Title 21 Food and Drugs Parts 300 to 499

Revised as of April 1, 2011

Containing a codification of documents of general applicability and future effect

As of April 1, 2011

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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Legal Status and Use of Seals and Logos The seal of the National Archives and Records Administration (NARA) authenticates the Code of Federal Regulations (CFR) as the official codification of Federal regulations established under the Federal Register Act. Under the provisions of 44 U.S.C. 1507, the contents of the CFR, a special edition of the Federal Register, shall be judicially noticed. The CFR is prima facie evidence of the original documents published in the Federal Register (44 U.S.C. 1510). It is prohibited to use NARA’s official seal and the stylized Code of Federal Regulations logo on any republication of this material without the express, written permission of the Archivist of the United States or the Archivist’s designee. Any person using NARA’s official seals and logos in a manner inconsistent with the provisions of 36 CFR part 1200 is subject to the penalties specified in 18 U.S.C. 506, 701, and 1017.

Use of ISBN Prefix This is the Official U.S. Government edition of this publication and is herein identified to certify its authenticity. Use of the 0–16 ISBN prefix is for U.S. Government Printing Office Official Edi- tions only. The Superintendent of Documents of the U.S. Govern- ment Printing Office requests that any reprinted edition clearly be labeled as a copy of the authentic work with a new ISBN.

U.S. GOVERNMENT PRINTING OFFICE U.S. Superintendent of Documents • Washington, DC 20402–0001 http://bookstore.gpo.gov Phone: toll-free (866) 512-1800; DC area (202) 512-1800

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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 ...... 341

Alphabetical List of Agencies Appearing in the CFR ...... 361

List of CFR Sections Affected ...... 371

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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, 2011), 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 Mar<15>2010 13:22 May 12, 2011 Jkt 223069 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\223069.XXX 223069 WReier-Aviles on DSKGBLS3C1PROD 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. OBSOLETE PROVISIONS Provisions that become obsolete before the revision date stated on the cover of each volume are not carried. Code users may find the text of provisions in effect on a given date in the past by using the appropriate numerical list of sections affected. For the period before April 1, 2001, consult either the List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, or 1986–2000, published in eleven separate volumes. For the period beginning April 1, 2001, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. ‘‘[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. An index to the text of ‘‘Title 3—The President’’ is carried within that volume.

VerDate Mar<15>2010 13:22 May 12, 2011 Jkt 223069 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\223069.XXX 223069 WReier-Aviles on DSKGBLS3C1PROD with CFR 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 Printing 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 Printing 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 Printing 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.

RAYMOND A. MOSLEY, Director, Office of the Federal Register. April 1, 2011.

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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, 2011.

For this volume, Susannah C. Hurley was Chief Editor. The Code of Federal Regulations publication program is under the direction of Michael L. White, as- sisted by Ann Worley.

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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 ...... 49 314 Applications for FDA approval to market a new drug ...... 91 315 Diagnostic radiopharmaceuticals...... 176 316 Orphan drugs...... 178 320 Bioavailability and bioequivalence requirements ... 190 328 Over-the-counter drug products intended for oral ingestion that contain alcohol ...... 205 330 Over-the-counter (OTC) human drugs which are generally recognized as safe and effective and not misbranded ...... 206 331 Antacid products for over-the-counter (OTC) human use ...... 223 332 Antiflatulent products for over-the-counter human use ...... 227 333 Topical antimicrobial drug products for over-the- counter human use ...... 228 335 Antidiarrheal drug products for over-the-counter human use ...... 236 336 Antiemetic drug products for over-the-counter human use ...... 238 338 Nighttime sleep-aid drug products for over-the- counter human use ...... 240 340 Stimulant drug products for over-the-counter human use ...... 241

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Part Page 341 Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use ...... 242 343 Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use .... 265 344 Topical OTIC drug products for over-the-counter human use ...... 273 346 Anorectal drug products for over-the-counter human use ...... 275 347 Skin protectant drug products for over-the-counter human use ...... 280 348 External analgesic drug products for over-the- counter human use ...... 288 349 Ophthalmic drug products for over-the-counter human use ...... 289 350 Antiperspirant drug products for over-the-counter human use ...... 295 352 Sunscreen drug products for over-the-counter human use [stayed indefinitely] ...... 297 355 Anticaries drug products for over-the-counter human use ...... 307 357 Miscellaneous internal drug products for over-the- counter human use ...... 312 358 Miscellaneous external drug products for over-the- counter human use ...... 316 361 Prescription drugs for human use generally recognized as safe and effective and not misbranded: Drugs used in research ...... 325 369 Interpretative statements re warnings on drugs and devices for over-the-counter sale ...... 330 370–499 [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 310.538 Drug products containing active ingredients offered over-the-counter (OTC) 310.303 Continuation of long-term studies, for use for ingrown toenail relief. records, and reports on certain drugs for 310.540 Drug products containing active in- which new drug applications have been gredients offered over-the-counter (OTC) approved. for use as stomach acidifiers. 310.305 Records and reports concerning ad- 310.541 Over-the-counter (OTC) drug prod- verse drug experiences on marketed pre- ucts containing active ingredients of- scription drugs for human use without fered for use in the treatment of hypo- approved new drug applications. phosphatemia. 310.542 Over-the-counter (OTC) drug prod- Subpart E—Requirements for Specific New ucts containing active ingredients of- Drugs or Devices fered for use in the treatment of hyperphosphatemia. 310.501 Patient package inserts for oral con- 310.543 Drug products containing active in- traceptives. gredients offered over-the-counter (OTC) 310.502 Certain drugs accorded new drug sta- for human use in exocrine pancreatic in- tus through rulemaking procedures. sufficiency. 310.503 Requirements regarding certain ra- 310.544 Drug products containing active in- dioactive drugs. gredients offered over-the-counter (OTC) 310.509 Parenteral drug products in plastic for use as a smoking deterrent. containers. 310.545 Drug products containing certain ac- 310.515 Patient package inserts for estro- tive ingredients offered over-the-counter gens. (OTC) for certain uses. 310.517 Labeling for oral hypoglycemic 310.546 Drug products containing active in- drugs of the sulfonylurea class. gredients offered over-the-counter (OTC) 310.518 Drug products containing iron or for the treatment and/or prevention of iron salts. nocturnal leg muscle cramps. 310.519 Drug products marketed as over-the- counter (OTC) daytime sedatives. 310.547 Drug products containing quinine offered over-the-counter (OTC) for the 310.527 Drug products containing active in- treatment and/or prevention of malaria. gredients offered over-the-counter (OTC) for external use as hair growers or for 310.548 Drug products containing colloidal hair loss prevention. silver ingredients or silver salts offered 310.528 Drug products containing active in- over-the-counter (OTC) for the treatment gredients offered over-the-counter (OTC) and/or prevention of disease. for use as an aphrodisiac. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 310.529 Drug products containing active in- 355, 360b–360f, 360j, 361(a), 371, 374, 375, 379e; 42 gredients offered over-the-counter (OTC) U.S.C. 216, 241, 242(a), 262, 263b–263n. for oral use as insect repellents. 310.530 Topically applied hormone-containing drug products for over-the- Subpart A—General Provisions counter (OTC) human use. 310.531 Drug products containing active in- § 310.3 Definitions and interpretations. gredients offered over-the-counter (OTC) As used in this part: for the treatment of boils. 310.532 Drug products containing active in- (a) The term act means the Federal gredients offered over-the-counter (OTC) Food, Drug, and Cosmetic Act, as to relieve the symptoms of benign pros- amended (secs. 201–902, 52 Stat. 1040 et tatic hypertrophy. seq., as amended; 21 U.S.C. 321–392). 310.533 Drug products containing active in- (b) Department means the Department gredients offered over-the-counter (OTC) of Health and Human Services. for human use as an anticholinergic in (c) Secretary means the Secretary of cough-cold drug products. 310.534 Drug products containing active in- Health and Human Services. gredients offered over-the-counter (OTC) (d) Commissioner means the Commis- for human use as oral wound healing sioner of Food and Drugs. agents. (e) The term person includes individ- 310.536 Drug products containing active in- uals, partnerships, corporations, and gredients offered over-the-counter (OTC) associations. for use as a nailbiting or thumbsucking (f) The definitions and interpreta- deterrent. 310.537 Drug products containing active in- tions of terms contained in section 201 gredients offered over-the-counter (OTC) of the act shall be applicable to such for oral administration for the treatment terms when used in the regulations in of fever blisters and cold sores. this part.

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(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 spontaneous disintegration of unstable new drug when used in another disease nuclei with the emission of nuclear or to affect another structure or func- particles or photons and includes any tion of the body. nonradioactive reagent kit or nuclide (5) The newness of a dosage, or meth- generator which is intended to be used od or duration of administration or ap- in the preparation of any such sub- plication, or other condition of use pre- stance but does not include drugs such scribed, recommended, or suggested in as carbon-containing compounds or po- the labeling of such drug, even though tassium-containing salts which contain such drug when used in other dosage, trace quantities of naturally occurring or other method or duration of admin- radionuclides. The term ‘‘radioactive istration or application, or different drug’’ includes a ‘‘radioactive biologi- condition, is not a new drug. cal product’’ as defined in § 600.3(ee) of (i) [Reserved] this chapter. (j) The term sponsor means the per- [39 FR 11680, Mar. 29, 1974, as amended at 39 son or agency who assumes responsi- FR 20484, June 11, 1974; 40 FR 31307, July 25, bility for an investigation of a new 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. drug, including responsibility for com- 22, 1985] pliance with applicable provisions of the act and regulations. The ‘‘sponsor’’ § 310.4 Biologics; products subject to may be an individual, partnership, cor- license control. poration, or Government agency and (a) If a drug has an approved license may be a manufacturer, scientific in- under section 351 of the Public Health stitution, or an investigator regularly Service Act (42 U.S.C. 262 et seq.) or and lawfully engaged in the investiga- under the animal virus, serum, and tion of new drugs. toxin law of March 4, 1913 (21 U.S.C. 151 (k) The phrase related drug(s) includes et seq.), it is not required to have an ap- other brands, potencies, dosage forms, proved application under section 505 of salts, and esters of the same drug moi- the act. ety, including articles prepared or (b) To obtain marketing approval for manufactured by other manufacturers: radioactive biological products for and any other drug containing a com- human use, as defined in § 600.3(ee) of

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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 [64 FR 56448, Oct. 20, 1999, as amended at 70 drug includes other brands, potencies, 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 for hearing to identical, related, (2) Where experts qualified by sci- and similar drug products. entific training and experience to 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- cacy Study Implementation (DESI) No- hearing, that a drug product is a ‘‘new tices and as Notices of Opportunity for drug’’ or that there is a lack of evi- Hearing. The specific products listed in dence to show that a drug product is these notices include only those that safe or effective are applicable to an were introduced into the market identical, related, or similar drug prod- through the new drug procedures from uct, such product is affected by the no- 1938–62 and were submitted for review tice. A combination drug product con- by the National Academy of Sciences- taining a drug that is identical, re- National Research Council (NAS-NRC), lated, or similar to a drug named in a Drug Efficacy Study Group. Many notice may also be subject to the find- products which are identical to, related ings and conclusions in a notice that a to, or similar to the products listed in drug product is a ‘‘new drug’’ or that these notices have been marketed there is a lack of evidence to show that under different names or by different a drug product is safe or effective. firms during this same period or since (3) Any person may request an opin- 1962 without going through the new ion on the applicability of such a no- drug procedures or the Academy re- tice to a specific product by writing to view. Even though these products are the Food and Drug Administration at not listed in the notices, they are cov- the address shown in paragraph (e) of ered by the new drug applications re- this section. viewed and thus are subject to these (c) Manufacturers and distributors of notices. All persons with an interest in drugs should review their products as a product that is identical, related, or drug efficacy notices are published and similar to a drug listed in a drug effi- assure that identical, related, or simi- cacy notice or a notice of opportunity lar products comply with all applicable for a hearing will be given the same opportunity as the applicant to submit provisions of the notices. data and information, to request a (d) The published notices and sum- hearing, and to participate in any hear- mary lists of the conclusions are of ing. It is not feasible for the Food and particular interest to drug purchasing Drug Administration to list all prod- agents. These agents should take par- ucts which are covered by an NDA and ticular care to assure that the same thus subject to each notice. However, purchasing policy applies to drug prod- it is essential that the findings and ucts that are identical, related, or conclusions that a drug product is a similar to those named in the drug effi- ‘‘new drug’’ or that there is a lack of cacy notices. The Food and Drug Ad- evidence to show that a drug product is ministration applies the same regu- safe or effective be applied to all iden- latory policy to all such products. In tical, related, and similar drug prod- many instances a determination can ucts to which they are reasonably ap- readily be made as to the applicability plicable. Any product not in compli- of a drug efficacy notice by an indi- ance with an applicable drug efficacy vidual who is knowledgeable about notice is in violation of section 505 drugs and their indications for use.

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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 portance by reason of proposed actions Hampshire Ave., Silver Spring, MD 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. respect to the safety or effectiveness of 26, 2009] a drug may result in its becoming a ‘‘new drug’’ even though it was pre- Subpart B—Specific Administrative viously 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 (Public Law 87–781; 76 Stat. 788–89). In

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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 shall 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 Life-threatening adverse drug experi- which a new drug application has been ence. Any adverse drug experience that approved may be made by the Commis- places the patient, in the view of the sioner on his own initiative or on the initial reporter, at immediate risk of petition of any interested person, pur- death from the adverse drug experience suant to part 10 of this chapter. Prior as it occurred, i.e., it does not include to issuance of such a proposal, the ap- an adverse drug experience that, had it plicant will be provided an opportunity occurred in a more severe form, might for a conference with representatives of have caused death. the Food and Drug Administration. Serious adverse drug experience. Any When appropriate, investigators or adverse drug experience occurring at other individuals may be invited to any dose that results in any of the fol- participate in the conference. All re- lowing outcomes: Death, a life-threat- quirements for special studies, records, ening adverse drug experience, inpa- and reports will be published in tient hospitalization or prolongation of § 310.304. existing hospitalization, a persistent or significant disability/incapacity, or a [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, congenital anomaly/birth defect. Im- 1977] portant medical events that may not result in death, be life-threatening, or § 310.305 Records and reports con- require hospitalization may be consid- cerning adverse drug experiences ered a serious adverse drug experience on marketed prescription drugs for when, based upon appropriate medical human use without approved new judgment, they may jeopardize the pa- drug applications. tient or subject and may require med- (a) Scope. FDA is requiring manufac- ical or surgical intervention to prevent turers, packers, and distributors of one of the outcomes listed in this defi- marketed prescription drug products nition. Examples of such medical that are not the subject of an approved events include allergic bronchospasm new drug or abbreviated new drug ap- requiring intensive treatment in an plication to establish and maintain emergency room or at home, blood records and make reports to FDA of all dyscrasias or convulsions that do not serious, unexpected adverse drug expe- result in inpatient hospitalization, or riences associated with the use of their the development of drug dependency or drug products. Any person subject to drug abuse.

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Unexpected adverse drug experience. sonable possibility that the drug Any adverse drug experience that is caused the adverse experience. not listed in the current labeling for (2) Postmarketing 15-day ‘‘Alert re- the drug product. This includes events ports’’—followup. Each person identified that may be symptomatically and in paragraph (c)(1)(i) of this section pathophysiologically related to an shall promptly investigate all serious, event listed in the labeling, but differ unexpected adverse drug experiences from the event because of greater se- that are the subject of these post- verity or specificity. For example, marketing 15-day Alert reports and under this definition, hepatic necrosis shall submit followup reports within 15 would be unexpected (by virtue of calendar days of receipt of new infor- greater severity) if the labeling only mation or as requested by FDA. If addi- referred to elevated hepatic enzymes or tional information is not obtainable, hepatitis. Similarly, cerebral thrombo- records should be maintained of the un- embolism and cerebral vasculitis would successful steps taken to seek addi- be unexpected (by virtue of greater specificity) if the labeling only listed tional information. Postmarketing 15- cerebral vascular accidents. ‘‘Unex- day Alert reports and followups to pected,’’ as used in this definition, re- them shall be submitted under separate fers to an adverse drug experience that cover. has not been previously observed (i.e., (3) Submission of reports. To avoid un- included in the labeling) rather than necessary duplication in the submis- from the perspective of such experience sion of, and followup to, reports re- not being anticipated from the pharma- quired in this section, a packer’s or dis- cological properties of the pharma- tributor’s obligations may be met by ceutical product. submission of all reports of serious ad- (c) Reporting requirements. Each per- verse drug experiences to the manufac- son identified in paragraph (c)(1)(i) of turer of the drug product. If a packer this section shall report to FDA ad- or distributor elects to submit these verse drug experience information as adverse drug experience reports to the described in this section and shall sub- manufacturer rather than to FDA, it mit one copy of each report to the Cen- shall submit each report to the manu- tral Document Room, Center for Drug facturer within 5 calendar days of its Evaluation and Research, Food and receipt by the packer or distributor, Drug Administration, 5901–B and the manufacturer shall then com- Ammendale Rd., Beltsville, MD 20705– ply with the requirements of this sec- 1266. tion even if its name does not appear (1) Postmarketing 15-day ‘‘Alert re- on the label of the drug product. Under ports’’. (i) Any person whose name ap- this circumstance, the packer or dis- pears on the label of a marketed pre- tributor shall maintain a record of this scription drug product as its manufac- action which shall include: turer, packer, or distributor shall re- (i) A copy of each adverse drug expe- port to FDA each adverse drug experi- rience report; ence received or otherwise obtained (ii) The date the report was received that is both serious and unexpected as by the packer or distributor; soon as possible, but in no case later (iii) The date the report was sub- than 15 calendar days of initial receipt of the information by the person whose mitted to the manufacturer; and name appears on the label. Each report (iv) The name and address of the shall be accompanied by a copy of the manufacturer. current labeling for the drug product. (4) Each report submitted to FDA (ii) A person identified in paragraph under this section shall bear prominent (c)(1)(i) of this section is not required identification as to its contents, i.e., to submit a 15-day ‘‘Alert report’’ for ‘‘15-day Alert report,’’ or ‘‘15-day Alert an adverse drug experience obtained report-followup.’’ from a postmarketing study (whether (5) A person identified in paragraph or not conducted under an investiga- (c)(1)(i) of this section is not required tional new drug application) unless the to resubmit to FDA adverse drug expe- applicant concludes that there is a rea- rience reports forwarded to that person

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by FDA; however, the person must sub- drug experiences, and the records re- mit all followup information on such quired to be maintained under para- reports to FDA. graph (c)(4) of this section. (d) Reporting form. (1) Except as pro- (2) Manufacturers and packers may vided in paragraph (d)(3) of this sec- retain the records required in para- tion, each person identified in paragraph (f)(1) of this section as part of its graph (c)(1)(i) of this section shall sub- complaint files maintained under mit each report of a serious and unex- § 211.198 of this chapter. pected adverse drug experience on an (3) Manufacturers, packers, and dis- FDA Form 3500A (foreign events may tributors shall permit any authorized be submitted either on an FDA Form FDA employee, at all reasonable times, 3500A or, if preferred, on a CIOMS I to have access to and copy and verify form). the records established and maintained (2) Each completed FDA Form 3500A under this section. should pertain only to an individual (g) Disclaimer. A report or informa- patient. tion submitted by a manufacturer, (3) Instead of using Form FDA Form packer, or distributor under this sec- 3500A, a manufacturer, packer, or dis- tion (and any release by FDA of that tributor may use a computer-generated report or information) does not nec- FDA Form 3500A or other alternative essarily reflect a conclusion by the format (e.g., a computer-generated manufacturer, packer, or distributor, tape or tabular listing) provided that: or by FDA, that the report or informa- (i) The content of the alternative for- tion constitutes an admission that the mat is equivalent in all elements of in- drug caused or contributed to an ad- formation to those specified in FDA verse effect. The manufacturer, packer, Form 3500A, and or distributor need not admit, and may (ii) The format is agreed to in ad- deny, that the report or information vance by MedWatch: The FDA Medical submitted under this section con- Products Reporting Program. stitutes an admission that the drug (4) FDA Form 3500A and instructions caused or contributed to an adverse ef- for completing the form are available fect. on the Internet at http://www.fda.gov/ medwatch/index.html. [51 FR 24479, July 3, 1986, as amended at 52 (e) Patient privacy. Manufacturers, FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, packers, and distributors should not in- 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR clude in reports under this section the 9585, Mar. 4, 2002; 74 FR 13113, Mar. 26, 2009] names and addresses of individual patients; instead, the manufacturer, packer, and distributor should assign a Subpart E—Requirements for unique code number to each report, Specific New Drugs or Devices preferably not more than eight characters in length. The manufacturer, § 310.501 Patient package inserts for packer, and distributor should include oral contraceptives. the name of the reporter from whom (a) Requirement for a patient package the information was received. Names of insert. The safe and effective use of oral patients, individual reporters, health contraceptive drug products requires care professionals, hospitals, and geo- that patients be fully informed of the graphical identifiers in adverse drug benefits and the risks involved in their experience reports are not releasable to use. An oral contraceptive drug prod- the public under FDA’s public informa- uct that does not comply with the re- tion regulations in part 20 of this chap- quirements of this section is mis- ter. branded under section 502 of the Fed- (f) Recordkeeping. (1) Each manufac- eral Food, Drug, and Cosmetic Act. turer, packer, and distributor shall Each dispenser of an oral contraceptive maintain for a period of 10 years drug product shall provide a patient records of all adverse drug experiences package insert to each patient (or to required under this section to be re- an agent of the patient) to whom the ported, including raw data and any cor- product is dispensed, except that the respondence relating to the adverse dispenser may provide the insert to the

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

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§ 10.90(b)(9) of this chapter to provide (9) Oral prenatal drugs containing assistance in meeting the requirements fluorides intended for human use. of this section. A request for a copy of (10) Parenteral drug products in plas- the guidance texts should be directed tic containers. to the Center for Drug Evaluation and (11) Sterilization of drugs by irradia- Research, Division of Reproductive and tion. Urologic Products, Food and Drug Ad- (12) Sweet spirits of nitre drug prod- ministration, 10903 New Hampshire ucts. Ave., Silver Spring, MD 20993–0002. (13) Thorium dioxide for drug use. (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) of this chapter to provide for the label- [62 FR 12084, Mar. 14, 1997, as amended at 64 ing required by this section. Such la- FR 401, Jan. 5, 1999] beling may be put into use without advance approval by the Food and Drug § 310.503 Requirements regarding certain 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 § 310.502 Certain drugs accorded new drugs from part 312 of this chapter pro- drug status through rulemaking vided they were shipped in complete procedures. conformity with the regulations issued (a) The drugs listed in this paragraph by the Nuclear Regulatory Commis- have been determined by rulemaking sion. This exemption also applied to in- procedures to be new drugs within the vestigational radioactive biologics. meaning of section 201(p) of the act. An (b) It is the opinion of the Nuclear approved new drug application under Regulatory Commission, and the Food section 505 of the act and part 314 of and Drug Administration that this ex- this chapter is required for marketing emption should not apply for certain the following drugs: specific drugs and that these drugs (1) Aerosol drug products for human should be appropriately labeled for uses use containing 1,1,1-trichloroethane. for which safety and effectiveness can (2) Aerosol drug products containing be demonstrated by new drug applica- zirconium. tions or through licensing under the (3) Amphetamines (amphetamine, Public Health Service Act (42 U.S.C. 262 dextroamphetamine, and their salts, et seq.) in the case of biologics. Contin- and levamfetamine and its salts) for ued distribution under the investiga- human use. tional exemption when the drugs are (4) Camphorated oil drug products. intended for established uses will not (5) Certain halogenated salicyl- be permitted. anilides (tribromsalan (TBS, 3,4′,5-tri- (c) Based on its experience in regu- bromosalicylanilide), dibromsalan lating investigational radioactive (DBS, 4′, 5-dibromosalicylanilide), pharmaceuticals, the Nuclear Regu- metabromsalan (MBS, 3, 5-dibromo- latory Commission has compiled a list salicylanilide), and 3,3′, 4,5′-tetra- of reactor-produced isotopes for which chlorosalicylanilide (TC-SA)) as an in- it considers that applicants may rea- gredient in drug products. sonably be expected to submit ade- (6) Chloroform used as an ingredient quate evidence of safety and effective- (active or inactive) in drug products. ness for use as recommended in appro- (7) Cobalt preparations intended for priate labeling. Such use may include, use by man. among others, the uses in this tabula- (8) Intrauterine devices for human tion: use for the purpose of contraception that incorporate heavy metals, drugs, Isotope Chemical form Use or other active substances. Chromium 51 ... Chromate ...... Spleen scans.

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Isotope Chemical form Use Isotope Chemical form Use

Do ...... do ...... Placenta localiza- Do ...... Iodopyracet, sodium Kidney function tion. iodohippurate, so- studies. Do ...... do ...... Red blood cell label- dium diatrizoate, ing and survival diatrizoate methyl- studies. glucamine, so- Do ...... Labeled human Gastrointestinal pro- dium diprotrizoate, serum albumin. tein loss studies. sodium acetri- Do ...... do ...... Placenta localiza- zoate, or sodium tion. iothalamate. Do ...... Labeled red blood Do. Do ...... Labeled fats and/or Fat absorption stud- cells. fatty acids. ies. Iron 59 ...... Chloride, citrate Iron turnover stud- Cobalt 58 or Labeled cyano- Intestinal absorption and/or sulfate. ies. Cobalt 60. cobalamin. studies. Krypton 85 ...... Gas ...... Diagnosis of cardiac Gold 198 ...... Colloidal ...... Liver scans. abnormalities. Do ...... do ...... Intracavitary treat- Mercury 197 .... Chlormerodrin ...... Kidney scans. ment of pleural ef- Do ...... do ...... Brain scans. fusions and/or as- Mercury 203 1 ...... do ...... Kidney scans. cites. Do ...... do ...... Brain scans. Do ...... do ...... Interstitial treatment Phosphorus 32 Soluble phosphate .. Treatment of poly- of cancer. cythemia vera. Iodine 131 ...... Iodide ...... Diagnosis of thyroid Do ...... do ...... Treatment of leu- functions. kemia and bone Do ...... do ...... Thyroid scans. metastasis. Do ...... do ...... Treatment of hyper- Do ...... Colloidal chromic Intracavitary treat- thyroidism and/or phosphate. ment of pleural ef- cardiac dysfunc- fusions and/or as- tion. cites. Do ...... do ...... Treatment of thyroid Do ...... do ...... Interstitial treatment carcinoma. of cancer. Potassium 42 .. Chloride ...... Potassium space Do ...... Iodinated human Blood volume deter- studies. serum albumin. minations. Selenium 75 .... Labeled methionine Pancreas scans. Do ...... do ...... Cisternography. Strontium 85 .... Nitrate or chloride ... Bone scans on pa- Do ...... do ...... Brain tumor localiza- tients with diag- tion. nosed cancer. Do ...... do ...... Placenta localiza- Technetium Pertechnetate ...... Brain scans. tion. 99m. Do ...... do ...... Cardiac scans for Do ...... do ...... Thyroid scans. determination of Do ...... Sulfur colloid ...... Liver and spleen pericardial effu- scans. sions. Do ...... Pertechnetate ...... Placenta localiza- Do ...... Rose Bengal ...... Liver function stud- tion. ies. Do ...... do ...... Blood pool scans. Do ...... do ...... Liver scans. Do ...... do ...... Salivary gland Do ...... Iodopyracet, sodium Kidney function scans. iodohippurate, so- studies and kid- Do ...... Diethylenetri-amine Kidney scans. dium diatrizoate, ney scans. pentaacetic acid diatrizoate methyl- (DTPA). glucamine, so- Xenon 133 ...... Gas ...... Diagnosis of cardia dium diprotrizoate, abnormalities. sodium acetri- Cerebral blood- zoate, or sodium flow studies. Pul- iothalamate. monary function 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. (d)(1) In view of the extent of experi- Do ...... Macroaggregated io- Lung scans. 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 and Drug Administration conclude that human serum albumin. such isotopes should not be distributed Iodine 125 ...... Iodide ...... Diagnosis of thyroid under investigational-use labeling function. when they are actually intended for Do ...... Iodinated human Blood volume deter- use in medical practice. serum albumin. minations. Do ...... Rose Bengal ...... Liver function stud- (2) The exemption referred to in para- ies. graph (a) of this section, as applied to

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any drug or biologic containing any of Isotope Chemical form Use the isotopes listed in paragraph (c) of Do ...... do ...... Brain imaging. this section, in the ‘‘chemical form’’ Do ...... Polyphosphates ...... Bone imaging. and intended for the uses stated, is ter- Do ...... Technetated aggre- Lung imaging. minated on March 3, 1972, except as gated albumin provided in paragraph (d)(3) of this sec- (human). Do ...... Disodium etidronate Bone imaging. tion. (3) The exemption referred to in para- (2) In view of the extent of experience graph (a) of this section, as applied to with the isotopes listed in paragraph any drug or biologic containing any of (f)(1) of this section, the Nuclear Regu- the isotopes listed in paragraph (c) of latory Commission and the Food and this section, in the ‘‘chemical form’’ Drug Administration conclude that and intended for the uses stated, for they should not be distributed under which drug a new drug application or a investigational-use labeling when they ‘‘Investigational New Drug Applica- are actually intended for use in med- tion’’ was submitted prior to March 3, ical practice. 1972, or for which biologic an applica- (3) Any manufacturer or distributor tion for product license or ‘‘Investiga- interested in continuing to ship in tional New Drug Application’’ was sub- interstate commerce drugs containing mitted prior to March 3, 1972, is termi- the isotopes listed in paragraph (f)(1) of nated on August 20, 1976, unless an ap- this section for any of the indications provable notice was issued on or before listed, shall submit, on or before Au- August 20, 1976, in which case the ex- gust 25, 1975 to the Center for Drug emption is terminated either upon the Evaluation and Research, Food and subsequent issuance of a nonapprovable Drug Administration, 5600 Fishers notice for the new drug application or Lane, Rockville, MD 20857, a new drug on November 20, 1976, whichever occurs application or a ‘‘Investigational New first. Drug Application’’ for each such drug (e) No exemption from section 505 of for which the manufacturer or dis- the act or from part 312 of this chapter tributor does not have an approved new is in effect or has been in effect for ra- drug application pursuant to section dioactive drugs prepared from accel- 505(b) of the act. If the drug is a bio- erator-produced radioisotopes, natu- logic, a ‘‘Investigational New Drug Ap- rally occurring isotopes, or nonradio- plication’’ or an application for a li- active substances used in conjunction cense under section 351 of the Public with isotopes. Health Service Act shall be submitted (f)(1) Based on its experience in regu- to the Center for Biologics Evaluation lating investigational radioactive and Research, Food and Drug Adminis- pharmaceuticals, the Nuclear Regu- tration, 8800 Rockville Pike, Bethesda, latory Commission has compiled a list MD 20014, in lieu of any submission to of reactor-produced isotopes for which the Center for Drug Evaluation and Re- it considers that applicants may rea- search. sonably be expected to submit ade- (4) The exemption referred to in para- quate evidence of safety and effective- graph (a) of this section, as applied to ness for use as recommended in appro- any drug or biologic containing any of priate labeling; such use may include, the isotopes listed in paragraph (f)(1) of among others, the uses in this tabula- this section, in the ‘‘chemical form’’ tion: and intended for the uses stated, is ter- Isotope Chemical form Use minated on August 26, 1975 except as provided in paragraph (f)(5) of this sec- Fluorine 18 ...... Fluoride ...... Bone imaging. Indium-113m ... Diethylenetriamine Brain imaging; kid- tion. pentaacetic acid ney imaging. (5)(i) Except as provided in paragraph (DTPA). (f)(5)(ii) of this section, the exemption Do ...... Chloride ...... Placenta imaging; referred to in paragraph (a) of this sec- blood pool imaging. tion, as applied to any drug containing Technetium Human serum albu- Lung imaging. any of the isotopes listed in paragraph 99m. min microspheres. (f)(1) of this section, in the ‘‘chemical Do ...... Diethylenetriamine Kidney imaging; kid- pentaacetic acid ney function stud- form’’ and intended for the uses stated, (Sn). ies. for which drug a new drug application

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

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Public Health Service Act of July 1, thereafter, as long as the therapy con- 1944 (42 U.S.C. 201). tinues. [62 FR 12084, Mar. 14, 1997] (c) Patient package insert contents. A patient package insert for an estrogen § 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 prescription distribution, including (5) A description of the most serious products containing estrogens in fixed risks associated with the use of estro- combinations with other drugs, shall gens. be dispensed to patients with a patient (6) A brief summary of other side ef- package insert containing information fects of estrogens. concerning the drug’s benefits and (7) Instructions on how a patient may risks. An estrogen drug product that reduce the risks of estrogen use. does not comply with the requirements (8) The date, identified as such, of the of this section is misbranded under sec- most recent revision of the patient tion 502(a) of the Federal Food, Drug, package insert. and Cosmetic Act. (d) Guidance language. The Food and (b) Distribution requirements. (1) For Drug Administration issues informal estrogen drug products, the manufac- labeling guidance texts under turer and distributor shall provide a § 10.90(b)(9) of this chapter to provide patient package insert in or with each package of the drug product that the assistance in meeting the requirements manufacturer or distributor intends to of paragraph (c) of this section. Re- be dispensed to a patient. quests for a copy of the guidance text (2) In the case of estrogen drug prod- should be directed to the Center for ucts in bulk packages intended for Drug Evaluation and Research, Divi- multiple dispensing, and in the case of sion of Reproductive and Urologic injectables in multiple-dose vials, a Products, Food and Drug Administra- sufficient number of patient labeling tion, 10903 New Hampshire Ave., Silver pieces shall be included in or with each Spring, MD 20993–0002. package to assure that one piece can be (e) Exemptions. This section does not included with each package or dose dis- apply to estrogen-progestogen oral con- pensed or administered to every pa- traceptives. Labeling requirements for tient. Each bulk package shall be la- these products are set forth in § 310.501. beled with instructions to the (f) Requirement to supplement approved dispensor to include one patient label- application. Holders of approved appli- ing piece with each package dispensed cations for estrogen drug products that or, in the case of injectables, with each are subject to the requirements of this dose administered to the patient. This section must submit supplements section does not preclude the manufac- under § 314.70(c) of this chapter to pro- turer or labeler from distributing additional patient labeling pieces to the vide for the labeling required by para- dispensor. graph (a) of this section. Such labeling (3) Patient package inserts for estro- may be put into use without advance gens dispensed in acute-care hospitals approval by the Food and Drug Admin- or long-term care facilities will be con- istration. sidered to have been provided in ac- [55 FR 18723, May 4, 1990, as amended at 74 cordance with this section if provided FR 13113, Mar. 26, 2009] to the patient before administration of the first estrogen and every 30 days

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§ 310.517 Labeling for oral hypo- The patient should be informed of the poten- glycemic drugs of the sulfonylurea tial risks and advantages of (name of drug) class. and of alternative modes of therapy. Although only one drug in the sulfonylurea (a) The University Group Diabetes class (tolbutamide) was included in this Program clinical trial has reported an study, it is prudent from a safety standpoint association between the administration to consider that this warning may also apply of tolbutamide and increased cardio- to other oral hypoglycemic drugs in this vascular mortality. The Food and Drug class, in view of their close similarities in Administration has concluded that this mode of action and chemical structure. reported association provides adequate [49 FR 14331, Apr. 11, 1984] basis for a warning in the labeling. In view of the similarities in chemical § 310.518 Drug products containing structure and mode of action, the Food iron or iron salts. and Drug Administration also believes Drug products containing elemental it is prudent from a safety standpoint iron or iron salts as an active ingre- to consider that the possible increased dient in solid oral dosage form, e.g., risk of cardiovascular mortality from tablets or capsules shall meet the fol- tolbutamide applies to all other sulfo- lowing requirements: nylurea drugs as well. Therefore, the (a) Labeling. (1) The label of any drug labeling for oral hypoglycemic drugs of in solid oral dosage form (e.g., tablets the sulfonylurea class shall include a or capsules) that contains iron or iron warning concerning the possible in- salts for use as an iron source shall creased risk of cardiovascular mor- bear the following statement: tality associated with such use, as set forth in paragraph (b) of this section. WARNING: Accidental overdose or iron- (b) Labeling for oral hypoglycemic containing products is a leading cause of drugs of the sulfonylurea class shall in- fatal poisoning in children under 6. Keep this clude in boldface type at the beginning product out of reach of children. In case of of the ‘‘Warnings’’ section of the label- accidental overdose, call a doctor or poison control center immediately. ing the following statement: (2)(i) The warning statement required SPECIAL WARNING ON INCREASED RISK OF by paragraph (a)(1) of this section shall CARDIOVASCULAR MORTALITY 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 (ii) If a drug product is packaged in compared to treatment with diet alone or unit-dose packaging, and if the imme- diet plus insulin. This warning is based on diate container bears labeling but not a the study conducted by the University Group label, the warning statement required Diabetes Program (UGDP), a long-term pro- by paragraph (a)(1) of this section shall spective clinical trial designed to evaluate 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 that the warning is intact until all of who were randomly assigned to one of four the dosage units to which it applies are treatment groups (Diabetes, 19 (supp. 2): 747– used. 830, 1970). (3) Where the immediate container is UGDP reported that patients treated for 5 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 mor- mation panel of the retail package tality was not observed, but the use of tol- label. butamide was discontinued based on the in- (4) The warning statement shall ap- crease in cardiovascular mortality, thus lim- pear on any labeling that contains iting the opportunity for the study to show 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. be set off in a box by use of hairlines.

