulations System

1 Federal Acquisition Regulation (Parts 1—99) 2 Defense Acquisition Regulations System, Department of Defense (Parts 200—299) 3 Department of Health and Human Services (Parts 300—399) 4 Department of Agriculture (Parts 400—499) 5 General Services Administration (Parts 500—599) 6 Department of State (Parts 600—699) 7 Agency for International Development (Parts 700—799) 8 Department of Veterans Affairs (Parts 800—899) 9 Department of Energy (Parts 900—999) 10 Department of the Treasury (Parts 1000—1099) 12 Department of Transportation (Parts 1200—1299) 13 Department of Commerce (Parts 1300—1399) 14 Department of the Interior (Parts 1400—1499) 15 Environmental Protection Agency (Parts 1500—1599) 16 Office of Personnel Management, Federal Employees Health Benefits Acquisition Regulation (Parts 1600—1699) 17 Office of Personnel Management (Parts 1700—1799) 18 National Aeronautics and Space Administration (Parts 1800— 1899) 19 Broadcasting Board of Governors (Parts 1900—1999) 20 Nuclear Regulatory Commission (Parts 2000—2099) 21 Office of Personnel Management, Federal Employees Group Life Insurance Federal Acquisition Regulation (Parts 2100—2199) 23 Social Security Administration (Parts 2300—2399) 24 Department of Housing and Urban Development (Parts 2400— 2499) 25 National Science Foundation (Parts 2500—2599) 28 Department of Justice (Parts 2800—2899) 29 Department of Labor (Parts 2900—2999) 30 Department of Homeland Security, Homeland Security Acquisi- tion Regulation (HSAR) (Parts 3000—3099) 34 Department of Education Acquisition Regulation (Parts 3400— 3499) 51 Department of the Army Acquisition Regulations (Parts 5100— 5199) 52 Department of the Navy Acquisition Regulations (Parts 5200— 5299) 53 Department of the Air Force Federal Acquisition Regulation Supplement (Parts 5300—5399) [Reserved]

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54 Defense Logistics Agency, Department of Defense (Parts 5400— 5499) 57 African Development Foundation (Parts 5700—5799) 61 Civilian Board of Contract Appeals, General Services Adminis- tration (Parts 6100—6199) 99 Cost Accounting Standards Board, Office of Federal Procure- ment Policy, Office of Management and Budget (Parts 9900— 9999)

Title 49—Transportation

SUBTITLE A—OFFICE OF THE SECRETARY OF TRANSPORTATION (PARTS 1—99) SUBTITLE B—OTHER REGULATIONS RELATING TO TRANSPORTATION I Pipeline and Hazardous Materials Safety Administration, De- partment of Transportation (Parts 100—199) II Federal Railroad Administration, Department of Transportation (Parts 200—299) III Federal Motor Carrier Safety Administration, Department of Transportation (Parts 300—399) IV Coast Guard, Department of Homeland Security (Parts 400—499) V National Highway Traffic Safety Administration, Department of Transportation (Parts 500—599) VI Federal Transit Administration, Department of Transportation (Parts 600—699) VII National Railroad Passenger Corporation (AMTRAK) (Parts 700—799) VIII National Transportation Safety Board (Parts 800—999) X Surface Transportation Board (Parts 1000—1399) XI Research and Innovative Technology Administration, Depart- ment of Transportation (Parts 1400—1499) [Reserved] XII Transportation Security Administration, Department of Home- land Security (Parts 1500—1699)

Title 50—Wildlife and Fisheries

I United States Fish and Wildlife Service, Department of the Inte- rior (Parts 1—199) II National Marine Fisheries Service, National Oceanic and Atmos- pheric Administration, Department of Commerce (Parts 200— 299) III International Fishing and Related Activities (Parts 300—399) IV Joint Regulations (United States Fish and Wildlife Service, De- partment of the Interior and National Marine Fisheries Serv- ice, National Oceanic and Atmospheric Administration, De- partment of Commerce); Endangered Species Committee Reg- ulations (Parts 400—499) V Marine Mammal Commission (Parts 500—599)

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VI Fishery Conservation and Management, National Oceanic and Atmospheric Administration, Department of Commerce (Parts 600—699)