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(b) The iron-containing inert tablets is not in compliance with this section supplied in monthly packages of oral is subject to regulatory action. contraceptives are categorically ex- [44 FR 36380, June 22, 1979; 45 FR 47422, July empt from the requirements of para- 15, 1980, as amended at 55 FR 11579, Mar. 29, graph (a) of this section. 1990]

[68 FR 59715, Oct. 17, 2003] § 310.527 Drug products containing active ingredients offered over-the- § 310.519 Drug products marketed as counter (OTC) for external use as over-the-counter (OTC) daytime hair growers or for hair loss pre- sedatives. vention. (a) Antihistamines, bromides, and (a) Amino acids, aminobenzoic acid, scopolamine compounds, either singly ascorbic acid, benzoic acid, biotin and or in combinations, have been mar- all other B-vitamins, dexpanthenol, es- keted as ingredients in over-the- tradiol and other topical hormones, counter (OTC) drug products for use as jojoba oil, lanolin, nucleic acids, poly- daytime sedatives. The following sorbate 20, polysorbate 60, sulfa- claims have been made for daytime nilamide, sulfur 1 percent on carbon in sedative products: ‘‘occasional simple a fraction of paraffinic hydrocarbons, nervous tension,’’ ‘‘nervous irrita- tetracaine hydrochloride, urea, and bility,’’ ‘‘nervous tension headache,’’ wheat germ oil have been marketed as ‘‘simple nervousness due to common ingredients in OTC drug products for every day overwork and fatigue,’’ ‘‘a external use as hair growers or for hair relaxed feeling,’’ ‘‘calming down and loss prevention. There is a lack of adequate data to establish general rec- relaxing,’’ ‘‘gently soothe away the ognition of the safety and effectiveness tension,’’ ‘‘calmative,’’ ‘‘resolving that of these or any other ingredients in- irritability that ruins your day,’’ tended for OTC external use as a hair ‘‘helps you relax,’’ ‘‘restlessness,’’ grower or for hair loss prevention. ‘‘when you’re under occasional stress . Based on evidence currently available, . . helps you work relaxed.’’ Based on all labeling claims for OTC hair grower evidence presently available, there are and hair loss prevention drug products no ingredients that can be generally for external use are either false, mis- recognized as safe and effective for use leading, or unsupported by scientific as OTC daytime sedatives. data. Therefore, any OTC drug product (b) Any OTC drug product that is la- for external use containing an ingre- beled, represented, or promoted as an dient offered for use as a hair grower or OTC daytime sedative (or any similar for hair loss prevention cannot be con- or related indication) is regarded as a sidered generally recognized as safe new drug within the meaning of section and effective for its intended use. 201(p) of the Federal Food, Drug, and (b) Any OTC drug product that is la- Cosmetic Act for which an approved beled, represented, or promoted for ex- new drug application under section 505 ternal use as a hair grower or for hair of the act and part 314 of this chapter loss prevention is regarded as a new is required for marketing. drug within the meaning of section (c) Clinical investigations designed 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which an to obtain evidence that any drug prod- approved new drug application under uct labeled, represented, or promoted section 505 of the act and part 314 of as an OTC daytime sedative (or any this chapter is required for marketing. similar or related indication) is safe In the absence of an approved new drug and effective for the purpose intended application, such product is also mis- must comply with the requirements branded under section 502 of the act. and procedures governing the use of in- (c) Clinical investigations designed vestigational new drugs set forth in to obtain evidence that any drug prod- part 312 of this chapter. uct labeled, represented, or promoted (d) Any OTC daytime sedative drug for OTC external use as a hair grower product introduced into interstate or for hair loss prevention is safe and commerce after December 24, 1979, that effective for the purpose intended must

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comply with the requirements and pro- drug within the meaning of section cedures governing the use of investiga- 201(p) of the Federal Food, Drug, and tional new drugs set forth in part 312 of Cosmetic Act, (the act), for which an this chapter. approved new drug application under (d) After January 8, 1990, any such section 505 of the act and part 314 of OTC drug product initially introduced this chapter is required for marketing. 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 [54 FR 28777, July 7, 1989] to obtain evidence that any drug product 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- saparilla, strychnine, testosterone, vi- [54 FR 28786, July 7, 1989] tamins, yohimbine, yohimbine hydrochloride, and yohimbinum have been § 310.529 Drug products containing ac- present as ingredients in such drug tive ingredients offered over-the- products. Androgens (e.g., testosterone counter (OTC) for oral use as insect repellents. and methyltestosterone) and estrogens are powerful hormones when adminis- (a) Thiamine hydrochloride (vitamin tered internally and are not safe for B–1) has been marketed as an ingre- use except under the supervision of a dient in over-the-counter (OTC) drug physician. There is a lack of adequate products for oral use as an insect repel- data to establish general recognition of lent (an orally administered drug prod- the safety and effectiveness of any of uct intended to keep insects away). these ingredients, or any other ingre- There is a lack of adequate data to es- dient, for OTC use as an aphrodisiac. tablish the effectiveness of this, or any Labeling claims for aphrodisiacs for other ingredient for OTC oral use as an OTC use are either false, misleading, or insect repellent. Labeling claims for unsupported by scientific data. The fol- OTC orally administered insect repel- lowing claims are examples of some lent drug products are either false, that have been made for aphrodisiac misleading, or unsupported by sci- drug products for OTC use: ‘‘acts as an entific data. The following claims are aphrodisiac;’’ ‘‘arouses or increases examples of some that have been made sexual desire and improves sexual per- for orally administered OTC insect re- formance;’’ ‘‘helps restore sexual vigor, pellent drug products: ‘‘Oral mosquito potency, and performance;’’ ‘‘improves repellent,’’ ‘‘mosquitos avoid you,’’ performance, staying power, and sexual ‘‘bugs stay away,’’ ‘‘keep mosquitos potency;’’ and ‘‘builds virility and sex- away for 12 to 24 hours,’’ and ‘‘the new- ual potency.’’ Based on evidence cur- est way to fight mosquitos.’’ Therefore, rently available, any OTC drug product any drug product containing ingredi- containing ingredients for use as an ents offered for oral use as an insect re- aphrodisiac cannot be generally recog- pellent cannot be generally recognized nized as safe and effective. as safe and effective. (b) Any OTC drug product that is la- (b) Any OTC drug product that is labeled, represented, or prompted for use beled, represented, or promoted for oral as an aphrodisiac is regarded as a new use as an insect repellent is regarded as

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

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

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(b) Any OTC drug product that is la- been used in marketed cough-cold beled, represented, or promoted to re- products (0.2 milligram) but there are lieve the symptoms of benign prostatic inadequate data to establish general hypertrophy is regarded as a new drug recognition of the effectiveness of within the meaning of section 201(p) of these ingredients as an anticholinergic the Federal Food, Drug, and Cosmetic for cough-cold use. Belladonna alka- Act (the act), for which an approved loids for inhalation use, as contained in application under section 505 of the act Atropa belladonna and Datura stramo- and part 314 of this chapter is required nium, are neither safe nor effective as for marketing. In the absence of an ap- an OTC anticholinergic. There are in- proved application, such product is also adequate safety and effectiveness data 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

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for use as oral wound healing agents. (e.g., cayenne pepper) for OTC use as a Oral wound healing agents have been nailbiting or thumbsucking deterrent. marketed as aids in the healing of Based on evidence currently available, minor oral wounds by means other any OTC drug product containing in- than cleansing and irrigating, or by gredients offered for use as a nailbiting serving as a protectant. Allantoin, car- or thumbsucking deterrent cannot be bamide peroxide in anhydrous glycerin, generally recognized as safe and effec- water soluble chlorophyllins, and hy- tive. drogen peroxide in aqueous solution (b) Any OTC drug product that is la- are safe for use as oral wound healing beled, represented, and promoted as a agents, but there are inadequate data nailbiting or thumbsucking deterrent 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 requirements and procedures governing (d) After March 2, 1994, any such OTC the use of investigational new drugs drug product initially introduced or set forth in part 312 of this chapter. initially delivered for introduction into (d) After the effective date of the interstate commerce that is not in final regulation, any OTC drug product compliance with this section is subject that is labeled, represented, or pro- to regulatory action. moted for use as an oral wound healing [58 FR 46754, Sept. 2, 1993] agent may not be initially introduced or initially delivered for introduction § 310.537 Drug products containing ac- into interstate commerce unless it is tive ingredients offered over-the- the subject of an approved new drug ap- counter (OTC) for oral administra- plication. tion for the treatment of fever blisters and cold sores. [51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990] (a) L-lysine (lysine, lysine hydrochloride), Lactobacillus acidophilus, and § 310.536 Drug products containing ac- Lactobacillus bulgaricus have been tive ingredients offered over-the- present in orally administered OTC counter (OTC) for use as a nail- drug products to treat fever blisters biting or thumbsucking deterrent. and cold sores. There is a lack of ade- (a) Denatonium benzoate and sucrose quate data to establish general rec- octaacetate have been present in OTC ognition of the safety and effectiveness nailbiting and thumbsucking deterrent of these or any other orally adminis- drug products. There is a lack of ade- tered ingredients for OTC use to treat quate data to establish general rec- or relieve the symptoms or discomfort ognition of the safety and effectiveness of fever blisters and cold sores. Based of these and any other ingredients on evidence currently available, any

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OTC drug product for oral administra- taining ingredients offered for use for tion containing ingredients offered for ingrown toenail relief cannot be gen- use in treating or relieving the symp- erally recognized as safe and effective. toms or discomfort of fever blisters and (b) Any OTC drug product that is la- cold sores cannot be generally recog- beled, represented, or promoted for in- nized as safe and effective. grown toenail relief is regarded as a (b) Any OTC drug product for oral ad- new drug within the meaning of section ministration that is labeled, rep- 201(p) of the Federal Food, Drug, and resented, or promoted to treat or re- Cosmetic Act (the act), for which an lieve the symptoms or discomfort of approved application or abbreviated fever blisters and cold sores is regarded application under section 505 of the act as a new drug within the meaning of and part 314 of this chapter is required 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, tended must comply with the require- represented, or promoted for OTC use ments and procedures governing the to treat or relieve the symptoms or dis- use of investigational new drugs set comfort of fever blisters and cold sores 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 part 358, subpart D of this chapter, [57 FR 29173, June 30, 1992] after June 6, 2003. § 310.538 Drug products containing ac- [58 FR 47605, Sept. 9, 1993, as amended at 68 tive ingredients offered over-the- FR 24348, May 7, 2003] counter (OTC) for use for ingrown toenail relief. § 310.540 Drug products containing ac- (a) Any product that bears labeling tive 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 (a) Betaine hydrochloride, glutamic ‘‘ingrown toenail reliever,’’ or similar acid hydrochloride, diluted hydro- claims is considered an ingrown toenail chloric acid, and pepsin have been relief drug product. Benzocaine, chloro- present as ingredients in over-the- butanol, chloroxylenol, dibucaine, tan- counter (OTC) drug products for use as nic acid, and urea have been present as stomach acidifiers. Because of the lack ingredients in such products. There is of adequate data to establish the effec- lack of adequate data to establish gen- tiveness of these or any other ingredi- eral recognition of the safety and effec- ents for use in treating achlorhydria tiveness of these or any other ingredi- and hypochlorhydria, and because such ents for OTC use for ingrown toenail conditions are asymptomatic, any OTC relief. Based on evidence currently drug product containing ingredients of- available, any OTC drug product con- fered for use as a stomach acidifier

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

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or initially delivered for introduction (c) Clinical investigations designed into interstate commerce that is not in to obtain evidence that any drug prod- compliance with this section is subject uct labeled, represented, or promoted to regulatory action. for OTC use in the treatment of exocrine pancreatic insufficiency is safe [55 FR 19858, May 11, 1990] and effective for the purpose intended must comply with the requirements § 310.543 Drug products containing ac- and procedures governing the use of in- tive ingredients offered over-the- counter (OTC) for human use in vestigational new drugs set forth in exocrine pancreatic insufficiency. part 312 of this chapter. (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 is not in compliance with this section using these drug products. The bio- is subject to regulatory action. availability of pancreatic enzymes is dependent on the process used to man- [60 FR 20165, Apr. 24, 1995] ufacture the drug products. Informa- § 310.544 Drug products containing action on this process is not included in tive ingredients offered over-the- an OTC drug monograph. Therefore, counter (OTC) for use as a smoking the safe and effective use of these en- deterrent. zymes for treating exocrine pancreatic (a) Any product that bears labeling insufficiency cannot be regulated ade- claims that it ‘‘helps stop or reduce the quately by an OTC drug monograph. cigarette urge,’’ ‘‘helps break the ciga- Information on the product’s formula- rette habit,’’ ‘‘helps stop or reduce tion, manufacture, quality control pro- smoking,’’ or similar claims is a smok- cedures, and final formulation effec- ing deterrent drug product. Cloves, co- tiveness testing are necessary in an ap- riander, eucalyptus oil, ginger (Ja- proved application to ensure that a maica), lemon oil (terpeneless), licorice company has the ability to manufac- root extract, lobeline (in the form of ture a proper bioactive formulation. In lobeline sulfate or natural lobelia alka- addition, continuous physician moni- loids or Lobelia inflata herb), menthol, toring of patients who take these drug methyl salicylate, povidone-silver ni- products is a collateral measure nec- trate, quinine ascorbate, silver acetate, essary to the safe and effective use of silver nitrate, and thymol have been these enzymes, causing such products present as ingredients in such drug to be available by prescription only. products. There is a lack of adequate (b) Any drug product that is labeled, data to establish general recognition of represented, or promoted for OTC use the safety and effectiveness of these or in the treatment of exocrine pancreatic any other ingredients for OTC use as a insufficiency is regarded as a new drug smoking deterrent. Based on evidence within the meaning of section 201(p) of currently available, any OTC drug the Federal Food, Drug, and Cosmetic product containing ingredients offered Act (the act), for which an approved for use as a smoking deterrent cannot application under section 505 of the act be generally recognized as safe and ef- and part 314 of this chapter is required fective. for marketing. In the absence of an ap- (b) Any OTC drug product that is la- proved application, such product is also beled, represented, or promoted as a misbranded under section 502 of the smoking deterrent is regarded as a new act. drug within the meaning of section

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201(p) of the Federal Food, Drug, and Benzocaine Cosmetic Act (the act), for which an Benzoic acid approved application or abbreviated Boric acid application under section 505 of the act Calcium polysulfide Calcium thiosulfate and part 314 of this chapter is required Camphor 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 502 of the act. Estrone (c) Clinical investigations designed Magnesium aluminum silicate to obtain evidence that any drug prod- Magnesium sulfate uct labeled, represented, or promoted Phenol 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 ingre- forth in part 312 of this chapter. dient) (d) After May 7, 1991, any such OTC Salicylic acid (over 2 up to 5 percent) drug product containing cloves, cori- Sodium borate 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 taining lobeline (in the form of lobeline Sodium carbonate 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 data to establish general recognition of Homatropine methylbromide Hyoscyamine sulfate the safety and effectiveness of these in- Lactobacillus acidophilus gredients for the specified uses: Lactobacillus bulgaricus (1) Topical acne drug products. Alcloxa 1 These ingredients are nonmonograph ex- Alkyl isoquinolinium bromide cept when used to prepare acidulated phos- Aluminum chlorohydrex phate fluoride treatment rinses identified in Aluminum hydroxide § 355.10(a)(3) of this chapter.

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Opium, powdered Thymol Opium tincture Thymol (lozenge) Paregoric Thymol (mouthwash) Phenyl salicylate Turpentine oil Scopolamine hydrobromide Zinc phenolsulfonate (B) Approved as of August 23, 1995. (ii) Approved as of April 19, 2004; April Bornyl acetate (topical) Cedar leaf oil (topical) 18, 2005, for products with annual sales Creosote, beechwood (topical) less than $25,000. Ephedrine (oral) Attapulgite, activated Ephedrine hydrochloride (oral) Bismuth subnitrate Ephedrine sulfate (oral) Calcium hydroxide Racephedrine hydrochloride (oral/topical) 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 Potassium carbonate dient(s) labeled with claims or direc- Rhubarb fluidextract tions for use for sinusitis or for relief 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 Iodides (calcium iodide anyhydrous, hydroid- June 9, 2005, for products with annual ic acid syrup, iodized lime, potassium io- sales less than $25,000. dide) 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) Potassium guaiacolsulfonate dients. Sodium citrate Methapyrilene hydrochloride Squill preparations (squill, squill extract) Methapyrilene fumarate Terpin hydrate preparations (terpin hydrate, Thenyldiamine hydrochloride terpin hydrate elixir) Tolu preparations (tolu, tolu balsam, tolu (B) Ingredients. balsam tincture) Turpentine oil (spirits of turpentine) Phenyltoloxamine dihydrogen citrate Methapyrilene hydrochloride (iv) Bronchodilator drug products—(A) Methapyrilene fumarate Approved as of October 2, 1987. Thenyldiamine hydrochloride Aminophylline (ii) Nasal decongestant drug products— Belladonna alkaloids (A) Approved as of May 7, 1991. Euphorbia pilulifera Metaproterenol sulfate Allyl isothiocyanate Methoxyphenamine hydrochloride Camphor (lozenge) Pseudoephedrine hydrochloride Creosote, beechwood (oral) Pseudoephedrine sulfate Eucalyptol (lozenge) Theophylline, anhydrous Eucalyptol (mouthwash) Theophylline calcium salicylate Eucalyptus oil (lozenge) Theophylline sodium glycinate Eucalyptus oil (mouthwash) Menthol (mouthwash) (B) Approved as of January 29, 1996. Peppermint oil (mouthwash) Any combination drug product con- Thenyldiamine hydrochloride taining theophylline (e.g., theophylline

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and ephedrine, or theophylline and Pepsin ephedrine and phenobarbital). Sodium bicarbonate (C) Approved as of June 19, 1996. Any Sodium citrate Sorbitol ingredient(s) in a pressurized metered- dose inhaler container. (ii) Approved as of November 10, 1993. (D) Approved as of October 29, 2001. Alcohol Any oral bronchodilator active ingre- Aluminum hydroxide dient (e.g., ephedrine, ephedrine hydro- Amylase chloride, ephedrine sulfate, Anise seed racephedrine hydrochloride, or any Aromatic powder other ephedrine salt) in combination Asafetida with any analgesic(s) or analgesic-anti- Aspergillus oryza enzymes (except lactase 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 asis drug products. Betaine hydrochloride 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) (8) Digestive aid drug products—(i) Ap- Hectorite proved as of May 7, 1991. Horsetail Huckleberry Bismuth sodium tartrate Hydrastis fluid extract Calcium carbonate Hydrochloric acid Cellulase Iodine Dehydrocholic acid Iron ox bile Dihydroxyaluminum sodium carbonate Johnswort Duodenal substance Juniper Garlic, dehydrated Kaolin, colloidal Glutamic acid hydrochloride Knotgrass Hemicellulase Lactic acid Homatropine methylbromide Lactose Magnesium hydroxide Lavender compound, tincture of Magnesium trisilicate Linden Ox bile extract Lipase Pancreatin Lysine hydrochloride Pancrelipase Mannitol Papain Mycozyme Peppermint oil Myrrh, fluid extract of

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Nettle Eucalyptus oil Nickel-pectin Eugenol Nux vomica extract Glycol salicylate Orthophosphoric acid Hexylresorcinol Papaya, natural Histamine dihydrochloride Pectin Menthol (exceeding 1 percent) 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 (i) Analgesic and anesthetic drug prod- Panthenol 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 drug products. Glycol salicylate 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

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

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(B) Ingredients—Approved as of June 4, Cysteine hydrochloride 2004; June 6, 2005, for products with an- Glycerin nual sales less than $25,000. Protein hydrolysate Racemethionine Beeswax Sulfur Bismuth subnitrate Tannic acid Boric acid Zinc acetate Cetyl alcohol Zinc carbonate Glyceryl stearate Isopropyl palmitate (iv) Fever blister and cold sore treat- Live yeast cell derivative ment drug products. Shark liver oil Bismuth subnitrate Stearyl alcohol Boric acid (ii) Astringent drug products. Pyridoxine hydrochloride Sulfur Acetone Tannic acid Alcohol Topical starch Alum, ammonium Trolamine Alum, potassium Zinc sulfate Aluminum chlorhydroxy complex Aromatics (v) Insect bite and sting drug products— Benzalkonium chloride (A) Ingredients—Approved as of November 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

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Cetalkonium chloride Calcium pantothenate Chloral hydrate Carboxymethylcellulose sodium Chlorpheniramine maleate Carrageenan Creosote Cholecalcierol Diperodon hydrochloride Choline Diphenhydramine hydrochloride Chondrus Eucalyptus oil Citric acid Ferric chloride Cnicus benedictus 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

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Rice polishings Benzethonium chloride Saccharin Benzoic acid Sea minerals Benzoxiquine Sesame seed Boric acid Sodium Camphor Sodium bicarbonate Candicidin Sodium caseinate Chlorothymol Sodium chloride (salt) Coal tar 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 Pheniramine maleate (22) Topical antifungal drug products. 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.

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

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Bismuth oxide Ethyl 4-[bis(hydroxypropyl)] aminobenzoate Bismuth subcarbonate Glyceryl aminobenzoate Bismuth subgallate Lawsone with dihydroxyacetone Bismuth subnitrate Red petrolatum Lanolin alcohols (30) [Reserved] (ix) Vasoconstrictor drug products. (b) Any OTC drug product that is la- Epinephrine undecylenate beled, represented, or promoted for the uses specified and containing any ac- (x) Wound healinq drug products. tive ingredient(s) as specified in para- Cholecalciferol graph (a) of this section is regarded as Cod liver oil a new drug within the meaning of sec- Live yeast cell derivative tion 210(p) of the Federal Food, Drug, Peruvian balsam and Cosmetic Act (the Act), for which Shark liver oil Vitamin A an approved new drug application under section 505 of the Act and part (xi) Combination drug products. Any 314 of this chapter is required for mar- combination drug product containing keting. In the absence of an approved hydrocortisone and pramoxine hydro- new drug application, such product is chloride. also misbranded under section 502 of (27) Topical antimicrobial drug prod- the Act. ucts—(i) First aid antiseptic drug prod- (c) Clinical investigations designed ucts. to obtain evidence that any drug prod- Ammoniated mercury uct labeled, represented, or promoted Calomel (mercurous chloride) for the OTC uses and containing any Merbromin (mercurochrome) active ingredient(s) as specified in Mercufenol chloride (ortho- paragraph (a) of this section is safe and chloromercuriphenol, ortho- effective for the purpose intended must hydroxyphenylmercuric chloride) comply with the requirements and pro- Mercuric chloride (bichloride of mercury, cedures governing the use of investiga- mercury chloride) Mercuric oxide, yellow tional new drugs set forth in part 312 of Mercuric salicylate this chapter. Mercuric sulfide, red (d) Any OTC drug product that is not Mercury in compliance with this section is sub- Mercury oleate ject to regulatory action if initially in- Mercury sulfide troduced or initially delivered for in- Nitromersol troduction into interstate commerce Para-chloromercuriphenol Phenylmercuric nitrate after the dates specified in paragraphs Thimerosal (d)(1) through (d)(39) of this section. Vitromersol (1) May 7, 1991, for products subject Zyloxin to paragraphs (a)(1) through (a)(2)(i), (ii) Diaper rash drug products. (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except as covered by Para-chloromercuriphenol paragraph (d)(3) of this section), Any other ingredient containing mercury (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (28) Vaginal contraceptive drug prod- (a)(12)(i)(A), (a)(12)(ii) through ucts—(i) Approved as of October 22, 1998. (a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) Dodecaethylene glycol monolaurate (poly- (except as covered by paragraph (d)(22) ethylene glycol 600 monolaurate) Laureth 10S of this section), (a)(18)(iii), (a)(18)(iv), Methoxypolyoxyethyleneglycol 550 laurate (a)(18)(v)(A), and (a)(18)(vi)(A) of this Phenylmercuric acetate section. Phenylmercuric nitrate (2) February 10, 1992, for products Any other ingredient containing mercury subject to paragraph (a)(20) of this sec- (ii) Approved as of November 5, 2002. tion. Octoxynol 9 (3) December 4, 1992, for products subject to paragraph (a)(7) of this section (29) Sunscreen drug products. that contain menthol as an anti- Diethanolamine methoxycinnamate pruritic in combination with the anti- Digalloyl trioleate dandruff ingredient coal tar identified

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in § 358.710(a)(1) of this chapter. This tion. April 18, 2005, for products with section does not apply to products al- annual sales less than $25,000. lowed by § 358.720(b) of this chapter (18) August 15, 1995, for products sub- after April 5, 2007. ject to paragraph (a)(15)(ii) of this sec- (4) February 28, 1990, for products tion. subject to paragraph (a)(6)(iii) of this (19) October 2, 1987, for products sub- section, except those that contain ipe- ject to paragraph (a)(6)(iv)(A) of this cac. section. (5) September 14, 1993, for products (20) January 29, 1996, for products subject to paragraph (a)(6)(iii) of this subject to paragraph (a)(6)(iv)(B) of section that contain ipecac. this section. (6) December 9, 1993, for products sub- (21) April 21, 1994, for products subject to paragraph (a)(6)(i)(B) of this ject to paragraph (a)(8)(iii) of this sec- section. tion. (7) March 6, 1989, for products subject (22) April 21, 1993, for products sub- to paragraph (a)(21) of this section, ex- ject to paragraph (a)(18)(ii) of this sec- cept those that contain ophthalmic tion that contain ferric subsulfate. anti-infective ingredients listed in (23) August 23, 1995, for products sub- paragraph (a)(21)(ii). ject to paragraph (a)(6)(ii)(B) of this (8) June 18, 1993, for products subject section. to paragraph (a)(21) of this section that (24) October 7, 1996, for products sub- contain ophthalmic anti-infective in- ject to paragraph (a)(2)(ii) of this sec- gredients. tion. (9) June 18, 1993, for products subject (25) June 19, 1996, for products subject to paragraph (a)(10)(iv) of this section. to paragraph (a)(6)(iv)(C) of this sec- (10) June 18, 1993, for products subject tion. to paragraph (a)(22)(i) of this section. (26) February 22, 1999, for products (11) November 10, 1993, for products subject to paragraphs (a)(23)(ii) and subject to paragraphs (a)(8)(ii), (a)(24)(ii) of this section. (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) (except products that contain ferric (27) [Reserved] subsulfate as covered by paragraph (28) October 22, 1998, for products sub- (d)(22) of this section and except prod- ject to paragraphs (a)(27) and (a)(28)(i) ucts that contain calcium acetate of this section. monohydrate as covered by paragraph (29) January 29, 1999, for products (d)(39) of this section) through subject to paragraph (a)(12)(iv)(B) of (a)(18)(v)(A), (a)(18)(vi)(A), (a)(22)(ii), this section. (a)(23)(i), (a)(24)(i), and (a)(25) of this (30) November 5, 2002, for products section. subject to paragraph (a)(12)(iv)(C) of (12) March 2, 1994, for products sub- this section. ject to paragraph (a)(22)(iii) of this sec- (31) December 31, 2002, for products tion. subject to paragraph (a)(29) of this sec- (13) August 5, 1991, for products sub- tion. ject to paragraph (a)(26) of this section, (32) June 4, 2004, for products subject except for those that contain live yeast to paragraphs (a)(18)(i)(B), (a)(18)(v)(B), cell derivative and a combination of and (a)(18)(vi)(B) of this section. June hydrocortisone and pramoxine hydro- 6, 2005, for products with annual sales chloride. less than $25,000. (14) September 2, 1994, for products (33) October 29, 2001, for products sub- subject to paragraph (a)(26)(vii) and ject to paragraph (a)(6)(iv)(D) of this (a)(26)(x) of this section that contain section. live yeast cell derivative. (34) December 9, 2004, for products (15) September 23, 1994, for products subject to paragraph (a)(4)(ii) of this subject to paragraph (a)(22)(iv) of this section. June 9, 2005, for products with section. annual sales less than $25,000. (16) June 14, 1994, for products subject (35) [Reserved] to paragraph (a)(25)(ii) of this section. (36) November 5, 2002, for products (17) April 19, 2004, for products sub- subject to paragraph (a)(28)(ii) of this ject to paragraph (a)(3)(ii) of this sec- section.

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(37) September 25, 2003, for products any drug product containing quinine or subject to paragraph (a)(26)(xi) of this quinine sulfate cannot be considered section. generally recognized as safe for the (38) October 1, 2007, for products sub- treatment and/or prevention of noc- ject to paragraph (a)(12)(i)(B) of this turnal leg muscle cramps. section. (b) Any OTC drug product that is la- (39) September 6, 2010, for products beled, represented, or promoted for the subject to paragraph (a)(18)(ii) of this treatment and/or prevention of noc- section that contain calcium acetate turnal leg muscle cramps is regarded as monohydrate, except as provided in a new drug within the meaning of sec- § 347.20(b) of this chapter. tion 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which [55 FR 46919, Nov. 7, 1990] an approved application or abbreviated EDITORIAL NOTE: For FEDERAL REGISTER ci- application under section 505 of the act tations affecting § 310.545, see the List of CFR and part 314 of this chapter is required Sections Affected, which appears in the for marketing. In the absence of an ap- Finding Aids section of the printed volume proved new drug application or abbre- and at www.fdsys.gov. viated new drug application, such prod- EFFECTIVE DATE NOTE: At 61 FR 9571, Mar. uct is also misbranded under section 8, 1996, in § 310.545 in paragraph (a)(6)(ii)(B), 502 of the act. the entry for ‘‘l-desoxyephedrine (topical)’’ (c) Clinical investigations designed was stayed until further notice. to obtain evidence that any drug prod- § 310.546 Drug products containing ac- uct labeled, represented, or promoted tive ingredients offered over-the- for OTC use for the treatment and/or counter (OTC) for the treatment prevention of nocturnal leg muscle and/or prevention of nocturnal leg cramps is safe and effective for the pur- muscle cramps. pose intended must comply with the re- (a) Quinine sulfate alone or in com- quirements and procedures governing bination with vitamin E has been the use of investigational new drugs present in over-the-counter (OTC) drug set forth in part 312 of this chapter. products for the treatment and/or pre- (d) After February 22, 1995, any such vention of nocturnal leg muscle OTC drug product initially introduced cramps, i.e., a condition of localized or initially delivered for introduction pain in the lower extremities usually into interstate commerce that is not in occurring in middle life and beyond compliance with this section is subject with no regular pattern concerning to regulatory action. time or severity. There is a lack of ade- [59 FR 43252, Aug. 22, 1994] quate data to establish general recognition of the safety and effectiveness § 310.547 Drug products containing of quinine sulfate, vitamin E, or any quinine offered over-the-counter other ingredients for OTC use in the (OTC) for the treatment and/or pre- treatment and/or prevention of noc- vention of malaria. turnal leg muscle cramps. In the doses (a) Quinine and quinine salts have used to treat or prevent this condition, been used OTC for the treatment and/or quinine sulfate has caused adverse prevention of malaria, a serious and events such as transient visual and au- potentially life-threatening disease. ditory disturbances, dizziness, fever, Quinine is no longer the drug of choice nausea, vomiting, and diarrhea. Qui- for the treatment and/or prevention of nine sulfate may cause unpredictable most types of malaria. In addition, serious and life-threatening hyper- there are serious and complicating as- sensitivity reactions requiring medical pects of the disease itself and some po- intervention and hospitalization; fa- tentially serious and life-threatening talities have been reported. The risk risks associated with the use of quinine associated with use of quinine sulfate, at doses employed for the treatment of in the absence of evidence of its effec- malaria. There is a lack of adequate tiveness, outweighs any potential ben- data to establish general recognition of efit in treating and/or preventing this the safety of quinine drug products for benign, self-limiting condition. Based OTC use in the treatment and/or pre- upon the adverse benefit-to-risk ratio, vention of malaria. Therefore, quinine

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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 initially delivered for introduction into silver or silver salts initially intro- interstate commerce that is not in duced or initially delivered for intro- compliance with this section is subject duction into interstate commerce that to regulatory action. is not in compliance with this section [63 FR 13528, Mar. 20, 1998] is subject to regulatory action. [64 FR 44658, Aug. 17, 1999] § 310.548 Drug products containing colloidal silver ingredients or silver salts offered over-the-counter (OTC) PART 312—INVESTIGATIONAL NEW for the treatment and/or prevention DRUG APPLICATION of disease. (a) Colloidal silver ingredients and Subpart A—General Provisions silver salts have been marketed in Sec. over-the-counter (OTC) drug products 312.1 Scope. for the treatment and prevention of nu- 312.2 Applicability. merous disease conditions. There are 312.3 Definitions and interpretations. serious and complicating aspects to 312.6 Labeling of an investigational new many of the diseases these silver ingre- drug. 312.7 Promotion of investigational drugs. dients purport to treat or prevent. Fur- 312.8 Charging for investigational drugs ther, there is a lack of adequate data under an IND. to establish general recognition of the 312.10 Waivers. safety and effectiveness of colloidal silver ingredients or silver salts for OTC Subpart B—Investigational New Drug use in the treatment or prevention of Application (IND) any disease. These ingredients and 312.20 Requirement for an IND. salts include, but are not limited to, 312.21 Phases of an investigation. silver proteins, mild silver protein, 312.22 General principles of the IND submis- strong silver protein, silver, silver ion, sion. silver chloride, silver cyanide, silver 312.23 IND content and format.

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312.30 Protocol amendments. Subpart F—Miscellaneous 312.31 Information amendments. 312.32 IND safety reporting. 312.110 Import and export requirements. 312.33 Annual reports. 312.120 Foreign clinical studies not con- 312.38 Withdrawal of an IND. ducted under an IND. 312.130 Availability for public disclosure of Subpart C—Administrative Actions data and information in an IND. 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 laboratory research animals or in vitro 312.45 Inactive status. tests. 312.47 Meetings. 312.48 Dispute resolution. Subpart H [Reserved] Subpart D—Responsibilities of Sponsors Subpart I—Expanded Access to and Investigators Investigational Drugs for Treatment Use 312.50 General responsibilities of sponsors. 312.300 General. 312.52 Transfer of obligations to a contract 312.305 Requirements for all expanded ac- research organization. cess uses. 312.53 Selecting investigators and monitors. 312.310 Individual patients, including for 312.54 Emergency research under § 50.24 of emergency use. this chapter. 312.315 Intermediate-size patient popu- 312.55 Informing investigators. lations. 312.56 Review of ongoing investigations. 312.320 Treatment IND or treatment pro- 312.57 Recordkeeping and record retention. tocol. 312.58 Inspection of sponsor’s records and AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, reports. 355, 360bbb, 371; 42 U.S.C. 262. 312.59 Disposition of unused supply of investigational drug. SOURCE: 52 FR 8831, Mar. 19, 1987, unless 312.60 General responsibilities of investiga- otherwise noted. tors. EDITORIAL NOTE: Nomenclature changes to 312.61 Control of the investigational drug. part 312 can be found at 69 FR 13717, Mar. 24, 312.62 Investigator recordkeeping and 2004. record retention. 312.64 Investigator reports. 312.66 Assurance of IRB review. Subpart A—General Provisions 312.68 Inspection of investigator’s records and reports. § 312.1 Scope. 312.69 Handling of controlled substances. (a) This part contains procedures and 312.70 Disqualification of a clinical investi- requirements governing the use of in- gator. vestigational new drugs, including procedures and requirements for the sub- Subpart E—Drugs Intended to Treat Life- mission to, and review by, the Food threatening and Severely-debilitating and Drug Administration of investiga- Illnesses tional new drug applications (IND’s). 312.80 Purpose. An investigational new drug for which 312.81 Scope. an IND is in effect in accordance with 312.82 Early consultation. this part is exempt from the premar- 312.83 Treatment protocols. keting approval requirements that are 312.84 Risk-benefit analysis in review of otherwise applicable and may be marketing applications for drugs to treat shipped lawfully for the purpose of con- life-threatening and severely-debilitating ducting clinical investigations of that illnesses. 312.85 Phase 4 studies. drug. 312.86 Focused FDA regulatory research. (b) References in this part to regula- 312.87 Active monitoring of conduct and tions in the Code of Federal Regula- evaluation of clinical trials. tions are to chapter I of title 21, unless 312.88 Safeguards for patient safety. otherwise noted.

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§ 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. (4) FDA will not accept an applica- clinical investigations of products that tion for an investigation that is ex- are subject to section 505 of the Federal empt under the provisions of paragraph Food, Drug, and Cosmetic Act or to the (b)(1) of this section. licensing provisions of the Public (5) A clinical investigation involving Health Service Act (58 Stat. 632, as use of a placebo is exempt from the re- amended (42 U.S.C. 201 et seq.)). quirements of this part if the inves- (b) Exemptions. (1) The clinical investigation does not otherwise require tigation of a drug product that is law- submission of an IND. fully marketed in the United States is (6) A clinical investigation involving exempt from the requirements of this an exception from informed consent part if all the following apply: under § 50.24 of this chapter is not ex- (i) The investigation is not intended empt from the requirements of this to be reported to FDA as a well-con- part. trolled study in support of a new indi- (c) Bioavailability studies. The applica- cation for use nor intended to be used bility of this part to in vivo bio- to support any other significant change availability studies in humans is sub- in the labeling for the drug; (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, ceptability of the risks) associated FDA will advise on the applicability of with the use of the drug product; this part to a planned clinical inves- (iv) The investigation is conducted in tigation. compliance with the requirements for [52 FR 8831, Mar. 19, 1987, as amended at 61 institutional review set forth in part 56 FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999] and with the requirements for informed consent set forth in part 50; and § 312.3 Definitions and interpretations. (v) The investigation is conducted in (a) The definitions and interpreta- compliance with the requirements of tions of terms contained in section 201 § 312.7. of the Act apply to those terms when (2)(i) A clinical investigation involv- used in this part: ing an in vitro diagnostic biological (b) The following definitions of terms product listed in paragraph (b)(2)(ii) of also apply to this part: this section is exempt from the re- Act means the Federal Food, Drug, quirements of this part if (a) it is in- and Cosmetic Act (secs. 201–902, 52 tended to be used in a diagnostic proce- Stat. 1040 et seq., as amended (21 U.S.C. dure that confirms the diagnosis made 301–392)). by another, medically established, di- Clinical investigation means any ex- agnostic product or procedure and (b) it periment in which a drug is adminis- is shipped in compliance with § 312.160. tered or dispensed to, or used involv- (ii) In accordance with paragraph ing, one or more human subjects. For (b)(2)(i) of this section, the following the purposes of this part, an experi- products are exempt from the requirement is any use of a drug except for the ments of this part: (a) blood grouping use of a marketed drug in the course of serum; (b) reagent red blood cells; and medical practice. (c) anti-human globulin. Contract research organization means a (3) A drug intended solely for tests in person that assumes, as an independent vitro or in laboratory research animals contractor with the sponsor, one or

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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.’’ Independent ethics committee (IEC) than an individual. The requirements means a review panel that is respon- applicable to a sponsor-investigator sible for ensuring the protection of the under this part include both those ap- rights, safety, and well-being of human plicable to an investigator and a spon- subjects involved in a clinical inves- sor. tigation and is adequately constituted Subject means a human who partici- to provide assurance of that protec- pates in an investigation, either as a tion. An institutional review board recipient of the investigational new (IRB), as defined in § 56.102(g) of this drug or as a control. A subject may be chapter and subject to the require- a healthy human or a patient with a ments of part 56 of this chapter, is one disease. type of IEC. Investigational new drug means a new [52 FR 8831, Mar. 19, 1987, as amended at 64 drug or biological drug that is used in FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999; 73 FR 22815, Apr. 28, 2008] a clinical investigation. The term also includes a biological product that is § 312.6 Labeling of an investigational used in vitro for diagnostic purposes. new drug. The terms ‘‘investigational drug’’ and ‘‘investigational new drug’’ are deemed (a) The immediate package of an in- to be synonymous for purposes of this vestigational new drug intended for part. human use shall bear a label with the Investigator means an individual who statement ‘‘Caution: New Drug—Lim- actually conducts a clinical investiga- ited by Federal (or United States) law tion (i.e., under whose immediate direc- to investigational use.’’ tion the drug is administered or dis- (b) The label or labeling of an inves- pensed to a subject). In the event an in- tigational new drug shall not bear any vestigation is conducted by a team of statement that is false or misleading in individuals, the investigator is the re- any particular and shall not represent sponsible leader of the team. ‘‘Sub- that the investigational new drug is investigator’’ includes any other indi- safe or effective for the purposes for vidual member of that team. which it is being investigated. Marketing application means an appli- (c) The appropriate FDA Center Di- cation for a new drug submitted under rector, according to the procedures set section 505(b) of the act or a biologics forth in §§ 201.26 or 610.68 of this chap- license application for a biological ter, may grant an exception or alter- product submitted under the Public native to the provision in paragraph (a) Health Service Act. Sponsor means a person who takes re- of this section, to the extent that this sponsibility for and initiates a clinical provision is not explicitly required by investigation. The sponsor may be an statute, for specified lots, batches, or individual or pharmaceutical company, other units of a human drug product governmental agency, academic insti- that is or will be included in the Stra- tution, private organization, or other tegic National Stockpile. organization. The sponsor does not ac- [52 FR 8831, Mar. 19, 1987, as amended at 72 tually conduct the investigation unless FR 73599, Dec. 28, 2007] the sponsor is a sponsor-investigator. A

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§ 312.7 Promotion of investigational (3) A sponsor must obtain prior writ- drugs. ten 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 is approved for commercial distribu- prevention of a disease or condition; tion. (ii) Demonstrate that the data to be (b) Commercial distribution of an inves- obtained from the clinical trial would tigational new drug. A sponsor or inves- be essential to establishing that the tigator shall not commercially dis- drug is effective or safe for the purpose tribute or test market an investiga- of obtaining initial approval of a drug, tional new drug. or would support a significant change (c) Prolonging an investigation. A in the labeling of an approved drug sponsor shall not unduly prolong an in- (e.g., new indication, inclusion of com- vestigation after finding that the re- parative safety information); and sults of the investigation appear to es- (iii) Demonstrate that the clinical tablish sufficient data to support a trial could not be conducted without marketing application. charging because the cost of the drug is [52 FR 8831, Mar. 19, 1987, as amended at 52 extraordinary to the sponsor. The cost FR 19476, May 22, 1987; 67 FR 9585, Mar. 4, may be extraordinary due to manufac- 2002; 74 FR 40899, Aug. 13, 2009] turing complexity, scarcity of a natural resource, the large quantity of § 312.8 Charging for investigational drug needed (e.g., due to the size or du- drugs under an IND. ration of the trial), or some combina- (a) General criteria for charging. (1) A tion of these or other extraordinary sponsor must meet the applicable re- circumstances (e.g., resources available quirements in paragraph (b) of this sec- to a sponsor). tion for charging in a clinical trial or (2) Duration of charging in a clinical paragraph (c) of this section for charg- trial. Unless FDA specifies a shorter pe- ing for expanded access to an investiga- riod, charging may continue for the tional drug for treatment use under length of the clinical trial. subpart I of this part, except that spon- (c) Charging for expanded access to in- sors need not fulfill the requirements vestigational drug for treatment use. (1) A in this section to charge for an ap- sponsor who wishes to charge for ex- proved drug obtained from another en- panded access to an investigational tity not affiliated with the sponsor for drug for treatment use under subpart I use as part of the clinical trial evalua- of this part must provide reasonable tion (e.g., in a clinical trial of a new assurance that charging will not inter- use of the approved drug, for use of the fere with developing the drug for mar- approved drug as an active control). keting approval. (2) A sponsor must justify the (2) For expanded access under § 312.320 amount to be charged in accordance (treatment IND or treatment protocol), with paragraph (d) of this section. such assurance must include:

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(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 [74 FR 40899, Aug. 13, 2009] for additional periods. (d) Costs recoverable when charging for § 312.10 Waivers. an investigational drug. (1) A sponsor (a) A sponsor may request FDA to may recover only the direct costs of waive applicable requirement under making its investigational drug avail- this part. A waiver request may be sub- able. mitted either in an IND or in an infor- (i) Direct costs are costs incurred by mation amendment to an IND. In an a sponsor that can be specifically and emergency, a request may be made by exclusively attributed to providing the telephone or other rapid communica- drug for the investigational use for tion means. A waiver request is re- which FDA has authorized cost recov- quired to contain at least one of the ery. Direct costs include costs per unit following: to manufacture the drug (e.g., raw ma- (1) An explanation why the sponsor’s terials, labor, and nonreusable supplies compliance with the requirement is un- and equipment used to manufacture necessary or cannot be achieved; the quantity of drug needed for the use for which charging is authorized) or (2) A description of an alternative costs to acquire the drug from another submission or course of action that manufacturing source, and direct costs satisfies the purpose of the require- to ship and handle (e.g., store) the ment; or drug. (3) Other information justifying a (ii) Indirect costs include costs in- waiver. curred primarily to produce the drug (b) FDA may grant a waiver if it for commercial sale (e.g., costs for fa- finds that the sponsor’s noncompliance cilities and equipment used to manu- would not pose a significant and unrea- facture the supply of investigational sonable risk to human subjects of the drug, but that are primarily intended investigation and that one of the fol- to produce large quantities of drug for lowing is met: eventual commercial sale) and research (1) The sponsor’s compliance with the and development, administrative, requirement is unnecessary for the labor, or other costs that would be in- agency to evaluate the application, or curred even if the clinical trial or compliance cannot be achieved; treatment use for which charging is au- (2) The sponsor’s proposed alter- thorized did not occur. native satisfies the requirement; or

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(3) The applicant’s submission other- design of well-controlled, scientifically wise justifies a waiver. valid, Phase 2 studies. The total number of subjects and patients included in [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9585, Mar. 4, Phase 1 studies varies with the drug, 2002] but is generally in the range of 20 to 80. (2) Phase 1 studies also include stud- Subpart B—Investigational New ies of drug metabolism, structure-activity relationships, and mechanism of Drug Application (IND) action in humans, as well as studies in § 312.20 Requirement for an IND. which investigational drugs are used as research tools to explore biological (a) A sponsor shall submit an IND to phenomena or disease processes. FDA if the sponsor intends to conduct (b) Phase 2. Phase 2 includes the con- a clinical investigation with an inves- trolled clinical studies conducted to tigational new drug that is subject to evaluate the effectiveness of the drug § 312.2(a). for a particular indication or indica- (b) A sponsor shall not begin a clin- tions in patients with the disease or ical investigation subject to § 312.2(a) condition under study and to deter- until the investigation is subject to an mine the common short-term side ef- IND which is in effect in accordance fects and risks associated with the with § 312.40. drug. Phase 2 studies are typically well (c) A sponsor shall submit a separate controlled, closely monitored, and con- IND for any clinical investigation in- ducted in a relatively small number of volving an exception from informed patients, usually involving no more consent under § 50.24 of this chapter. than several hundred subjects. Such a clinical investigation is not (c) Phase 3. Phase 3 studies are ex- permitted to proceed without the prior panded controlled and uncontrolled written authorization from FDA. FDA trials. They are performed after pre- shall provide a written determination liminary evidence suggesting effective- 30 days after FDA receives the IND or ness of the drug has been obtained, and earlier. are intended to gather the additional [52 FR 8831, Mar. 19, 1987, as amended at 61 information about effectiveness and FR 51529, Oct. 2, 1996; 62 FR 32479, June 16, safety that is needed to evaluate the 1997] overall benefit-risk relationship of the drug and to provide an adequate basis § 312.21 Phases of an investigation. for physician labeling. Phase 3 studies An IND may be submitted for one or usually include from several hundred more phases of an investigation. The to several thousand subjects. clinical investigation of a previously untested drug is generally divided into § 312.22 General principles of the IND three phases. Although in general the submission. phases are conducted sequentially, (a) FDA’s primary objectives in re- they may overlap. These three phases viewing an IND are, in all phases of the of an investigation are a follows: investigation, to assure the safety and (a) Phase 1. (1) Phase 1 includes the rights of subjects, and, in Phase 2 and initial introduction of an investiga- 3, to help assure that the quality of the tional new drug into humans. Phase 1 scientific evaluation of drugs is ade- studies are typically closely monitored quate to permit an evaluation of the and may be conducted in patients or drug’s effectiveness and safety. There- normal volunteer subjects. These stud- fore, although FDA’s review of Phase 1 ies are designed to determine the me- submissions will focus on assessing the tabolism and pharmacologic actions of safety of Phase 1 investigations, FDA’s the drug in humans, the side effects as- review of Phases 2 and 3 submissions sociated with increasing doses, and, if will also include an assessment of the possible, to gain early evidence on ef- scientific quality of the clinical inves- fectiveness. During Phase 1, sufficient tigations and the likelihood that the information about the drug’s phar- investigations will yield data capable macokinetics and pharmacological ef- of meeting statutory standards for fects should be obtained to permit the marketing approval.

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(b) The amount of information on a § 312.23 IND content and format. particular drug that must be submitted (a) A sponsor who intends to conduct in an IND to assure the accomplish- a clinical investigation subject to this ment of the objectives described in part shall submit an ‘‘Investigational paragraph (a) of this section depends New Drug Application’’ (IND) includ- upon such factors as the novelty of the ing, in the following order: drug, the extent to which it has been (1) Cover sheet (Form FDA–1571). A studied previously, the known or sus- cover sheet for the application con- pected risks, and the developmental taining the following: phase of the drug. (i) The name, address, and telephone (c) The central focus of the initial number of the sponsor, the date of the IND submission should be on the gen- application, and the name of the inves- eral investigational plan and the proto- tigational new drug. cols for specific human studies. Subse- (ii) Identification of the phase or quent amendments to the IND that phases of the clinical investigation to contain new or revised protocols should be conducted. build logically on previous submissions (iii) A commitment not to begin clin- and should be supported by additional ical investigations until an IND covering 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 the available information. Section and progress of the clinical investiga- 312.23 outlines the information needed tions. for a commercially sponsored IND for a (vii) The name(s) and title(s) of the new molecular entity. A sponsor-inves- person(s) responsible under § 312.32 for tigator who uses, as a research tool, an review and evaluation of information investigational new drug that is al- relevant to the safety of the drug. (viii) If a sponsor has transferred any ready subject to a manufacturer’s IND obligations for the conduct of any clin- or marketing application should follow ical study to a contract research orga- the same general format, but ordi- nization, a statement containing the narily may, if authorized by the manu- name and address of the contract re- facturer, refer to the manufacturer’s search organization, identification of IND or marketing application in pro- the clinical study, and a listing of the viding the technical information sup- obligations transferred. If all obliga- porting the proposed clinical investigations governing the conduct of the tion. A sponsor-investigator who uses study have been transferred, a general an investigational drug not subject to statement of this transfer—in lieu of a a manufacturer’s IND or marketing ap- listing of the specific obligations trans- plication is ordinarily required to sub- ferred—may be submitted. mit all technical information sup- (ix) The signature of the sponsor or porting the IND, unless such informa- the sponsor’s authorized representation may be referenced from the sci- tive. If the person signing the applica- entific literature. tion does not reside or have a place of

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business within the United States, the (i) A brief description of the drug IND is required to contain the name substance and the formulation, includ- and address of, and be countersigned ing the structural formula, if known. by, an attorney, agent, or other au- (ii) A summary of the pharma- thorized official who resides or main- cological and toxicological effects of tains a place of business within the the drug in animals and, to the extent United States. known, in humans. (2) A table of contents. (iii) A summary of the pharmaco- (3) Introductory statement and general kinetics and biological disposition of investigational plan. (i) A brief introduc- the drug in animals and, if known, in tory statement giving the name of the humans. drug and all active ingredients, the (iv) A summary of information relat- drug’s pharmacological class, the ing to safety and effectiveness in hu- structural formula of the drug (if mans obtained from prior clinical stud- known), the formulation of the dosage ies. (Reprints of published articles on form(s) to be used, the route of admin- such studies may be appended when istration, and the broad objectives and useful.) planned duration of the proposed clin- (v) A description of possible risks and ical investigation(s). side effects to be anticipated on the (ii) A brief summary of previous basis of prior experience with the drug human experience with the drug, with under investigation or with related reference to other IND’s if pertinent, drugs, and of precautions or special and to investigational or marketing ex- monitoring to be done as part of the in- perience in other countries that may vestigational use of the drug. be relevant to the safety of the pro- (6) Protocols. (i) A protocol for each posed clinical investigation(s). planned study. (Protocols for studies (iii) If the drug has been withdrawn not submitted initially in the IND from investigation or marketing in any should be submitted in accordance with § 312.30(a).) In general, protocols for country for any reason related to safe- Phase 1 studies may be less detailed ty or effectiveness, identification of and more flexible than protocols for the country(ies) where the drug was Phase 2 and 3 studies. Phase 1 protocols withdrawn and the reasons for the should be directed primarily at pro- withdrawal. viding an outline of the investigation— (iv) A brief description of the overall an estimate of the number of patients plan for investigating the drug product to be involved, a description of safety for the following year. The plan should exclusions, and a description of the include the following: (a) The rationale dosing plan including duration, dose, or for the drug or the research study; (b) method to be used in determining the indication(s) to be studied; (c) the dose—and should specify in detail only general approach to be followed in those elements of the study that are evaluating the drug; (d) the kinds of critical to safety, such as necessary clinical trials to be conducted in the monitoring of vital signs and blood first year following the submission (if chemistries. Modifications of the ex- plans are not developed for the entire perimental design of Phase 1 studies year, the sponsor should so indicate); that do not affect critical safety as- (e) the estimated number of patients to sessments are required to be reported be given the drug in those studies; and to FDA only in the annual report. (f) any risks of particular severity or (ii) In Phases 2 and 3, detailed proto- seriousness anticipated on the basis of cols describing all aspects of the study the toxicological data in animals or should be submitted. A protocol for a prior studies in humans with the drug Phase 2 or 3 investigation should be de- or related drugs. signed in such a way that, if the spon- (4) [Reserved] sor anticipates that some deviation (5) Investigator’s brochure. If required from the study design may become nec- under § 312.55, a copy of the investiga- essary as the investigation progresses, tor’s brochure, containing the fol- alternatives or contingencies to pro- lowing information: vide for such deviation are built into

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the protocols at the outset. For exam- with the phase of the investigation, the ple, a protocol for a controlled short- proposed duration of the investigation, term study might include a plan for an the dosage form, and the amount of in- early crossover of nonresponders to an formation otherwise available. FDA alternative therapy. recognizes that modifications to the (iii) A protocol is required to contain method of preparation of the new drug the following, with the specific ele- substance and dosage form and changes ments and detail of the protocol rein the dosage form itself are likely as flecting the above distinctions depend- the investigation progresses. There- ing on the phase of study: fore, the emphasis in an initial Phase 1 (a) A statement of the objectives and submission should generally be placed purpose of the study. on the identification and control of the (b) The name and address and a state- raw materials and the new drug sub- ment of the qualifications (curriculum stance. Final specifications for the vitae or other statement of qualifica- drug substance and drug product are tions) of each investigator, and the not expected until the end of the inves- name of each subinvestigator (e.g., re- tigational process. search fellow, resident) working under (ii) It should be emphasized that the the supervision of the investigator; the amount of information to be submitted name and address of the research fa- depends upon the scope of the proposed cilities to be used; and the name and clinical investigation. For example, al- address of each reviewing Institutional though stability data are required in Review Board. all phases of the IND to demonstrate (c) The criteria for patient selection that the new drug substance and drug and for exclusion of patients and an es- product are within acceptable chemical timate of the number of patients to be and physical limits for the planned du- studied. ration of the proposed clinical inves- (d) A description of the design of the tigation, if very short-term tests are study, including the kind of control proposed, the supporting stability data group to be used, if any, and a descrip- can be correspondingly limited. tion of methods to be used to minimize (iii) As drug development proceeds bias on the part of subjects, investiga- and as the scale or production is tors, and analysts. changed from the pilot-scale produc- (e) The method for determining the tion appropriate for the limited initial dose(s) to be administered, the planned clinical investigations to the larger- maximum dosage, and the duration of scale production needed for expanded individual patient exposure to the clinical trials, the sponsor should sub- drug. mit information amendments to sup- (f) A description of the observations plement the initial information sub- and measurements to be made to fulfill mitted on the chemistry, manufac- the objectives of the study. turing, and control processes with in- (g) A description of clinical proce- formation appropriate to the expanded dures, laboratory tests, or other meas- scope of the investigation. ures to be taken to monitor the effects (iv) Reflecting the distinctions de- of the drug in human subjects and to scribed in this paragraph (a)(7), and minimize risk. based on the phase(s) to be studied, the (7) Chemistry, manufacturing, and con- submission is required to contain the trol information. (i) As appropriate for following: the particular investigations covered (a) Drug substance. A description of by the IND, a section describing the the drug substance, including its phys- composition, manufacture, and control ical, chemical, or biological character- of the drug substance and the drug istics; the name and address of its man- product. Although in each phase of the ufacturer; the general method of prepa- investigation sufficient information is ration of the drug substance; the ac- required to be submitted to assure the ceptable limits and analytical methods proper identification, quality, purity, used to assure the identity, strength, and strength of the investigational quality, and purity of the drug sub- drug, the amount of information need- stance; and information sufficient to ed to make that assurance will vary support stability of the drug substance

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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 composition of the investigational drug prod- A section describing the pharma- uct, including any reasonable vari- cological effects and mechanism(s) of ations that may be expected during the action of the drug in animals, and in- investigational stage; the name and ad- formation on the absorption, distribu- dress of the drug product manufac- tion, metabolism, and excretion of the turer; a brief general description of the drug, if known. manufacturing and packaging proce- (ii) Toxicology. (a) An integrated sum- dure as appropriate for the product; the mary of the toxicological effects of the acceptable limits and analytical meth- drug in animals and in vitro. Depend- ods used to assure the identity, ing on the nature of the drug and the strength, quality, and purity of the phase of the investigation, the descrip- drug product; and information suffi- tion is to include the results of acute, cient to assure the product’s stability subacute, and chronic toxicity tests; during the planned clinical studies. tests of the drug’s effects on reproduc- Reference to the current edition of the tion and the developing fetus; any spe- United States Pharmacopeia—National cial toxicity test related to the drug’s Formulary may satisfy certain require- particular mode of administration or ments in this paragraph. conditions of use (e.g., inhalation, der- (c) A brief general description of the mal, or ocular toxicology); and any in composition, manufacture, and control vitro studies intended to evaluate drug of any placebo used in a controlled toxicity. clinical trial. (b) For each toxicology study that is (d) Labeling. A copy of all labels and intended primarily to support the safe- labeling to be provided to each investi- ty of the proposed clinical investiga- gator. tion, a full tabulation of data suitable (e) Environmental analysis require- for detailed review. ments. A claim for categorical exclusion under § 25.30 or 25.31 or an environ- (iii) For each nonclinical laboratory mental assessment under § 25.40. study subject to the good laboratory (8) Pharmacology and toxicology infor- practice regulations under part 58, a mation. Adequate information about statement that the study was con- pharmacological and toxicological ducted in compliance with the good studies of the drug involving labora- laboratory practice regulations in part tory animals or in vitro, on the basis of 58, or, if the study was not conducted which the sponsor has concluded that in compliance with those regulations, a it is reasonably safe to conduct the brief statement of the reason for the proposed clinical investigations. The noncompliance. kind, duration, and scope of animal and (9) Previous human experience with the other tests required varies with the du- investigational drug. A summary of pre- ration and nature of the proposed clin- vious human experience known to the ical investigations. Guidance docu- applicant, if any, with the investiga- ments are available from FDA that de- tional drug. The information is re- scribe ways in which these require- quired to include the following:

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(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 countries in which the drug has been each original literature publication for marketed and a list of the countries in which an English translation is sub- which the drug has been withdrawn mitted. from marketing for reasons potentially (d) Number of copies. The sponsor related to safety or effectiveness. shall submit an original and two copies (10) Additional information. In certain of all submissions to the IND file, in- applications, as described below, infor- cluding the original submission and all mation on special topics may be need- amendments and reports. ed. Such information shall be sub- (e) Numbering of IND submissions. mitted in this section as follows: Each submission relating to an IND is (i) Drug dependence and abuse poten- required to be numbered serially using tial. If the drug is a psychotropic sub- a single, three-digit serial number. The stance or otherwise has abuse poten- initial IND is required to be numbered tial, a section describing relevant clin- 000; each subsequent submission (e.g., ical studies and experience and studies amendment, report, or correspondence) in test animals. is required to be numbered chrono- (ii) Radioactive drugs. If the drug is a logically in sequence. radioactive drug, sufficient data from (f) Identification of exception from in- animal or human studies to allow a formed consent. If the investigation in- reasonable calculation of radiation-ab- volves an exception from informed con- sorbed dose to the whole body and crit- sent under § 50.24 of this chapter, the

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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 procedure that is intended to improve [52 FR 8831, Mar. 19, 1987, as amended at 52 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 view and approval of the study in ac- shipped to the investigator and the in- cordance with the requirements of part vestigator may begin participating in 56. The sponsor may comply with these the study. The sponsor shall notify two conditions in either order. FDA of the new investigator within 30 (b) Changes in a protocol. (1) A sponsor days of the investigator being added. shall submit a protocol amendment de- (d) Content and format. A protocol scribing any change in a Phase 1 pro- amendment is required to be promi- tocol that significantly affects the nently identified as such (i.e., ‘‘Pro- safety of subjects or any change in a tocol Amendment: New Protocol’’, Phase 2 or 3 protocol that significantly ‘‘Protocol Amendment: Change in Pro- affects the safety of subjects, the scope tocol’’, or ‘‘Protocol Amendment: New of the investigation, or the scientific Investigator’’), and to contain the fol- quality of the study. Examples of lowing: changes requiring an amendment under (1)(i) In the case of a new protocol, a this paragraph include: copy of the new protocol and a brief de- (i) Any increase in drug dosage or du- scription of the most clinically signifi- ration of exposure of individual sub- cant differences between it and pre- jects to the drug beyond that in the vious protocols. current protocol, or any significant in- (ii) In the case of a change in pro- crease in the number of subjects under tocol, a brief description of the change study. and reference (date and number) to the

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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 sible, to include these all in a single places the patient or subject at imme- submission. diate risk of death. It does not include [52 FR 8831, Mar. 19, 1987, as amended at 52 an adverse event or suspected adverse FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, reaction that, had it occurred in a 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. more severe form, might have caused 4, 2002; 74 FR 40942, Aug. 13, 2009] death. Serious adverse event or serious sus- § 312.31 Information amendments. pected adverse reaction. An adverse (a) Requirement for information amend- event or suspected adverse reaction is ment. A sponsor shall report in an in- considered ‘‘serious’’ if, in the view of formation amendment essential infor- either the investigator or sponsor, it mation on the IND that is not within results in any of the following out- the scope of a protocol amendment, comes: Death, a life-threatening ad- IND safety reports, or annual report. verse event, inpatient hospitalization Examples of information requiring an or prolongation of existing hospitaliza- information amendment include: tion, a persistent or significant inca- (1) New toxicology, chemistry, or pacity or substantial disruption of the other technical information; or ability to conduct normal life func- (2) A report regarding the discontinu- tions, or a congenital anomaly/birth ance of a clinical investigation. defect. Important medical events that (b) Content and format of an informa- may not result in death, be life-threat- tion amendment. An information amend- ening, or require hospitalization may

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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 in the current application, as amended. that is both serious and unexpected. For example, under this definition, he- The sponsor must report an adverse patic necrosis would be unexpected (by event as a suspected adverse reaction virtue of greater severity) if the inves- only if there is evidence to suggest a tigator brochure referred only to ele- causal relationship between the drug vated hepatic enzymes or hepatitis. and the adverse event, such as: Similarly, cerebral thromboembolism (A) A single occurrence of an event and cerebral vasculitis would be unex- that is uncommon and known to be pected (by virtue of greater specificity) strongly associated with drug exposure if the investigator brochure listed only (e.g., angioedema, hepatic injury, Ste- cerebral vascular accidents. ‘‘Unex- vens-Johnson Syndrome); pected,’’ as used in this definition, also (B) One or more occurrences of an refers to adverse events or suspected event that is not commonly associated adverse reactions that are mentioned with drug exposure, but is otherwise in the investigator brochure as occur- uncommon in the population exposed ring with a class of drugs or as antici- to the drug (e.g., tendon rupture); pated from the pharmacological prop- (C) An aggregate analysis of specific erties of the drug, but are not specifi- events observed in a clinical trial (such cally mentioned as occurring with the as known consequences of the under- particular drug under investigation. lying disease or condition under inves- (b) Review of safety information. The tigation or other events that com- sponsor must promptly review all in- monly occur in the study population

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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 pects of the overall conduct of the clin- director of the FDA review division ical investigation. that has responsibility for review of (iv) Increased rate of occurrence of seri- the IND. ous suspected adverse reactions. The (4) Investigations of marketed drugs. A sponsor must report any clinically im- sponsor of a clinical study of a drug portant increase in the rate of a seri- marketed or approved in the United ous suspected adverse reaction over States that is conducted under an IND that listed in the protocol or investi- is required to submit IND safety re- gator brochure. ports for suspected adverse reactions (v) Submission of IND safety reports. that are observed in the clinical study, The sponsor must submit each IND at domestic or foreign study sites. The safety report in a narrative format or sponsor must also submit safety infor- on FDA Form 3500A or in an electronic mation from the clinical study as pre- format that FDA can process, review, scribed by the postmarketing safety re- and archive. FDA will periodically porting requirements (e.g., §§ 310.305, issue guidance on how to provide the 314.80, and 600.80 of this chapter). electronic submission (e.g., method of (5) Reporting study endpoints. Study transmission, media, file formats, prep- endpoints (e.g., mortality or major aration and organization of files). The morbidity) must be reported to FDA by sponsor may submit foreign suspected the sponsor as described in the protocol adverse reactions on a Council for and ordinarily would not be reported International Organizations of Medical under paragraph (c) of this section.

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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 tributed to an adverse event. A sponsor an understanding of the drug’s actions, need not admit, and may deny, that including, for example, information the report or information submitted by about dose response, information from the sponsor constitutes an admission controlled trials, and information that the drug caused or contributed to about bioavailability. an adverse event. (6) A list of the preclinical studies [75 FR 59961, Sept. 29, 2010] (including animal studies) completed or in progress during the past year and § 312.33 Annual reports. a summary of the major preclinical A sponsor shall within 60 days of the findings. anniversary date that the IND went (7) A summary of any significant into effect, submit a brief report of the manufacturing or microbiological progress of the investigation that in- changes made during the past year. cludes: (c) A description of the general inves- (a) Individual study information. A tigational plan for the coming year to brief summary of the status of each replace that submitted 1 year earlier. study in progress and each study com- The general investigational plan shall pleted during the previous year. The contain the information required under summary is required to include the fol- § 312.23(a)(3)(iv). lowing information for each study: (d) If the investigator brochure has (1) The title of the study (with any been revised, a description of the revi- appropriate study identifiers such as sion and a copy of the new brochure.

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(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. Institutional Review Boards, together (b) On the sponsor’s request, FDA with the reasons for such withdrawal. will provide advice on specific matters [52 FR 8831, Mar. 19, 1987, as amended at 52 relating to an IND. Examples of such FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, advice may include advice on the ade- 2002] quacy of technical data to support an investigational plan, on the design of a Subpart C—Administrative Actions clinical trial, and on whether proposed investigations are likely to produce the § 312.40 General requirements for use data and information that is needed to of an investigational new drug in a meet requirements for a marketing ap- clinical investigation. plication. (a) An investigational new drug may (c) Unless the communication is ac- be used in a clinical investigation if companied by a clinical hold order the following conditions are met: under § 312.42, FDA communications (1) The sponsor of the investigation with a sponsor under this section are submits an IND for the drug to FDA; solely advisory and do not require any the IND is in effect under paragraph (b) modification in the planned or ongoing of this section; and the sponsor com- clinical investigations or response to plies with all applicable requirements the agency. in this part and parts 50 and 56 with re- [52 FR 8831, Mar. 19, 1987, as amended at 52 spect to the conduct of the clinical in- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, vestigations; and 2002]

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§ 312.42 Clinical holds and requests for ical hold would not apply under this modification. paragraph to clinical studies con- (a) General. A clinical hold is an order ducted: issued by FDA to the sponsor to delay (A) Under special circumstances, a proposed clinical investigation or to such as studies pertinent only to one suspend an ongoing investigation. The gender (e.g., studies evaluating the ex- clinical hold order may apply to one or cretion of a drug in semen or the ef- more of the investigations covered by fects on menstrual function); an IND. When a proposed study is (B) Only in men or women, as long as placed on clinical hold, subjects may a study that does not exclude members not be given the investigational drug. of the other gender with reproductive When an ongoing study is placed on potential is being conducted concur- clinical hold, no new subjects may be rently, has been conducted, or will recruited to the study and placed on take place within a reasonable time the investigational drug; patients al- agreed upon by the agency; or ready in the study should be taken off (C) Only in subjects who do not suffer therapy involving the investigational from the disease or condition for which drug unless specifically permitted by the drug is being studied. FDA in the interest of patient safety. (2) Clinical hold of a Phase 2 or 3 study (b) Grounds for imposition of clinical 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: (iv) The IND does not contain suffi- (i) Final use. FDA may place a pro- cient information required under posed expanded access IND or treat- § 312.23 to assess the risks to subjects of ment use protocol on clinical hold if it the proposed studies. is determined that: (v) The IND is for the study of an in- (A) The pertinent criteria in subpart vestigational drug intended to treat a I of this part for permitting the ex- life-threatening disease or condition panded access use to begin are not sat- that affects both genders, and men or isfied; or women with reproductive potential who have the disease or condition (B) The expanded access IND or ex- being studied are excluded from eligi- panded access protocol does not comply bility because of a risk or potential with the requirements for expanded ac- risk from use of the investigational cess submissions in subpart I of this drug of reproductive toxicity (i.e., af- part. fecting reproductive organs) or devel- (ii) Ongoing use. FDA may place an opmental toxicity (i.e., affecting poten- ongoing expanded access IND or ex- tial offspring). The phrase ‘‘women panded access protocol on clinical hold with reproductive potential’’ does not if it is determined that the pertinent include pregnant women. For purposes criteria in subpart I of this part for of this paragraph, ‘‘life-threatening ill- permitting the expanded access are no nesses or diseases’’ are defined as ‘‘dis- longer satisfied. eases or conditions where the likeli- (4) Clinical hold of any study that is hood of death is high unless the course not designed to be adequate and well-con- of the disease is interrupted.’’ The clin- trolled. FDA may place a proposed or

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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 controlled investigation is not actively under the IND to which the hold ap- pursuing marketing approval of the in- plies, and will briefly explain the basis vestigational drug with due diligence; for the action. The clinical hold order or will be made by or on behalf of the Di- (viii) The Commissioner determines vision Director with responsibility for that it would not be in the public inter- review of the IND. As soon as possible, est for the study to be conducted or and no more than 30 days after imposi- continued. FDA ordinarily intends that tion of the clinical hold, the Division clinical holds under paragraphs Director will provide the sponsor a (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this written explanation of the basis for the section would only apply to additional hold. enrollment in nonconcurrently con- (e) Resumption of clinical investiga- trolled trials rather than eliminating tions. An investigation may only re- continued access to individuals already sume after FDA (usually the Division receiving the investigational drug. Director, or the Director’s designee, (5) Clinical hold of any investigation in- with responsibility for review of the volving an exception from informed con- IND) has notified the sponsor that the sent under § 50.24 of this chapter. FDA investigation may proceed. Resump- may place a proposed or ongoing inves- tion of the affected investigation(s) tigation involving an exception from will be authorized when the sponsor informed consent under § 50.24 of this corrects the deficiency(ies) previously chapter on clinical hold if it is deter- cited or otherwise satisfies the agency mined that: that the investigation(s) can proceed.

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FDA may notify a sponsor of its deter- (b) Grounds for termination—(1) Phase mination regarding the clinical hold by 1. FDA may propose to terminate an telephone or other means of rapid com- IND during Phase 1 if it finds that: munication. If a sponsor of an IND that (i) Human subjects would be exposed has been placed on clinical hold re- to an unreasonable and significant risk quests in writing that the clinical hold of illness or unjury. be removed and submits a complete re- (ii) The IND does not contain suffi- sponse to the issue(s) identified in the cient information required under clinical hold order, FDA shall respond § 312.23 to assess the safety to subjects in writing to the sponsor within 30-cal- of the clinical investigations. endar days of receipt of the request and (iii) The methods, facilities, and con- the complete response. FDA’s response trols used for the manufacturing, proc- will either remove or maintain the essing, and packing of the investiga- clinical hold, and will state the reasons tional drug are inadequate to establish for such determination. Notwith- and maintain appropriate standards of standing the 30-calendar day response identity, strength, quality, and purity time, a sponsor may not proceed with a as needed for subject safety. clinical trial on which a clinical hold (iv) The clinical investigations are has been imposed until the sponsor has being conducted in a manner substan- been notified by FDA that the hold has tially different than that described in been lifted. the protocols submitted in the IND. (f) Appeal. If the sponsor disagrees (v) The drug is being promoted or dis- with the reasons cited for the clinical tributed for commercial purposes not hold, the sponsor may request recon- justified by the requirements of the in- sideration of the decision in accord- vestigation or permitted by § 312.7. ance with § 312.48. (vi) The IND, or any amendment or (g) Conversion of IND on clinical hold report to the IND, contains an untrue to inactive status. If all investigations statement of a material fact or omits covered by an IND remain on clinical material information required by this hold for 1 year or more, the IND may part. be placed on inactive status by FDA (vii) The sponsor fails promptly to in- under § 312.45. vestigate and inform the Food and [52 FR 8831, Mar. 19, 1987, as amended at 52 Drug Administration and all investiga- FR 19477, May 22, 1987; 57 FR 13249, Apr. 15, tors of serious and unexpected adverse 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, experiences in accordance with § 312.32 Dec. 14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR or fails to make any other report re- 34971, June 1, 2000; 74 FR 40942, Aug. 13, 2009] quired under this part. (viii) The sponsor fails to submit an § 312.44 Termination. accurate annual report of the inves- (a) General. This section describes the tigations in accordance with § 312.33. procedures under which FDA may ter- (ix) The sponsor fails to comply with minate an IND. If an IND is termi- any other applicable requirement of nated, the sponsor shall end all clinical this part, part 50, or part 56. investigations conducted under the (x) The IND has remained on inactive IND and recall or otherwise provide for status for 5 years or more. the disposition of all unused supplies of (xi) The sponsor fails to delay a pro- the drug. A termination action may be posed investigation under the IND or based on deficiencies in the IND or in to suspend an ongoing investigation the conduct of an investigation under that has been placed on clinical hold an IND. Except as provided in para- under § 312.42(b)(4). graph (d) of this section, a termination (2) Phase 2 or 3. FDA may propose to shall be preceded by a proposal to ter- terminate an IND during Phase 2 or minate by FDA and an opportunity for Phase 3 if FDA finds that: the sponsor to respond. FDA will, in (i) Any of the conditions in para- general, only initiate an action under graphs (b)(1)(i) through (b)(1)(xi) of this this section after first attempting to section apply; or resolve differences informally or, when (ii) The investigational plan or pro- appropriate, through the clinical hold tocol(s) is not reasonable as a bona fide procedures described in § 312.42. scientific plan to determine whether or

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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. ical hold for 1 year or more, the IND may be placed by FDA on inactive sta- (c) Opportunity for sponsor response. tus. This action may be taken by FDA (1) If FDA proposes to terminate an either on request of the sponsor or on IND, FDA will notify the sponsor in FDA’s own initiative. If FDA seeks to writing, and invite correction or expla- act on its own initiative under this sec- nation within a period of 30 days. tion, it shall first notify the sponsor in (2) On such notification, the sponsor writing of the proposed inactive status. may provide a written explanation or Upon receipt of such notification, the correction or may request a conference sponsor shall have 30 days to respond with FDA to provide the requested ex- as to why the IND should continue to planation or correction. If the sponsor remain active. does not respond to the notification (b) If an IND is placed on inactive within the allocated time, the IND status, all investigators shall be so no- shall be terminated. tified and all stocks of the drug shall (3) If the sponsor responds but FDA be returned or otherwise disposed of in does not accept the explanation or cor- accordance with § 312.59. rection submitted, FDA shall inform (c) A sponsor is not required to sub- the sponsor in writing of the reason for mit annual reports to an IND on inac- the nonacceptance and provide the tive status. An inactive IND is, how- sponsor with an opportunity for a regu- ever, still in effect for purposes of the latory hearing before FDA under part public disclosure of data and informa- 16 on the question of whether the IND tion under § 312.130. should be terminated. The sponsor’s re- (d) A sponsor who intends to resume quest for a regulatory hearing must be clinical investigation under an IND made within 10 days of the sponsor’s placed on inactive status shall submit receipt of FDA’s notification of non- a protocol amendment under § 312.30 acceptance. containing the proposed general inves- (d) Immediate termination of IND. Not- tigational plan for the coming year and withstanding paragraphs (a) through appropriate protocols. If the protocol (c) of this section, if at any time FDA amendment relies on information pre- concludes that continuation of the in- viously submitted, the plan shall ref- vestigation presents an immediate and erence such information. Additional in- substantial danger to the health of information supporting the proposed individuals, the agency shall imme- vestigation, if any, shall be submitted diately, by written notice to the spon- in an information amendment. Not- sor from the Director of the Center for withstanding the provisions of § 312.30, Drug Evaluation and Research or the clinical investigations under an IND on Director of the Center for Biologics inactive status may only resume (1) 30 Evaluation and Research, terminate days after FDA receives the protocol the IND. An IND so terminated is sub- amendment, unless FDA notifies the ject to reinstatement by the Director sponsor that the investigations de- on the basis of additional submissions scribed in the amendment are subject that eliminate such danger. If an IND to a clinical hold under § 312.42, or (2) is terminated under this paragraph, the on earlier notification by FDA that the agency will afford the sponsor an op- clinical investigations described in the portunity for a regulatory hearing protocol amendment may begin.

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(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 sponsor, end-of-Phase 2 meetings (a) General. Meetings between a spon- should be held before major commit- sor and the agency are frequently use- ments of effort and resources to spe- ful in resolving questions and issues cific Phase 3 tests are made. The sched- raised during the course of a clinical uling of an end-of-Phase 2 meeting is investigation. FDA encourages such not, however, intended to delay the meetings to the extent that they aid in transition of an investigation from the evaluation of the drug and in the Phase 2 to Phase 3. solution of scientific problems con- (iv) Advance information. At least 1 cerning the drug, to the extent that month in advance of an end-of-Phase 2 FDA’s resources permit. The general meeting, the sponsor should submit principle underlying the conduct of background information on the spon- such meetings is that there should be sor’s plan for Phase 3, including sum- free, full, and open communication maries of the Phase 1 and 2 investiga- about any scientific or medical questions, the specific protocols for Phase 3 tion that may arise during the clinical clinical studies, plans for any addi- investigation. These meetings shall be tional nonclinical studies, plans for pe- conducted and documented in accord- diatric studies, including a time line ance with part 10. for protocol finalization, enrollment, (b) ‘‘End-of-Phase 2’’ meetings and completion, and data analysis, or infor- meetings held before submission of a mar- mation to support any planned request keting application. At specific times for waiver or deferral of pediatric stud- during the drug investigation process, ies, and, if available, tentative labeling meetings between FDA and a sponsor for the drug. The recommended con- can be especially helpful in minimizing tents of such a submission are de- wasteful expenditures of time and scribed more fully in FDA Staff Man- money and thus in speeding the drug ual Guide 4850.7 that is publicly avail- development and evaluation process. In able under FDA’s public information particular, FDA has found that meet- regulations in part 20. ings at the end of Phase 2 of an inves- (v) Conduct of meeting. Arrangements tigation (end-of-Phase 2 meetings) are for an end-of-Phase 2 meeting are to be of considerable assistance in planning made with the division in FDA’s Center later studies and that meetings held for Drug Evaluation and Research or near completion of Phase 3 and before the Center for Biologics Evaluation submission of a marketing application and Research which is responsible for (‘‘pre-NDA’’ meetings) are helpful in review of the IND. The meeting will be developing methods of presentation scheduled by FDA at a time convenient and submission of data in the mar- to both FDA and the sponsor. Both the keting application that facilitate re- sponsor and FDA may bring consult- view and allow timely FDA response. ants to the meeting. The meeting (1) End-of-Phase 2 meetings—(i) Pur- should be directed primarily at estab- pose. The purpose of an end-of-phase 2 lishing agreement between FDA and meeting is to determine the safety of the sponsor of the overall plan for proceeding to Phase 3, to evaluate the Phase 3 and the objectives and design Phase 3 plan and protocols and the ade- of particular studies. The adequacy of quacy of current studies and plans to the technical information to support assess pediatric safety and effective- Phase 3 studies and/or a marketing ap- ness, and to identify any additional in- plication may also be discussed. FDA formation necessary to support a mar- will also provide its best judgment, at keting application for the uses under that time, of the pediatric studies that investigation. will be required for the drug product

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and whether their submission will be (iv) Any other information for discus- deferred until after approval. Agree- sion at the meeting. ments reached at the meeting on these [52 FR 8831, Mar. 19, 1987, as amended at 52 matters will be recorded in minutes of FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, the conference that will be taken by 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. FDA in accordance with § 10.65 and pro- 4, 2002] vided to the sponsor. The minutes along with any other written material § 312.48 Dispute resolution. provided to the sponsor will serve as a (a) General. The Food and Drug Ad- permanent record of any agreements ministration is committed to resolving reached. Barring a significant sci- differences between sponsors and FDA entific development that requires oth- reviewing divisions with respect to re- erwise, studies conducted in accord- quirements for IND’s as quickly and ance with the agreement shall be pre- amicably as possible through the coop- sumed to be sufficient in objective and erative exchange of information and design for the purpose of obtaining views. marketing approval for the drug. (b) Administrative and procedural (2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet- issues. When administrative or proce- ings. FDA has found that delays associ- dural disputes arise, the sponsor should ated with the initial review of a mar- first attempt to resolve the matter keting application may be reduced by with the division in FDA’s Center for exchanges of information about a pro- Drug Evaluation and Research or Cen- posed marketing application. The pri- ter for Biologics Evaluation and Re- mary purpose of this kind of exchange search which is responsible for review is to uncover any major unresolved of the IND, beginning with the con- problems, to identify those studies that sumer safety officer assigned to the ap- the sponsor is relying on as adequate plication. If the dispute is not resolved, and well-controlled to establish the the sponsor may raise the matter with drug’s effectiveness, to identify the the person designated as ombudsman, status of ongoing or needed studies whose function shall be to investigate adequate to assess pediatric safety and what has happened and to facilitate a effectiveness, to acquaint FDA review- timely and equitable resolution. Appro- ers with the general information to be priate issues to raise with the ombuds- submitted in the marketing applica- man include resolving difficulties in tion (including technical information), scheduling meetings and obtaining to discuss appropriate methods for sta- timely replies to inquiries. Further de- tistical analysis of the data, and to dis- tails on this procedure are contained in cuss the best approach to the presen- FDA Staff Manual Guide 4820.7 that is tation and formatting of data in the publicly available under FDA’s public marketing application. Arrangements information regulations in part 20. for such a meeting are to be initiated (c) Scientific and medical disputes. (1) by the sponsor with the division re- When scientific or medical disputes arise during the drug investigation sponsible for review of the IND. To per- process, sponsors should discuss the mit FDA to provide the sponsor with matter directly with the responsible the most useful advice on preparing a reviewing officials. If necessary, spon- marketing application, the sponsor sors may request a meeting with the should submit to FDA’s reviewing divi- appropriate reviewing officials and sion at least 1 month in advance of the management representatives in order meeting the following information: to seek a resolution. Requests for such (i) A brief summary of the clinical meetings shall be directed to the direc- studies to be submitted in the applicator of the division in FDA’s Center for tion. Drug Evaluation and Research or Cen- (ii) A proposed format for organizing ter for Biologics Evaluation and Re- the submission, including methods for search which is responsible for review presenting the data. of the IND. FDA will make every at- (iii) Information on the status of tempt to grant requests for meetings needed or ongoing pediatric studies. that involve important issues and that

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can be scheduled at mutually conven- gations being assumed by the contract ient times. research organization. If all obligations (2) The ‘‘end-of-Phase 2’’ and ‘‘pre- are transferred, a general statement NDA’’ meetings described in § 312.47(b) that all obligations have been trans- will also provide a timely forum for ferred is acceptable. Any obligation not discussing and resolving scientific and covered by the written description medical issues on which the sponsor shall be deemed not to have been trans- disagrees with the agency. ferred. (3) In requesting a meeting designed (b) A contract research organization to resolve a scientific or medical dis- that assumes any obligation of a spon- pute, applicants may suggest that FDA sor shall comply with the specific regu- seek the advice of outside experts, in lations in this chapter applicable to which case FDA may, in its discretion, this obligation and shall be subject to invite to the meeting one or more of its the same regulatory action as a spon- advisory committee members or other sor for failure to comply with any obli- consultants, as designated by the agen- gation assumed under these regula- cy. Applicants may rely on, and may tions. Thus, all references to ‘‘sponsor’’ bring to any meeting, their own con- in this part apply to a contract re- sultants. For major scientific and med- search organization to the extent that ical policy issues not resolved by infor- it assumes one or more obligations of mal meetings, FDA may refer the mat- the sponsor. ter to one of its standing advisory committees for its consideration and rec- § 312.53 Selecting investigators and ommendations. monitors. [52 FR 8831, Mar. 19, 1987, as amended at 55 (a) Selecting investigators. A sponsor FR 11580, Mar. 29, 1990] shall select only investigators qualified by training and experience as appro- Subpart D—Responsibilities of priate experts to investigate the drug. Sponsors and Investigators (b) Control of drug. A sponsor shall ship investigational new drugs only to § 312.50 General responsibilities of investigators participating in the in- sponsors. vestigation. Sponsors are responsibile for select- (c) Obtaining information from the in- ing qualified investigators, providing vestigator. Before permitting an investi- them with the information they need gator to begin participation in an in- to conduct an investigation properly, vestigation, the sponsor shall obtain ensuring proper monitoring of the in- the following: vestigation(s), ensuring that the inves- (1) A signed investigator statement tigation(s) is conducted in accordance (Form FDA–1572) containing: with the general investigational plan (i) The name and address of the in- and protocols contained in the IND, vestigator; maintaining an effective IND with re- (ii) The name and code number, if spect to the investigations, and ensur- any, of the protocol(s) in the IND iden- ing that FDA and all participating in- tifying the study(ies) to be conducted vestigators are promptly informed of by the investigator; significant new adverse effects or risks (iii) The name and address of any with respect to the drug. Additional medical school, hospital, or other re- specific responsibilities of sponsors are search facility where the clinical inves- described elsewhere in this part. tigation(s) will be conducted; (iv) The name and address of any § 312.52 Transfer of obligations to a clinical laboratory facilities to be used contract research organization. in the study; (a) A sponsor may transfer responsi- (v) The name and address of the IRB bility for any or all of the obligations that is responsible for review and ap- set forth in this part to a contract re- proval of the study(ies); search organization. Any such transfer (vi) A commitment by the investi- shall be described in writing. If not all gator that he or she: obligations are transferred, the writing (a) Will conduct the study(ies) in ac- is required to describe each of the obli- cordance with the relevant, current

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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 chure, including the potential risks disclosure statements required under and side effects of the drug; and part 54 of this chapter. The sponsor (g) Will ensure that all associates, shall obtain a commitment from the colleagues, and employees assisting in clinical investigator to promptly up- the conduct of the study(ies) are in- date this information if any relevant formed about their obligations in changes occur during the course of the meeting the above commitments. investigation and for 1 year following (vii) A commitment by the investi- the completion of the study. gator that, for an investigation subject to an institutional review requirement (d) Selecting monitors. A sponsor shall under part 56, an IRB that complies select a monitor qualified by training with the requirements of that part will and experience to monitor the progress be responsible for the initial and con- of the investigation. tinuing review and approval of the clin- [52 FR 8831, Mar. 19, 1987, as amended at 52 ical investigation and that the investi- FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, gator will promptly report to the IRB 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. all changes in the research activity and 4, 2002] all unanticipated problems involving risks to human subjects or others, and § 312.54 Emergency research under will not make any changes in the re- § 50.24 of this chapter. search without IRB approval, except (a) The sponsor shall monitor the where necessary to eliminate apparent progress of all investigations involving immediate hazards to the human sub- an exception from informed consent jects. under § 50.24 of this chapter. When the (viii) A list of the names of the sub- sponsor receives from the IRB informa- investigators (e.g., research fellows, tion concerning the public disclosures residents) who will be assisting the in- required by § 50.24(a)(7)(ii) and (a)(7)(iii) vestigator in the conduct of the inves- of this chapter, the sponsor promptly tigation(s). shall submit to the IND file and to (2) Curriculum vitae. A curriculum Docket Number 95S–0158 in the Divi- vitae or other statement of qualifica- sion of Dockets Management (HFA– tions of the investigator showing the 305), Food and Drug Administration, education, training, and experience 5630 Fishers Lane, rm. 1061, Rockville, that qualifies the investigator as an ex- MD 20852, copies of the information

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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 (b) The sponsor shall, as the overall discontinuance, assure the disposition investigation proceeds, keep each par- of all stocks of the drug outstanding as ticipating investigator informed of new required by § 312.59, and furnish FDA observations discovered by or reported with a full report of the sponsor’s ac- to the sponsor on the drug, particu- tions. The sponsor shall discontinue larly with respect to adverse effects the investigation as soon as possible, and safe use. Such information may be and in no event later than 5 working distributed to investigators by means days after making the determination of periodically revised investigator that the investigation should be dis- brochures, reprints or published stud- continued. Upon request, FDA will con- ies, reports or letters to clinical inves- fer with a sponsor on the need to dis- tigators, or other appropriate means. continue an investigation. Important safety information is re- [52 FR 8831, Mar. 19, 1987, as amended at 52 quired to be relayed to investigators in FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, accordance with § 312.32. 2002] [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, § 312.57 Recordkeeping and record re- 2002] tention. (a) A sponsor shall maintain ade- § 312.56 Review of ongoing investiga- quate records showing the receipt, tions. shipment, or other disposition of the (a) The sponsor shall monitor the investigational drug. These records are progress of all clinical investigations required to include, as appropriate, the being conducted under its IND. name of the investigator to whom the (b) A sponsor who discovers that an drug is shipped, and the date, quantity, investigator is not complying with the and batch or code mark of each such signed agreement (Form FDA–1572), the shipment. general investigational plan, or the re- (b) A sponsor shall maintain com- quirements of this part or other appli- plete and accurate records showing any cable parts shall promptly either se- financial interest in § 54.4(a)(3)(i), cure compliance or discontinue ship- (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this ments of the investigational new drug chapter paid to clinical investigators to the investigator and end the inves- by the sponsor of the covered study. A

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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 in any of the bioequivalence or bio- The sponsor shall assure the return availability studies described in, of all unused supplies of the investiga- § 320.38 or § 320.63 of this chapter, and tional drug from each individual inves- release the reserve samples to FDA tigator whose participation in the in- upon request, in accordance with, and vestigation is discontinued or termi- for the period specified in § 320.38. nated. The sponsor may authorize al- [52 FR 8831, Mar. 19, 1987, as amended at 52 ternative disposition of unused supplies FR 23031, June 17, 1987; 58 FR 25926, Apr. 28, of the investigational drug provided 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. this alternative disposition does not 4, 2002] expose humans to risks from the drug. The sponsor shall maintain written § 312.58 Inspection of sponsor’s records of any disposition of the drug records and reports. in accordance with § 312.57. (a) FDA inspection. A sponsor shall upon request from any properly au- [52 FR 8831, Mar. 19, 1987, as amended at 52 thorized officer or employee of the FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, Food and Drug Administration, at rea- 2002] sonable times, permit such officer or § 312.60 General responsibilities of in- employee to have access to and copy vestigators. and verify any records and reports relating to a clinical investigation con- An investigator is responsible for en- ducted under this part. Upon written suring that an investigation is con- request by FDA, the sponsor shall sub- ducted according to the signed investi- mit the records or reports (or copies of gator statement, the investigational them) to FDA. The sponsor shall dis- plan, and applicable regulations; for continue shipments of the drug to any protecting the rights, safety, and wel- investigator who has failed to maintain fare of subjects under the investiga- or make available records or reports of tor’s care; and for the control of drugs the investigation as required by this under investigation. An investigator part. shall, in accordance with the provi- (b) Controlled substances. If an inves- sions of part 50 of this chapter, obtain tigational new drug is a substance list- the informed consent of each human ed in any schedule of the Controlled subject to whom the drug is adminis- Substances Act (21 U.S.C. 801; 21 CFR tered, except as provided in §§ 50.23 or part 1308), records concerning ship- 50.24 of this chapter. Additional spe- ment, delivery, receipt, and disposition cific responsibilities of clinical inves- of the drug, which are required to be kept under this part or other applica- tigators are set forth in this part and ble parts of this chapter shall, upon the in parts 50 and 56 of this chapter. request of a properly authorized em- [52 FR 8831, Mar. 19, 1987, as amended at 61 ployee of the Drug Enforcement Ad- FR 51530, Oct. 2, 1996] ministration of the U.S. Department of Justice, be made available by the in-