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CFR Title, Subtitle or Agency Chapter Administrative Committee of the Federal Register 1, I Administrative Conference of the United States 1, III Advisory Council on Historic Preservation 36, VIII Advocacy and Outreach, Office of 7, XXV Afghanistan Reconstruction, Special Inspector General for 5, LXXXIII African Development Foundation 22, XV Federal Acquisition Regulation 48, 57 Agency for International Development 2, VII; 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture Department 2, IV; 5, LXXIII Advocacy and Outreach, Office of 7, XXV Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Animal and Plant Health Inspection Service 7, III; 9, I Chief Financial Officer, Office of 7, XXX Commodity Credit Corporation 7, XIV Economic Research Service 7, XXXVII Energy Policy and New Uses, Office of 2, IX; 7, XXIX Environmental Quality, Office of 7, XXXI Farm Service Agency 7, VII, XVIII Federal Acquisition Regulation 48, 4 Federal Crop Insurance Corporation 7, IV Food and Nutrition Service 7, II Food Safety and Inspection Service 9, III Foreign Agricultural Service 7, XV Forest Service 36, II Grain Inspection, Packers and Stockyards Administration 7, VIII; 9, II Information Resources Management, Office of 7, XXVII Inspector General, Office of 7, XXVI National Agricultural Library 7, XLI National Agricultural Statistics Service 7, XXXVI National Institute of Food and Agriculture 7, XXXIV Natural Resources Conservation Service 7, VI Operations, Office of 7, XXVIII Procurement and Property Management, Office of 7, XXXII Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force Department 32, VII Federal Acquisition Regulation Supplement 48, 53 Air Transportation Stabilization Board 14, VI Alcohol and Tobacco Tax and Trade Bureau 27, I Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II AMTRAK 49, VII American Battle Monuments Commission 36, IV American Indians, Office of the Special Trustee 25, VII

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VerDate Sep<11>2014 11:29 Jun 12, 2018 Jkt 244074 PO 00000 Frm 00400 Fmt 8092 Sfmt 8092 Y:\SGML\244074.XXX 244074 nshattuck on DSK9F9SC42PROD with CFR List of CFR Sections Affected All changes in this volume of the Code of Federal Regulations (CFR) that were made by documents published in the FEDERAL REGISTER since January 1, 2013 are enumerated in the following list. Entries indicate the nature of the changes effected. Page numbers refer to FEDERAL REGISTER pages. The user should consult the entries for chapters, parts and subparts as well as sections for revisions. For changes to this volume of the CFR prior to this listing, consult the annual edition of the monthly List of CFR Sections Affected (LSA). The LSA is available at www.fdsys.gov. For changes to this volume of the CFR prior to 2001, see the ‘‘List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, and 1986–2000’’ published in 11 separate volumes. The ‘‘List of CFR Sections Affected 1986–2000’’ is available at www.fdsys.gov.

2013 21 CFR—Continued 78 FR Page 21 CFR 78 FR 310.305 Amended; (e), (f) and (g) re- Page 316.1 (a)(1)(iii) and (2) revised ...... 35132 designated as (f), (g) and (h); 316.3 (b)(3) introductory text, (i) new (e) added; (b), (c)(2), (3) in- and (12) revised; (b)(13) and (14) troductory text and new (g)(1) redesignated as (b)(14) and (15); amended; (c) introductory new (b)(13) added...... 35132 text, (1)(i), (d) and new (f) re- 316.4 Revised ...... 35133 vised; (c)(4) removed; eff. 6-10- 316.20 (a), (b)(2), (3), (4), (5) and (6) 15...... 33087 revised; (b)(9) removed...... 35133 314 Authority citation revised; 316.21 (a)(1) and (b) introductory eff. 6-10-15 ...... 33088 text revised ...... 35133 Technical correction ...... 47655, 53134 316.22 Revised ...... 35133 314.53 (e) amended...... 68115 316.23 Revised ...... 35133 314.80 Amended; (c)(1)(iv), (d)(2) 316.24 Heading revised; (a) and (b) and (e)(2) removed; (d)(1), (e)(1) redesignated as (b) and (c); new and (g) through (k) redesig- (a) and (d) added ...... 35133 nated as (d), (e) and (h) through 316.25 (a)(1)(ii), (3) and (b) re- (l); (a), (c)(1)(i), (ii), (iii) intro- vised...... 35134 ductory text and new (d) 316.26 Revised ...... 35134 amended; (c) introductory 316.28 Revised ...... 35134 text, (2)(ii), (f) and new (i) re- 316.29 (d) added ...... 35134 vised; new (g) added; eff. 6-10- 316.31 (b) redesignated as (c); (a) 15...... 33088 introductory text, new (c) revised; new (b) added...... 35134 314.98 Revised; eff. 6-10-15 ...... 33089 316.34 Revised ...... 35135 316 Policy statement ...... 76888 316.50 Revised ...... 35135 317 Added ...... 32480 329 Added; eff. 6-10-15...... 33089 2014 Technical correction ...... 47655, 53134 350.60 Amended...... 68115 21 CFR 78 FR Page 310 Authority citation revised; eff. 6-10-15 ...... 33087 Technical correction ...... 47655, 53134