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§ 312.61 Control of the investigational § 312.64 Investigator reports. drug. (a) Progress reports. The investigator An investigator shall administer the shall furnish all reports to the sponsor drug only to subjects under the inves- of the drug who is responsible for col- tigator’s personal supervision or under lecting and evaluating the results ob- the supervision of a subinvestigator retained. The sponsor is required under sponsible to the investigator. The in- § 312.33 to submit annual reports to vestigator shall not supply the inves- FDA on the progress of the clinical in- tigational drug to any person not au- vestigations. (b) Safety reports. An investigator thorized under this part to receive it. must immediately report to the spon- § 312.62 Investigator recordkeeping sor any serious adverse event, whether and record retention. or not considered drug related, including 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. The investigator must record non- required to prepare and maintain ade- serious adverse events and report them quate and accurate case histories that to the sponsor according to the time- record all observations and other data table for reporting specified in the pro- pertinent to the investigation on each tocol. individual administered the investiga- (c) Final report. An investigator shall tional drug or employed as a control in provide the sponsor with an adequate the investigation. Case histories in- report shortly after completion of the clude the case report forms and sup- investigator’s participation in the in- porting data including, for example, vestigation. signed and dated consent forms and (d) Financial disclosure reports. The medical records including, for example, clinical investigator shall provide the progress notes of the physician, the in- sponsor with sufficient accurate finan- dividual’s hospital chart(s), and the cial information to allow an applicant nurses’ notes. The case history for each to submit complete and accurate cer- individual shall document that in- tification or disclosure statements as formed consent was obtained prior to required under part 54 of this chapter. participation in the study. The clinical investigator shall prompt- (c) Record retention. An investigator ly update this information if any rel- shall retain records required to be evant changes occur during the course of the investigation and for 1 year fol- maintained under this part for a period lowing the completion of the study. of 2 years following the date a marketing application is approved for the [52 FR 8831, Mar. 19, 1987, as amended at 52 drug for the indication for which it is FR 23031, June 17, 1987; 63 FR 5252, Feb. 2, being investigated; or, if no application 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963, Sept. 29, 2010] is to be filed or if the application is not approved for such indication, until 2 § 312.66 Assurance of IRB review. years after the investigation is discon- An investigator shall assure that an tinued and FDA is notified. IRB that complies with the require- [52 FR 8831, Mar. 19, 1987, as amended at 52 ments set forth in part 56 will be re- FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, sponsible for the initial and continuing 1996; 67 FR 9586, Mar. 4, 2002] review and approval of the proposed

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clinical study. The investigator shall complained of and offer the investi- also assure that he or she will prompt- gator an opportunity to explain the ly report to the IRB all changes in the matter in writing, or, at the option of research activity and all unanticipated the investigator, in an informal con- problems involving risk to human sub- ference. If an explanation is offered but jects or others, and that he or she will not accepted by the Center for Drug not make any changes in the research Evaluation and Research or the Center without IRB approval, except where for Biologics Evaluation and Research, necessary to eliminate apparent imme- the investigator will be given an oppor- diate hazards to human subjects. tunity for a regulatory hearing under [52 FR 8831, Mar. 19, 1987, as amended at 52 part 16 on the question of whether the FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, investigator is entitled to receive in- 2002] vestigational new drugs. (b) After evaluating all available in- § 312.68 Inspection of investigator’s formation, including any explanation records and reports. presented by the investigator, if the An investigator shall upon request Commissioner determines that the in- from any properly authorized officer or vestigator has repeatedly or delib- employee of FDA, at reasonable times, erately failed to comply with the re- permit such officer or employee to quirements of this part, part 50, or part have access to, and copy and verify any 56 of this chapter, or has deliberately records or reports made by the investi- or repeatedly submitted false informa- gator pursuant to § 312.62. The investi- tion to FDA or to the sponsor in any gator is not required to divulge subject required report, the Commissioner will names unless the records of particular notify the investigator and the sponsor individuals require a more detailed of any investigation in which the in- study of the cases, or unless there is vestigator has been named as a partici- reason to believe that the records do pant that the investigator is not enti- not represent actual case studies, or do tled to receive investigational drugs. not represent actual results obtained. The notification will provide a state- § 312.69 Handling of controlled sub- ment of basis for such determination. stances. (c) Each IND and each approved ap- If the investigational drug is subject plication submitted under part 314 con- to the Controlled Substances Act, the taining data reported by an investi- investigator shall take adequate pre- gator who has been determined to be cautions, including storage of the in- ineligible to receive investigational vestigational drug in a securely locked, drugs will be examined to determine substantially constructed cabinet, or whether the investigator has submitted other securely locked, substantially unreliable data that are essential to constructed enclosure, access to which the continuation of the investigation is limited, to prevent theft or diversion or essential to the approval of any of the substance into illegal channels marketing application. of distribution. (d) If the Commissioner determines, after the unreliable data submitted by § 312.70 Disqualification of a clinical the investigator are eliminated from investigator. consideration, that the data remaining (a) If FDA has information indicating are inadequate to support a conclusion that an investigator (including a spon- that it is reasonably safe to continue sor-investigator) has repeatedly or de- the investigation, the Commissioner liberately failed to comply with the re- will notify the sponsor who shall have quirements of this part, part 50, or part an opportunity for a regulatory hear- 56 of this chapter, or has submitted to ing under part 16. If a danger to the FDA or to the sponsor false informa- public health exists, however, the Com- tion in any required report, the Center missioner shall terminate the IND im- for Drug Evaluation and Research or mediately and notify the sponsor of the the Center for Biologics Evaluation determination. In such case, the spon- and Research will furnish the investi- sor shall have an opportunity for a reg- gator written notice of the matter ulatory hearing before FDA under part

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16 on the question of whether the IND the recognition that physicians and pa- should be reinstated. tients are generally willing to accept (e) If the Commissioner determines, greater risks or side effects from prod- after the unreliable data submitted by ucts that treat life-threatening and se- the investigator are eliminated from verely-debilitating illnesses, than they consideration, that the continued ap- would accept from products that treat proval of the drug product for which less serious illnesses. These procedures the data were submitted cannot be jus- also reflect the recognition that the tified, the Commissioner will proceed benefits of the drug need to be evalu- to withdraw approval of the drug prod- ated in light of the severity of the dis- uct in accordance with the applicable ease being treated. The procedure out- provisions of the act. lined in this section should be inter- (f) An investigator who has been de- preted consistent with that purpose. termined to be ineligible to receive investigational drugs may be reinstated § 312.81 Scope. as eligible when the Commissioner de- This section applies to new drug and termines that the investigator has pre- biological products that are being stud- sented adequate assurances that the in- ied for their safety and effectiveness in vestigator will employ investigational treating life-threatening or severely- drugs solely in compliance with the debilitating diseases. provisions of this part and of parts 50 (a) For purposes of this section, the and 56. term ‘‘life-threatening’’ means: (1) Diseases or conditions where the [52 FR 8831, Mar. 19, 1987, as amended at 52 likelihood of death is high unless the FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, course of the disease is interrupted; 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586, Mar. 4, 2002] and (2) Diseases or conditions with potentially fatal outcomes, where the end Subpart E—Drugs Intended to point of clinical trial analysis is sur- Treat Life-threatening and Se- vival. verely-debilitating Illnesses (b) For purposes of this section, the term ‘‘severely debilitating’’ means AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371; diseases or conditions that cause major 42 U.S.C. 262. irreversible morbidity. SOURCE: 53 FR 41523, Oct. 21, 1988, unless (c) Sponsors are encouraged to con- otherwise noted. sult with FDA on the applicability of these procedures to specific products. § 312.80 Purpose. [53 FR 41523, Oct. 21, 1988, as amended at 64 The purpose of this section is to es- FR 401, Jan. 5, 1999] tablish procedures designed to expedite the development, evaluation, and mar- § 312.82 Early consultation. keting of new therapies intended to For products intended to treat life- treat persons with life-threatening and threatening or severely-debilitating ill- severely-debilitating illnesses, espe- nesses, sponsors may request to meet cially where no satisfactory alter- with FDA-reviewing officials early in native therapy exists. As stated the drug development process to review § 314.105(c) of this chapter, while the and reach agreement on the design of statutory standards of safety and effec- necessary preclinical and clinical stud- tiveness apply to all drugs, the many ies. Where appropriate, FDA will invite kinds of drugs that are subject to to such meetings one or more outside them, and the wide range of uses for expert scientific consultants or advi- those drugs, demand flexibility in ap- sory committee members. To the ex- plying the standards. The Food and tent FDA resources permit, agency re- Drug Administration (FDA) has deter- viewing officials will honor requests mined that it is appropriate to exercise for such meetings the broadest flexibility in applying the (a) Pre-investigational new drug (IND) statutory standards, while preserving meetings. Prior to the submission of the appropriate guarantees for safety and initial IND, the sponsor may request a effectiveness. These procedures reflect meeting with FDA-reviewing officials.

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The primary purpose of this meeting is § 312.84 Risk-benefit analysis in review to review and reach agreement on the of marketing applications for drugs design of animal studies needed to ini- to treat life-threatening and se- tiate human testing. The meeting may verely-debilitating illnesses. also provide an opportunity for dis- (a) FDA’s application of the statu- cussing the scope and design of phase 1 tory standards for marketing approval testing, plans for studying the drug shall recognize the need for a medical product in pediatric populations, and risk-benefit judgment in making the the best approach for presentation and final decision on approvability. As part formatting of data in the IND. of this evaluation, consistent with the statement of purpose in § 312.80, FDA (b) End-of-phase 1 meetings. When data will consider whether the benefits of from phase 1 clinical testing are avail- the drug outweigh the known and po- able, the sponsor may again request a tential risks of the drug and the need meeting with FDA-reviewing officials. to answer remaining questions about The primary purpose of this meeting is risks and benefits of the drug, taking to review and reach agreement on the into consideration the severity of the design of phase 2 controlled clinical disease and the absence of satisfactory trials, with the goal that such testing alternative therapy. will be adequate to provide sufficient (b) In making decisions on whether data on the drug’s safety and effective- to grant marketing approval for prod- ness to support a decision on its ap- ucts that have been the subject of an provability for marketing, and to dis- end-of-phase 1 meeting under § 312.82, cuss the need for, as well as the design FDA will usually seek the advice of and timing of, studies of the drug in pe- outside expert scientific consultants or diatric patients. For drugs for life- advisory committees. Upon the filing threatening diseases, FDA will provide of such a marketing application under its best judgment, at that time, wheth- § 314.101 or part 601 of this chapter, FDA will notify the members of the relevant er pediatric studies will be required standing advisory committee of the ap- and whether their submission will be plication’s filing and its availability deferred until after approval. The pro- for review. cedures outlined in § 312.47(b)(1) with (c) If FDA concludes that the data respect to end-of-phase 2 conferences, presented are not sufficient for mar- including documentation of agree- keting approval, FDA will issue a comments reached, would also be used for plete response letter under § 314.110 of end-of-phase 1 meetings. this chapter or the biological product licensing procedures. Such letter, in [53 FR 41523, Oct. 21, 1988, as amended at 63 FR 66669, Dec. 2, 1998] describing the deficiencies in the application, will address why the results of § 312.83 Treatment protocols. the research design agreed to under § 312.82, or in subsequent meetings, If the preliminary analysis of phase 2 have not provided sufficient evidence test results appears promising, FDA for marketing approval. Such letter may ask the sponsor to submit a treat- will also describe any recommenda- ment protocol to be reviewed under the tions made by the advisory committee procedures and criteria listed in regarding the application. §§ 312.305 and 312.320. Such a treatment (d) Marketing applications submitted protocol, if requested and granted, under the procedures contained in this would normally remain in effect while section will be subject to the require- the complete data necessary for a mar- ments and procedures contained in part keting application are being assembled 314 or part 600 of this chapter, as well by the sponsor and reviewed by FDA as those in this subpart. (unless grounds exist for clinical hold [53 FR 41523, Oct. 21, 1988, as amended at 73 of ongoing protocols, as provided in FR 39607, July 10, 2008] § 312.42(b)(3)(ii)). § 312.85 Phase 4 studies. [53 FR 41523, Oct. 21, 1988, as amended at 76 FR 13880, Mar. 15, 2011] Concurrent with marketing approval, FDA may seek agreement from the

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sponsor to conduct certain post- Subpart F—Miscellaneous marketing (phase 4) studies to delin- eate additional information about the § 312.110 Import and export require- drug’s risks, benefits, and optimal use. ments. These studies could include, but would (a) Imports. An investigational new not be limited to, studying different drug offered for import into the United doses or schedules of administration States complies with the requirements than were used in phase 2 studies, use of this part if it is subject to an IND of the drug in other patient popu- that is in effect for it under § 312.40 and: lations or other stages of the disease, (1) The consignee in the United States or use of the drug over a longer period is the sponsor of the IND; (2) the con- of time. signee is a qualified investigator named in the IND; or (3) the consignee § 312.86 Focused FDA regulatory re- is the domestic agent of a foreign spon- search. sor, is responsible for the control and At the discretion of the agency, FDA distribution of the investigational may undertake focused regulatory re- drug, and the IND identifies the con- search on critical rate-limiting aspects signee and describes what, if any, ac- of the preclinical, chemical/manufac- tions the consignee will take with re- turing, and clinical phases of drug de- spect to the investigational drug. velopment and evaluation. When initi- (b) Exports. An investigational new ated, FDA will undertake such re- drug may be exported from the United search efforts as a means for meeting a States for use in a clinical investiga- public health need in facilitating the tion under any of the following condi- development of therapies to treat life- tions: threatening or severely debilitating ill- (1) An IND is in effect for the drug nesses. under § 312.40, the drug complies with the laws of the country to which it is § 312.87 Active monitoring of conduct being exported, and each person who and evaluation of clinical trials. receives the drug is an investigator in a study submitted to and allowed to For drugs covered under this section, proceed under the IND; or the Commissioner and other agency of- (2) The drug has valid marketing au- ficials will monitor the progress of the thorization in Australia, Canada, conduct and evaluation of clinical Israel, Japan, New Zealand, Switzer- trials and be involved in facilitating land, South Africa, or in any country their appropriate progress. in the European Union or the European Economic Area, and complies with the § 312.88 Safeguards for patient safety. laws of the country to which it is being All of the safeguards incorporated exported, section 802(b)(1)(A), (f), and within parts 50, 56, 312, 314, and 600 of (g) of the act, and § 1.101 of this chap- this chapter designed to ensure the ter; or safety of clinical testing and the safety (3) The drug is being exported to Aus- of products following marketing ap- tralia, Canada, Israel, Japan, New Zea- proval apply to drugs covered by this land, Switzerland, South Africa, or to section. This includes the requirements any country in the European Union or for informed consent (part 50 of this the European Economic Area, and com- chapter) and institutional review plies with the laws of the country to boards (part 56 of this chapter). These which it is being exported, the applica- safeguards further include the review ble provisions of section 802(c), (f), and of animal studies prior to initial (g) of the act, and § 1.101 of this chap- human testing (§ 312.23), and the moni- ter. Drugs exported under this para- toring of adverse drug experiences graph that are not the subject of an through the requirements of IND safe- IND are exempt from the label require- ty reports (§ 312.32), safety update re- ment in § 312.6(a); or ports during agency review of a mar- (4) Except as provided in paragraph keting application (§ 314.50 of this chap- (b)(5) of this section, the person export- ter), and postmarketing adverse reac- ing the drug sends a written certifi- tion reporting (§ 314.80 of this chapter). cation to the Office of International

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Programs (HFG–1), Food and Drug Ad- an affirmation with respect to any one ministration, 5600 Fishers Lane, Rock- or more of paragraphs (b)(4)(i), ville, MD 20857, at the time the drug is (b)(4)(iv), (b)(4)(vi), (b)(4)(vii), first exported and maintains records (b)(4)(viii), and/or (b)(4)(ix) of this sec- documenting compliance with this tion, provided that he or she: paragraph. The certification shall de- (1) Provides a written statement ex- scribe the drug that is to be exported plaining why compliance with each (i.e., trade name (if any), generic name, such paragraph is not feasible or is and dosage form), identify the country contrary to the best interests of the in- or countries to which the drug is to be dividuals who may receive the inves- exported, and affirm that: tigational new drug; (i) The drug is intended for export; (2) Provides a written statement (ii) The drug is intended for inves- from an authorized official of the im- tigational use in a foreign country; porting country’s government. The (iii) The drug meets the foreign pur- statement must attest that the official chaser’s or consignee’s specifications; agrees with the exporter’s statement (iv) The drug is not in conflict with made under paragraph (b)(5)(i)(A)(1) of the importing country’s laws; this section; explain that the drug is to (v) The outer shipping package is la- be stockpiled solely for use of the im- beled to show that the package is in- porting country in a national emer- tended for export from the United gency; and describe the potential na- States; tional emergency that warrants expor- (vi) The drug is not sold or offered for tation of the investigational new drug sale in the United States; under this provision; and (vii) The clinical investigation will (3) Provides a written statement be conducted in accordance with showing that the Secretary of Health § 312.120; and Human Services (the Secretary), or (viii) The drug is manufactured, proc- his or her designee, agrees with the essed, packaged, and held in substan- findings of the authorized official of tial conformity with current good man- the importing country’s government. ufacturing practices; Persons who wish to obtain a written (ix) The drug is not adulterated with- statement from the Secretary should in the meaning of section 501(a)(1), direct their requests to Secretary’s Op- (a)(2)(A), (a)(3), (c), or (d) of the act; erations Center, Office of Emergency (x) The drug does not present an im- Operations and Security Programs, Of- minent hazard to public health, either fice of Public Health Emergency Pre- in the United States, if the drug were paredness, Office of the Secretary, De- to be reimported, or in the foreign partment of Health and Human Serv- country; and ices, 200 Independence Ave. SW., Wash- (xi) The drug is labeled in accordance ington, DC 20201. Requests may be also with the foreign country’s laws. be sent by FAX: 202–619–7870 or by e- (5) In the event of a national emer- mail: [email protected]. gency in a foreign country, where the (B) Exportation may not proceed national emergency necessitates expor- until FDA has authorized exportation tation of an investigational new drug, of the investigational new drug. FDA the requirements in paragraph (b)(4) of may deny authorization if the state- this section apply as follows: ments provided under paragraphs (i) Situations where the investigational (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) of this new drug is to be stockpiled in anticipa- section are inadequate or if expor- tion of a national emergency. There may tation is contrary to public health. be instances where exportation of an (ii) Situations where the investigational investigational new drug is needed so new drug is to be used for a sudden and that the drug may be stockpiled and immediate national emergency. There made available for use by the import- may be instances where exportation of ing country if and when a national an investigational new drug is needed emergency arises. In such cases: so that the drug may be used in a sud- (A) A person may export an inves- den and immediate national emergency tigational new drug under paragraph that has developed or is developing. In (b)(4) of this section without making such cases:

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(A) A person may export an inves- graph (b)(5) of this section are no tigational new drug under paragraph longer met; or (b)(4) of this section without making (5) For any investigational new drugs an affirmation with respect to any one under this section, the drug no longer or more of paragraphs (b)(4)(i), complies with the laws of the import- (b)(4)(iv), (b)(4)(v), (b)(4)(vi), (b)(4)(vii), ing country. (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), (d) Insulin and antibiotics. New insulin provided that he or she: and antibiotic drug products may be (1) Provides a written statement ex- exported for investigational use in ac- plaining why compliance with each cordance with section 801(e)(1) of the such paragraph is not feasible or is act without complying with this sec- contrary to the best interests of the in- tion. dividuals who are expected to receive [52 FR 8831, Mar. 19, 1987, as amended at 52 the investigational new drug and FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999; (2) Provides sufficient information 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23, from an authorized official of the im- 2005] porting country’s government to en- § 312.120 Foreign clinical studies not able the Secretary, or his or her des- conducted under an IND. ignee, to decide whether a national emergency has developed or is devel- (a) Acceptance of studies. (1) FDA will oping in the importing country, wheth- accept as support for an IND or appli- er the investigational new drug will be cation for marketing approval (an ap- used solely for that national emer- plication under section 505 of the act or gency, and whether prompt exportation section 351 of the Public Health Service of the investigational new drug is nec- Act (the PHS Act) (42 U.S.C. 262)) a essary. Persons who wish to obtain a well-designed and well-conducted for- determination from the Secretary eign clinical study not conducted under an IND, if the following conditions are should direct their requests to Sec- met: retary’s Operations Center, Office of (i) The study was conducted in ac- Emergency Operations and Security cordance with good clinical practice Programs, Office of Public Health (GCP). For the purposes of this section, Emergency Preparedness, Office of the GCP is defined as a standard for the de- Secretary, Department of Health and sign, conduct, performance, moni- Human Services, 200 Independence Ave. toring, auditing, recording, analysis, SW., Washington, DC 20201. Requests and reporting of clinical trials in a way may be also be sent by FAX: 202–619– that provides assurance that the data 7870 or by e-mail: [email protected]. and reported results are credible and (B) Exportation may proceed without accurate and that the rights, safety, prior FDA authorization. and well-being of trial subjects are pro- (c) Limitations. Exportation under tected. GCP includes review and ap- paragraph (b) of this section may not proval (or provision of a favorable occur if: opinion) by an independent ethics com- (1) For drugs exported under para- mittee (IEC) before initiating a study, graph (b)(1) of this section, the IND continuing review of an ongoing study pertaining to the clinical investigation by an IEC, and obtaining and docu- is no longer in effect; menting the freely given informed con- (2) For drugs exported under para- sent of the subject (or a subject’s le- graph (b)(2) of this section, the require- gally authorized representative, if the ments in section 802(b)(1), (f), or (g) of subject is unable to provide informed the act are no longer met; consent) before initiating a study. GCP (3) For drugs exported under para- does not require informed consent in graph (b)(3) of this section, the require- life-threatening situations when the ments in section 802(c), (f), or (g) of the IEC reviewing the study finds, before act are no longer met; initiation of the study, that informed (4) For drugs exported under para- consent is not feasible and either that graph (b)(4) of this section, the condi- the conditions present are consistent tions underlying the certification or with those described in § 50.23 or the statements submitted under para- § 50.24(a) of this chapter, or that the

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measures described in the study pro- (6) The name and address of the IEC tocol or elsewhere will protect the that reviewed the study and a state- rights, safety, and well-being of sub- ment that the IEC meets the definition jects; and in § 312.3 of this chapter. The sponsor or (ii) FDA is able to validate the data applicant must maintain records sup- from the study through an onsite in- porting such statement, including spection if the agency deems it nec- records of the names and qualifications essary. of IEC members, and make these (2) Although FDA will not accept as records available for agency review support for an IND or application for upon request; marketing approval a study that does (7) A summary of the IEC’s decision not meet the conditions of paragraph to approve or modify and approve the (a)(1) of this section, FDA will examine study, or to provide a favorable opin- data from such a study. ion; (3) Marketing approval of a new drug (8) A description of how informed based solely on foreign clinical data is consent was obtained; governed by § 314.106 of this chapter. (9) A description of what incentives, (b) Supporting information. A sponsor if any, were provided to subjects to or applicant who submits data from a participate in the study; foreign clinical study not conducted (10) A description of how the spon- under an IND as support for an IND or sor(s) monitored the study and ensured application for marketing approval that the study was carried out consist- must submit to FDA, in addition to in- ently with the study protocol; and formation required elsewhere in parts (11) A description of how investiga- 312, 314, or 601 of this chapter, a de- tors were trained to comply with GCP scription of the actions the sponsor or (as described in paragraph (a)(1)(i) of applicant took to ensure that the re- this section) and to conduct the study search conformed to GCP as described in accordance with the study protocol, in paragraph (a)(1)(i) of this section. The description is not required to du- and a statement on whether written plicate information already submitted commitments by investigators to com- in the IND or application for mar- ply with GCP and the protocol were ob- keting approval. Instead, the descrip- tained. Any signed written commit- tion must provide either the following ments by investigators must be main- information or a cross-reference to an- tained by the sponsor or applicant and other section of the submission where made available for agency review upon the information is located: request. (1) The investigator’s qualifications; (c) Waivers. (1) A sponsor or applicant (2) A description of the research fa- may ask FDA to waive any applicable cilities; requirements under paragraphs (a)(1) (3) A detailed summary of the pro- and (b) of this section. A waiver re- tocol and results of the study and, quest may be submitted in an IND or in should FDA request, case records main- an information amendment to an IND, tained by the investigator or addi- or in an application or in an amend- tional background data such as hos- ment or supplement to an application pital or other institutional records; submitted under part 314 or 601 of this (4) A description of the drug subchapter. A waiver request is required stance and drug product used in the to contain at least one of the following: study, including a description of the (i) An explanation why the sponsor’s components, formulation, specifica- or applicant’s compliance with the re- tions, and, if available, bioavailability quirement is unnecessary or cannot be of the specific drug product used in the achieved; clinical study; (ii) A description of an alternative (5) If the study is intended to support submission or course of action that the effectiveness of a drug product, in- satisfies the purpose of the require- formation showing that the study is ment; or adequate and well controlled under (iii) Other information justifying a § 314.126 of this chapter; waiver.

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(2) FDA may grant a waiver if it finds shall submit a request under the Free- that doing so would be in the interest dom of Information Act. of the public health. [52 FR 8831, Mar. 19, 1987. Redesignated at 53 (d) Records. A sponsor or applicant FR 41523, Oct. 21, 1988, as amended at 61 FR must retain the records required by 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 this section for a foreign clinical study FR 24879, May 9, 2003] not conducted under an IND as follows: § 312.140 Address for correspondence. (1) If the study is submitted in support of an application for marketing (a) A sponsor must send an initial approval, for 2 years after an agency IND submission to the Center for Drug decision on that application; Evaluation and Research (CDER) or to the Center for Biologics Evaluation (2) If the study is submitted in sup- and Research (CBER), depending on the port of an IND but not an application Center responsible for regulating the for marketing approval, for 2 years product as follows: after the submission of the IND. (1) For drug products regulated by [73 FR 22815, Apr. 28, 2008] CDER. Send the IND submission to the Central Document Room, Center for § 312.130 Availability for public disclo- Drug Evaluation and Research, Food sure of data and information in an and Drug Administration, 5901–B IND. Ammendale Rd., Beltsville, MD 20705– (a) The existence of an investiga- 1266; except send an IND submission for tional new drug application will not be an in vivo bioavailability or bioequivalence study in humans to support an disclosed by FDA unless it has pre- abbreviated new drug application to viously been publicly disclosed or ac- the Office of Generic Drugs (HFD–600), knowledged. Center for Drug Evaluation and Re- (b) The availability for public disclo- search, Food and Drug Administration, sure of all data and information in an Metro Park North VII, 7620 Standish investigational new drug application Pl., Rockville, MD 20855. for a new drug will be handled in ac- (2) For biological products regulated by cordance with the provisions estab- CDER. Send the IND submission to the lished in § 314.430 for the confidentiality CDER Therapeutic Biological Products of data and information in applications Document Room, Center for Drug Eval- submitted in part 314. The availability uation and Research, Food and Drug for public disclosure of all data and in- Administration, 12229 Wilkins Ave., formation in an investigational new Rockville, MD 20852. drug application for a biological prod- (3) For biological products regulated by uct will be governed by the provisions CBER. Send the IND submission to the of §§ 601.50 and 601.51. Document Control Center (HFM–99), (c) Notwithstanding the provisions of Center for Biologics Evaluation and § 314.430, FDA shall disclose upon re- Research, Food and Drug Administra- quest to an individual to whom an in- tion, 1401 Rockville Pike, suite 200N, vestigational new drug has been given Rockville, MD 20852–1448. (b) On receiving the IND, the respon- a copy of any IND safety report relat- sible Center will inform the sponsor ing to the use in the individual. which one of the divisions in CDER or (d) The availability of information CBER is responsible for the IND. required to be publicly disclosed for in- Amendments, reports, and other cor- vestigations involving an exception respondence relating to matters cov- from informed consent under § 50.24 of ered by the IND should be sent to the this chapter will be handled as follows: appropriate center at the address indi- Persons wishing to request the publicly cated in this section and marked to the disclosable information in the IND that attention of the responsible division. was required to be filed in Docket The outside wrapper of each submis- Number 95S–0158 in the Division of sion shall state what is contained in Dockets Management (HFA–305), Food the submission, for example, ‘‘IND Ap- and Drug Administration, 5630 Fishers plication’’, ‘‘Protocol Amendment’’, Lane, rm. 1061, Rockville, MD 20852, etc.

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(c) All correspondence relating to ex- animals, or for tests in vitro. Not for use in port of an investigational drug under humans. § 312.110(b)(2) shall be submitted to the (ii) A person may ship a biological International Affairs Staff (HFY–50), product for investigational in vitro di- Office of Health Affairs, Food and Drug agnostic use that is listed in Administration, 5600 Fishers Lane, § 312.2(b)(2)(ii) if it is labeled as follows: Rockville, MD 20857. CAUTION: Contains a biological product [70 FR 14981, Mar. 24, 2005, as amended at 74 for investigational in vitro diagnostic tests FR 13113, Mar. 26, 2009; 74 FR 55771, Oct. 29, only. 2009; 75 FR 37295, June 29, 2010] (2) A person shipping a drug under § 312.145 Guidance documents. paragraph (a) of this section shall use due diligence to assure that the con- (a) FDA has made available guidance signee is regularly engaged in con- documents under § 10.115 of this chapter ducting such tests and that the ship- to help you to comply with certain re- ment of the new drug will actually be quirements of this part. used for tests in vitro or in animals (b) The Center for Drug Evaluation used only for laboratory research. and Research (CDER) and the Center (3) A person who ships a drug under for Biologics Evaluation and Research paragraph (a) of this section shall (CBER) maintain lists of guidance doc- maintain adequate records showing the uments that apply to the centers’ regu- name and post office address of the ex- lations. The lists are maintained on pert to whom the drug is shipped and the Internet and are published annu- the date, quantity, and batch or code ally in the FEDERAL REGISTER. A re- mark of each shipment and delivery. quest for a copy of the CDER list Records of shipments under paragraph should be directed to the Office of (a)(1)(i) of this section are to be main- Training and Communications, Divi- tained for a period of 2 years after the sion of Drug Information, Center for shipment. Records and reports of data Drug Evaluation and Research, Food and shipments under paragraph and Drug Administration, 10903 New (a)(1)(ii) of this section are to be main- Hampshire Ave., Silver Spring, MD tained in accordance with § 312.57(b). 20993–0002. A request for a copy of the The person who ships the drug shall CBER list should be directed to the Of- upon request from any properly au- fice of Communication, Training, and thorized officer or employee of the Manufacturers Assistance (HFM–40), Food and Drug Administration, at rea- Center for Biologics Evaluation and sonable times, permit such officer or Research, Food and Drug Administra- employee to have access to and copy tion, 1401 Rockville Pike, Rockville, and verify records required to be main- MD 20852–1448. tained under this section. [65 FR 56479, Sept. 19, 2000, as amended at 74 (b) Termination of authorization to FR 13113, Mar. 26, 2009] ship. FDA may terminate authorization to ship a drug under this section if Subpart G—Drugs for Investiga- it finds that: tional Use in Laboratory Re- (1) The sponsor of the investigation has failed to comply with any of the search Animals or In Vitro conditions for shipment established Tests under this section; or (2) The continuance of the investiga- § 312.160 Drugs for investigational use in laboratory research animals or tion is unsafe or otherwise contrary to in vitro tests. the public interest or the drug is used for purposes other than bona fide sci- (a) Authorization to ship. (1)(i) A per- entific investigation. FDA will notify son may ship a drug intended solely for the person shipping the drug of its find- tests in vitro or in animals used only ing and invite immediate correction. If for laboratory research purposes if it is correction is not immediately made, labeled as follows: the person shall have an opportunity CAUTION: Contains a new drug for inves- for a regulatory hearing before FDA tigational use only in laboratory research pursuant to part 16.

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(c) Disposition of unused drug. The ally not be sufficient, but the mor- person who ships the drug under para- bidity need not be irreversible, pro- graph (a) of this section shall assure vided it is persistent or recurrent. the return of all unused supplies of the Whether a disease or condition is seri- drug from individual investigators ous is a matter of clinical judgment, whenever the investigation discon- based on its impact on such factors as tinues or the investigation is termi- survival, day-to-day functioning, or the nated. The person who ships the drug likelihood that the disease, if left un- may authorize in writing alternative treated, will progress from a less severe disposition of unused supplies of the condition to a more serious one. drug provided this alternative disposition does not expose humans to risks § 312.305 Requirements for all ex- from the drug, either directly or indi- panded access uses. rectly (e.g., through food-producing The criteria, submission require- animals). The shipper shall maintain ments, safeguards, and beginning treat- records of any alternative disposition. ment information set out in this section apply to all expanded access uses [52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987. Redesignated at 53 described in this subpart. Additional FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, criteria, submission requirements, and 2002] safeguards that apply to specific types of expanded access are described in Subpart H [Reserved] §§ 312.310 through 312.320. (a) Criteria. FDA must determine that: Subpart I—Expanded Access to (1) The patient or patients to be Investigational Drugs for Treat- treated have a serious or immediately ment Use life-threatening disease or condition, and there is no comparable or satisfac- SOURCE: 74 FR 40942, Aug. 13, 2009, unless tory alternative therapy to diagnose, otherwise noted. monitor, or treat the disease or condition; § 312.300 General. (2) The potential patient benefit jus- (a) Scope. This subpart contains the tifies the potential risks of the treat- requirements for the use of investiga- ment use and those potential risks are tional new drugs and approved drugs not unreasonable in the context of the where availability is limited by a risk disease or condition to be treated; and evaluation and mitigation strategy (3) Providing the investigational drug (REMS) when the primary purpose is to for the requested use will not interfere diagnose, monitor, or treat a patient’s with the initiation, conduct, or com- disease or condition. The aim of this pletion of clinical investigations that subpart is to facilitate the availability could support marketing approval of of such drugs to patients with serious the expanded access use or otherwise diseases or conditions when there is no compromise the potential development comparable or satisfactory alternative of the expanded access use. therapy to diagnose, monitor, or treat (b) Submission. (1) An expanded access the patient’s disease or condition. submission is required for each type of (b) Definitions. The following defini- expanded access described in this sub- tions of terms apply to this subpart: part. The submission may be a new Immediately life-threatening disease or IND or a protocol amendment to an ex- condition means a stage of disease in isting IND. Information required for a which there is reasonable likelihood submission may be supplied by refer- that death will occur within a matter ring to pertinent information con- of months or in which premature death tained in an existing IND if the sponsor is likely without early treatment. of the existing IND grants a right of Serious disease or condition means a reference to the IND. disease or condition associated with (2) The expanded access submission morbidity that has substantial impact must include: 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);

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(ii) The rationale for the intended use (2) An individual or entity that sub- of the drug, including a list of available mits an expanded access IND or pro- therapeutic options that would ordi- tocol under this subpart is considered a narily be tried before resorting to the sponsor, for purposes of this part, and investigational drug or an explanation must comply with the responsibilities of why the use of the investigational for sponsors set forth in subpart D of drug is preferable to the use of avail- this part to the extent they are appli- able therapeutic options; cable to the expanded access use. (iii) The criteria for patient selection (3) A licensed physician under whose or, for an individual patient, a descrip- immediate direction an investigational tion of the patient’s disease or condi- drug is administered or dispensed, and tion, including recent medical history who submits an IND for expanded ac- and previous treatments of the disease cess use under this subpart is consid- or condition; ered a sponsor-investigator, for purposes (iv) The method of administration of of this part, and must comply with the the drug, dose, and duration of ther- responsibilities for sponsors and inves- apy; tigators set forth in subpart D of this (v) A description of the facility where part to the extent they are applicable the drug will be manufactured; to the expanded access use. (vi) Chemistry, manufacturing, and (4) Investigators. In all cases of ex- controls information adequate to en- panded access, investigators are re- sure the proper identification, quality, sponsible for reporting adverse drug purity, and strength of the investiga- events to the sponsor, ensuring that tional drug; the informed consent requirements of (vii) Pharmacology and toxicology part 50 of this chapter are met, ensur- information adequate to conclude that ing that IRB review of the expanded ac- the drug is reasonably safe at the dose and duration proposed for expanded access use is obtained in a manner con- cess use (ordinarily, information that sistent with the requirements of part would be adequate to permit clinical 56 of this chapter, and maintaining ac- testing of the drug in a population of curate case histories and drug disposi- the size expected to be treated); and tion records and retaining records in a (viii) A description of clinical proce- manner consistent with the require- dures, laboratory tests, or other moni- ments of § 312.62. Depending on the type toring necessary to evaluate the effects of expanded access, other investigator of the drug and minimize its risks. responsibilities under subpart D may (3) The expanded access submission also apply. and its mailing cover must be plainly (5) Sponsors. In all cases of expanded marked ‘‘EXPANDED ACCESS SUB- access, sponsors are responsible for MISSION.’’ If the expanded access sub- submitting IND safety reports and an- mission is for a treatment IND or nual reports (when the IND or protocol treatment protocol, the applicable box continues for 1 year or longer) to FDA on Form FDA 1571 must be checked. as required by §§ 312.32 and 312.33, en- (c) Safeguards. The responsibilities of suring that licensed physicians are sponsors and investigators set forth in qualified to administer the investiga- subpart D of this part are applicable to tional drug for the expanded access expanded access use under this subpart use, providing licensed physicians with as described in this paragraph. the information needed to minimize (1) A licensed physician under whose the risk and maximize the potential immediate direction an investigational benefits of the investigational drug drug is administered or dispensed for (the investigator’s brochure must be an expanded access use under this sub- provided if one exists for the drug), part is considered an investigator, for maintaining an effective IND for the purposes of this part, and must comply expanded access use, and maintaining with the responsibilities for investiga- adequate drug disposition records and tors set forth in subpart D of this part retaining records in a manner con- to the extent they are applicable to the expanded access use. sistent with the requirements of

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§ 312.57. Depending on the type of existing IND to include a protocol for in- panded access, other sponsor respon- dividual patient expanded access. sibilities under subpart D may also (3) A licensed physician may satisfy apply. the submission requirements by ob- (d) Beginning treatment—(1) INDs. An taining from the sponsor permission expanded access IND goes into effect 30 for FDA to refer to any information in days after FDA receives the IND or on the IND that would be needed to sup- earlier notification by FDA that the port the expanded access request (right expanded access use may begin. of reference) and by providing any (2) Protocols. With the following ex- other required information not con- ceptions, expanded access use under a tained in the IND (usually only the in- protocol submitted under an existing formation specific to the individual pa- IND may begin as described in tient). § 312.30(a). (c) Safeguards. (1) Treatment is gen- (i) Expanded access use under the erally limited to a single course of emergency procedures described in therapy for a specified duration unless § 312.310(d) may begin when the use is FDA expressly authorizes multiple authorized by the FDA reviewing offi- courses or chronic therapy. cial. (2) At the conclusion of treatment, (ii) Expanded access use under the licensed physician or sponsor must § 312.320 may begin 30 days after FDA provide FDA with a written summary receives the protocol or upon earlier of the results of the expanded access notification by FDA that use may use, including adverse effects. begin. (3) FDA may require sponsors to (3) Clinical holds. FDA may place any monitor an individual patient ex- expanded access IND or protocol on panded access use if the use is for an clinical hold as described in § 312.42. extended duration. (4) When a significant number of § 312.310 Individual patients, includ- similar individual patient expanded ac- ing for emergency use. cess requests have been submitted, FDA may ask the sponsor to submit an Under this section, FDA may permit IND or protocol for the use under an investigational drug to be used for § 312.315 or § 312.320. the treatment of an individual patient (d) Emergency procedures. If there is by a licensed physician. an emergency that requires the patient (a) Criteria. The criteria in § 312.305(a) to be treated before a written submis- must be met; and the following deter- sion can be made, FDA may authorize minations must be made: the expanded access use to begin with- (1) The physician must determine out a written submission. The FDA re- that the probable risk to the person viewing official may authorize the from the investigational drug is not emergency use by telephone. greater than the probable risk from the (1) Emergency expanded access use disease or condition; and may be requested by telephone, fac- (2) FDA must determine that the pa- simile, or other means of electronic tient cannot obtain the drug under an- communications. For investigational other IND or protocol. biological drug products regulated by (b) Submission. The expanded access the Center for Biologics Evaluation submission must include information and Research, the request should be di- adequate to demonstrate that the cri- rected to the Office of Communication, teria in § 312.305(a) and paragraph (a) of Outreach and Development, Center for this section have been met. The ex- Biologics Evaluation and Research, panded access submission must meet 301–827–1800 or 1–800–835–4709, e-mail: the requirements of § 312.305(b). [email protected]. For all other inves- (1) If the drug is the subject of an ex- tigational drugs, the request for au- isting IND, the expanded access sub- thorization should be directed to the mission may be made by the sponsor or Division of Drug Information, Center by a licensed physician. for Drug Evaluation and Research, 301– (2) A sponsor may satisfy the submis- 796–3400, e-mail: [email protected]. sion requirements by amending its ex- After normal working hours (8 a.m. to

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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. ter, 866–300–4374, e-mail: emer- (b) Criteria. The criteria in § 312.305(a) [email protected]. must be met; and FDA must determine (2) The licensed physician or sponsor that: must explain how the expanded access (1) There is enough evidence that the use will meet the requirements of drug is safe at the dose and duration §§ 312.305 and 312.310 and must agree to proposed for expanded access use to submit an expanded access submission justify a clinical trial of the drug in within 15 working days of FDA’s au- the approximate number of patients ex- thorization of the use. pected to receive the drug under expanded access; and [74 FR 40942, Aug. 13, 2009, as amended at 75 (2) There is at least preliminary clin- FR 32659, June 9, 2010] ical evidence of effectiveness of the § 312.315 Intermediate-size patient drug, or of a plausible pharmacologic populations. effect of the drug to make expanded access use a reasonable therapeutic op- Under this section, FDA may permit tion in the anticipated patient popu- an investigational drug to be used for lation. the treatment of a patient population (c) Submission. The expanded access smaller than that typical of a treat- submission must include information ment IND or treatment protocol. FDA adequate to satisfy FDA that the cri- may ask a sponsor to consolidate ex- teria in § 312.305(a) and paragraph (b) of panded access under this section when this section have been met. The ex- the agency has received a significant panded access submission must meet number of requests for individual pa- the requirements of § 312.305(b). In addi- tient expanded access to an investigation: tional drug for the same use. (1) The expanded access submission (a) Need for expanded access. Expanded must state whether the drug is being access under this section may be need- developed or is not being developed and ed in the following situations: describe the patient population to be (1) Drug not being developed. The drug treated. is not being developed, for example, be- (2) If the drug is not being actively cause the disease or condition is so developed, the sponsor must explain rare that the sponsor is unable to re- why the drug cannot currently be de- cruit patients for a clinical trial. veloped for the expanded access use and (2) Drug being developed. The drug is under what circumstances the drug being studied in a clinical trial, but pa- could be developed. tients requesting the drug for expanded (3) If the drug is being studied in a access use are unable to participate in clinical trial, the sponsor must explain the trial. For example, patients may why the patients to be treated cannot not be able to participate in the trial be enrolled in the clinical trial and because they have a different disease or under what circumstances the sponsor stage of disease than the one being would conduct a clinical trial in these studied or otherwise do not meet the patients. enrollment criteria, because enroll- (d) Safeguards. (1) Upon review of the ment in the trial is closed, or because IND annual report, FDA will determine the trial site is not geographically ac- whether it is appropriate for the ex- cessible. panded access to continue under this (3) Approved or related drug. (i) The section. drug is an approved drug product that (i) If the drug is not being actively is no longer marketed for safety rea- developed or if the expanded access use sons or is unavailable through mar- is not being developed (but another use keting due to failure to meet the con- is being developed), FDA will consider ditions of the approved application, or whether it is possible to conduct a clin- (ii) The drug contains the same ac- ical study of the expanded access use. tive moiety as an approved drug prod- (ii) If the drug is being actively de- uct that is unavailable through mar- veloped, FDA will consider whether keting due to failure to meet the con- providing the investigational drug for

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expanded access use is interfering with panded access submission must meet the clinical development of the drug. the requirements of § 312.305(b). (iii) As the number of patients en- (c) Safeguard. The sponsor is respon- rolled increases, FDA may ask the sible for monitoring the treatment pro- sponsor to submit an IND or protocol tocol to ensure that licensed physi- for the use under § 312.320. cians comply with the protocol and the (2) The sponsor is responsible for regulations applicable to investigators. monitoring the expanded access protocol to ensure that licensed physi- PART 314—APPLICATIONS FOR FDA cians comply with the protocol and the APPROVAL TO MARKET A NEW regulations applicable to investigators. DRUG § 312.320 Treatment IND or treatment protocol. Subpart A—General Provisions Under this section, FDA may permit Sec. an investigational drug to be used for 314.1 Scope of this part. widespread treatment use. 314.2 Purpose. (a) Criteria. The criteria in § 312.305(a) 314.3 Definitions. must be met, and FDA must determine that: Subpart B—Applications (1) Trial status. (i) The drug is being 314.50 Content and format of an application. investigated in a controlled clinical 314.52 Notice of certification of invalidity trial under an IND designed to support or noninfringement of a patent. a marketing application for the ex- 314.53 Submission of patent information. panded access use, or 314.54 Procedure for submission of an appli- (ii) All clinical trials of the drug cation requiring investigations for ap- have been completed; and proval of a new indication for, or other (2) Marketing status. The sponsor is change from, a listed drug. actively pursuing marketing approval 314.55 Pediatric use information. 314.60 Amendments to an unapproved appli- of the drug for the expanded access use cation, supplement, or resubmission. with due diligence; and 314.65 Withdrawal by the applicant of an un- (3) Evidence. (i) When the expanded approved application. access use is for a serious disease or 314.70 Supplements and other changes to an condition, there is sufficient clinical approved application. evidence of safety and effectiveness to 314.71 Procedures for submission of a sup- support the expanded access use. Such plement to an approved application. evidence would ordinarily consist of 314.72 Change in ownership of an applica- data from phase 3 trials, but could con- tion. 314.80 Postmarketing reporting of adverse sist of compelling data from completed drug experiences. phase 2 trials; or 314.81 Other postmarketing reports. (ii) When the expanded access use is 314.90 Waivers. for an immediately life-threatening disease or condition, the available sci- Subpart C—Abbreviated Applications entific evidence, taken as a whole, provides a reasonable basis to conclude 314.91 Obtaining a reduction in the discontinuance notification period. that the investigational drug may be 314.92 Drug products for which abbreviated effective for the expanded access use applications may be submitted. and would not expose patients to an 314.93 Petition to request a change from a unreasonable and significant risk of ill- listed drug. ness or injury. This evidence would or- 314.94 Content and format of an abbreviated dinarily consist of clinical data from application. phase 3 or phase 2 trials, but could be 314.95 Notice of certification of invalidity based on more preliminary clinical evi- or noninfringement of a patent. dence. 314.96 Amendments to an unapproved abbreviated application. (b) Submission. The expanded access 314.97 Supplements and other changes to an submission must include information approved abbreviated application. adequate to satisfy FDA that the cri- 314.98 Postmarketing reports. teria in § 312.305(a) and paragraph (a) of 314.99 Other responsibilities of an applicant this section have been met. The ex- of an abbreviated application.

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Subpart D—FDA Action on Applications 314.430 Availability for public disclosure of and Abbreviated Applications data and information in an application or abbreviated application. 314.100 Timeframes for reviewing applica- 314.440 Addresses for applications and ab- tions and abbreviated applications. breviated applications. 314.101 Filing an application and receiving 314.445 Guidance documents. an abbreviated new drug application. 314.102 Communications between FDA and Subpart H—Accelerated Approval of New applicants. Drugs for Serious or Life-Threatening Ill- 314.103 Dispute resolution. nesses 314.104 Drugs with potential for abuse. 314.105 Approval of an application and an 314.500 Scope. abbreviated application. 314.510 Approval based on a surrogate end- 314.106 Foreign data. point or on an effect on a clinical end- 314.107 Effective date of approval of a point other than survival or irreversible 505(b)(2) application or abbreviated new morbidity. drug application under section 505(j) of 314.520 Approval with restrictions to assure the act. safe use. 314.108 New drug product exclusivity. 314.530 Withdrawal procedures. 314.110 Complete response letter to the ap- 314.540 Postmarketing safety reporting. plicant. 314.120 [Reserved] 314.550 Promotional materials. 314.122 Submitting an abbreviated applica- 314.560 Termination of requirements. tion for, or a 505(j)(2)(C) petition that relies on, a listed drug that is no longer Subpart I—Approval of New Drugs When marketed. Human Efficacy Studies Are Not Ethical 314.125 Refusal to approve an application. or Feasible 314.126 Adequate and well-controlled studies. 314.600 Scope. 314.127 Refusal to approve an abbreviated 314.610 Approval based on evidence of effec- new drug application. tiveness from studies in animals. 314.150 Withdrawal of approval of an appli- 314.620 Withdrawal procedures. cation or abbreviated application. 314.630 Postmarketing safety reporting. 314.151 Withdrawal of approval of an abbre- 314.640 Promotional materials. viated new drug application under sec- 314.650 Termination of requirements. tion 505(j)(5) of the act. AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, 314.152 Notice of withdrawal of approval of 355, 356, 356a, 356b, 356c, 371, 374, 379e. an application or abbreviated application for a new drug. SOURCE: 50 FR 7493, Feb. 22, 1985, unless 314.153 Suspension of approval of an abbre- otherwise noted. viated new drug application. 314.160 Approval of an application or abbre- EDITORIAL NOTE: Nomenclature changes to viated application for which approval part 314 can be found at 69 FR 13717, Mar. 24, was previously refused, suspended, or 2004. withdrawn. 314.161 Determination of reasons for vol- Subpart A—General Provisions untary withdrawal of a listed drug. 314.162 Removal of a drug product from the § 314.1 Scope of this part. list. 314.170 Adulteration and misbranding of an (a) This part sets forth procedures approved drug. and requirements for the submission to, and the review by, the Food and Subpart E—Hearing Procedures for New Drug Administration of applications Drugs and abbreviated applications to market a new drug under section 505 of the 314.200 Notice of opportunity for hearing; notice of participation and request for Federal Food, Drug, and Cosmetic Act, hearing; grant or denial of hearing. as well as amendments, supplements, 314.201 Procedure for hearings. and postmarketing reports to them. 314.235 Judicial review. (b) This part does not apply to drug products subject to licensing by FDA Subpart F [Reserved] under the Public Health Service Act (58 Stat. 632 as amended (42 U.S.C. 201 et Subpart G—Miscellaneous Provisions seq.)) and subchapter F of chapter I of 314.410 Imports and exports of new drugs. title 21 of the Code of Federal Regula- 314.420 Drug master files. tions.

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(c) References in this part to regula- whom the investigations were con- tions in the Code of Federal Regula- ducted. tions are to chapter I of title 21, unless Approval letter means a written com- otherwise noted. munication to an applicant from FDA [50 FR 7493, Feb. 22, 1985, as amended at 57 approving an application or an abbre- FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999] viated application. Assess the effects of the change means § 314.2 Purpose. to evaluate the effects of a manufac- The purpose of this part is to estab- turing change on the identity, lish an efficient and thorough drug re- strength, quality, purity, and potency view process in order to: (a) Facilitate of a drug product as these factors may the approval of drugs shown to be safe relate to the safety or effectiveness of and effective; and (b) ensure the dis- the drug product. approval of drugs not shown to be safe Authorized generic drug means a listed and effective. These regulations are drug, as defined in this section, that also intended to establish an effective has been approved under section 505(c) system for FDA’s surveillance of mar- of the act and is marketed, sold, or dis- keted drugs. These regulations shall be tributed directly or indirectly to retail construed in light of these objectives. class of trade with labeling, packaging (other than repackaging as the listed § 314.3 Definitions. drug in blister packs, unit doses, or (a) The definitions and interpreta- similar packaging for use in institutions contained in section 201 of the act tions), product code, labeler code, trade apply to those terms when used in this name, or trademark that differs from part. that of the listed drug. (b) The following definitions of terms Class 1 resubmission means the resub- apply to this part: mission of an application or efficacy Abbreviated application means the ap- supplement, following receipt of a com- plication described under § 314.94, in- plete response letter, that contains one cluding all amendments and supple- or more of the following: Final printed ments to the application. ‘‘Abbreviated labeling, draft labeling, certain safety application’’ applies to both an abbre- updates, stability updates to support viated new drug application and an ab- provisional or final dating periods, breviated antibiotic application. Act means the Federal Food, Drug, commitments to perform post- and Cosmetic Act (sections 201–901 (21 marketing studies (including proposals U.S.C. 301–392)). for such studies), assay validation Applicant means any person who sub- data, final release testing on the last mits an application or abbreviated ap- lots used to support approval, minor plication or an amendment or supple- reanalyses of previously submitted ment to them under this part to obtain data, and other comparatively minor FDA approval of a new drug or an anti- information. biotic drug and any person who owns Class 2 resubmission means the resub- an approved application or abbreviated mission of an application or efficacy application. supplement, following receipt of a com- Application means the application de- plete response letter, that includes any scribed under § 314.50, including all item not specified in the definition of amendements and supplements to the ‘‘Class 1 resubmission,’’ including any application. item that would require presentation 505(b)(2) Application means an appli- to an advisory committee. cation submitted under section Complete response letter means a writ- 505(b)(1) of the act for a drug for which ten communication to an applicant the investigations described in section from FDA usually describing all of the 505(b)(1)(A) of the act and relied upon deficiencies that the agency has identi- by the applicant for approval of the ap- fied in an application or abbreviated plication were not conducted by or for application that must be satisfactorily the applicant and for which the appli- addressed before it can be approved. cant has not obtained a right of ref- Drug product means a finished dosage erence or use from the person by or for form, for example, tablet, capsule, or

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solution, that contains a drug sub- or abbreviated application for that stance, generally, but not necessarily, drug product. in association with one or more other Newly acquired information means ingredients. data, analyses, or other information Drug substance means an active ingre- not previously submitted to the agen- dient that is intended to furnish phar- cy, which may include (but are not lim- macological activity or other direct ef- ited to) data derived from new clinical fect in the diagnosis, cure, mitigation, studies, reports of adverse events, or treatment, or prevention of disease or new analyses of previously submitted to affect the structure or any function data (e.g., meta-analyses) if the stud- of the human body, but does not in- ies, events or analyses reveal risks of a clude intermediates use in the syn- different type or greater severity or thesis of such ingredient. frequency than previously included in Efficacy supplement means a supple- submissions to FDA. ment to an approved application pro- Original application means a pending posing to make one or more related application for which FDA has never changes from among the following issued a complete response letter or ap- changes to product labeling: proval letter, or an application that (1) Add or modify an indication or was submitted again after FDA had re- claim; fused to file it or after it was with- (2) Revise the dose or dose regimen; drawn without being approved. (3) Provide for a new route of admin- Reference listed drug means the listed istration; drug identified by FDA as the drug (4) Make a comparative efficacy product upon which an applicant relies claim naming another drug product; in seeking approval of its abbreviated (5) Significantly alter the intended application. patient population; (6) Change the marketing status from Resubmission means submission by prescription to over-the-counter use; the applicant of all materials needed to (7) Provide for, or provide evidence of fully address all deficiencies identified effectiveness necessary for, the tradi- in the complete response letter. An ap- tional approval of a product originally plication or abbreviated application for approved under subpart H of part 314; which FDA issued a complete response or letter, but which was withdrawn before (8) Incorporate other information approval and later submitted again, is based on at least one adequate and not a resubmission. well-controlled clinical study. Right of reference or use means the au- FDA means the Food and Drug Ad- thority to rely upon, and otherwise ministration. use, an investigation for the purpose of Listed drug means a new drug product obtaining approval of an application, that has an effective approval under including the ability to make available section 505(c) of the act for safety and the underlying raw data from the in- effectiveness or under section 505(j) of vestigation for FDA audit, if necessary. the act, which has not been withdrawn Specification means the quality stand- or suspended under section 505(e)(1) ard (i.e., tests, analytical procedures, through (e)(5) or (j)(5) of the act, and and acceptance criteria) provided in an which has not been withdrawn from approved application to confirm the sale for what FDA has determined are quality of drug substances, drug prod- reasons of safety or effectiveness. List- ucts, intermediates, raw materials, re- ed drug status is evidenced by the drug agents, components, in-process mate- product’s identification as a drug with rials, container closure systems, and an effective approval in the current other materials used in the production edition of FDA’s ‘‘Approved Drug Prod- of a drug substance or drug product. ucts with Therapeutic Equivalence For the purpose of this definition, ac- Evaluations’’ (the list) or any current ceptance criteriameans numerical lim- supplement thereto, as a drug with an its, ranges, or other criteria for the effective approval. A drug product is tests described. deemed to be a listed drug on the date The list means the list of drug prod- of effective approval of the application ucts with effective approvals published

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in the current edition of FDA’s publi- etary, code, and chemical names; the cation ‘‘Approved Drug Products with dosage form and strength; the route of Therapeutic Equivalence Evaluations’’ administration; the identification and any current supplement to the numbers of all investigational new publication. drug applications that are referenced [50 FR 7493, Feb. 22, 1985, as amended at 57 in the application; the identification FR 17981, Apr. 28, 1992; 69 FR 18763, Apr. 8, numbers of all drug master files and 2004; 73 FR 39607, July 10, 2008; 73 FR 49609, other applications under this part that Aug. 22, 2008; 74 FR 37167, July 28, 2009] are referenced in the application; and the drug product’s proposed indications Subpart B—Applications for use. (2) A statement whether the submis- § 314.50 Content and format of an ap- sion is an original submission, a plication. 505(b)(2) application, a resubmission, or Applications and supplements to ap- a supplement to an application under proved applications are required to be § 314.70. submitted in the form and contain the (3) A statement whether the appli- information, as appropriate for the par- cant proposes to market the drug prod- ticular submission, required under this uct as a prescription or an over-the- section. Three copies of the application counter product. are required: An archival copy, a re- (4) A check-list identifying what en- view copy, and a field copy. An applica- closures required under this section the tion for a new chemical entity will gen- applicant is submitting. erally contain an application form, an (5) The applicant, or the applicant’s index, a summary, five or six technical attorney, agent, or other authorized of- sections, case report tabulations of pa- ficial shall sign the application. If the tient data, case report forms, drug samples, and labeling, including, if ap- person signing the application does not plicable, any Medication Guide re- reside or have a place of business with- quired under part 208 of this chapter. in the United States, the application is Other applications will generally con- required to contain the name and ad- tain only some of those items, and in- dress of, and be countersigned by, an formation will be limited to that need- attorney, agent, or other authorized of- ed to support the particular submis- ficial who resides or maintains a place sion. These include an application of of business within the United States. the type described in section 505(b)(2) (b) Index. The archival copy of the of the act, an amendment, and a sup- application is required to contain a plement. The application is required to comprehensive index by volume num- contain reports of all investigations of ber and page number to the summary the drug product sponsored by the ap- under paragraph (c) of this section, the plicant, and all other information technical sections under paragraph (d) about the drug pertinent to an evalua- of this section, and the supporting in- tion of the application that is received formation under paragraph (f) of this or otherwise obtained by the applicant section. from any source. FDA will maintain (c) Summary. (1) An application is re- guidance documents on the format and quired to contain a summary of the ap- content of applications to assist appli- plication in enough detail that the cants in their preparation. reader may gain a good general under- (a) Application form. The applicant standing of the data and information in shall submit a completed and signed the application, including an under- application form that contains the fol- standing of the quantitative aspects of lowing: the data. The summary is not required (1) The name and address of the ap- for supplements under § 314.70. Re- plicant; the date of the application; the submissions of an application should application number if previously issued contain an updated summary, as appro- (for example, if the application is a re- priate. The summary should discuss all submission, an amendment, or a sup- aspects of the application, and syn- plement); the name of the drug prod- thesize the information into a well- uct, including its established, propri- structured and unified document. The

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summary should be written at approxi- (iv) A summary of the chemistry, mately the level of detail required for manufacturing, and controls section of publication in, and meet the editorial the application. standards generally applied by, ref- (v) A summary of the nonclinical ereed scientific and medical journals. pharmacology and toxicology section In addition to the agency personnel re- of the application. viewing the summary in the context of (vi) A summary of the human phar- their review of the application, FDA macokinetics and bioavailability sec- may furnish the summary to FDA advi- tion of the application. sory committee members and agency (vii) A summary of the microbiology officials whose duties require an under- section of the application (for anti-in- standing of the application. To the ex- fective drugs only). tent possible, data in the summary (viii) A summary of the clinical data should be presented in tabular and section of the application, including graphic forms. FDA has prepared a the results of statistical analyses of guideline under § 10.90(b) that provides the clinical trials. information about how to prepare a (ix) A concluding discussion that pre- summary. The summary required sents the benefit and risk consider- under this paragraph may be used by ations related to the drug, including a FDA or the applicant to prepare the discussion of any proposed additional Summary Basis of Approval document studies or surveillance the applicant for public disclosure (under intends to conduct postmarketing. § 314.430(e)(2)(ii)) when the application (d) Technical sections. The application is approved. is required to contain the technical (2) The summary is required to con- sections described below. Each tech- tain the following information: nical section is required to contain (i) The proposed text of the labeling, data and information in sufficient de- including, if applicable, any Medica- tail to permit the agency to make a tion Guide required under part 208 of knowledgeable judgment about wheth- this chapter, for the drug, with annota- er to approve the application or wheth- tions to the information in the sumer grounds exist under section 505(d) of mary and technical sections of the ap- the act to refuse to approve the appli- plication that support the inclusion of cation. The required technical sections each statement in the labeling, and, if are as follows: the application is for a prescription (1) Chemistry, manufacturing, and con- drug, statements describing the rea- trols section. A section describing the sons for omitting a section or sub- composition, manufacture, and speci- section of the labeling format in § 201.57 fication of the drug substance and the 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 the drug, its intended use, and the po- and stability; the name and address of tential clinical benefits of the drug its manufacturer; the method of syn- product. thesis (or isolation) and purification of (iii) A brief description of the mar- the drug substance; the process con- keting history, if any, of the drug out- trols used during manufacture and side the United States, including a list packaging; and the specifications nec- of the countries in which the drug has essary to ensure the identity, strength, been marketed, a list of any countries quality, and purity of the drug sub- in which the drug has been withdrawn stance and the bioavailability of the from marketing for any reason related drug products made from the sub- to safety or effectiveness, and a list of stance, including, for example, tests, countries in which applications for analytical procedures, and acceptance marketing are pending. The descrip- criteria relating to stability, sterility, tion is required to describe both mar- particle size, and crystalline form. The keting by the applicant and, if known, application may provide additionally the marketing history of other persons. for the use of alternatives to meet any

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of these requirements, including alter- by § 211.84(d) of this chapter and on the native sources, process controls, and drug product as required by § 211.165 of analytical procedures. Reference to the this chapter. current edition of the U.S. Pharma- (c) The proposed or actual master copeia and the National Formulary production record, including a descrip- may satisfy relevant requirements in tion of the equipment, to be used for this paragraph. the manufacture of a commercial lot of (ii)(a) Drug product. A list of all com- the drug product or a comparably de- ponents used in the manufacture of the tailed description of the production drug product (regardless of whether process for a representative batch of they appear in the drug product) and a the drug product. statement of the composition of the (iii) Environmental impact. The appli- drug product; the specifications for cation is required to contain either a each component; the name and address claim for categorical exclusion under of each manufacturer of the drug prod- § 25.30 or 25.31 of this chapter or an en- uct; a description of the manufacturing vironmental assessment under § 25.40 of and packaging procedures and in-proc- this chapter. ess controls for the drug product; the (iv) The applicant may, at its option, specifications necessary to ensure the submit a complete chemistry, manu- identity, strength, quality, purity, po- facturing, and controls section 90 to 120 tency, and bioavailability of the drug days before the anticipated submission product, including, for example, tests, of the remainder of the application. analytical procedures, and acceptance FDA will review such early submis- criteria relating to sterility, dissolu- sions as resources permit. tion rate, container closure systems; (v) The applicant shall include a and stability data with proposed expi- statement certifying that the field ration dating. The application may copy of the application has been pro- provide additionally for the use of al- vided to the applicant’s home FDA dis- ternatives to meet any of these re- trict office. quirements, including alternative com- (2) Nonclinical pharmacology and toxi- ponents, manufacturing and packaging cology section. A section describing, procedures, in-process controls, and an- with the aid of graphs and tables, ani- alytical procedures. Reference to the mal and in vitro studies with drug, in- current edition of the U.S. Pharma- cluding the following: copeia and the National Formulary (i) Studies of the pharmacological ac- may satisfy relevant requirements in tions of the drug in relation to its pro- 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 batch production record; the specifica- the drug’s acute, subacute, and chronic tion for each component and for the toxicity; carcinogenicity; and studies drug product; the names and addresses of toxicities related to the drug’s par- of the sources of the active and ticular mode of administration or con- noncompendial inactive components ditions of use. and of the container and closure sys- (iii) Studies, as appropriate, of the ef- tem for the drug product; the name and fects of the drug on reproduction and address of each contract facility in- on the developing fetus. volved in the manufacture, processing, (iv) Any studies of the absorption, packaging, or testing of the drug prod- distribution, metabolism, and excre- uct and identification of the operation tion of the drug in animals. performed by each contract facility; (v) For each nonclinical laboratory and the results of any test performed study subject to the good laboratory on the components used in the manu- practice regulations under part 58 a facture of the drug product as required statement that it was conducted in

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compliance with the good laboratory including results of any known epi- practice regulations in part 58, or, if demiologic studies to demonstrate the study was not conducted in compli- prevalence of resistance factors. ance with those regulations, a brief (iv) A description of clinical microbi- statement of the reason for the non- ology 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 application describes in the of the protocol and a brief description chemistry, manufacturing, and con- of the results and status of the study. trols section tests, analytical proce- (iii) A description of each uncon- dures, and acceptance criteria needed trolled clinical study, a summary of to assure the bioavailability of the the results, and a brief statement ex- drug product or drug substance, or plaining why the study is classified as both, a statement in this section of the uncontrolled. rationale for establishing the tests, an- (iv) A description and analysis of any alytical procedures, and acceptance other data or information relevant to criteria, including data and informa- an evaluation of the safety and effec- tion supporting 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 and the bioavailability or bioequiva- clinical investigations, including con- lence, or both, of the drug product. trolled and uncontrolled studies of uses (4) Microbiology section. If the drug is of the drug other than those proposed an anti-infective drug, a section de- in the application, commercial mar- scribing the microbiology data, includ- keting experience, reports in the sci- ing the following: entific literature, and unpublished sci- (i) A description of the biochemical entific papers. basis of the drug’s action on microbial (v) An integrated summary of the physiology. data demonstrating substantial evi- (ii) A description of the anti- dence of effectiveness for the claimed microbial spectra of the drug, includ- indications. Evidence is also required ing results of in vitro preclinical stud- to support the dosage and administra- ies to demonstrate concentrations of tion section of the labeling, including the drug required for effective use. support for the dosage and dose inter- (iii) A description of any known val recommended. The effectiveness mechanisms of resistance to the drug, data shall be presented by gender, age,

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and racial subgroups and shall identify sponse letter; and (3) at other times as any modifications of dose or dose inter- requested by FDA. Prior to the submis- val needed for specific subgroups. Ef- sion of the first such report, applicants fectiveness data from other subgroups are encouraged to consult with FDA re- of the population of patients treated, garding further details on its form and when appropriate, such as patients content. 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 shall 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 shall 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 shall 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 shall 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 shall, under section nization, a statement containing the 505(i) of the act, update periodically its name and address of the contract re- pending application with new safety in- search organization, identification of formation learned about the drug that the clinical study, and a listing of the may reasonably affect the statement of obligations transferred. If all obliga- contraindications, warnings, pre- tions governing the conduct of the cautions, and adverse reactions in the study have been transferred, a general draft labeling and, if applicable, any statement of this transfer—in lieu of a Medication Guide required under part listing of the specific obligations trans- 208 of this chapter. These ‘‘safety up- ferred—may be submitted. date reports’’ are required to include (xi) If original subject records were the same kinds of information (from audited or reviewed by the sponsor in clinical studies, animal studies, and the course of monitoring any clinical other sources) and are required to be study to verify the accuracy of the case submitted in the same format as the reports submitted to the sponsor, a list integrated summary in paragraph identifying each clinical study so au- (d)(5)(vi)(a) of this section. In addition, dited or reviewed. the reports are required to include the (6) Statistical section. A section de- case report forms for each patient who scribing the statistical evaluation of died during a clinical study or who did clinical data, including the following: not complete the study because of an (i) A copy of the information sub- adverse event (unless this requirement mitted under paragraph (d)(5)(ii) of this is waived). The applicant shall submit section concerning the description and these reports (1) 4 months after the ini- analysis of each controlled clinical tial submission; (2) in a resubmission study, and the documentation and sup- following receipt of a complete reporting statistical analyses used in

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evaluating the controlled clinical stud- (i) Three copies of the analytical pro- ies. cedures and related descriptive infor- (ii) A copy of the information sub- mation contained in the chemistry, mitted under paragraph (d)(5)(vi)(a) of manufacturing, and controls section this section concerning a summary of under paragraph (d)(1) of this section information about the safety of the for the drug substance and the drug drug product, and the documentation product that are necessary for FDA’s and supporting statistical analyses laboratories to perform all necessary used in evaluating the safety informa- tests on the samples and to validate tion. the applicant’s analytical procedures. (7) Pediatric use section. A section de- The related descriptive information in- scribing the investigation of the drug cludes a description of each sample; for use in pediatric populations, includ- the proposed regulatory specifications ing an integrated summary of the infor the drug; a detailed description of formation (the clinical pharmacology the methods of analysis; supporting studies, controlled clinical studies, or data for accuracy, specificity, precision uncontrolled clinical studies, or other and ruggedness; and complete results data or information) that is relevant to of the applicant’s tests on each sample. the safety and effectiveness and bene- (ii) Copies of the label and all label- fits and risks of the drug in pediatric ing for the drug product (including, if populations for the claimed indica- applicable, any Medication Guide re- tions, a reference to the full descrip- quired under part 208 of this chapter) tions of such studies provided under for the drug product (4 copies of draft paragraphs (d)(3) and (d)(5) of this sec- labeling or 12 copies of final printed lation, and information required to be beling). submitted under § 314.55. (f) Case report forms and tabulations. (e) Samples and labeling. (1) Upon re- The archival copy of the application is quest from FDA, the applicant shall required to contain the following case submit the samples described below to the places identified in the agency’s re- report tabulations and case report quest. FDA will generally ask appli- forms: cants to submit samples directly to (1) Case report tabulations. The appli- two or more agency laboratories that cation is required to contain tabula- will perform all necessary tests on the tions of the data from each adequate samples and validate the applicant’s and well-controlled study under analytical procedures. § 314.126 (Phase 2 and Phase 3 studies as (i) Four representative samples of the described in §§ 312.21 (b) and (c) of this following, each sample in sufficient chapter), tabulations of the data from quantity to permit FDA to perform the earliest clinical pharmacology three times each test described in the studies (Phase 1 studies as described in application to determine whether the § 312.21(a) of this chapter), and tabula- drug substance and the drug product tions of the safety data from other meet the specifications given in the ap- clinical studies. Routine submission of plication: other patient data from uncontrolled (a) The drug product proposed for studies is not required. The tabulations marketing; are required to include the data on (b) The drug substance used in the each patient in each study, except that drug product from which the samples the applicant may delete those tabula- of the drug product were taken; and tions which the agency agrees, in ad- (c) Reference standards and blanks vance, are not pertinent to a review of (except that reference standards recog- the drug’s safety or effectiveness. Upon nized in an official compendium need request, FDA will discuss with the ap- not be submitted). plicant in a ‘‘pre-NDA’’ conference (ii) Samples of the finished market those tabulations that may be appro- package, if requested by FDA. priate for such deletion. Barring un- (2) The applicant shall submit the foreseen circumstances, tabulations following in the archival copy of the agreed to be deleted at such a con- application: ference will not be requested during

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the conduct of FDA’s review of the ap- ume, and page number in the agency’s plication. If such unforeseen cir- records where the information can be cumstances do occur, any request for found. A reference to information sub- deleted tabulations will be made by the mitted to the agency by a person other director of the FDA division respon- than the applicant is required to con- sible for reviewing the application, in tain a written statement that author- accordance with paragraph (f)(3) of this izes the reference and that is signed by section. the person who submitted the informa- (2) Case report forms. The application tion. is required to contain copies of indi- (2) The applicant shall submit an ac- vidual case report forms for each pa- curate and complete English trans- tient who died during a clinical study lation of each part of the application or who did not complete the study be- that is not in English. The applicant cause of an adverse event, whether be- shall submit a copy of each original lit- lieved to be drug related or not, includ- erature publication for which an ing patients receiving reference drugs English translation is submitted. or placebo. This requirement may be (3) If an applicant who submits a new waived by FDA for specific studies if drug application under section 505(b) of the case report forms are unnecessary the act obtains a ‘‘right of reference or for a proper review of the study. use,’’ as defined under § 314.3(b), to an (3) Additional data. The applicant investigation described in clause (A) of shall submit to FDA additional case re- section 505(b)(1) of the act, the appli- port forms and tabulations needed to cant shall include in its application a conduct a proper review of the applica- written statement signed by the owner tion, as requested by the director of of the data from each such investiga- the FDA division responsible for re- tion that the applicant may rely on in viewing the application. The appli- support of the approval of its applica- cant’s failure to submit information re- tion, and provide FDA access to, the quested by FDA within 30 days after re- underlying raw data that provide the ceipt of the request may result in the basis for the report of the investigation agency viewing any eventual submis- submitted in its application. sion as a major amendment under § 314.60 and extending the review period (h) Patent information. The applica- as necessary. If desired by the appli- tion is required to contain the patent cant, the FDA division director will information described under § 314.53. verify in writing any request for addi- (i) Patent certification—(1) Contents. A tional data that was made orally. 505(b)(2) application is required to con- (4) Applicants are invited to meet tain the following: with FDA before submitting an appli- (i) Patents claiming drug, drug product, cation to discuss the presentation and or method of use. (A) Except as provided format of supporting information. If in paragraph (i)(2) of this section, a the applicant and FDA agree, the appli- certification with respect to each pat- cant may submit tabulations of patient ent issued by the United States Patent data and case report forms in a form and Trademark Office that, in the opin- other than hard copy, for example, on ion of the applicant and to the best of microfiche or computer tapes. its knowledge, claims a drug (the drug (g) Other. The following general re- product or drug substance that is a quirements apply to the submission of component of the drug product) on information within the summary under which investigations that are relied paragraph (c) of this section and within upon by the applicant for approval of the technical sections under paragraph its application were conducted or that (d) of this section. claims an approved use for such drug (1) The applicant ordinarily is not re- and for which information is required quired to resubmit information pre- to be filed under section 505(b) and (c) viously submitted, but may incor- of the act and § 314.53. For each such porate the information by reference. A patent, the applicant shall provide the reference to information submitted patent number and certify, in its opin- previously is required to identify the ion and to the best of its knowledge, file by name, reference number, vol- one of the following circumstances:

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(1) That the patent information has (iii) Method of use patent. (A) If infor- not been submitted to FDA. The appli- mation that is submitted under section cant shall entitle such a certification 505(b) or (c) of the act and § 314.53 is for ‘‘Paragraph I Certification’’; a method of use patent, and the label- (2) That the patent has expired. The ing for the drug product for which the applicant shall entitle such a certifi- applicant is seeking approval does not cation ‘‘Paragraph II Certification’’; include any indications that are cov- (3) The date on which the patent will ered by the use patent, a statement ex- expire. The applicant shall entitle such plaining that the method of use patent a certification ‘‘Paragraph III Certifi- does not claim any of the proposed in- cation’’; or dications. (4) That the patent is invalid, unen- (B) If the labeling of the drug product forceable, or will not be infringed by for which the applicant is seeking ap- the manufacture, use, or sale of the proval includes an indication that, ac- drug product for which the application cording to the patent information sub- is submitted. The applicant shall enti- mitted under section 505(b) or (c) of the tle such a certification ‘‘Paragraph IV act and § 314.53 or in the opinion of the Certification’’. This certification shall applicant, is claimed by a use patent, be submitted in the following form: the applicant shall submit an applicable certification under paragraph I, (name of applicant), certify that Patent No. (i)(1)(i) of this section. llllll (is invalid, unenforceable, or will (2) Method of manufacturing patent. not be infringed by the manufacture, use, or sale of) (name of proposed drug product) for An applicant is not required to make a which this application is submitted. certification with respect to any patent that claims only a method of man- The certification shall be accompanied ufacturing the drug product for which by a statement that the applicant will the applicant is seeking approval. comply with the requirements under (3) Licensing agreements. If a 505(b)(2) § 314.52(a) with respect to providing a application is for a drug or method of notice to each owner of the patent or using a drug claimed by a patent and their representatives and to the holder the applicant has a licensing agree- of the approved application for the ment with the patent owner, the appli- drug product which is claimed by the cant shall submit a certification under patent or a use of which is claimed by paragraph (i)(1)(i)(A)(4) of this section the patent and with the requirements (‘‘Paragraph IV Certification’’) as to under § 314.52(c) with respect to the that patent and a statement that it has content of the notice. been granted a patent license. If the (B) If the drug on which investiga- patent owner consents to an immediate tions that are relied upon by the appli- effective date upon approval of the cant were conducted is itself a licensed 505(b)(2) application, the application generic drug of a patented drug first shall contain a written statement from approved under section 505(b) of the the patent owner that it has a licens- act, the appropriate patent certifi- ing agreement with the applicant and cation under this section with respect that it consents to an immediate effec- to each patent that claims the first-ap- tive date. proved patented drug or that claims an (4) Late submission of patent informa- approved use for such a drug. tion. If a patent described in paragraph (ii) No relevant patents. If, in the opin- (i)(1)(i)(A) of this section is issued and ion of the applicant and to the best of the holder of the approved application its knowledge, there are no patents de- for the patented drug does not submit scribed in paragraph (i)(1)(i) of this sec- the required information on the patent tion, a certification in the following within 30 days of issuance of the pat- form: ent, an applicant who submitted a 505(b)(2) application that, before the In the opinion and to the best knowledge of submission of the patent information, (name of applicant), there are no patents that claim the drug or drugs on which investiga- contained an appropriate patent cer- tions that are relied upon in this application tification is not required to submit an were conducted or that claim a use of such amended certification. An applicant drug or drugs. whose 505(b)(2) application is filed after

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a late submission of patent informa- fective date) who has made a certifi- tion or whose 505(b)(2) application was cation with respect to such patent previously filed but did not contain an shall amend its certification. The ap- appropriate patent certification at the plicant shall certify under paragraph time of the patent submission shall (i)(1)(ii) of this section that no patents submit a certification under paragraph described in paragraph (i)(1)(i) of this (i)(1)(i) or (i)(1)(ii) of this section or a section claim the drug or, if other rel- statement under paragraph (i)(1)(iii) of evant patents claim the drug, shall this section as to that patent. amend the certification to refer only to (5) Disputed patent information. If an those relevant patents. In the amend- applicant disputes the accuracy or rel- ment, the applicant shall state the rea- evance of patent information sub- son for the change in certification mitted to FDA, the applicant may seek (that the patent is or has been removed a confirmation of the correctness of from the list). A patent that is the sub- the patent information in accordance ject of a lawsuit under § 314.107(c) shall with the procedures under § 314.53(f). not be removed from the list until FDA Unless the patent information is with- determines either that no delay in ef- drawn or changed, the applicant must fective dates of approval is required submit an appropriate certification for under that section as a result of the each relevant patent. lawsuit, that the patent has expired, or (6) Amended certifications. A certifi- that any such period of delay in effec- cation submitted under paragraphs tive dates of approval is ended. An ap- (i)(1)(i) through (i)(1)(iii) of this section plicant shall submit an amended cer- may be amended at any time before the tification as an amendment to a pend- effective date of the approval of the ap- ing application. Once an amendment plication. An applicant shall submit an for the change has been submitted, the amended certification as an amend- application will no longer be consid- ment to a pending application or by ered to be one containing a certifi- letter to an approved application. If an cation under paragraph (i)(1)(i)(A)(4) of applicant with a pending application this section. voluntarily makes a patent certifi- (iii) Other amendments. (A) Except as cation for an untimely filed patent, the provided in paragraphs (i)(4) and applicant may withdraw the patent (i)(6)(iii)(B) of this section, an appli- certification for the untimely filed pat- cant shall amend a submitted certifi- ent. Once an amendment or letter for cation if, at any time before the effec- the change in certification has been tive date of the approval of the applica- submitted, the application will no tion, the applicant learns that the sub- longer be considered to be one con- mitted certification is no longer accu- taining the prior certification. rate. (i) After finding of infringement. An ap- (B) An applicant is not required to plicant who has submitted a certifi- amend a submitted certification when cation under paragraph (i)(1)(i)(A)(4) of information on an otherwise applicable this section and is sued for patent in- patent is submitted after the effective fringement within 45 days of the re- date of approval for the 505(b)(2) appli- ceipt of notice sent under § 314.52 shall cation. amend the certification if a final judg- (j) Claimed exclusivity. A new drug ment in the action is entered finding product, upon approval, may be enti- the patent to be infringed unless the tled to a period of marketing exclu- final judgment also finds the patent to sivity under the provisions of § 314.108. be invalid. In the amended certifi- If an applicant believes its drug prod- cation, the applicant shall certify uct is entitled to a period of exclu- under paragraph (i)(1)(i)(A)(3) of this sivity, it shall submit with the new section that the patent will expire on a drug application prior to approval the specific date. following information: (ii) After removal of a patent from the (1) A statement that the applicant is list. If a patent is removed from the claiming exclusivity. list, any applicant with a pending ap- (2) A reference to the appropriate plication (including a tentatively ap- paragraph under § 314.108 that supports proved application with a delayed ef- its claim.

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(3) If the applicant claims exclusivity certification. To demonstrate ‘‘sub- under § 314.108(b)(2), information to stantial support,’’ an applicant must show that, to the best of its knowledge either provide a certified statement or belief, a drug has not previously from a certified public accountant that been approved under section 505(b) of the applicant provided 50 percent or the act containing any active moiety more of the cost of conducting the in the drug for which the applicant is study or provide an explanation of why seeking approval. FDA should consider the applicant to (4) If the applicant claims exclusivity have conducted or sponsored the study under § 314.108(b)(4) or (b)(5), the fol- if the applicant’s financial contribu- lowing information to show that the tion to the study is less than 50 percent application contains ‘‘new clinical in- or the applicant did not sponsor the investigations’’ that are ‘‘essential to ap- vestigational new drug. A predecessor proval of the application or supple- in interest is an entity, e.g., a corpora- ment’’ and were ‘‘conducted or spon- tion, that the applicant has taken over, sored by the applicant:’’ merged with, or purchased, or from (i) ‘‘New clinical investigations.’’ A cer- which the applicant has purchased all tification that to the best of the appli- rights to the drug. Purchase of non- cant’s knowledge each of the clinical exclusive rights to a clinical investiga- investigations included in the application after it is completed is not suffi- tion meets the definition of ‘‘new clin- cient to satisfy this definition. ical investigation’’ set forth in (k) Financial certification or disclosure § 314.108(a). statement. The application shall contain (ii) ‘‘Essential to approval.’’ A list of a financial certification or disclosure all published studies or publicly avail- statement or both as required by part able reports of clinical investigations 54 of this chapter. known to the applicant through a literature search that are relevant to the (l) Format of an original application— conditions for which the applicant is (1) Archival copy. The applicant must seeking approval, a certification that submit a complete archival copy of the the applicant has thoroughly searched application that contains the informa- the scientific literature and, to the tion required under paragraphs (a) best of the applicant’s knowledge, the through (f) of this section. FDA will list is complete and accurate and, in maintain the archival copy during the the applicant’s opinion, such published review of the application to permit in- studies or publicly available reports do dividual reviewers to refer to informa- not provide a sufficient basis for the tion that is not contained in their par- approval of the conditions for which ticular technical sections of the appli- the applicant is seeking approval with- cation, to give other agency personnel out reference to the new clinical inves- access to the application for official tigation(s) in the application, and an business, and to maintain in one place explanation as to why the studies or a complete copy of the application. Ex- reports are insufficient. cept as required by paragraph (l)(1)(i) (iii) ‘‘Conducted or sponsored by.’’ If of this section, applicants may submit the applicant was the sponsor named in the archival copy on paper or in elec- the Form FDA–1571 for an investiga- tronic format provided that electronic tional new drug application (IND) submissions are made in accordance under which the new clinical investiga- with part 11 of this chapter. tion(s) that is essential to the approval (i) Labeling. The content of labeling of its application was conducted, iden- required under § 201.100(d)(3) of this tification of the IND by number. If the chapter (commonly referred to as the applicant was not the sponsor of the package insert or professional label- IND under which the clinical investiga- ing), including all text, tables, and fig- tion(s) was conducted, a certification ures, must be submitted to the agency that the applicant or its predecessor in in electronic format as described in interest provided substantial support paragraph (l)(5) of this section. This re- for the clinical investigation(s) that is quirement is in addition to the require- essential to the approval of its applica- ments of paragraph (e)(2)(ii) of this section, and information supporting the tion that copies of the formatted label

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and all labeling be submitted. Submis- drugs and which the applicant certifies sions under this paragraph must be under § 314.50(i)(1)(i)(A)(4) that a patent made in accordance with part 11 of this is invalid, unenforceable, or will not be chapter, except for the requirements of infringed, the applicant shall send no- § 11.10(a), (c) through (h), and (k), and tice of such certification by registered the corresponding requirements of or certified mail, return receipt re- § 11.30. quested to each of the following per- (ii) [Reserved] sons: (2) Review copy. The applicant must (1) Each owner of the patent that is submit a review copy of the applica- the subject of the certification or the tion. Each of the technical sections, de- representative designated by the owner scribed in paragraphs (d)(1) through to receive the notice. The name and ad- (d)(6) of this section, in the review copy dress of the patent owner or its rep- is required to be separately bound with resentative may be obtained from the a copy of the application form required United States Patent and Trademark under paragraph (a) of this section and Office; and a copy of the summary required under (2) The holder of the approved appli- paragraph (c) of this section. cation under section 505(b) of the act (3) Field copy. The applicant must for each drug product which is claimed submit a field copy of the application by the patent or a use of which is that contains the technical section de- claimed by the patent and for which scribed in paragraph (d)(1) of this sec- the applicant is seeking approval, or, if tion, a copy of the application form re- the application holder does not reside quired under paragraph (a) of this sec- or maintain a place of business within tion, a copy of the summary required the United States, the application under paragraph (c) of this section, and holder’s attorney, agent, or other au- a certification that the field copy is a thorized official. The name and address true copy of the technical section de- of the application holder or its attor- scribed in paragraph (d)(1) of this sec- ney, agent, or authorized official may tion contained in the archival and review copies of the application. be obtained from the Orange Book (4) Binding folders. The applicant may Staff, Office of Generic Drugs, 7500 obtain from FDA sufficient folders to Standish Pl., Rockville, MD 20855. bind the archival, the review, and the (3) This paragraph does not apply to field copies of the application. a use patent that claims no uses for (5) Electronic format submissions. Elec- which the applicant is seeking ap- tronic format submissions must be in a proval. form that FDA can process, review, and (b) Sending the notice. The applicant archive. FDA will periodically issue shall send the notice required by para- guidance on how to provide the elec- graph (a) of this section when it re- tronic submission (e.g., method of ceives from FDA an acknowledgment transmission, media, file formats, prep- letter stating that its application has aration and organization of files). been filed. At the same time, the applicant shall amend its application to in- [50 FR 7493, Feb. 22, 1985] clude a statement certifying that the EDITORIAL NOTE: For FEDERAL REGISTER ci- notice has been provided to each person tations affecting § 314.50, see the List of CFR identified under paragraph (a) of this Sections Affected, which appears in the section and that the notice met the Finding Aids section of the printed volume content requirement under paragraph and at www.fdsys.gov. (c) of this section. § 314.52 Notice of certification of inva- (c) Content of a notice. In the notice, lidity or noninfringement of a pat- the applicant shall cite section ent. 505(b)(3)(B) of the act and shall include, (a) Notice of certification. For each but not be limited to, the following in- patent which claims the drug or drugs formation: on which investigations that are relied (1) A statement that a 505(b)(2) appli- upon by the applicant for approval of cation submitted by the applicant has its application were conducted or been filed by FDA. which claims a use for such drug or (2) The application number.