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2015 21 CFR—Continued 81 FR Page 21 CFR 80 FR Chapter I—Continued Page 314.50 (a) introductory text, (5), Chapter I (b), (c)(1), (2)(i), (iv) through 310 Authority citation revised ...... 38938 (viii), (d) introductory text, 310.305 Regulation at 79 FR 33087 (1)(i), (ii)(a), (iii), (iv), (v), compliance date delayed to 9– (3)(ii), (5)(iv), (v), (vi)(a), (b), 8–15...... 30151 (e)(1)(i) introductory text, (2) introductory text, (f) introduc- 310.306 Added ...... 38938 tory text, (1), (2), (3), (g)(2), (h), 310.503 (f)(3) amended...... 18091 (j) introductory text, (3), (4) in- 312 Policy statement...... 7318 troductory text, (i), (ii), (iii), 312.140 (a)(3) amended ...... 18091 (k), (l) heading, (1) introduc- 312.145 (b) amended ...... 18091 tory text and (4) amended; 312.310 (d)(1) amended ...... 18091 heading, introductory text, 314 Regulation at 79 FR 33088 com- (a)(1), (e)(1) introductory text, pliance date delayed to 9–8– (f)(4), (g)(3), (i), (l)(2) and (3) re- 15...... 30151 vised...... 69639 Authority citation revised ...... 38938 314.52 Revised ...... 69641 314.80 Regulation at 79 FR 33088 314.53 Revised ...... 69643 compliance date delayed to 9– 314.54 (a)(1) introductory text, (i) and (3) amended; heading, (a) 8–15...... 30151 introductory text, (1)(iii), (v), 314.81 (b)(3)(iii) revised ...... 38938 (vi), (2), (4) and (b) revised...... 69647 314.91 Removed...... 38939 314.60 Amended; (b)(1), (4), 314.98 Regulation at 79 FR 33089 (c)(1)(i) and (2) amended; (b) compliance date delayed to 9– heading, (c) heading, (e) and (f) 8–15...... 30151 added; heading, (a), (c)(1)(iii) 314.440 (b) introductory text re- and (d) revised...... 69648 vised...... 18091 314.70 (a) heading, (1)(i), (ii), (6), 317 Order ...... 50559 (b)(2)(i), (viii), (4), (c)(6) intro- 329 Regulation at 79 FR 33089 com- ductory text, (7), (d)(2)(v), (vi), pliance date delayed to 9–8– (vii), (3)(i) and (e) amended; 15...... 30151 heading, (a)(2) and (f) revised; (h) added...... 69648 314.81 (b)(3)(iv) revised ...... 60221 2016 314.90 Amended; (c) added ...... 69649 21 CFR 81 FR 314.93 (a), (b), (c), (d)(3), Page (e)(1)(iii)(C), (v) and (3) amend- Chapter I ed; (f) redesignated as (f)(1); (e)(1)(vi) and (f)(2) added...... 69649 310 Authority citation revised; 314.94 (a) introductory text, (1), eff. 9-6-17...... 61129 (5)(ii)(A), (6)(ii), (7)(i), (ii) in- 310.545 (a)(27)(iii), (iv) and (d)(41) troductory text, (C), (8)(i), (iv), added; (d) introductory text (9)(ii) through (v), (12)(i)(A)(1) amended; eff. 9-6-17 ...... 61129 through (4), (13), (b), (d)(1)(i), 312.140 (a)(2) amended ...... 17066 (4) and (5) amended; (a)(12)(iv) 314 Authority citation revised ...... 69636 removed; heading, introduc- Technical correction ...... 89848 tory text, (a) heading, (2), (3), 314.3 Revised ...... 69636 (7)(iii), (9)(i), (12)(i) heading, (A) introductory text, (4), (B), (ii) through (viii), (d) heading, (1) introductory text and (2) revised...... 69649 314.95 Revised ...... 69651 314.96 Heading revised; (a) heading, (1) and (b) amended; (b) heading, (c) and (d) added ...... 69652

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21 CFR—Continued 81 FR 21 CFR—Continued 81 FR Page Page Chapter I—Continued Chapter I—Continued 314.97 Revised ...... 69653 320.33 (f)(3) amended ...... 17066 314.99 Revised ...... 69653 330 Authority citation revised ...... 84475 314.101 Revised ...... 69653 330.14 (a) redesignated as intro- 314.105 Revised ...... 69654 ductory text; new introductory 314.107 Revised ...... 69655 314.108 (a) introductory text, (b) text, (f) heading, introductory heading and (2) through (5) re- text and (g)(4) revised; new (a), vised; (a) amended ...... 69657 (j) and (k) added ...... 84475 314.125 (b)(11) amended...... 60221 330.15 Added ...... 84477 (a) introductory text, (2), (b)(2), (7), (9), (10), (11), (12) and (14) 2017 through (18) amended; heading and (b) introductory text re- 21 CFR 82 FR vised; (b)(19) added ...... 69658 Page 314.127 (a) introductory text, (3) Chapter I through (7), (3)(iii)(A)(2), 310.545 (a)(27)(v), (vi), (vii), (viii), (8)(ii)(A) introductory text, (9), (ix), (x) and (d)(42) added; (d) in- (10), (12) and (b) amended; head- troductory text amended; eff. ing, (a) introductory text, (2), 12–20–18...... 60502 (8)(i) introductory text, (ii)(B) and (C) revised; (a)(14) added...... 69658 2018 320.1 Revised ...... 69658 (No regulations published from 320.23 (a)(1) and (2) amended; (b) January 1, 2018, through April 1, 2018) redesignated as (b)(1); (b)(2) added...... 69658 Æ

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