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(3) The established name, if any, as sufficient, and it will count the day fol- defined in section 502(e)(3) of the act, of lowing the date of receipt of the notice the proposed drug product. by the patent owner or its representa- (4) The active ingredient, strength, tive and by the approved application and dosage form of the proposed drug holder as the first day of the 45-day pe- product. riod provided for in section 505(c)(3)(C) (5) The patent number and expiration of the act. FDA may, if the applicant date, as submitted to the agency or as amends its application with a written known to the applicant, of each patent statement that a later date should be alleged to be invalid, unenforceable, or used, count from such later date. not infringed. [59 FR 50362, Oct. 3, 1994, as amended at 68 FR (6) A detailed statement of the fac- 36703, June 18, 2003; 69 FR 11310, Mar. 10, 2004; tual and legal basis of the applicant’s 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, opinion that the patent is not valid, 2009] unenforceable, or will not be infringed. The applicant shall include in the de- § 314.53 Submission of patent informa- tailed statement: tion. (i) For each claim of a patent alleged (a) Who must submit patent informa- not to be infringed, a full and detailed tion. This section applies to any appli- explanation of why the claim is not in- cant who submits to FDA a new drug fringed. application or an amendment to it (ii) For each claim of a patent al- under section 505(b) of the act and leged to be invalid or unenforceable, a § 314.50 or a supplement to an approved full and detailed explanation of the application under § 314.70, except as grounds supporting the allegation. provided in paragraph (d)(2) of this sec- (7) If the applicant does not reside or tion. have a place of business in the United (b) Patents for which information must States, the name and address of an be submitted and patents for which infor- agent in the United States authorized mation must not be submitted—(1) General to accept service of process for the ap- requirements. An applicant described in plicant. paragraph (a) of this section shall sub- (d) Amendment to an application. If an mit the required information on the application is amended to include the declaration form set forth in paragraph certification described in § 314.50(i), the (c) of this section for each patent that applicant shall send the notice required claims the drug or a method of using by paragraph (a) of this section at the the drug that is the subject of the new same time that the amendment to the drug application or amendment or sup- application is submitted to FDA. plement to it and with respect to which (e) Documentation of receipt of notice. a claim of patent infringement could The applicant shall amend its applica- reasonably be asserted if a person not tion to document receipt of the notice licensed by the owner of the patent en- required under paragraph (a) of this gaged in the manufacture, use, or sale section by each person provided the no- of the drug product. For purposes of tice. The applicant shall include a copy this part, such patents consist of drug of the return receipt or other similar substance (active ingredient) patents, evidence of the date the notification drug product (formulation and com- was received. FDA will accept as ade- position) patents, and method-of-use quate documentation of the date of re- patents. For patents that claim the ceipt a return receipt or a letter ac- drug substance, the applicant shall knowledging receipt by the person pro- submit information only on those pat- vided the notice. An applicant may ents that claim the drug substance rely on another form of documentation that is the subject of the pending or ap- only if FDA has agreed to such docu- proved application or that claim a drug mentation in advance. A copy of the substance that is the same as the ac- notice itself need not be submitted to tive ingredient that is the subject of the agency. the approved or pending application. (f) Approval. If the requirements of For patents that claim a polymorph this section are met, the agency will that is the same as the active ingre- presume the notice to be complete and dient described in the approved or

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pending application, the applicant product that contains the polymorphic shall certify in the declaration forms form of the drug substance and the that the applicant has test data, as set drug product as described in the NDA; forth in paragraph (b)(2) of this section, (iv) A list of all components used in demonstrating that a drug product the manufacture of the drug product containing the polymorph will perform containing the polymorphic form and a the same as the drug product described statement of the composition of the in the new drug application. For pat- drug product; a statement of the speci- ents that claim a drug product, the ap- fications and analytical methods for plicant shall submit information only each component; a description of the on those patents that claim a drug manufacturing and packaging proce- product, as is defined in § 314.3, that is dures and in-process controls for the described in the pending or approved drug product; such specifications and application. For patents that claim a analytical methods as are necessary to method of use, the applicant shall sub- assure the identity, strength, quality, mit information only on those patents purity, and bioavailability of the drug that claim indications or other condi- product, including release and stability tions of use that are described in the data complying with the approved pending or approved application. The applicant shall separately identify product specifications to demonstrate each pending or approved method of pharmaceutical equivalence and com- use and related patent claim. For ap- parable product stability; and proved applications, the applicant sub- (v) Comparative in vitro dissolution mitting the method-of-use patent shall testing on 12 dosage units each of the identify with specificity the section of executed test batch and the new drug the approved labeling that corresponds application product. to the method of use claimed by the (c) Reporting requirements—(1) General patent submitted. Process patents, pat- requirements. An applicant described in ents claiming packaging, patents paragraph (a) of this section shall sub- claiming metabolites, and patents mit the required patent information claiming intermediates are not covered described in paragraph (c)(2) of this by this section, and information on section for each patent that meets the these patents must not be submitted to requirements described in paragraph FDA. (b) of this section. We will not accept (2) Test Data for Submission of Patent the patent information unless it is Information for Patents That Claim a complete and submitted on the appro- Polymorph. The test data, referenced in priate forms, FDA Forms 3542 or 3542a. paragraph (b)(1) of this section, must These forms may be obtained on the include the following: Internet at http://www.fda.gov by (i) A full description of the poly- 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 shall submit FDA Form essary to assure the identity, strength, 3542a. The following information and quality, and purity of the polymorphic verification is required: form of the drug substance; (A) New drug application number; (ii) The executed batch record for a drug product containing the poly- (B) Name of new drug application morphic form of the drug substance sponsor; and documentation that the batch was (C) Trade name (or proposed trade manufactured under current good man- name) of new drug; ufacturing practice requirements; (D) Active ingredient(s) of new drug; (iii) Demonstration of bioequivalence (E) Strength(s) of new drug; between the executed batch of the drug (F) Dosage form of new drug;

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(G) United States patent number, (1) Whether the patent claims the issue date, and expiration date of pat- drug product for which approval is ent submitted; being sought, as defined in § 314.3; and (H) The patent owner’s name, full ad- (2) Whether the patent claims only dress, phone number and, if available, an intermediate; fax number and e-mail address; (O) Information on each method-of- (I) The name, full address, phone use patent including the following: number and, if available, fax number (1) Whether the patent claims one or and e-mail address of an agent or rep- more methods of using the drug product for which use approval is being resentative who resides or maintains a sought and a description of each pend- place of business within the United ing method of use or related indication States authorized to receive notice of and related patent claim of the patent patent certification under sections being submitted; and 505(b)(3) and 505(j)(2)(B) of the act and (2) Identification of the specific sec- §§ 314.52 and 314.95 (if patent owner or tion of the proposed labeling for the new drug application applicant or hold- drug product that corresponds to the er does not reside or have a place of method of use claimed by the patent business within the United States); submitted; (J) Information on whether the pat- (P) Whether there are no relevant ent has been submitted previously for patents that claim the drug substance the new drug application; (active ingredient), drug product (for- (K) Information on whether the expi- mulation or composition) or method(s) ration date is a new expiration date if of use, for which the applicant is seek- the patent had been submitted pre- ing approval and with respect to which viously for listing; a claim of patent infringement could (L) Information on whether the pat- reasonably be asserted if a person not ent is a product-by-process patent in licensed by the owner of the patent en- which the product claimed is novel; gaged in the manufacture, use, or sale (M) Information on the drug sub- of the drug product; (Q) A signed verification which stance (active ingredient) patent in- states: cluding the following: (1) Whether the patent claims the ‘‘The undersigned declares that this is an drug substance that is the active ingre- accurate and complete submission of patent dient in the drug product described in information for the NDA, amendment or supplement pending under section 505 of the the new drug application or supple- Federal Food, Drug, and Cosmetic Act. This ment; time-sensitive patent information is sub- (2) Whether the patent claims a poly- mitted pursuant to 21 CFR 314.53. I attest morph that is the same active ingre- that I am familiar with 21 CFR 314.53 and dient that is described in the pending this submission complies with the requirements of the regulation. I verify under pen- application or supplement; alty of perjury that the foregoing is true and (3) Whether the applicant has test correct.’’; and data, described in paragraph (b)(2) of (R) Information on whether the ap- this section, demonstrating that a drug plicant, patent owner or attorney, product containing the polymorph will agent, representative or other author- perform the same as the drug product ized official signed the form; the name described in the new drug application of the person; and the full address, or supplement, and a description of the phone number and, if available, the fax polymorphic form(s) claimed by the number and e-mail address. patent for which such test data exist; (ii) Submission of patent information (4) Whether the patent claims only a upon and after approval. Within 30 days metabolite of the active ingredient; after the date of approval of its appli- and cation or supplement, the applicant (5) Whether the patent claims only shall submit FDA Form 3542 for each an intermediate; patent that claims the drug substance (N) Information on the drug product (active ingredient), drug product (for- (composition/formulation) patent in- mulation and composition), or ap- cluding the following: proved method of use. FDA will rely

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only on the information submitted on (M) Information on whether the pat- this form and will not list or publish ent is a product-by-process patent in patent information if the patent dec- which the product claimed is novel; laration is incomplete or indicates the (N) Information on the drug sub- patent is not eligible for listing. Patent stance (active ingredient) patent in- information must also be submitted for cluding the following: patents issued after the date of ap- (1) Whether the patent claims the proval of the new drug application as drug substance that is the active ingre- required in paragraph (c)(2)(ii) of this dient in the drug product described in section. As described in paragraph the approved application; (d)(4) of this section, patent informa- (2) Whether the patent claims a poly- tion must be submitted to FDA within morph that is the same as the active 30 days of the date of issuance of the ingredient that is described in the ap- patent. If the applicant submits the re- proved application; quired patent information within the (3) Whether the applicant has test 30 days, but we notify an applicant that data, described at paragraph (b)(2) of a declaration form is incomplete or this section, demonstrating that a drug shows that the patent is not eligible product containing the polymorph will for listing, the applicant must submit perform the same as the drug product an acceptable declaration form within described in the approved application 15 days of FDA notification to be con- and a description of the polymorphic sidered timely filed. The following inform(s) claimed by the patent for formation and verification statement which such test data exist; is required: (4) Whether the patent claims only a (A) New drug application number; metabolite of the active ingredient; (B) Name of new drug application and sponsor; (5) Whether the patent claims only (C) Trade name of new drug; an intermediate; (D) Active ingredient(s) of new drug; (O) Information on the drug product (E) Strength(s) of new drug; (composition/formulation) patent in- (F) Dosage form of new drug; cluding the following: (G) Approval date of new drug appli- (1) Whether the patent claims the ap- cation or supplement; proved drug product as defined in (H) United States patent number, § 314.3; and issue date, and expiration date of pat- (2) Whether the patent claims only ent submitted; an intermediate; (I) The patent owner’s name, full ad- (P) Information on each method-of- dress, phone number and, if available, use patent including the following: fax number and e-mail address; (1) Whether the patent claims one or (J) The name, full address, phone more approved methods of using the number and, if available, fax number approved drug product and a descrip- and e-mail address of an agent or rep- tion of each approved method of use or resentative who resides or maintains a indication and related patent claim of place of business within the United the patent being submitted; States authorized to receive notice of (2) Identification of the specific sec- patent certification under sections tion of the approved labeling for the 505(b)(3) and 505(j)(2)(B) of the act and drug product that corresponds to the §§ 314.52 and 314.95 (if patent owner or method of use claimed by the patent new drug application applicant or hold- submitted; and er does not reside or have a place of (3) The description of the patented business within the United States); method of use as required for publica- (K) Information on whether the pat- tion; ent has been submitted previously for (Q) Whether there are no relevant the new drug application; patents that claim the approved drug (L) Information on whether the expi- substance (active ingredient), the ap- ration date is a new expiration date if proved drug product (formulation or the patent had been submitted pre- composition) or approved method(s) of viously for listing; use and with respect to which a claim

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of patent infringement could reason- with FDA and for which patent infor- ably be asserted if a person not li- mation is required to be submitted censed by the owner of the patent en- under this section. If a patent is issued gaged in the manufacture, use, or sale after the application is filed with FDA of the drug product; but before the application is approved, (R) A signed verification which the applicant shall, within 30 days of states: ‘‘The undersigned declares that the date of issuance of the patent, sub- this is an accurate and complete submit the required patent information in mission of patent information for the an amendment to the application under NDA, amendment or supplement ap- § 314.60. proved under section 505 of the Federal (2) Supplements. (i) An applicant shall Food, Drug, and Cosmetic Act. This submit patent information required time-sensitive patent information is under paragraph (c) of this section for submitted pursuant to 21 CFR 314.53. I a patent that claims the drug, drug attest that I am familiar with 21 CFR product, or method of use for which ap- 314.53 and this submission complies proval is sought in any of the following with the requirements of the regula- supplements: tion. I verify under penalty of perjury (A) To change the formulation; that the foregoing is true and cor- (B) To add a new indication or other rect.’’; and condition of use, including a change in (S) Information on whether the appli- route of administration; cant, patent owner or attorney, agent, (C) To change the strength; representative or other authorized offi- (D) To make any other patented cial signed the form; the name of the change regarding the drug, drug prod- person; and the full address, phone uct, or any method of use. number and, if available, the fax num- (ii) If the applicant submits a supple- ber and e-mail address. ment for one of the changes listed (3) No relevant patents. If the appli- under paragraph (d)(2)(i) of this section cant believes that there are no relevant and existing patents for which informa- patents that claim the drug substance tion has already been submitted to (active ingredient), drug product (for- FDA claim the changed product, the mulation or composition), or the meth- applicant shall submit a certification od(s) of use for which the applicant has with the supplement identifying the received approval, and with respect to patents that claim the changed prod- which a claim of patent infringement uct. could reasonably be asserted if a person (iii) If the applicant submits a sup- not licensed by the owner of the patent plement for one of the changes listed engaged in the manufacture, use, or under paragraph (d)(2)(i) of this section sale of the drug product, the applicant and no patents, including previously will verify this information in the ap- submitted patents, claim the changed propriate forms, FDA Forms 3542 or product, it shall so certify. 3542a. (iv) The applicant shall comply with (4) Authorized signature. The declara- the requirements for amendment of tions required by this section shall be formulation or composition and meth- signed by the applicant or patent od of use patent information under owner, or the applicant’s or patent paragraphs (c)(2)(ii) and (d)(3) of this owner’s attorney, agent (representa- section. tive), or other authorized official. (3) Patent information deadline. If a (d) When and where to submit patent patent is issued for a drug, drug prod- information—(1) Original application. An uct, or method of use after an applica- applicant shall submit with its original tion is approved, the applicant shall application submitted under this part, submit to FDA the required patent in- including an application described in formation within 30 days of the date of section 505(b)(2) of the act, the infor- issuance of the patent. mation described in paragraph (c) of (4) Copies. The applicant shall submit this section on each drug (ingredient), two copies of each submission of patent drug product (formulation and com- information, an archival copy and a position), and method of use patent copy for the chemistry, manufacturing, issued before the application is filed and controls section of the review

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copy, to the Central Document Room, cy in writing stating the grounds for Center for Drug Evaluation and Re- disagreement. Such notification should search, Food and Drug Administration, be directed to the Office of Generic 5901–B Ammendale Rd., Beltsville, MD Drugs, OGD Document Room, Atten- 20705–1266. The applicant shall submit tion: Orange Book Staff, 7500 Standish the patent information by letter sepa- Pl., Rockville, MD 20855. The agency rate from, but at the same time as, will then request of the applicable new submission of the supplement. drug application holder that the cor- (5) Submission date. Patent informa- rectness of the patent information or tion shall be considered to be sub- omission of patent information be con- mitted to FDA as of the date the infor- firmed. Unless the application holder mation is received by the Central Doc- withdraws or amends its patent infor- ument Room. mation in response to FDA’s request, (6) Identification. Each submission of the agency will not change the patent patent information, except information information in the list. If the new drug submitted with an original application, application holder does not change the and its mailing cover shall bear promi- patent information submitted to FDA, nent identification as to its contents, a 505(b)(2) application or an abbre- i.e., ‘‘Patent Information,’’ or, if sub- viated new drug application under sec- mitted after approval of an application 505(j) of the act submitted for a tion, ‘‘Time Sensitive Patent Informa- drug that is claimed by a patent for tion.’’ which information has been submitted (e) Public disclosure of patent informa- must, despite any disagreement as to tion. FDA will publish in the list the the correctness of the patent informa- patent number and expiration date of tion, contain an appropriate certifi- each patent that is required to be, and cation for each listed patent. is, submitted to FDA by an applicant, [59 FR 50363, Oct. 3, 1994, as amended at 68 FR and for each use patent, the approved 36703, June 18, 2003; 69 FR 13473, Mar. 23, 2004; indications or other conditions of use 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, covered by a patent. FDA will publish 2009] such patent information upon approval of the application, or, if the patent in- § 314.54 Procedure for submission of formation is submitted by the appli- an application requiring investiga- cant after approval of an application as tions for approval of a new indica- provided under paragraph (d)(2) of this tion for, or other change from, a section, as soon as possible after the listed drug. submission to the agency of the patent (a) The act does not permit approval information. Patent information sub- of an abbreviated new drug application mitted by the last working day of a for a new indication, nor does it permit month will be published in that approval of other changes in a listed month’s supplement to the list. Patent drug if investigations, other than bio- information received by the agency be- availability or bioequivalence studies, tween monthly publication of supple- are essential to the approval of the ments to the list will be placed on pub- change. Any person seeking approval of lic display in FDA’s Freedom of Infor- a drug product that represents a modi- mation Staff. A request for copies of fication of a listed drug (e.g., a new in- the file shall be sent in writing to the dication or new dosage form) and for Freedom of Information Staff (HFI–35), which investigations, other than bio- Food and Drug Administration, rm. availability or bioequivalence studies, 12A–16, 5600 Fishers Lane, Rockville, are essential to the approval of the MD 20857. changes may, except as provided in (f) Correction of patent information er- paragraph (b) of this section, submit a rors. If any person disputes the accu- 505(b)(2) application. This application racy or relevance of patent information need contain only that information submitted to the agency under this sec- needed to support the modification(s) tion and published by FDA in the list, of the listed drug. or believes that an applicant has failed (1) The applicant shall submit a com- to submit required patent information, plete archival copy of the application that person must first notify the agen- that contains the following:

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(i) The information required under manufacture of a commercial lot of the § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and drug product, and paragraph (d)(3), and (g), except that § 314.50(d)(1)(ii)(c) shall the technical sections described in contain the proposed or actual master paragraphs (d)(2), (d)(4), (d)(5), (d)(6), production record, including a descrip- and (f) when needed to support the tion of the equipment, to be used for modification. Each of the technical the manufacture of a commercial lot of sections in the review copy is required the drug product. to be separately bound with a copy of (ii) The information required under the information required under § 314.50 § 314.50 (d)(2), (d)(4) (if an anti-infective (a), (b), and (c) and a copy of the pro- drug), (d)(5), (d)(6), and (f) as needed to posed labeling. support the safety and effectiveness of (3) The information required by the drug product. § 314.50 (d)(2), (d)(4) (if an anti-infective (iii) Identification of the listed drug drug), (d)(5), (d)(6), and (f) for the listed for which FDA has made a finding of drug on which the applicant relies shall safety and effectiveness and on which be satisfied by reference to the listed finding the applicant relies in seeking drug under paragraph (a)(1)(iii) of this approval of its proposed drug product section. by established name, if any, propri- (4) The applicant shall submit a field etary name, dosage form, strength, copy of the application that contains route of administration, name of listed the technical section described in drug’s application holder, and listed § 314.50(d)(1), a copy of the information drug’s approved application number. required under § 314.50(a) and (c), and (iv) If the applicant is seeking ap- certification that the field copy is a proval only for a new indication and true copy of the technical section de- not for the indications approved for the scribed in § 314.50(d)(1) contained in the listed drug on which the applicant re- archival and review copies of the appli- lies, a certification so stating. cation. (v) Any patent information required (b) An application may not be sub- under section 505(b)(1) of the act with mitted under this section for a drug respect to any patent which claims the product whose only difference from the drug for which approval is sought or a reference listed drug is that: method of using such drug and to (1) The extent to which its active in- which a claim of patent infringement gredient(s) is absorbed or otherwise could reasonably be asserted if a person made available to the site of action is not licensed by the owner of the patent less than that of the reference listed engaged in the manufacture, use, or drug; or sale of the drug product. (2) The rate at which its active ingre- (vi) Any patent certification or state- dient(s) is absorbed or otherwise made ment required under section 505(b)(2) of available to the site of action is unin- the act with respect to any relevant tentionally less than that of the ref- patents that claim the listed drug or erence listed drug. that claim any other drugs on which [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. investigations relied on by the appli- 28, 1992, as amended at 58 FR 47351, Sept. 8, cant for approval of the application 1993; 59 FR 50364, Oct. 3, 1994] were conducted, or that claim a use for the listed or other 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 shall 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 § 314.50(d)(1)(ii)(c) shall con- product for the claimed indications in tain the proposed or actual master pro- all relevant pediatric subpopulations, duction record, including a description and to support dosing and administra- of the equipment, to be used for the tion for each pediatric subpopulation

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

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

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will notify the applicant of the exten- by the applicant under § 314.65 on the sion. The initial review cycle for a date of receipt by FDA of the amend- manufacturing supplement may be ex- ment. The amendment will be consid- tended only once due to submission of ered a resubmission of the application, a major amendment. FDA may, at its which may not be accepted except as discretion, review any subsequent provided in accordance with section major amendment during the initial 505(c)(3)(D)(ii) of the act. review cycle (as extended) or defer re- (d) The applicant shall submit a field view until the subsequent review cycle. copy of each amendment to (5) Submission of an amendment to a § 314.50(d)(1). The applicant shall in- supplement other than an efficacy or clude in its submission of each such manufacturing supplement will not ex- amendment to FDA a statement certi- tend the initial review cycle. FDA fying that a field copy of the amend- may, at its discretion, review such an ment has been sent to the applicant’s amendment during the initial review home FDA district office. cycle or defer review until the subse- [50 FR 7493, Feb. 22, 1985, as amended at 57 quent review cycle. FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, (6) A major amendment may not in- 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. clude data to support an indication or 8, 2004; 73 FR 39608, July 10, 2008] claim that was not included in the original application, supplement, or re- § 314.65 Withdrawal by the applicant submission, but it may include data to of an unapproved application. support a minor modification of an in- An applicant may at any time with- dication or claim that was included in draw an application that is not yet ap- the original application, supplement, proved by notifying the Food and Drug or resubmission. Administration in writing. If, by the (7) When FDA defers review of an time it receives such notice, the agen- amendment until the subsequent re- cy has identified any deficiencies in view cycle, the agency will notify the the application, we will list such defi- applicant of the deferral in the com- ciencies in the letter we send the appli- plete response letter sent to the applicant acknowledging the withdrawal. A cant under § 314.110 of this part. decision to withdraw the application is (c)(1) An unapproved application may without prejudice to refiling. The agen- not be amended if all of the following cy will retain the application and will conditions apply: provide a copy to the applicant on re- (i) The unapproved application is for quest under the fee schedule in § 20.45 of a drug for which a previous application FDA’s public information regulations. has been approved and granted a period [50 FR 7493, Feb. 22, 1985, as amended at 68 of exclusivity in accordance with sec- FR 25287, May 12, 2003; 73 FR 39609, July 10, tion 505(c)(3)(D)(ii) of the act that has 2008] not expired; (ii) The applicant seeks to amend the § 314.70 Supplements and other unapproved application to include a changes to an approved application. published report of an investigation (a) Changes to an approved application. that was conducted or sponsored by the (1)(i) Except as provided in paragraph applicant entitled to exclusivity for (a)(1)(ii) of this section, the applicant the drug; must notify FDA about each change in (iii) The applicant has not obtained a each condition established in an ap- right of reference to the investigation proved application beyond the vari- described in paragraph (c)(1)(ii) of this ations already provided for in the ap- section; and plication. The notice is required to de- (iv) The report of the investigation scribe the change fully. Depending on described in paragraph (c)(1)(ii) of this the type of change, the applicant must section would be essential to the ap- notify FDA about the change in a sup- proval of the unapproved application. plement under paragraph (b) or (c) of (2) The submission of an amendment this section or by inclusion of the in- described in paragraph (c)(1) of this formation in the annual report to the section will cause the unapproved ap- application under paragraph (d) of this plication to be deemed to be withdrawn section.

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(ii) The submission and grant of a (2) These changes include, but are not written request for an exception or al- limited to: ternative under § 201.26 of this chapter (i) Except those described in para- satisfies the applicable requirements in graphs (c) and (d) of this section, paragraphs (a) through (c) of this sec- changes in the qualitative or quan- tion. However, any grant of a request titative formulation of the drug prod- for an exception or alternative under uct, including inactive ingredients, or § 201.26 of this chapter must be reported in the specifications provided in the as part of the annual report to the ap- approved application; plication under paragraph (d) of this (ii) Changes requiring completion of section. studies in accordance with part 320 of (2) The holder of an approved applica- this chapter to demonstrate the tion under section 505 of the act must equivalence of the drug product to the assess the effects of the change before drug product as manufactured without distributing a drug product made with the change or to the reference listed a manufacturing change. drug; (3) Notwithstanding the requirements (iii) Changes that may affect drug of paragraphs (b) and (c) of this sec- substance or drug product sterility as- tion, an applicant must make a change surance, such as changes in drug sub- provided for in those paragraphs in ac- stance, drug product, or component cordance with a regulation or guidance sterilization method(s) or an addition, that provides for a less burdensome no- deletion, or substitution of steps in an tification of the change (for example, aseptic processing operation; by submission of a supplement that (iv) Changes in the synthesis or man- does not require approval prior to dis- ufacture of the drug substance that tribution of the product or in an an- may affect the impurity profile and/or nual report). the physical, chemical, or biological (4) The applicant must promptly re- properties of the drug substance; vise all promotional labeling and ad- (v) The following labeling changes: vertising to make it consistent with (A) Changes in labeling, except those any labeling change implemented in described in paragraphs (c)(6)(iii), accordance with paragraphs (b) and (c) (d)(2)(ix), or (d)(2)(x) of this section; of this section. (B) If applicable, any change to a (5) Except for a supplement providing Medication Guide required under part for a change in the labeling, the appli- 208 of this chapter, except for changes cant must include in each supplement in the information specified in and amendment to a supplement pro- § 208.20(b)(8)(iii) and (b)(8)(iv) of this viding for a change under paragraph (b) chapter; and or (c) of this section a statement certi- (C) Any change to the information fying that a field copy has been pro- required by § 201.57(a) of this chapter, vided in accordance with § 314.440(a)(4). with the following exceptions that may (6) A supplement or annual report be reported in an annual report under must include a list of all changes con- paragraph (d)(2)(x) of this section: tained in the supplement or annual re- (1) Removal of a listed section(s) port. For supplements, this list must specified in § 201.57(a)(5) of this chapter; be provided in the cover letter. and (b) Changes requiring supplement sub- (2) Changes to the most recent revi- mission and approval prior to distribution sion date of the labeling as specified in of the product made using the change § 201.57(a)(15) of this chapter. (major changes). (1) A supplement must (vi) Changes in a drug product con- be submitted for any change in the tainer closure system that controls the drug substance, drug product, produc- drug product delivered to a patient or tion process, quality controls, equip- changes in the type (e.g., glass to high ment, or facilities that has a substan- density polyethylene (HDPE), HDPE to tial potential to have an adverse effect polyvinyl chloride, vial to syringe) or on the identity, strength, quality, pu- composition (e.g., one HDPE resin to rity, or potency of the drug product as another HDPE resin) of a packaging these factors may relate to the safety component that may affect the impu- or effectiveness of the drug product. rity profile of the drug product.

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(vii) Changes solely affecting a nat- ship on the applicant. Such a supple- ural product, a recombinant DNA-de- ment and its mailing cover should be rived protein/polypeptide, or a complex plainly marked: ‘‘Prior Approval Sup- or conjugate of a drug substance with a plement-Expedited Review Requested.’’ monoclonal antibody for the following: (c) Changes requiring supplement sub- (A) Changes in the virus or adven- mission at least 30 days prior to distribu- titious agent removal or inactivation tion of the drug product made using the method(s); change (moderate changes). (1) A supple- (B) Changes in the source material or ment must be submitted for any cell line; and change in the drug substance, drug (C) Establishment of a new master product, production process, quality cell bank or seed. controls, equipment, or facilities that (viii) Changes to a drug product has a moderate potential to have an under an application that is subject to adverse effect on the identity, a validity assessment because of sig- strength, quality, purity, or potency of nificant questions regarding the integ- the drug product as these factors may rity of the data supporting that appli- relate to the safety or effectiveness of cation. the drug product. If the supplement (3) The applicant must obtain ap- provides for a labeling change under proval of a supplement from FDA prior paragraph (c)(6)(iii) of this section, 12 to distribution of a drug product made copies of the final printed labeling using a change under paragraph (b) of must be included. this section. Except for submissions (2) These changes include, but are not under paragraph (e) of this section, the limited to: following information must be con- (i) A change in the container closure tained in the supplement: system that does not affect the quality (i) A detailed description of the proof the drug product, except those de- posed change; scribed in paragraphs (b) and (d) of this (ii) The drug product(s) involved; section; and (iii) The manufacturing site(s) or area(s) affected; (ii) Changes solely affecting a nat- (iv) A description of the methods ural protein, a recombinant DNA-de- used and studies performed to assess rived protein/polypeptide or a complex the effects of the change; or conjugate of a drug substance with a (v) The data derived from such stud- monoclonal antibody, including: ies; (A) An increase or decrease in pro- (vi) For a natural product, a recom- duction scale during finishing steps binant DNA-derived protein/ that involves different equipment; and polypeptide, or a complex or conjugate (B) Replacement of equipment with of a drug substance with a monoclonal that of a different design that does not antibody, relevant validation protocols affect the process methodology or proc- and a list of relevant standard oper- ess operating parameters. ating procedures must be provided in (iii) Relaxation of an acceptance cri- addition to the requirements in para- terion or deletion of a test to comply graphs (b)(3)(iv) and (b)(3)(v) of this with an official compendium that is section; and consistent with FDA statutory and reg- (vii) For sterilization process and ulatory requirements. test methodologies related to steriliza- (3) A supplement submitted under tion process validation, relevant vali- paragraph (c)(1) of this section is re- dation protocols and a list of relevant quired to give a full explanation of the standard operating procedures must be basis for the change and identify the provided in addition to the require- date on which the change is to be ments in paragraphs (b)(3)(iv) and made. The supplement must be labeled (b)(3)(v) of this section. ‘‘Supplement—Changes Being Effected (4) An applicant may ask FDA to ex- in 30 Days’’ or, if applicable under pedite its review of a supplement for paragraph (c)(6) of this section, ‘‘Sup- public health reasons or if a delay in plement—Changes Being Effected.’’ making the change described in it (4) Pending approval of the supple- would impose an extraordinary hard- ment by FDA, except as provided in

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paragraph (c)(6) of this section, dis- standard for inclusion in the labeling tribution of the drug product made under § 201.57(c) of this chapter; using the change may begin not less (B) To add or strengthen a statement than 30 days after receipt of the supple- about drug abuse, dependence, psycho- ment by FDA. The information listed logical effect, or overdosage; in paragraphs (b)(3)(i) through (C) To add or strengthen an instruc- (b)(3)(vii) of this section must be con- tion about dosage and administration tained in the supplement. that is intended to increase the safe (5) The applicant must not distribute use of the drug product; the drug product made using the (D) To delete false, misleading, or un- change if within 30 days following supported indications for use or claims FDA’s receipt of the supplement, FDA for effectiveness; or informs the applicant that either: (E) Any labeling change normally re- (i) The change requires approval quiring a supplement submission and prior to distribution of the drug prod- approval prior to distribution of the uct in accordance with paragraph (b) of drug product that FDA specifically re- this section; or quests be submitted under this provi- (ii) Any of the information required sion. under paragraph (c)(4) of this section is (7) If the agency disapproves the sup- missing; the applicant must not dis- plemental application, it may order tribute the drug product made using the manufacturer to cease distribution the change until the supplement has of the drug product(s) made with the been amended to provide the missing manufacturing change. information. (d) Changes to be described in an an- (6) The agency may designate a cat- nual report (minor changes). (1) Changes egory of changes for the purpose of pro- in the drug substance, drug product, viding that, in the case of a change in production process, quality controls, such category, the holder of an ap- equipment, or facilities that have a proved application may commence dis- minimal potential to have an adverse tribution of the drug product involved effect on the identity, strength, qual- upon receipt by the agency of a supple- ity, purity, or potency of the drug ment for the change. These changes in- product as these factors may relate to clude, but are not limited to: the safety or effectiveness of the drug (i) Addition to a specification or product must be documented by the ap- changes in the methods or controls to plicant in the next annual report in ac- provide increased assurance that the cordance with § 314.81(b)(2). drug substance or drug product will (2) These changes include, but are not have the characteristics of identity, limited to: strength, quality, purity, or potency (i) Any change made to comply with that it purports or is represented to a change to an official compendium, possess; except a change described in paragraph (ii) A change in the size and/or shape (c)(2)(iii) of this section, that is con- of a container for a nonsterile drug sistent with FDA statutory and regu- product, except for solid dosage forms, latory requirements. without a change in the labeled (ii) The deletion or reduction of an amount of drug product or from one ingredient intended to affect only the container closure system to another; color of the drug product; (iii) Changes in the labeling to reflect (iii) Replacement of equipment with newly acquired information, except for that of the same design and operating changes to the information required in principles except those equipment § 201.57(a) of this chapter (which must changes described in paragraph (c) of be made under paragraph (b)(2)(v)(C) of this section; this section), to accomplish any of the (iv) A change in the size and/or shape following: of a container containing the same (A) To add or strengthen a contra- number of dosage units for a nonsterile indication, warning, precaution, or ad- solid dosage form drug product, with- verse reaction for which the evidence out a change from one container clo- of a causal association satisfies the sure system to another;

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(v) A change within the container process validation, a cross-reference to closure system for a nonsterile drug relevant validation protocols and/or product, based upon a showing of standard operating procedures. equivalency to the approved system (e) Protocols. An applicant may sub- under a protocol approved in the appli- mit one or more protocols describing cation or published in an official com- the specific tests and studies and ac- pendium; 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 appli- quality, purity, and potency of the cation; drug product as these factors may re- (vii) The addition or revision of an al- late to the safety or effectiveness of ternative analytical procedure that the drug product. Any such protocols, provides the same or increased assur- if not included in the approved applica- ance of the identity, strength, quality, tion, or changes to an approved pro- purity, or potency of the material tocol, must be submitted as a supple- being tested as the analytical proce- ment requiring approval from FDA dure described in the approved applica- prior to distribution of a drug product tion, or deletion of an alternative ana- produced with the manufacturing lytical procedure; change. The supplement, if approved, (viii) The addition by embossing, de- may subsequently justify a reduced re- bossing, or engraving of a code imprint porting category for the particular to a solid oral dosage form drug prod- change because the use of the protocol uct other than a modified release dos- for that type of change reduces the po- age form, or a minor change in an ex- tential risk of an adverse effect. isting code imprint; (f) Patent information. The applicant (ix) A change in the labeling con- must comply with the patent informa- cerning the description of the drug tion requirements under section product or in the information about 505(c)(2) of the act. how the drug product is supplied, that (g) Claimed exclusivity. If an applicant does not involve a change in the dosage claims exclusivity under § 314.108 upon strength or dosage form; and approval of a supplement for change to (x) An editorial or similar minor its previously approved drug product, change in labeling, including a change the applicant must include with its to the information allowed by para- supplement the information required graphs (b)(2)(v)(C)(1) and (2) of this sec- under § 314.50(j). tion. [69 FR 18764, Apr. 8, 2004, as amended at 71 (3) For changes under this category, FR 3997, Jan. 24, 2006; 72 FR 73600, Dec. 28, the applicant is required to submit in 2007; 73 FR 49609, Aug. 22, 2008] the annual report: (i) A statement by the holder of the § 314.71 Procedures for submission of approved application that the effects of a supplement to an approved appli- the change have been assessed; cation. (ii) A full description of the manufac- (a) Only the applicant may submit a turing and controls changes, including supplement to an application. the manufacturing site(s) or area(s) in- (b) All procedures and actions that volved; apply to an application under § 314.50 (iii) The date each change was imple- also apply to supplements, except that mented; the information required in the supple- (iv) Data from studies and tests per- ment is limited to that needed to sup- formed to assess the effects of the port the change. A supplement is re- change; and, quired to contain an archival copy and (v) For a natural product, recom- a review copy that include an applica- binant DNA-derived protein/ tion form and appropriate technical polypeptide, complex or conjugate of a sections, samples, and labeling; except drug substance with a monoclonal anti- that a supplement for a change other body, sterilization process or test than a change in labeling is required methodology related to sterilization also to contain a field copy.

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(c) All procedures and actions that § 314.80 Postmarketing reporting of apply to applications under this part, adverse drug experiences. including actions by applicants and the (a) Definitions. The following defini- Food and Drug Administration, also tions of terms apply to this section: apply to supplements except as speci- Adverse drug experience. Any adverse fied otherwise in this part. event associated with the use of a drug in humans, whether or not considered [50 FR 7493, Feb. 22, 1985, as amended at 50 drug related, including the following: FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, An adverse event occurring in the July 10, 2008] course of the use of a drug product in professional practice; an adverse event § 314.72 Change in ownership of an ap- occurring from drug overdose whether plication. accidental or intentional; an adverse event occurring from drug abuse; an (a) An applicant may transfer owner- adverse event occurring from drug ship of its application. At the time of withdrawal; and any failure of expected transfer the new and former owners are pharmacological action. required to submit information to the Disability. A substantial disruption of Food and Drug Administration as fol- a person’s ability to conduct normal lows: life functions. (1) The former owner shall submit a Life-threatening adverse drug experi- letter or other document that states ence. Any adverse drug experience that that all rights to the application have places the patient, in the view of the been transferred to the new owner. initial reporter, at immediate risk of (2) The new owner shall submit an death from the adverse drug experience application form signed by the new as it occurred, i.e., it does not include owner and a letter or other document an adverse drug experience that, had it containing the following: occurred in a more severe form, might have caused death. (i) The new owner’s commitment to Serious adverse drug experience. Any agreements, promises, and conditions adverse drug experience occurring at made by the former owner and con- any dose that results in any of the fol- tained in the application; lowing outcomes: Death, a life-threat- (ii) The date that the change in own- ening adverse drug experience, inpa- ership is effective; and tient hospitalization or prolongation of (iii) Either a statement that the new existing hospitalization, a persistent or owner has a complete copy of the ap- significant disability/incapacity, or a proved application, including supple- congenital anomaly/birth defect. Im- ments and records that are required to portant medical events that may not be kept under § 314.81, or a request for a result in death, be life-threatening, or copy of the application from FDA’s require hospitalization may be consid- files. FDA will provide a copy of the ered a serious adverse drug experience application to the new owner under the when, based upon appropriate medical fee schedule in § 20.45 of FDA’s public judgment, they may jeopardize the pa- information regulations. tient or subject and may require med- (b) The new owner shall advise FDA ical or surgical intervention to prevent about any change in the conditions in one of the outcomes listed in this defi- the approved application under § 314.70, nition. Examples of such medical events include allergic bronchospasm except the new owner may advise FDA requiring intensive treatment in an in the next annual report about a emergency room or at home, blood change in the drug product’s label or dyscrasias or convulsions that do not labeling to change the product’s brand result in inpatient hospitalization, or or the name of its manufacturer, pack- the development of drug dependency or er, or distributor. drug abuse. [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, Unexpected adverse drug experience. 1985, as amended at 50 FR 21238, May 23, 1985; Any adverse drug experience that is 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, not listed in the current labeling for 2003] the drug product. This includes events

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that may be symptomatically and (1)(i) Postmarketing 15-day ‘‘Alert re- pathophysiologically related to an ports’’. The applicant shall report each event listed in the labeling, but differ adverse drug experience that is both se- from the event because of greater serious and unexpected, whether foreign verity or specificity. For example, or domestic, as soon as possible but in under this definition, hepatic necrosis no case later than 15 calendar days of would be unexpected (by virtue of initial receipt of the information by greater severity) if the labeling only the applicant. referred to elevated hepatic enzymes or (ii) Postmarketing 15-day ‘‘Alert re- hepatitis. Similarly, cerebral thrombo- ports’’—followup. The applicant shall embolism and cerebral vasculitis would promptly investigate all adverse drug be unexpected (by virtue of greater experiences that are the subject of specificity) if the labeling only listed these postmarketing 15-day Alert re- cerebral vascular accidents. ‘‘Unex- ports and shall submit followup reports pected,’’ as used in this definition, re- within 15 calendar days of receipt of fers to an adverse drug experience that new information or as requested by has not been previously observed (i.e., FDA. If additional information is not included in the labeling) rather than obtainable, records should be main- from the perspective of such experience tained of the unsuccessful steps taken not being anticipated from the pharma- to seek additional information. Post- cological properties of the pharma- marketing 15-day Alert reports and ceutical product. followups to them shall be submitted (b) Review of adverse drug experiences. under separate cover. Each applicant having an approved ap- (iii) Submission of reports. The re- plication under § 314.50 or, in the case quirements of paragraphs (c)(1)(i) and of a 505(b)(2) application, an effective (c)(1)(ii) of this section, concerning the approved application, shall promptly submission of postmarketing 15-day review all adverse drug experience in- Alert reports, shall also apply to any formation obtained or otherwise re- person other than the applicant (non- ceived by the applicant from any applicant) whose name appears on the source, foreign or domestic, including label of an approved drug product as a information derived from commercial manufacturer, packer, or distributor. marketing experience, postmarketing To avoid unnecessary duplication in clinical investigations, postmarketing the submission to FDA of reports re- epidemiological/surveillance studies, quired by paragraphs (c)(1)(i) and reports in the scientific literature, and (c)(1)(ii) of this section, obligations of a unpublished scientific papers. Appli- cants are not required to resubmit to nonapplicant may be met by submis- FDA adverse drug experience reports sion of all reports of serious adverse forwarded to the applicant by FDA; drug experiences to the applicant. If a however, applicants must submit all nonapplicant elects to submit adverse followup information on such reports drug experience reports to the appli- to FDA. Any person subject to the re- cant rather than to FDA, the non- porting requirements under paragraph applicant shall submit each report to (c) of this section shall also develop the applicant within 5 calendar days of written procedures for the surveillance, receipt of the report by the non- receipt, evaluation, and reporting of applicant, and the applicant shall then postmarketing adverse drug experi- comply with the requirements of this ences to FDA. section. Under this circumstance, the (c) Reporting requirements. The appli- nonapplicant shall maintain a record of cant shall report to FDA adverse drug this action which shall include: experience information, as described in (A) A copy of each adverse drug expe- this section. The applicant shall sub- rience report; mit two copies of each report described (B) The date the report was received in this section to the Central Docu- by the nonapplicant; ment Room, 5901–B Ammendale Rd., (C) The date the report was sub- Beltsville, MD 20705–1266. FDA may mitted to the applicant; and waive the requirement for the second (D) The name and address of the ap- copy in appropriate instances. plicant.

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(iv) Report identification. Each report new drug application), from reports in submitted under this paragraph shall the scientific literature, and from for- bear prominent identification as to its eign marketing experience. contents, i.e., ‘‘15-day Alert report,’’ or (d) Scientific literature. (1) A 15-day ‘‘15-day Alert report-followup.’’ Alert report based on information from (2) Periodic adverse drug experience re- the scientific literature is required to ports. (i) The applicant shall report be accompanied by a copy of the pub- each adverse drug experience not re- lished article. The 15-day reporting reported under paragraph (c)(1)(i) of this quirements in paragraph (c)(1)(i) of this section at quarterly intervals, for 3 section (i.e., serious, unexpected ad- years from the date of approval of the verse drug experiences) apply only to application, and then at annual inter- reports found in scientific and medical vals. The applicant shall submit each quarterly report within 30 days of the journals either as case reports or as the close of the quarter (the first quarter result of a formal clinical trial. beginning on the date of approval of (2) As with all reports submitted the application) and each annual report under paragraph (c)(1)(i) of this sec- within 60 days of the anniversary date tion, reports based on the scientific lit- of approval of the application. Upon erature shall be submitted on FDA written notice, FDA may extend or re- Form 3500A or comparable format as establish the requirement that an ap- prescribed by paragraph (f) of this sec- plicant submit quarterly reports, or re- tion. In cases where the applicant be- quire that the applicant submit reports lieves that preparing the FDA Form under this section at different times 3500A constitutes an undue hardship, than those stated. For example, the the applicant may arrange with the Of- agency may reestablish a quarterly re- fice of Surveillance and Epidemiology porting requirement following the ap- for an acceptable alternative reporting proval of a major supplement. Fol- format. lowup information to adverse drug ex- (e) Postmarketing studies. (1) An appli- periences submitted in a periodic re- cant is not required to submit a 15-day port may be submitted in the next peri- Alert report under paragraph (c) of this odic report. section for an adverse drug experience (ii) Each periodic report is required obtained from a postmarketing study to contain: (a) a narrative summary (whether or not conducted under an in- and analysis of the information in the report and an analysis of the 15-day vestigational new drug application) un- Alert reports submitted during the re- less the applicant concludes that there porting interval (all 15-day Alert re- is a reasonable possibility that the ports being appropriately referenced by drug caused the adverse experience. the applicant’s patient identification (2) The applicant shall separate and number, adverse reaction term(s), and clearly mark reports of adverse drug date of submission to FDA); (b) a FDA experiences that occur during a post- Form 3500A (Adverse Reaction Report) marketing study as being distinct from for each adverse drug experience not those experiences that are being re- reported under paragraph (c)(1)(i) of ported spontaneously to the applicant. this section (with an index consisting (f) Reporting FDA Form 3500A. (1) Ex- of a line listing of the applicant’s pa- cept as provided in paragraph (f)(3) of tient identification number and ad- this section, the applicant shall com- verse reaction term(s)); and (c) a his- plete FDA Form 3500A for each report tory of actions taken since the last re- of an adverse drug experience (foreign port because of adverse drug experi- events may be submitted either on an ences (for example, labeling changes or FDA Form 3500A or, if preferred, on a studies initiated). CIOMS I form). (iii) Periodic reporting, except for in- (2) Each completed FDA Form 3500A formation regarding 15-day Alert reports, does not apply to adverse drug should refer only to an individual pa- experience information obtained from tient or a single attached publication. postmarketing studies (whether or not conducted under an investigational

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(3) Instead of using FDA Form 3500A, drug product that is the subject of the an applicant may use a computer-gen- application. erated FDA Form 3500A or other alter- (k) Disclaimer. A report or informa- native format (e.g., a computer-gen- tion submitted by an applicant under erated tape or tabular listing) provided this section (and any release by FDA of that: that report or information) does not (i) The content of the alternative for- necessarily reflect a conclusion by the mat is equivalent in all elements of in- applicant or FDA that the report or information to those specified in FDA formation constitutes an admission Form 3500A; and that the drug caused or contributed to (ii) The format is agreed to in ad- an adverse effect. An applicant need vance by the Office of Surveillance and not admit, and may deny, that the re- Epidemiology. port or information submitted under (4) FDA Form 3500A and instructions this section constitutes an admission for completing the form are available that the drug caused or contributed to on the Internet at http://www.fda.gov/ an adverse effect. For purposes of this medwatch/index.html. provision, the term ‘‘applicant’’ also (g) Multiple reports. An applicant includes any person reporting under should not include in reports under paragraph (c)(1)(iii) of this section. this section any adverse drug experiences that occurred in clinical trials if [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, they were previously submitted as part 1985, as amended at 50 FR 21238, May 23, 1985; of the approved application. If a report 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, 1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, applies to a drug for which an appli- Apr. 28, 1992; 62 FR 34168, June 25, 1997; 62 FR cant holds more than one approved ap- 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 1998; plication, the applicant should submit 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, the report to the application that was 2004; 74 FR 13113, Mar. 26, 2009] first approved. If a report refers to more than one drug marketed by an ap- § 314.81 Other postmarketing reports. plicant, the applicant should submit (a) Applicability. Each applicant shall the report to the application for the make the reports for each of its ap- drug listed first in the report. proved applications and abbreviated (h) Patient privacy. An applicant applications required under this sec- should not include in reports under tion and section 505(k) of the act. this section the names and addresses of (b) Reporting requirements. The appli- individual patients; instead, the applicant shall submit to the Food and Drug cant should assign a unique code number to each report, preferably not more Administration at the specified times than eight characters in length. The two copies of the following reports: applicant should include the name of (1) NDA—Field alert report. The appli- the reporter from whom the informa- cant shall submit information of the tion was received. Names of patients, following kinds about distributed drug health care professionals, hospitals, products and articles to the FDA dis- and geographical identifiers in adverse trict office that is responsible for the drug experience reports are not releas- facility involved within 3 working days able to the public under FDA’s public of receipt by the applicant. The infor- information regulations in part 20. mation may be provided by telephone (i) Recordkeeping. The applicant shall or other rapid communication means, maintain for a period of 10 years with prompt written followup. The re- records of all adverse drug experiences port and its mailing cover should be known to the applicant, including raw plainly marked: ‘‘NDA—Field Alert Re- data and any correspondence relating port.’’ to adverse drug experiences. (i) Information concerning any inci- (j) Withdrawal of approval. If an appli- dent that causes the drug product or cant fails to establish and maintain its labeling to be mistaken for, or ap- records and make reports required plied to, another article. under this section, FDA may withdraw (ii) Information concerning any bac- approval of the application and, thus, teriological contamination, or any sig- prohibit continued marketing of the nificant chemical, physical, or other

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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 mestic use and the quantities distrib- (e.g., method of transmission, media, uted for foreign use. Disclosure of fi- file formats, preparation and organiza- nancial or pricing data is not required. tion of files). Submissions under this

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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 involving chemical or physical prop- appropriate labeling for the pediatric erties, or any other properties of the population shall be included. drug (such as the drug’s behavior or (vii) Status reports of postmarketing properties in relation to microorga- study commitments. A status report of nisms, including both the effects of the each postmarketing study of the drug drug on microorganisms and the effects product concerning clinical safety, of microorganisms on the drug). These clinical efficacy, clinical pharma- reports are only required for new infor- cology, and nonclinical toxicology that mation that may affect FDA’s previous is required by FDA (e.g., accelerated conclusions about the safety or effec- approval clinical benefit studies, pedi- tiveness of the drug product. atric studies) or that the applicant has (b) A full description of the manufac- committed, in writing, to conduct ei- turing and controls changes not requir- ther at the time of approval of an ap- ing a supplemental application under plication for the drug product or a sup- § 314.70 (b) and (c), listed by date in the plement to an application, or after ap- order in which they were implemented. proval of the application or a supple- (v) Nonclinical laboratory studies. Cop- ment. For pediatric studies, the status ies of unpublished reports and sum- report shall include a statement indi- maries of published reports of new toxi- cating whether postmarketing clinical cological findings in animal studies studies in pediatric populations were and in vitro studies (e.g., mutage- required by FDA under § 201.23 of this nicity) conducted by, or otherwise ob- chapter. The status of these post- tained by, the applicant concerning the ingredients in the drug product. The marketing studies shall be reported an- applicant shall submit a copy of a pub- nually until FDA notifies the appli- lished report if requested by FDA. cant, in writing, that the agency con- (vi) Clinical data. (a) Published clin- curs with the applicant’s determina- ical trials of the drug (or abstracts of tion that the study commitment has them), including clinical trials on safe- been fulfilled or that the study is ei- ty and effectiveness; clinical trials on ther no longer feasible or would no new uses; biopharmaceutic, pharmaco- longer provide useful information. kinetic, and clinical pharmacology (a) Content of status report. The fol- studies; and reports of clinical experi- lowing information must be provided ence pertinent to safety (for example, for each postmarketing study reported epidemiologic studies or analyses of ex- under this paragraph: perience in a monitored series of pa- (1) Applicant’s name. tients) conducted by or otherwise ob- (2) Product name. Include the ap- tained by the applicant. Review arti- proved drug product’s established name cles, papers describing the use of the and proprietary name, if any. drug product in medical practice, pa- (3) NDA, ANDA, and supplement num- pers and abstracts in which the drug is ber. used as a research tool, promotional articles, press clippings, and papers (4) Date of U.S. approval of NDA or that do not contain tabulations or ANDA. summaries of original data should not (5) Date of postmarketing study commit- be reported. 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- the anticipated date that manufac- tisement for a prescription drug prod- turing will cease. uct. Mailing pieces and labeling that (iv) Withdrawal of approved drug prod- are designed to contain samples of a uct from sale. (a) The applicant shall drug product are required to be com- submit on Form FDA 2657 (Drug Prod- plete, except the sample of the drug uct Listing), within 15 working days of product may be omitted. Each submis- the withdrawal from sale of a drug sion is required to be accompanied by a product, the following information: completed transmittal Form FDA–2253 (1) The National Drug Code (NDC) (Transmittal of Advertisements and number. Promotional Labeling for Drugs for (2) The identity of the drug product Human Use) and is required to include by established name and by proprietary a copy of the product’s current profes- name. sional labeling. Form FDA–2253 is (3) The new drug application or ab- available on the Internet at http:// breviated application number. www.fda.gov/opacom/morechoices/ ( ) The date of withdrawal from sale. fdaforms/cder.html. 4 (ii) Special reports. Upon written re- It is requested but not required that quest the agency may require that the the reason for withdrawal of the drug applicant submit the reports under this product from sale be included with the section at different times than those information. stated. (b) The applicant shall submit each (iii) Notification of discontinuance. (a) Form FDA–2657 to the Records Reposi- An applicant who is the sole manufac- tory Team (HFD–143), Center for Drug turer of an approved drug product must Evaluation and Research, Food and notify FDA in writing at least 6 Drug Administration, 5600 Fishers months prior to discontinuing manu- Lane, Rockville, MD 20857. facture of the drug product if: (c) Reporting under paragraph (1) The drug product is life sup- (b)(3)(iv) of this section constitutes porting, life sustaining, or intended for compliance with the requirements use in the prevention of a serious dis- under § 207.30(a) of this chapter to re- ease or condition; and port ‘‘at the discretion of the reg- (2) The drug product was not origi- istrant when the change occurs.’’ nally derived from human tissue and (c) General requirements—(1) Multiple replaced by a recombinant product. applications. For all reports required by (b) For drugs regulated by the Center this section, the applicant shall submit for Drug Evaluation and Research the information common to more than (CDER) or the Center for Biologics one application only to the application Evaluation and Research (CBER), one first approved, and shall not report sep- copy of the notification required by arately on each application. The sub- paragraph (b)(3)(iii)(a) of this section mission is required to identify all the must be sent to the CDER Drug Short- applications to which the report ap- age Coordinator, at the address of the plies. Director of CDER; one copy to the (2) Patient identification. Applicants CDER Drug Registration and Listing should not include in reports under Team, Division of Compliance Risk this section the names and addresses of Management and Surveillance; and one individual patients; instead, the appli- copy to either the director of the re- cant should code the patient names view division in CDER that is respon- whenever possible and retain the code sible for reviewing the application, or in the applicant’s files. The applicant the director of the office in CBER that shall maintain sufficient patient iden- is responsible for reviewing the appli- tification information to permit FDA, cation. by using that information alone or (c) FDA will publicly disclose a list of along with records maintained by the all drug products to be discontinued investigator of a study, to identify the under paragraph (b)(3)(iii)(a) of this name and address of individual pa- section. If the notification period is re- tients; this will ordinarily occur only duced under § 314.91, the list will state when the agency needs to investigate the reason(s) for such reduction and the reports further or when there is

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reason to believe that the reports do (3) The applicant’s submission other- not represent actual results obtained. wise justifies a waiver. (d) Withdrawal of approval. If an ap- [50 FR 7493, Feb. 22, 1985, as amended at 50 plicant fails to make reports required FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, under this section, FDA may withdraw 2002] approval of the application and, thus, prohibit continued marketing of the § 314.91 Obtaining a reduction in the discontinuance notification period. drug product that is the subject of the application. (a) What is the discontinuance notification period? The discontinuance notifi- (Collection of information requirements ap- cation period is the 6-month period re- proved by the Office of Management and quired under § 314.81(b)(3)(iii)(a). The Budget under control number 0910–0001) discontinuance notification period be- [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, gins when an applicant who is the sole 1985, as amended at 50 FR 21238, May 23, 1985; manufacturer of certain products noti- 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, fies FDA that it will discontinue manu- 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. facturing the product. The discontinu- 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815, ance notification period ends when Feb. 20, 2001; 68 FR 69019, Dec. 11, 2003; 69 FR manufacturing ceases. 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; (b) When can FDA reduce the dis- 72 FR 58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, continuance notification period? FDA can 2009; 74 FR 37167, July 28, 2009] reduce the 6-month discontinuance notification period when it finds good § 314.90 Waivers. cause exists for the reduction. FDA (a) An applicant may ask the Food may find good cause exists based on in- and Drug Administration to waive formation certified by an applicant in a under this section any requirement request for a reduction of the dis- that applies to the applicant under continuance notification period. In §§ 314.50 through 314.81. An applicant limited circumstances, FDA may find may ask FDA to waive under good cause exists based on information § 314.126(c) any criteria of an adequate already known to the agency. These circumstances can include the with- and well-controlled study described in drawal of the drug from the market § 314.126(b). A waiver request under this based upon formal FDA regulatory ac- section is required to be submitted tion (e.g., under the procedures de- with supporting documentation in an scribed in § 314.150 for the publication application, or in an amendment or of a notice of opportunity for a hearing supplement to an application. The describing the basis for the proposed waiver request is required to contain withdrawal of a drug from the market) one of the following: or resulting from the applicant’s con- (1) An explanation why the appli- sultations with the agency. cant’s compliance with the require- (c) How can an applicant request a re- ment is unnecessary or cannot be duction in the discontinuance notification achieved; period? (1) The applicant must certify (2) A description of an alternative in a written request that, in its opinion submission that satisfies the purpose of and to the best of its knowledge, good the requirement; or cause exists for the reduction. The ap- (3) Other information justifying a plicant must submit the following cer- waiver. tification: (b) FDA may grant a waiver if it The undersigned certifies that good cause exists for a reduction in the 6-month notifi- finds one of the following: cation period required in § 314.81(b)(3)(iii)(a) (1) The applicant’s compliance with for discontinuing the manufacture of (name the requirement is unnecessary for the of the drug product). The following cir- agency to evaluate the application or cumstances establish good cause (one or more compliance cannot be achieved; of the circumstances in paragraph (d) of this section). (2) The applicant’s alternative sub- (2) The certification must be signed mission satisfies the requirement; or by the applicant or the applicant’s attorney, agent (representative), or other

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authorized official. If the person sign- (5) The manufacturer has filed for ing the certification does not reside or bankruptcy under chapter 7 or 11 of have a place of business within the title 11, United States Code (11 U.S.C. United States, the certification must 701 et seq. and 1101 et seq.). This certifi- contain the name and address of, and cation must be accompanied by docu- must also be signed by, an attorney, mentation of the filing or proof that agent, or other authorized official who the filing occurred. resides or maintains a place of business (6) The manufacturer can continue within the United States. distribution of the drug product to sat- (3) For drugs regulated by the Center isfy existing market need for 6 months. for Drug Evaluation and Research This certification must include a de- (CDER) or the Center for Biologics tailed description of the manufactur- Evaluation and Research (CBER), one er’s processes to ensure such distribu- copy of the certification must be sub- tion for the 6-month period. mitted to the Drug Shortage Coordi- (7) Other good cause exists for the re- nator at the address of the Director of duction. This certification must in- CDER, one copy to the CDER Drug clude a detailed description of the need Registration and Listing Team, Divi- for a reduction. sion of Compliance Risk Management and Surveillance in CDER, and one [72 FR 58999, Oct. 18, 2007] copy to either the director of the review division in CDER responsible for Subpart C—Abbreviated reviewing the application, or the direc- Applications tor of the office in CBER responsible for reviewing the application. SOURCE: 57 FR 17983, Apr. 28, 1992, unless (d) What circumstances and information otherwise noted. can establish good cause for a reduction in the discontinuance notification period? § 314.92 Drug products for which ab- (1) A public health problem may result breviated applications may be sub- from continuation of manufacturing mitted. for the 6-month period. This certifi- (a) Abbreviated applications are suit- cation must include a detailed descrip- able for the following drug products tion of the potential threat to the pub- within the limits set forth under lic health. § 314.93: (2) A biomaterials shortage prevents (1) Drug products that are the same the continuation of the manufacturing as a listed drug. A ‘‘listed drug’’ is de- for the 6-month period. This certifi- fined in § 314.3. For determining the cation must include a detailed descrip- suitability of an abbreviated new drug tion of the steps taken by the applicant application, the term ‘‘same as’’ means in an attempt to secure an adequate identical in active ingredient(s), dosage supply of biomaterials to enable manu- form, strength, route of administra- facturing to continue for the 6-month tion, and conditions of use, except that period and an explanation of why the conditions of use for which approval biomaterials could not be secured. cannot be granted because of exclu- (3) A liability problem may exist for sivity or an existing patent may be the manufacturer if the manufacturing omitted. If a listed drug has been vol- is continued for the 6-month period. untarily withdrawn from or not offered This certification must include a de- for sale by its manufacturer, a person tailed description of the potential li- who wishes to submit an abbreviated ability problem. new drug application for the drug shall (4) Continuation of the manufac- comply with § 314.122. turing for the 6-month period may (2) [Reserved] cause substantial economic hardship (3) Drug products that have been de- for the manufacturer. This certifi- clared suitable for an abbreviated new cation must include a detailed descrip- drug application submission by FDA tion of the financial impact of con- through the petition procedures set tinuing to manufacture the drug prod- forth under § 10.30 of this chapter and uct over the 6-month period. § 314.93.

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

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reference listed drug that is to be § 314.94 Content and format of an ab- changed and that the drug product can breviated application. be expected to have the same thera- Abbreviated applications are re- peutic effect as the reference listed quired to be submitted in the form and drug when administered to patients for contain the information required under each condition of use in the listed this section. Three copies of the appli- drug’s labeling for which the applicant cation are required, an archival copy, a seeks approval; or review copy, and a field copy. FDA will (C) The different active ingredient is maintain guidance documents on the not an active ingredient in a listed format and content of applications to drug or a drug that meets the require- assist applicants in their preparation. ments of section 201(p) of the act; or (a) Abbreviated new drug applications. Except as provided in paragraph (b) of (D) The remaining active ingredients this section, the applicant shall submit are not identical to those of the listed a complete archival copy of the abbre- combination drug; or viated new drug application that in- (iv) Any of the proposed changes cludes the following: from the listed drug would jeopardize (1) Application form. The applicant the safe or effective use of the product shall submit a completed and signed so as to necessitate significant labeling application form that contains the in- changes to address the newly intro- formation described under § 314.50(a)(1), duced safety or effectiveness problem; (a)(3), (a)(4), and (a)(5). The applicant or shall state whether the submission is (v) FDA has determined that the ref- an abbreviated application under this erence listed drug has been withdrawn section or a supplement to an abbre- from sale for safety or effectiveness viated application under § 314.97. reasons under § 314.161, or the reference (2) Table of contents. the archival copy listed drug has been voluntarily with- of the abbreviated new drug applica- drawn from sale and the agency has tion is required to contain a table of not determined whether the with- contents that shows the volume num- drawal is for safety or effectiveness ber and page number of the contents of reasons. the submission. (3) Basis for abbreviated new drug ap- (2) For purposes of this paragraph, plication submission. An abbreviated ‘‘investigations must be conducted’’ new drug application must refer to a means that information derived from listed drug. Ordinarily, that listed drug animal or clinical studies is necessary will be the drug product selected by the to show that the drug product is safe or agency as the reference standard for effective. Such information may be conducting bioequivalence testing. The contained in published or unpublished application shall contain: reports. (i) The name of the reference listed (3) If FDA approves a petition sub- drug, including its dosage form and mitted under this section, the agency’s strength. For an abbreviated new drug response may describe what additional application based on an approverd peti- information, if any, will be required to tion under § 10.30 of this chapter or support an abbreviated new drug appli- § 314.93, the reference listed drug must cation for the drug product. FDA may, be the same as the listed drug approved at any time during the course of its rein the petition. view of an abbreviated new drug appli- (ii) A statement as to whether, ac- cation, request additional information cording to the information published in required to evaluate the change ap- the list, the reference listed drug is en- proved under the petition. titled to a period of marketing exclusivity under section 505(j)(4)(D) of the (f) FDA may withdraw approval of a act. petition if the agency receives any in- (iii) For an abbreviated new drug ap- formation demonstrating that the peti- plication based on an approved petition tion no longer satisfies the conditions under § 10.30 of this chapter or § 314.93, a under paragraph (e) of this section. reference to FDA-assigned docket number for the petition and a copy of

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FDA’s correspondence approving the erence listed drug provided under para- petition. graph (a)(8) of this section. (4) Conditions of use. (i) A statement (6) Route of administration, dosage that the conditions of use prescribed, form, and strength. (i) Information to recommended, or suggested in the la- show that the route of administration, beling proposed for the drug product dosage form, and strength of the drug have been previously approved for the product are the same as those of the reference listed drug. reference listed drug except for any dif- (ii) A reference to the applicant’s an- ferences that have been the subject of notated proposed labeling and to the an approved petition, as follows: currently approved labeling for the ref- (A) A statement that the route of ad- erence listed drug provided under para- ministration, dosage form, and graph (a)(8) of this section. strength of the proposed drug product (5) Active ingredients. (i) For a single- are the same as those of the reference active-ingredient drug product, infor- listed drug. mation to show that the active ingre- (B) A reference to the applicant’s an- dient is the same as that of the ref- notated proposed labeling and to the erence single-active-ingredient listed currently approved labeling for the ref- drug, as follows: erence listed drug provided under para- (A) A statement that the active in- graph (a)(8) of this section. gredient of the proposed drug product (ii) If the route of administration, is the same as that of the reference dosage form, or strength of the drug listed drug. product differs from the reference list- (B) A reference to the applicant’s an- ed drug and the abbreviated applica- notated proposed labeling and to the tion is submitted under an approved currently approved labeling for the ref- petition under § 314.93, such informa- erence listed drug provided under para- tion about the different route of ad- graph (a)(8) of this section. ministration, dosage form, or strength (ii) For a combination drug product, that FDA may require. information to show that the active in- (7) Bioequivalence. (i) Information gredients are the same as those of the that shows that the drug product is reference listed drug except for any dif- bioequivalent to the reference listed ferent active ingredient that has been drug upon which the applicant relies. A the subject of an approved petition, as complete study report must be sub- follows: mitted for the bioequivalence study (A) A statement that the active in- upon which the applicant relies for ap- gredients of the proposed drug product proval. For all other bioequivalence are the same as those of the reference studies conducted on the same drug listed drug, or if one of the active in- product formulation as defined in gredients differs from one of the active § 320.1(g) of this chapter, the applicant ingredients of the reference listed drug must submit either a complete or sum- and the abbreviated application is sub- mary report. If a summary report of a mitted under the approval of a petition bioequivalence study is submitted and under § 314.93 to vary such active ingre- FDA determines that there may be bio- dient, information to show that the equivalence issues or concerns with the other active ingredients of the drug product, FDA may require that the ap- product are the same as the other ac- plicant submit a complete report of the tive ingredients of the reference listed bioequivalence study to FDA; or drug, information to show that the dif- (ii) If the abbreviated new drug appli- ferent active ingredient is an active in- cation is submitted under a petition gredient of another listed drug or of a approved under § 314.93, the results of drug that does not meet the definition any bioavailability of bioequivalence of ‘‘new drug’’ in section 201(p) of the testing required by the agency, or any act, and such other information about other information required by the the different active ingredient that agency to show that the active ingredi- FDA may require. ents of the proposed drug product are (B) A reference to the applicant’s an- of the same pharmacological or thera- notated proposed labeling and to the peutic class as those in the reference currently approved labeling for the ref- listed drug and that the proposed drug

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product can be expected to have the drug product including, if applicable, same therapeutic effect as the ref- any Medication Guide required under erence listed drug. If the proposed drug part 208 of this chapter (4 copies of product contains a different active in- draft labeling or 12 copies of final gredient than the reference listed drug, printed labeling). FDA will consider the proposed drug (iii) Statement on proposed labeling. A product to have the same therapeutic statement that the applicant’s pro- effect as the reference listed drug if the posed labeling including, if applicable, applicant provides information dem- any Medication Guide required under onstrating that: part 208 of this chapter is the same as (A) There is an adequate scientific the labeling of the reference listed drug basis for determining that substitution except for differences annotated and of the specific proposed dose of the dif- explained under paragraph (a)(8)(iv) of ferent active ingredient for the dose of this section. the member of the same pharma- (iv) Comparison of approved and pro- cological or therapeutic class in the posed labeling. A side-by-side compari- reference listed drug will yield a re- son of the applicant’s proposed labeling sulting drug product whose safety and including, if applicable, any Medica- effectiveness have not been adversely tion Guide required under part 208 of affected. this chapter with the approved labeling (B) The unchanged active ingredients for the reference listed drug with all in the proposed drug product are bio- differences annotated and explained. equivalent to those in the reference Labeling (including the container listed drug. label, package insert, and, if applica- (C) The different active ingredient in ble, Medication Guide) proposed for the the proposed drug product is bioequiva- drug product must be the same as the lent to an approved dosage form con- labeling approved for the reference list- taining that ingredient and approved ed drug, except for changes required be- for the same indication as the proposed cause of differences approved under a drug product or is bioequivalent to a petition filed under § 314.93 or because drug product offered for that indication the drug product and the reference list- which does not meet the definition of ‘‘new drug’’ under section 201(p) of the ed drug are produced or distributed by act. different manufacturers. Such dif- (iii) For each in vivo bioequivalence ferences between the applicant’s pro- study contained in the abbreviated new posed labeling and labeling approved drug application, a description of the for the reference listed drug may in- analytical and statistical methods used clude differences in expiration date, in each study and a statement with re- formulation, bioavailability, or phar- spect to each study that it either was macokinetics, labeling revisions made conducted in compliance with the in- to comply with current FDA labeling stitutional review board regulations in guidelines or other guidance, or omis- part 56 of this chapter, or was not sub- sion of an indication or other aspect of ject to the regulations under § 56.104 or labeling protected by patent or ac- § 56.105 of this chapter and that each corded exclusivity under section study was conducted in compliance 505(j)(5)(F) of the act. with the informed consent regulations (9) Chemistry, manufacturing, and con- in part 50 of this chapter. trols. (i) The information required (8) Labeling—(i) Listed drug labeling. A under § 314.50(d)(1), except that copy of the currently approved labeling § 314.50(d)(1)(ii)(c) shall contain the pro- (including, if applicable, any Medica- posed or actual master production tion Guide required under part 208 of record, including a description of the this chapter) for the listed drug re- equipment, to be used for the manufac- ferred to in the abbreviated new drug ture of a commercial lot of the drug application, if the abbreviated new product. drug application relies on a reference (ii) Inactive ingredients. Unless other- listed drug. wise stated in paragraphs (a)(9)(iii) (ii) Copies of proposed labeling. Copies through (a)(9)(v) of this section, an ap- of the label and all labeling for the plicant shall identify and characterize

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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 abbreviated application product. may include different inactive ingredi- (iii) Inactive ingredient changes per- ents provided that the applicant identi- mitted in drug products intended for par- fies and characterizes the differences enteral use. Generally, a drug product and provides information dem- intended for parenteral use shall con- onstrating that the differences do not tain the same inactive ingredients and affect the safety or efficacy of the pro- in the same concentration as the ref- posed drug product. erence listed drug identified by the ap- (10) Samples. The information re- plicant under paragraph (a)(3) of this quired under § 314.50(e)(1) and (e)(2)(i). section. However, an applicant may Samples need not be submitted until seek approval of a drug product that requested by FDA. differs from the reference listed drug in (11) Other. The information required preservative, buffer, or antioxidant under § 314.50(g). provided that the applicant identifies (12) Patent certification—(i) Patents and characterizes the differences and claiming drug, drug product, or method of provides information demonstrating use. (A) Except as provided in para- that the differences do not affect the graph (a)(12)(iv) of this section, a cer- safety or efficacy of the proposed drug tification with respect to each patent product. issued by the United States Patent and (iv) Inactive ingredient changes per- Trademark Office that, in the opinion mitted in drug products intended for oph- of the applicant and to the best of its thalmic or otic use. Generally, a drug knowledge, claims the reference listed product intended for ophthalmic or drug or that claims a use of such listed otic use shall contain the same inac- drug for which the applicant is seeking tive ingredients and in the same con- approval under section 505(j) of the act centration as the reference listed drug and for which information is required identified by the applicant under para- to be filed under section 505(b) and (c) graph (a)(3) of this section. However, of the act and § 314.53. For each such an applicant may seek approval of a patent, the applicant shall provide the drug product that differs from the ref- patent number and certify, in its opin- erence listed drug in preservative, buff- ion and to the best of its knowledge, er, substance to adjust tonicity, or one of the following circumstances: thickening agent provided that the ap- (1) That the patent information has plicant identifies and characterizes the not been submitted to FDA. The appli- differences and provides information cant shall entitle such a certification demonstrating that the differences do ‘‘Paragraph I Certification’’; not affect the safety or efficacy of the (2) That the patent has expired. The proposed drug product, except that, in applicant shall entitle such a certifi- a product intended for ophthalmic use, cation ‘‘Paragraph II Certification’’; an applicant may not change a buffer (3) The date on which the patent will or substance to adjust tonicity for the expire. The applicant shall entitle such purpose of claiming a therapeutic ad- a certification ‘‘Paragraph III Certifi- vantage over or difference from the cation’’; or listed drug, e.g., by using a balanced (4) That the patent is invalid, unen- salt solution as a diluent as opposed to forceable, or will not be infringed by an isotonic saline solution, or by mak- the manufacture, use, or sale of the ing a significant change in the pH or drug product for which the abbreviated other change that may raise questions application is submitted. The applicant of irritability. shall entitle such a certification (v) Inactive ingredient changes per- ‘‘Paragraph IV Certification’’. This cer- mitted in drug products intended for top- tification shall be submitted in the fol- ical use. Generally, a drug product in- lowing form: tended for topical use, solutions for I, (name of applicant), certify that Patent aerosolization or nebulization, and No. llllll (is invalid, unenforceable, or

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will not be infringed by the manufacture, use, or ent that claims only a method of man- sale of) (name of proposed drug product) for ufacturing the listed drug. which this application is submitted. (v) Licensing agreements. If the abbre- The certification shall be accompanied viated new drug application is for a by a statement that the applicant will drug or method of using a drug claimed comply with the requirements under by a patent and the applicant has a li- § 314.95(a) with respect to providing a censing agreement with the patent notice to each owner of the patent or owner, a certification under paragraph their representatives and to the holder (a)(12)(i)(A)(4) of this section (‘‘Para- of the approved application for the list- graph IV Certification’’) as to that pated drug, and with the requirements ent and a statement that it has been under § 314.95(c) with respect to the granted a patent license. content of the notice. (vi) Late submission of patent informa- (B) If the abbreviated new drug appli- tion. If a patent on the listed drug is cation refers to a listed drug that is issued and the holder of the approved itself a licensed generic product of a application for the listed drug does not patented drug first approved under sec- submit the required information on the tion 505(b) of the act, the appropriate patent within 30 days of issuance of the patent certification under paragraph patent, an applicant who submitted an (a)(12)(i) of this section with respect to abbreviated new drug application for each patent that claims the first-ap- that drug that contained an appro- proved patented drug or that claims a priate patent certification before the use for such drug. submission of the patent information is (ii) No relevant patents. If, in the opin- not required to submit an amended cer- ion of the applicant and to the best of tification. An applicant whose abbre- its knowledge, there are no patents de- viated new drug application is sub- scribed in paragraph (a)(12)(i) of this mitted after a late submission of pat- section, a certification in the following ent information, or whose pending ab- form: breviated application was previously submitted but did not contain an ap- In the opinion and to the best knowledge of propriate patent certification at the (name of applicant), there are no patents that time of the patent submission, shall claim the listed drug referred to in this ap- submit a certification under paragraph plication or that claim a use of the listed (a)(12)(i) of this section or a statement drug. under paragraph (a)(12)(iii) of this sec- (iii) Method of use patent. (A) If pat- tion as to that patent. ent information is submitted under (vii) Disputed patent information. If an section 505(b) or (c) of the act and applicant disputes the accuracy or rel- § 314.53 for a patent claiming a method evance of patent information sub- of using the listed drug, and the label- mitted to FDA, the applicant may seek ing for the drug product for which the a confirmation of the correctness of applicant is seeking approval does not the patent information in accordance include any indications that are cov- with the procedures under § 314.53(f). ered by the use patent, a statement ex- Unless the patent information is with- plaining that the method of use patent drawn or changed, the applicant shall does not claim any of the proposed in- submit an appropriate certification for dications. each relevant patent. (B) If the labeling of the drug product (viii) Amended certifications. A certifi- for which the applicant is seeking ap- cation submitted under paragraphs proval includes an indication that, ac- (a)(12)(i) through (a)(12)(iii) of this sec- cording to the patent information sub- tion may be amended at any time be- mitted under section 505(b) or (c) of the fore the effective date of the approval act and § 314.53 or in the opinion of the of the application. However, an appli- applicant, is claimed by a use patent, cant who has submitted a paragraph IV an applicable certification under para- patent certification may not change it graph (a)(12)(i) of this section. to a paragraph III certification if a pat- (iv) Method of manufacturing patent. ent infringement suit has been filed An applicant is not required to make a against another paragraph IV applicant certification with respect to any pat- unless the agency has determined that

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no applicant is entitled to 180-day ex- not be removed from the list until FDA clusivity or the patent expires before determines either that no delay in ef- the lawsuit is resolved or expires after fective dates of approval is required the suit is resolved but before the end under that section as a result of the of the 180-day exclusivity period. If an lawsuit, that the patent has expired, or applicant with a pending application that any such period of delay in effec- voluntarily makes a patent certifi- tive dates of approval is ended. An ap- cation for an untimely filed patent, the plicant shall submit an amended cer- applicant may withdraw the patent tification. Once an amendment or let- certification for the untimely filed pat- ter for the change has been submitted, ent. An applicant shall submit an the application will no longer be con- amended certification by letter or as sidered to be one containing a certifi- an amendment to a pending application cation under paragraph (a)(12)(i)(A)(4) or by letter to an approved application. of this section. Once an amendment or letter is sub- (C) Other amendments. (1) Except as mitted, the application will no longer provided in paragraphs (a)(12)(vi) and be considered to contain the prior cer- (a)(12)(viii)(C)(2) of this section, an ap- tification. plicant shall amend a submitted cer- (A) After finding of infringement. An tification if, at any time before the ef- applicant who has submitted a certifi- fective date of the approval of the ap- cation under paragraph (a)(12)(i)(A)(4) plication, the applicant learns that the of this section and is sued for patent submitted certification is no longer ac- infringement within 45 days of the re- curate. ceipt of notice sent under § 314.95 shall (2) An applicant is not required to amend the certification if a final judg- amend a submitted certification when ment in the action against the appli- information on a patent on the listed cant is entered finding the patent to be drug is submitted after the effective infringed. In the amended certification, date of approval of the abbreviated ap- the applicant shall certify under para- plication. graph (a)(12)(i)(A)(3) of this section (13) Financial certification or disclosure that the patent will expire on a specific statement. An abbreviated application date. Once an amendment or letter for shall contain a financial certification the change has been submitted, the ap- or disclosure statement as required by plication will no longer be considered part 54 of this chapter. to be one containing a certification (b) Drug products subject to the Drug under paragraph (a)(12)(i)(A)(4) of this Efficacy Study Implementation (DESI) re- section. If a final judgment finds the view. If the abbreviated new drug appli- patent to be invalid and infringed, an cation is for a duplicate of a drug prod- amended certification is not required. uct that is subject to FDA’s DESI re- (B) After removal of a patent from the view (a review of drug products ap- list. If a patent is removed from the proved as safe between 1938 and 1962) or list, any applicant with a pending ap- other DESI-like review and the drug plication (including a tentatively ap- product evaluated in the review is a proved application with a delayed ef- listed drug, the applicant shall comply fective date) who has made a certifi- with the provisions of paragraph (a) of cation with respect to such patent this section. shall amend its certification. The ap- (c) [Reserved] plicant shall certify under paragraph (d) Format of an abbreviated applica- (a)(12)(ii) of this section that no pat- tion. (1) The applicant must submit a ents described in paragraph (a)(12)(i) of complete archival copy of the abbre- this section claim the drug or, if other viated application as required under relevant patents claim the drug, shall paragraphs (a) and (c) of this section. amend the certification to refer only to FDA will maintain the archival copy those relevant patents. In the amend- during the review of the application to ment, the applicant shall state the rea- permit individual reviewers to refer to son for the change in certification information that is not contained in (that the patent is or has been removed their particular technical sections of from the list). A patent that is the sub- the application, to give other agency ject of a lawsuit under § 314.107(c) shall personnel access to the application for

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official business, and to maintain in (4) The applicant may obtain from one place a complete copy of the appli- FDA sufficient folders to bind the ar- cation. chival, the review, and the field copies (i) Format of submission. An applicant of the abbreviated application. may submit portions of the archival (5) The applicant shall submit a field copy of the abbreviated application in copy of the abbreviated application any form that the applicant and FDA that contains the technical section de- agree is acceptable, except as provided scribed in paragraph (a)(9) of this sec- in paragraph (d)(1)(ii) of this section. tion, a copy of the application form re- (ii) Labeling. The content of labeling quired under paragraph (a)(1) of this required under § 201.100(d)(3) of this section, and a certification that the chapter (commonly referred to as the field copy is a true copy of the tech- package insert or professional label- nical section described in paragraph (a)(9) of this section contained in the ing), including all text, tables, and fig- archival and review copies of the ab- ures, must be submitted to the agency breviated application. in electronic format as described in paragraph (d)(1)(iii) of this section. [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July This requirement applies to the con- 1, 1992, as amended at 58 FR 47352, Sept. 8, tent of labeling for the proposed drug 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, product only and is in addition to the Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR requirements of paragraph (a)(8)(ii) of 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003; this section that copies of the for- 69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, matted label and all proposed labeling 2009; 76 FR 13880, Mar. 15, 2011] be submitted. Submissions under this paragraph must be made in accordance § 314.95 Notice of certification of inva- with part 11 of this chapter, except for lidity or noninfringement of a patent. the requirements of § 11.10(a), (c) through (h), and (k), and the cor- (a) Notice of certification. For each responding requirements of § 11.30. patent that claims the listed drug or (iii) Electronic format submissions. that claims a use for such listed drug Electronic format submissions must be for which the applicant is seeking ap- in a form that FDA can process, re- proval and that the applicant certifies view, and archive. FDA will periodi- under § 314.94(a)(12) is invalid, unenforceable, or will not be infringed, the cally issue guidance on how to provide applicant shall send notice of such cer- the electronic submission (e.g., method tification by registered or certified of transmission, media, file formats, mail, return receipt requested to each preparation and organization of files). of the following persons: (2) For abbreviated new drug applica- (1) Each owner of the patent which is tions, the applicant shall submit a re- the subject of the certification or the view copy of the abbreviated applica- representative designated by the owner tion that contains two separate sec- to receive the notice. The name and ad- tions. One section shall contain the in- dress of the patent owner or its rep- formation described under paragraphs resentative may be obtained from the (a)(2) through (a)(6), (a)(8), and (a)(9) of United States Patent and Trademark this section 505(j)(2)(A)(vii) of the act Office; and and one copy of the analytical proce- (2) The holder of the approved appli- dures and descriptive information cation under section 505(b) of the act needed by FDA’s laboratories to per- for the listed drug that is claimed by form tests on samples of the proposed the patent and for which the applicant drug product and to validate the appli- is seeking approval, or, if the applica- cant’s analytical procedures. The other tion holder does not reside or maintain section shall contain the information a place of business within the United described under paragraphs (a)(3), States, the application holder’s attor- (a)(7), and (a)(8) of this section. Each of ney, agent, or other authorized official. the sections in the review copy is re- The name and address of the applica- quired to contain a copy of the application holder or its attorney, agent, or tion form described under § 314.50(a). authorized official may be obtained (3) [Reserved] from the Orange Book Staff, Office of

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Generic Drugs, 7500 Standish Pl., Rock- (7) If the applicant does not reside or ville, MD 20855. have a place of business in the United (3) This paragraph does not apply to States, the name and address of an a use patent that claims no uses for agent in the United States authorized which the applicant is seeking ap- to accept service of process for the approval. plicant. (b) Sending the notice. The applicant (d) Amendment to an abbreviated appli- shall send the notice required by para- cation. If an abbreviated application is graph (a) of this section when it re- amended to include the certification ceives from FDA an acknowledgment described in § 314.94(a)(12)(i)(A)(4), the letter stating that its abbreviated new applicant shall send the notice required drug application is sufficiently com- by paragraph (a) of this section at the plete to permit a substantive review. same time that the amendment to the At the same time, the applicant shall abbreviated application is submitted to amend its abbreviated new drug appli- FDA. cation to include a statement certi- (e) Documentation of receipt of notice. fying that the notice has been provided The applicant shall amend its abbre- to each person identified under para- viated application to document receipt graph (a) of this section and that the of the notice required under paragraph notice met the content requirements (a) of this section by each person pro- under paragraph (c) of this section. vided the notice. The applicant shall (c) Contents of a notice. In the notice, include a copy of the return receipt or the applicant shall cite section other similar evidence of the date the 505(j)(2)(B)(ii) of the act and shall in- notification was received. FDA will ac- clude, but not be limited to, the fol- cept as adequate documentation of the lowing information: date of receipt a return receipt or a let- (1) A statement that FDA has re- ter acknowledging receipt by the per- ceived an abbreviated new drug appli- son provided the notice. An applicant cation submitted by the applicant con- may rely on another form of docu- taining any required bioavailability or mentation only if FDA has agreed to bioequivalence data or information. such documentation in advance. A copy of the notice itself need not be sub- (2) The abbreviated application num- mitted to the agency. ber. (f) Approval. If the requirements of (3) The established name, if any, as this section are met, FDA will presume defined in section 502(e)(3) of the act, of the notice to be complete and suffi- the proposed drug product. cient, and it will count the day fol- (4) The active ingredient, strength, lowing the date of receipt of the notice and dosage form of the proposed drug by the patent owner or its representa- product. tive and by the approved application (5) The patent number and expiration holder as the first day of the 45-day pe- date, as submitted to the agency or as riod provided for in section known to the applicant, of each patent 505(j)(4)(B)(iii) of the act. FDA may, if alleged to be invalid, unenforceable, or the applicant provides a written state- not infringed. ment to FDA that a later date should (6) A detailed statement of the fac- be used, count from such later date. tual and legal basis of the applicant’s opinion that the patent is not valid, [59 FR 50366, Oct. 3, 1994, as amended at 68 FR 36705, June 18, 2003; 69 FR 11310, Mar. 10, 2004; unenforceable, or will not be infringed. 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, The applicant shall include in the de- 2009] tailed statement: (i) For each claim of a patent alleged § 314.96 Amendments to an unap- not to be infringed, a full and detailed proved abbreviated application. explanation of why the claim is not in- (a) Abbreviated new drug application. fringed. (1) An applicant may amend an abbre- (ii) For each claim of a patent al- viated new drug application that is leged to be invalid or unenforceable, a submitted under § 314.94, but not yet full and detailed explanation of the approved, to revise existing informa- grounds supporting the allegation. tion or provide additional information.

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Amendments containing bioequiva- application under § 314.94 that is effec- lence studies must contain reports of tive shall comply with the require- all bioequivalence studies conducted by ments of § 314.80 regarding the report- the applicant on the same drug product ing and recordkeeping of adverse drug formulation, unless the information experiences. has previously been submitted to FDA (b) Each applicant shall submit one in the abbreviated new drug applica- copy of each report required under tion. A complete study report must be § 314.80 to the Central Document Room, submitted for any bioequivalence study Center for Drug Evaluation and Re- upon which the applicant relies for ap- search, Food and Drug Administration, proval. For all other bioequivalence 5901–B Ammendale Rd., Beltsville, MD studies conducted on the same drug 20705–1266. product formulation as defined in (c) Each applicant shall make the re- § 320.1(g) of this chapter, the applicant ports required under § 314.81 and section must submit either a complete or sum- 505(k) of the act for each of its ap- mary report. If a summary report of a proved abbreviated applications. bioequivalence study is submitted and [57 FR 17983, Apr. 28, 1992, as amended at 64 FDA determines that there may be bio- FR 401, Jan. 5, 1999; 74 FR 13113, Mar. 26, 2009] equivalence issues or concerns with the product, FDA may require that the ap- § 314.99 Other responsibilities of an plicant submit a complete report of the applicant of an abbreviated applica- bioequivalence study to FDA. tion. (2) Submission of an amendment con- (a) An applicant shall comply with taining significant data or information the requirements of § 314.65 regarding before the end of the initial review withdrawal by the applicant of an un- cycle constitutes an agreement be- approved abbreviated application and tween FDA and the applicant to extend § 314.72 regarding a change in ownership the initial review cycle only for the of an abbreviated application. time necessary to review the signifi- (b) An applicant may ask FDA to cant data or information and for no waive under this section any require- more than 180 days. ment that applies to the applicant (b) The applicant shall submit a field under §§ 314.92 through 314.99. The appli- copy of each amendment to cant shall comply with the require- § 314.94(a)(9). The applicant, other than ments for a waiver under § 314.90. a foreign applicant, shall include in its submission of each such amendment to Subpart D—FDA Action on Appli- FDA a statement certifying that a field cations and Abbreviated Ap- copy of the amendment has been sent plications to the applicant’s home FDA district office. SOURCE: 50 FR 7493, Feb. 22, 1985, unless [57 FR 17983, Apr. 28, 1992, as amended at 58 otherwise noted. Redesignated at 57 FR 17983, FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999; Apr. 28, 1992. 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 16, 2009] § 314.100 Timeframes for reviewing applications and abbreviated applica- § 314.97 Supplements and other tions. changes to an approved abbre- (a) Except as provided in paragraph viated application. (c) of this section, within 180 days of The applicant shall comply with the receipt of an application for a new drug requirements of §§ 314.70 and 314.71 re- under section 505(b) of the act or an ab- garding the submission of supple- breviated application for a new drug mental applications and other changes under section 505(j) of the act, FDA to an approved abbreviated applica- will review it and send the applicant ei- tion. ther an approval letter under § 314.105 or a complete response letter under § 314.98 Postmarketing reports. § 314.110. This 180-day period is called (a) Except as provided in paragraph the ‘‘initial review cycle.’’ (b) of this section, each applicant hav- (b) At any time before approval, an ing an approved abbreviated new drug applicant may withdraw an application

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under § 314.65 or an abbreviated application, the applicant may amend the ap- tion under § 314.99 and later submit it plication and resubmit it, and the again for consideration. agency will make a determination (c) The initial review cycle may be under this section whether it may be adjusted by mutual agreement between filed. FDA and an applicant or as provided in (b)(1) An abbreviated new drug appli- §§ 314.60 and 314.96, as the result of a cation will be reviewed after it is sub- major amendment. mitted to determine whether the ab- [73 FR 39609, July 10, 2008] breviated application may be received. Receipt of an abbreviated new drug ap- § 314.101 Filing an application and re- plication means that FDA has made a ceiving an abbreviated new drug threshold determination that the ab- application. breviated application is sufficiently (a)(1) Within 60 days after FDA re- complete to permit a substantive receives an application, the agency will view. determine whether the application may (2) If FDA finds that none of the rea- be filed. The filing of an application sons in paragraphs (d) and (e) of this means that FDA has made a threshold section for considering the abbreviated determination that the application is new drug application not to have been sufficiently complete to permit a sub- received applies, the agency will re- stantive review. ceive the abbreviated new drug applica- (2) If FDA finds that none of the rea- tion and notify the applicant in writ- sons in paragraphs (d) and (e) of this ing. section for refusing to file the applica- (3) If FDA considers the abbreviated tion apply, the agency will file the ap- new drug application not to have been plication and notify the applicant in received under paragraph (d) or (e) of writing. The date of filing will be the this section, FDA will notify the appli- date 60 days after the date FDA re- cant, ordinarily by telephone. The ap- ceived the application. The date of fil- plicant may then: ing begins the 180-day period described (i) Withdraw the abbreviated new in section 505(c) of the act. This 180-day drug application under § 314.99; or period is called the ‘‘filing clock.’’ (ii) Amend the abbreviated new drug (3) If FDA refuses to file the applica- application to correct the deficiencies; tion, the agency will notify the appli- or cant in writing and state the reason (iii) Take no action, in which case under paragraph (d) or (e) of this sec- FDA will refuse to receive the abbre- tion for the refusal. If FDA refuses to viated new drug application. file the application under paragraph (d) (c) [Reserved] of this section, the applicant may re- (d) FDA may refuse to file an applica- quest in writing within 30 days of the tion or may not consider an abbre- date of the agency’s notification an in- viated new drug application to be re- formal conference with the agency ceived if any of the following applies: about whether the agency should file (1) The application does not contain a the application. If, following the infor- completed application form. mal conference, the applicant requests (2) The application is not submitted that FDA file the application (with or in the form required under § 314.50 or without amendments to correct the de- § 314.94. ficiencies), the agency will file the ap- (3) The application or abbreviated application over protest under paragraph plication is incomplete because it does (a)(2) of this section, notify the appli- not on its face contain information re- cant in writing, and review it as filed. quired under section 505(b), section If the application is filed over protest, 505(j), or section 507 of the act and the date of filing will be the date 60 § 314.50 or § 314.94. days after the date the applicant re- (4) The applicant fails to submit a quested the informal conference. The complete environmental assessment, applicant need not resubmit a copy of which addresses each of the items spec- an application that is filed over pro- ified in the applicable format under test. If FDA refuses to file the applica- § 25.40 of this chapter or fails to provide tion under paragraph (e) of this sec- sufficient information to establish that

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the requested action is subject to cat- cation, the drug product contains the egorical exclusion under § 25.30 or § 25.31 same active moiety as a drug that: of this chapter. (i) Was approved after September 24, (5) The application or abbreviated ap- 1984, in an application under section plication does not contain an accurate 505(b) of the act, and and complete English translation of (ii) Is entitled to a 5-year period of each part of the application that is not exclusivity under section in English. 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the (6) The application does not contain a act and § 314.108(b)(2), unless the 5-year statement for each nonclinical labora- exclusivity period has elapsed or unless tory study that it was conducted in 4 years of the 5-year period have compliance with the requirements set elapsed and the application or abbre- forth in part 58 of this chapter, or, for viated application contains a certifi- each study not conducted in compli- cation of patent invalidity or non- ance with part 58 of this chapter, a infringement described in brief statement of the reason for the § 314.50(i)(1)(i)(A)(4) or noncompliance. § 314.94(a)(12)(i)(A)(4). (7) The application does not contain a (f)(1) Within 180 days after the date of statement for each clinical study that filing, plus the period of time the re- it was conducted in compliance with view period was extended (if any), FDA the institutional review board regula- will either: tions in part 56 of this chapter, or was (i) Approve the application; or not subject to those regulations, and (ii) Issue a notice of opportunity for that it was conducted in compliance a hearing if the applicant asked FDA with the informed consent regulations to provide it an opportunity for a hear- in part 50 of this chapter, or, if the ing on an application in response to a study was subject to but was not con- complete response letter. (2) Within 180 days after the date of ducted in compliance with those regu- receipt, plus the period of time the relations, the application does not con- view clock was extended (if any), FDA tain a brief statement of the reason for will either approve or disapprove the the noncompliance. abbreviated new drug application. If (8) The drug product that is the sub- FDA disapproves the abbreviated new ject of the submission is already cov- drug application, FDA will issue a no- ered by an approved application or ab- tice of opportunity for hearing if the breviated application and the applicant applicant asked FDA to provide it an of the submission: opportunity for a hearing on an abbre- (i) Has an approved application or ab- viated new drug application in response breviated application for the same drug to a complete response letter. product; or (3) This paragraph does not apply to (ii) Is merely a distributor and/or re- applications or abbreviated applica- packager of the already approved drug tions that have been withdrawn from product. FDA review by the applicant. (9) The application is submitted as a 505(b)(2) application for a drug that is a [57 FR 17987, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 59 FR 50366, Oct. 3, duplicate of a listed drug and is eligible 1994; 62 FR 40599, July 29, 1997; 64 FR 402, Jan. for approval under section 505(j) of the 5, 1999; 73 FR 39609, July 10, 2008] act. (e) The agency will refuse to file an § 314.102 Communications between application or will consider an abbre- FDA and applicants. viated new drug application not to (a) General principles. During the have been received if any of the fol- course of reviewing an application or lowing applies: an abbreviated application, FDA shall (1) The drug product is subject to li- communicate with applicants about censing by FDA under the Public scientific, medical, and procedural Health Service Act (42 U.S.C. 201 et issues that arise during the review seq.) and subchapter F of this chapter. process. Such communication may (2) In the case of a 505(b)(2) applica- take the form of telephone conversa- tion or an abbreviated new drug appli- tions, letters, or meetings, whichever

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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 such meetings must be directed to the nicate promptly to applicants easily director of the division responsible for correctable deficiencies found in an ap- reviewing the application. plication or an abbreviated application (e) Other meetings. Other meetings be- when those deficiencies are discovered, tween FDA and applicants may be held, particularly deficiencies concerning with advance notice, to discuss sci- chemistry, manufacturing, and con- entific, medical, and other issues that trols issues. The agency will also in- arise during the review process. Re- form applicants promptly of its need quests for meetings shall be directed to for more data or information or for the director of the division responsible technical changes in the application or for reviewing the application or abbre- the abbreviated application needed to viated application. FDA will make facilitate the agency’s review. This every attempt to grant requests for early communication is intended to meetings that involve important issues permit applicants to correct such read- and that can be scheduled at mutually ily identified deficiencies relatively convenient times. However, ‘‘drop-in’’ early in the review process and to sub- visits (i.e., an unannounced and un- mit an amendment before the review scheduled visit by a company rep- period has elapsed. Such early commu- resentative) are discouraged except for nication would not ordinarily apply to urgent matters, such as to discuss an major scientific issues, which require important new safety issue. consideration of the entire pending application or abbreviated application by [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 73 FR 39609, July 10, agency managers as well as reviewing 2008] staff. Instead, major scientific issues will ordinarily be addressed in a com- § 314.103 Dispute resolution. plete response letter. (a) General. FDA is committed to re- (c) Ninety-day conference. Approxi- solving differences between applicants mately 90 days after the agency re- and FDA reviewing divisions with receives the application, FDA will pro- spect to technical requirements for ap- vide applicants with an opportunity to plications or abbreviated applications meet with agency reviewing officials. as quickly and amicably as possible The purpose of the meeting will be to through the cooperative exchange of inform applicants of the general information and views. progress and status of their applica- (b) Administrative and procedural tions, and to advise applicants of defi- issues. When administrative or proce- ciencies that have been identified by dural disputes arise, the applicant that time and that have not already should first attempt to resolve the been communicated. This meeting will matter with the division responsible be available on applications for all new for reviewing the application or abbre- chemical entities and major new indi- viated application, beginning with the cations of marketed drugs. Such meet- consumer safety officer assigned to the ings will be held at the applicant’s op- application or abbreviated application. tion, and may be held by telephone if If resolution is not achieved, the appli- mutually agreed upon. Such meetings cant may raise the matter with the would not ordinarily be held on abbre- person designated as ombudsman, viated applications because they are whose function shall be to investigate

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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 contained in a staff manual guide that abuse. 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 application disagrees with the agency. In addition, and an abbreviated application. the ‘‘ninety-day conference’’ described (a) The Food and Drug Administra- in § 314.102(c) will provide a timely tion will approve an application and forum for discussing and resolving, if send the applicant an approval letter if possible, issues identified by that date. none of the reasons in § 314.125 for re- (2) When scientific or medical dis- fusing to approve the application ap- putes arise at other times during the plies. An approval becomes effective on review process, applicants should dis- the date of the issuance of the approval cuss the matter directly with the re- letter, except with regard to an ap- sponsible reviewing officials. If nec- proval under section 505(b)(2) of the act essary, applicants may request a meet- with a delayed effective date. An ap- ing with the appropriate reviewing offi- proval with a delayed effective date is cials and management representatives tentative and does not become final in order to seek a resolution. Ordi- until the effective date. A new drug narily, such meetings would be held product or antibiotic approved under first with the Division Director, then this paragraph may not be marketed with the Office Director, and finally until an approval is effective. with the Center Director if the matter (b) FDA will approve an application is still unresolved. Requests for such and issue the applicant an approval let- meetings shall be directed to the direc- ter on the basis of draft labeling if the tor of the division responsible for re- only deficiencies in the application viewing the application or abrreviated concern editorial or similar minor defi- application. FDA will make every at- ciencies in the draft labeling. Such ap- tempt to grant requests for meetings proval will be conditioned upon the ap- that involve important issues and that plicant incorporating the specified la- can be scheduled at mutually conven- beling changes exactly as directed, and ient times. upon the applicant submitting to FDA (3) In requesting a meeting designed a copy of the final printed labeling to resolve a scientific or medical dis- prior to marketing. pute, applicants may suggest that FDA (c) FDA will approve an application seek the advice of outside experts, in after it determines that the drug meets which case FDA may, in its discretion, the statutory standards for safety and invite to the meeting one or more of its effectiveness, manufacturing and con- advisory committee members or other trols, and labeling, and an abbreviated consultants, as designated by the agen- application after it determines that the cy. Applicants may also bring their drug meets the statutory standards for own consultants. For major scientific manufacturing and controls, labeling, and medical policy issues not resolved and, where applicable, bioequivalence. by informal meetings, FDA may refer While the statutory standards apply to

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all drugs, the many kinds of drugs that plication not being approvable based on are subject to the statutory standards the foreign data alone. FDA will apply and the wide range of uses for those this policy in a flexible manner accord- drugs demand flexibility in applying ing to the nature of the drug and the the standards. Thus FDA is required to data being considered. exercise its scientific judgment to de- (c) Consultation between FDA and ap- termine the kind and quantity of data plicants. Applicants are encouraged to and information an applicant is re- meet with agency officials in a ‘‘pre- quired to provide for a particular drug submission’’ meeting when approval to meet the statutory standards. FDA based solely on foreign data will be makes its views on drug products and sought. classes of drugs available through guidance documents, recommendations, [50 FR 7493, Feb. 22, 1985, as amended at 55 and other statements of policy. FR 11580, Mar. 29, 1990] (d) FDA will approve an abbreviated new drug application and send the ap- § 314.107 Effective date of approval of a 505(b)(2) application or abbre- plicant an approval letter if none of the viated new drug application under reasons in § 314.127 for refusing to ap- section 505(j) of the act. prove the abbreviated new drug application applies. The approval becomes (a) General. A drug product may be effective on the date of the issuance of introduced or delivered for introduc- the agency’s approval letter unless the tion into interstate commerce when approval letter provides for a delayed approval of the application or abbre- effective date. An approval with a de- viated application for the drug product layed effective date is tentative and becomes effective. Except as provided does not become final until the effec- in this section, approval of an applica- tive date. A new drug product approved tion or abbreviated application for a under this paragraph may not be intro- drug product becomes effective on the duced or delivered for introduction into date FDA issues an approval letter interstate commerce until approval of under § 314.105 for the application or ab- the abbreviated new drug application is breviated application. effective. Ordinarily, the effective date (b) Effect of patent on the listed drug. If of approval will be stated in the ap- approval of an abbreviated new drug proval letter. application submitted under section 505(j) of the act or of a 505(b)(2) applica- [57 FR 17989, Apr. 28, 1992, as amended at 64 tion is granted, that approval will be- FR 402, Jan. 5, 1999; 65 FR 56479, Sept. 19, come effective in accordance with the 2000; 73 FR 39609, July 10, 2008] following: § 314.106 Foreign data. (1) Date of approval letter. Except as (a) General. The acceptance of foreign provided in paragraphs (b)(3), (b)(4), data in an application generally is gov- and (c) of this section, approval will be- erned by § 312.120 of this chapter. come effective on the date FDA issues (b) As sole basis for marketing approval. an approval letter under § 314.105 if the An application based solely on foreign applicant certifies under § 314.50(i) or clinical data meeting U.S. criteria for § 314.94(a)(12) that: marketing approval may be approved (i) There are no relevant patents; or if: (1) The foreign data are applicable (ii) The applicant is aware of a rel- to the U.S. population and U.S. med- evant patent but the patent informa- ical practice; (2) the studies have been tion required under section 505 (b) or performed by clinical investigators of (c) of the act has not been submitted to recognized competence; and (3) the FDA; or data may be considered valid without (iii) The relevant patent has expired; the need for an on-site inspection by or FDA or, if FDA considers such an in- (iv) The relevant patent is invalid, spection to be necessary, FDA is able unenforceable, or will not be infringed. to validate the data through an on-site (2) Patent expiration. If the applicant inspection or other appropriate means. certifies under § 314.50(i) or Failure of an application to meet any § 314.94(a)(12) that the relevant patent of these criteria will result in the ap- will expire on a specified date, approval

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will become effective on the specified ufacture or sale of the drug product date. until the court decides the issues of (3) Disposition of patent litigation. patent validity and infringement, and (i)(A) Except as provided in paragraphs if the court later decides that the pat- (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this ent is invalid, unenforceable, or not in- section, if the applicant certifies under fringed, approval may be made effec- § 314.50(i) or § 314.94(a)(12) that the rel- tive on the date the court enters a final evant patent is invalid, unenforceable, order or judgment that the patent is or will not be infringed, and the patent invalid, unenforceable, or not in- owner or its representative or the ex- fringed. clusive patent licensee brings suit for (v) FDA will issue a tentative ap- patent infringement within 45 days of proval letter when tentative approval receipt by the patent owner of the no- is appropriate in accordance with para- tice of certification from the applicant graph (b)(3) of this section. In order for under § 314.52 or § 314.95, approval may an approval to be made effective under be made effective 30 months after the paragraph (b)(3) of this section, the ap- date of the receipt of the notice of cer- plicant must receive an approval letter tification by the patent owner or by from the agency indicating that the ap- the exclusive licensee (or their rep- plication has received final approval. resentatives) unless the court has ex- Tentative approval of an application tended or reduced the period because of does not constitute ‘‘approval’’ of an a failure of either the plaintiff or de- application and cannot, absent a final fendant to cooperate reasonably in ex- approval letter from the agency, result pediting the action; or in an effective approval under para- (B) If the patented drug product graph (b)(3) of this section. qualifies for 5 years of exclusive mar- (4) Multiple certifications. If the appli- keting under § 314.108(b)(2) and the pat- cant has submitted certifications under ent owner or its representative or the § 314.50(i) or § 314.94(a)(12) for more than exclusive patent licensee brings suit one patent, the date of approval will be for patent infringement during the 1- calculated for each certification, and year period beginning 4 years after the the approval will become effective on date the patented drug was approved the last applicable date. and within 45 days of receipt by the (c) Subsequent abbreviated new drug patent owner of the notice of certifi- application submission. (1) If an abbre- cation, the approval may be made ef- viated new drug application contains a fective at the expiration of the 71⁄2 certification that a relevant patent is years from the date of approval of the invalid, unenforceable, or will not be application for the patented drug prod- infringed and the application is for a uct. generic copy of the same listed drug for (ii) If before the expiration of the 30- which one or more substantially com- month period, or 71⁄2 years where appli- plete abbreviated new drug applica- cable, the court issues a final order tions were previously submitted con- that the patent is invalid, unenforce- taining a certification that the same able, or not infringed, approval may be patent was invalid, unenforceable, or made effective on the date the court would not be infringed, approval of the enters judgment; subsequent abbreviated new drug appli- (iii) If before the expiration of the 30- cation will be made effective no sooner month period, or 71⁄2 years where appli- than 180 days from whichever of the cable, the court issues a final order or following dates is earlier: judgment that the patent has been in- (i) The date the applicant submitting fringed, approval may be made effec- the first application first commences tive on the date the court determines commercial marketing of its drug that the patent will expire or otherwise product; or orders; or (ii) The date of a decision of the (iv) If before the expiration of the 30- court holding the relevant patent in- month period, or 71⁄2 years where appli- valid, unenforceable, or not infringed. cable, the court grants a preliminary (2) For purposes of paragraph (c)(1) of injunction prohibiting the applicant this section, the ‘‘applicant submitting from engaging in the commercial man- the first application’’ is the applicant

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that submits an application that is to the appropriate division in the Of- both substantially complete and con- fice of New Drugs within 10 working tains a certification that the patent days of a final judgment. was invalid, unenforceable, or not in- (f) Computation of 45-day time clock. (1) fringed prior to the submission of any The 45-day clock described in para- other application for the same listed graph (b)(3) of this section begins on drug that is both substantially com- the day after the date of receipt of the plete and contains the same certifi- applicant’s notice of certification by cation. A ‘‘substantially complete’’ ap- the patent owner or its representative, plication must contain the results of and by the approved application holder. any required bioequivalence studies, When the 45th day falls on Saturday, or, if applicable, a request for a waiver Sunday, or a Federal holiday, the 45th of such studies. day will be the next day that is not a (3) For purposes of paragraph (c)(1) of Saturday, Sunday, or a Federal holi- this section, if FDA concludes that the day. applicant submitting the first applica- (2) The abbreviated new drug appli- tion is not actively pursuing approval cant or the 505(b)(2) applicant shall no- of its abbreviated application, FDA tify FDA immediately of the filing of will make the approval of subsequent any legal action filed within 45 days of abbreviated applications immediately receipt of the notice of certification. If effective if they are otherwise eligible the applicant submitting the abbre- for an immediately effective approval. viated new drug application or the (4) For purposes of paragraph (c)(1)(i) 505(b)(2) application or patent owner or of this section, the applicant submit- its representative does not notify FDA ting the first application shall notify in writing before the expiration of the FDA of the date that it commences 45-day time period or the completion of commercial marketing of its drug the agency’s review of the application, product. Commercial marketing com- whichever occurs later, that a legal ac- mences with the first date of introduction for patent infringement was filed tion or delivery for introduction into within 45 days of receipt of the notice interstate commerce outside the con- of certification, approval of the abbre- trol of the manufacturer of a drug viated new drug application or the product, except for investigational use 505(b)(2) application will be made effec- under part 312 of this chapter, but does tive immediately upon expiration of not include transfer of the drug prod- the 45 days or upon completion of the uct for reasons other than sale within agency’s review and approval of the ap- the control of the manufacturer or application holder. If an applicant does plication, whichever is later. The noti- not promptly notify FDA of such date, fication to FDA of the legal action the effective date of approval shall be shall include: deemed to be the date of the com- (i) The abbreviated new drug applica- mencement of first commercial mar- tion or 505(b)(2) application number. keting. (ii) The name of the abbreviated new (d) Delay due to exclusivity. The agen- drug or 505(b)(2) application applicant. cy will also delay the effective date of (iii) The established name of the drug the approval of an abbreviated new product or, if no established name ex- drug application under section 505(j) of ists, the name(s) of the active ingre- the act or a 505(b)(2) application if dient(s), the drug product’s strength, delay is required by the exclusivity and dosage form. provisions in § 314.108. When the effec- (iv) A certification that an action for tive date of an application is delayed patent infringement identified by num- under both this section and § 314.108, ber, has been filed in an appropriate the effective date will be the later of court on a specified date. the 2 days specified under this section The applicant of an abbreviated new and § 314.108. drug application shall send the notifi- (e) Notification of court actions. The cation to FDA’s Office of Generic applicant shall submit a copy of the Drugs (HFD–600). A 505(b)(2) applicant entry of the order or judgment to the shall send the notification to the ap- Office of Generic Drugs (HFD–600), or propriate division in the Office of New

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Drugs reviewing the application. A pat- 10, 1962, or an application that was ent owner or its representative may ‘‘deemed approved’’ under section also notify FDA of the filing of any 107(c)(2) of Pub. L. 87–781. legal action for patent infringement. Clinical investigation means any ex- The notice should contain the informa- periment other than a bioavailability tion and be sent to the offices or divi- study in which a drug is administered sions described in this paragraph. or dispensed to, or used on, human sub- (3) If the patent owner or approved jects. application holder who is an exclusive Conducted or sponsored by the appli- patent licensee waives its opportunity cant with regard to an investigation to file a legal action for patent in- means that before or during the inves- fringement within 45 days of a receipt tigation, the applicant was named in of the notice of certification and the Form FDA–1571 filed with FDA as the patent owner or approved application sponsor of the investigational new drug holder who is an exclusive patent li- application under which the investiga- censee submits to FDA a valid waiver tion was conducted, or the applicant or before the 45 days elapse, approval of the applicant’s predecessor in interest, the abbreviated new drug application provided substantial support for the in- or the 505(b)(2) application will be vestigation. To demonstrate ‘‘substan- made effective upon completion of the tial support,’’ an applicant must either agency’s review and approval of the ap- provide a certified statement from a plication. FDA will only accept a waiv- certified public accountant that the ap- er in the following form: plicant provided 50 percent or more of (Name of patent owner or exclusive patent li- the cost of conducting the study or censee) has received notice from (name of ap- provide an explanation why FDA plicant) under (section 505(b)(3) or 505(j)(2)(B) should consider the applicant to have of the act) and does not intend to file an ac- conducted or sponsored the study if the tion for patent infringement against (name of applicant’s financial contribution to applicant) concerning the drug (name of drug) before (date on which 45 days elapses. (Name of the study is less than 50 percent or the patent owner or exclusive patent licensee) applicant did not sponsor the inves- waives the opportunity provided by (section tigational new drug. A predecessor in 505(c)(3)(C) or 505(j)(B)(iii) of the act) and does interest is an entity, e.g., a corpora- not object to FDA’s approval of (name of ap- tion, that the applicant has taken over, plicant)’s (505(b)(2) or abbreviated new drug ap- merged with, or purchased, or from plication) for (name of drug) with an imme- which the applicant has purchased all diate effective date on or after the date of this letter. rights to the drug. Purchase of non- exclusive rights to a clinical investiga- [59 FR 50367, Oct. 3, 1994, as amended at 63 FR tion after it is completed is not suffi- 59712, Nov. 5, 1998; 65 FR 43235, July 13, 2000; cient to satisfy this definition. 73 FR 39609, July 10, 2008; 74 FR 9766, Mar. 6, 2009] Date of approval means the date on the letter from FDA stating that the § 314.108 New drug product exclu- new drug application is approved, sivity. whether or not final printed labeling or (a) Definitions. The following defini- other materials must yet be submitted tions of terms apply to this section: as long as approval of such labeling or Active moiety means the molecule or materials is not expressly required. ion, excluding those appended portions ‘‘Date of approval’’ refers only to a of the molecule that cause the drug to final approval and not to a tentative be an ester, salt (including a salt with approval that may become effective at hydrogen or coordination bonds), or a later date. other noncovalent derivative (such as a Essential to approval means, with re- complex, chelate, or clathrate) of the gard to an investigation, that there are molecule, responsible for the physio- no other data available that could sup- logical or pharmacological action of port approval of the application. the drug substance. FDA means the Food and Drug Ad- Approved under section 505(b) means ministration. an application submitted under section New chemical entity means a drug that 505(b) and approved on or after October contains no active moiety that has

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been approved by FDA in any other ap- after receipt of the notice described at plication submitted under section § 314.52 or § 314.95, in which case, ap- 505(b) of the act. proval of the 505(b)(2) application or New clinical investigation means an in- abbreviated application will be made vestigation in humans the results of effective as provided in § 314.107(b)(3). which have not been relied on by FDA (4) If an application: to demonstrate substantial evidence of (i) Was submitted under section effectiveness of a previously approved 505(b) of the act; drug product for any indication or of (ii) Was approved after September 24, safety for a new patient population and 1984; do not duplicate the results of another investigation that was relied on by the (iii) Was for a drug product that con- agency to demonstrate the effective- tains an active moiety that has been ness or safety in a new patient popu- previously approved in another appli- lation of a previously approved drug cation under section 505(b) of the act; product. For purposes of this section, and data from a clinical investigation pre- (iv) Contained reports of new clinical viously submitted for use in the com- investigations (other than bio- prehensive evaluation of the safety of a availability studies) conducted or spon- drug product but not to support the ef- sored by the applicant that were essen- fectiveness of the drug product would tial to approval of the application, the be considered new. agency will not make effective for a pe- (b) Submission of and effective date of riod of 3 years after the date of ap- approval of an abbreviated new drug approval of the application the approval plication submitted under section 505(j) of of a 505(b)(2) application or an abbre- the act or a 505(b)(2) application. (1) [Re- viated new drug application for the served] conditions of approval of the original (2) If a drug product that contains a application, or an abbreviated new new chemical entity was approved drug application submitted pursuant to after September 24, 1984, in an applica- an approved petition under section tion submitted under section 505(b) of 505(j)(2)(C) of the act that relies on the the act, no person may submit a information supporting the conditions 505(b)(2) application or abbreviated new drug application under section 505(j) of of approval of an original new drug ap- the act for a drug product that con- plication. tains the same active moiety as in the (5) If a supplemental application: new chemical entity for a period of 5 (i) Was approved after September 24, years from the date of approval of the 1984; and first approved new drug application, (ii) Contained reports of new clinical except that the 505(b)(2) application or investigations (other than bio- abbreviated application may be sub- availability studies) that were con- mitted after 4 years if it contains a cer- ducted or sponsored by the applicant tification of patent invalidity or non- that were essential to approval of the infringement described in supplemental application, the agency § 314.50(i)(1)(i)(A)(4) or will not make effective for a period of § 314.94(a)(12)(i)(A)(4). 3 years after the date of approval of the (3) The approval of a 505(b)(2) applica- supplemental application the approval tion or abbreviated application de- of a 505(b)(2) application or an abbre- scribed in paragraph (b)(2) of this sec- viated new drug application for a tion will become effective as provided change, or an abbreviated new drug ap- in § 314.107(b)(1) or (b)(2), unless the plication submitted pursuant to an ap- owner of a patent that claims the drug, proved petition under section the patent owner’s representative, or exclusive licensee brings suit for pat- 505(j)(2)(C) of the act that relies on the ent infringement against the applicant information supporting a change ap- during the 1-year period beginning 48 proved in the supplemental new drug months after the date of approval of application. the new drug application for the new [59 FR 50368, Oct. 3, 1994] chemical entity and within 45 days

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§ 314.110 Complete response letter to sifies as a Class 2 resubmission con- the applicant. stitutes an agreement by the applicant (a) Complete response letter. FDA will to start a new 6-month review cycle be- send the applicant a complete response ginning on the date FDA receives the letter if the agency determines that we resubmission. will not approve the application or ab- (iii) A resubmission of an NDA sup- breviated application in its present plement other than an efficacy supple- form for one or more of the reasons ment constitutes an agreement by the given in § 314.125 or § 314.127, respec- applicant to start a new review cycle tively. the same length as the initial review (1) Description of specific deficiencies. A cycle for the supplement (excluding complete response letter will describe any extension due to a major amend- all of the specific deficiencies that the ment of the initial supplement), begin- agency has identified in an application ning on the date FDA receives the re- or abbreviated application, except as submission. stated in paragraph (a)(3) of this sec- (iv) A major resubmission of an ab- tion. breviated application constitutes an (2) Complete review of data. A com- agreement by the applicant to start a plete response letter reflects FDA’s new 6-month review cycle beginning on complete review of the data submitted the date FDA receives the resubmis- in an original application or abbre- sion. viated application (or, where appro- (v) A minor resubmission of an abbre- priate, a resubmission) and any amend- viated application constitutes an ments that the agency has reviewed. agreement by the applicant to start a 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 issue a complete response letter with- (3) Request opportunity for hearing. out first conducting required inspec- Ask the agency to provide the appli- tions and/or reviewing proposed prod- cant an opportunity for a hearing on uct labeling. the question of whether there are (4) Recommendation of actions for ap- grounds for denying approval of the approval. When possible, a complete re- plication or abbreviated application sponse letter will recommend actions under section 505(d) or (j)(4) of the act, that the applicant might take to place respectively. The applicant must sub- the application or abbreviated applica- mit the request to the Associate Direc- tion in condition for approval. tor for Policy, Center for Drug Evalua- (b) Applicant actions. After receiving tion and Research, Food and Drug Ad- a complete response letter, the appli- ministration, 10903 New Hampshire cant must take one of following ac- Ave., Silver Spring, MD 20993. Within tions: 60 days of the date of the request for an (1) Resubmission. Resubmit the appli- opportunity for a hearing, or within a cation or abbreviated application, ad- different time period to which FDA and dressing all deficiencies identified in the applicant agree, the agency will ei- 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

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or abbreviated application under sec- chapter and must contain all evidence tion 505(d) or (j)(4) of the act, respec- available to the petitioner concerning tively. the reasons for the withdrawal from (c) Failure to take action. (1) An appli- sale. cant agrees to extend the review period (b) When a petition described in para- under section 505(c)(1) or (j)(5)(A) of the graph (a) of this section is submitted, act until it takes any of the actions the agency will consider the evidence listed in paragraph (b) of this section. in the petition and any other evidence For an application or abbreviated ap- before the agency, and determine plication, FDA may consider an appli- whether the listed drug is withdrawn cant’s failure to take any of such ac- from sale for safety or effectiveness tions within 1 year after issuance of a reasons, in accordance with the proce- complete response letter to be a re- dures in § 314.161. quest by the applicant to withdraw the (c) An abbreviated new drug applica- application, unless the applicant has tion described in paragraph (a) of this requested an extension of time in section will be disapproved, under which to resubmit the application. § 314.127(a)(11), and a 505(j)(2)(C) peti- FDA will grant any reasonable request tion described in paragraph (a) of this for such an extension. FDA may con- section will be disapproved, under sider an applicant’s failure to resubmit § 314.93(e)(1)(iv), unless the agency de- the application within the extended termines that the withdrawal of the time period or to request an additional listed drug was not for safety or effec- extension to be a request by the appli- tiveness reasons. cant to withdraw the application. (d) Certain drug products approved (2) If FDA considers an applicant’s for safety and effectiveness that were failure to take action in accordance no longer marketed on September 24, with paragraph (c)(1) of this section to 1984, are not included in the list. Any be a request to withdraw the applica- person who wishes to obtain marketing tion, the agency will notify the appli- approval for such a drug product under cant in writing. The applicant will an abbreviated new drug application have 30 days from the date of the noti- must petition FDA for a determination fication to explain why the application whether the drug product was with- should not be withdrawn and to request drawn from the market for safety or ef- an extension of time in which to resub- fectiveness reasons and request that mit the application. FDA will grant the list be amended to include the drug any reasonable request for an exten- product. A person seeking such a deter- sion. If the applicant does not respond mination shall use the petition proce- to the notification within 30 days, the dures established in § 10.30 of this chap- application will be deemed to be with- ter. The petitioner shall include in the drawn. 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 product ceased. application for, or a 505(j)(2)(C) petition 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 appli- section 505(j)(2)(C) of the act and cation. § 314.93 that relies on, a listed drug that (a) The Food and Drug Administra- has been voluntarily withdrawn from tion will refuse to approve the applica- sale in the United States must be action and for a new drug give the appli- companied by a petition seeking a de- cant written notice of an opportunity termination whether the listed drug for a hearing under § 314.200 on the was withdrawn for safety or effective- question of whether there are grounds ness reasons. The petition must be sub- for denying approval of the application mitted under §§ 10.25(a) and 10.30 of this under section 505(d) of the act, if:

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(1) FDA sends the applicant a com- § 314.101(d), if the deficiency is not cor- plete response letter under § 314.110; rected. (2) The applicant requests an oppor- (11) The drug will be manufactured or tunity for hearing for a new drug on processed in whole or in part in an es- the question of whether the application tablishment that is not registered and is approvable; and not exempt from registration under (3) FDA finds that any of the reasons section 510 of the act and part 207. given in paragraph (b) of this section (12) The applicant does not permit a apply. properly authorized officer or employee (b) FDA may refuse to approve an ap- of the Department of Health and plication for any of the following rea- Human Services an adequate oppor- sons: tunity to inspect the facilities, con- (1) The methods to be used in, and trols, and any records relevant to the the facilities and controls used for, the application. manufacture, processing, packing, or (13) The methods to be used in, and holding of the drug substance or the the facilities and controls used for, the drug product are inadequate to pre- manufacture, processing, packing, or serve its identity, strength, quality, holding of the drug substance or the purity, stability, and bioavailability. drug product do not comply with the (2) The investigations required under current good manufacturing practice section 505(b) of the act do not include regulations in parts 210 and 211. adequate tests by all methods reason- (14) The application does not contain ably applicable to show whether or not the drug is safe for use under the condi- an explanation of the omission of a re- tions prescribed, recommended, or sug- port of any investigation of the drug gested in its proposed labeling. product sponsored by the applicant, or (3) The results of the tests show that an explanation of the omission of other the drug is unsafe for use under the information about the drug pertinent conditions prescribed, recommended, to an evaluation of the application or suggested in its proposed labeling or that is received or otherwise obtained the results do not show that the drug by the applicant from any source. product is safe for use under those con- (15) A nonclinical laboratory study ditions. that is described in the application and (4) There is insufficient information that is essential to show that the drug about the drug to determine whether is safe for use under the conditions pre- the product is safe for use under the scribed, recommended, or suggested in conditions prescribed, recommended, its proposed labeling was not con- or suggested in its proposed labeling. ducted in compliance with the good (5) There is a lack of substantial evi- laboratory practice regulations in part dence consisting of adequate and well- 58 of this chapter and no reason for the controlled investigations, as defined in noncompliance is provided or, if it is, § 314.126, that the drug product will the differences between the practices have the effect it purports or is rep- used in conducting the study and the resented to have under the conditions good laboratory practice regulations do of use prescribed, recommended, or not support the validity of the study. suggested in its proposed labeling. (16) Any clinical investigation in- (6) The proposed labeling is false or volving human subjects described in misleading in any particular. the application, subject to the institu- (7) The application contains an un- tional review board regulations in part true statement of a material fact. 56 of this chapter or informed consent (8) The drug product’s proposed label- regulations in part 50 of this chapter, ing does not comply with the require- was not conducted in compliance with ments for labels and labeling in part those regulations such that the rights 201. or safety of human subjects were not (9) The application does not contain adequately protected. bioavailability or bioequivalence data (17) The applicant or contract re- 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 application under described in § 320.38 or § 320.63 of this

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chapter that is contained in the appli- (b) An adequate and well-controlled cation refuses to permit an inspection study has the following characteristics: of facilities or records relevant to the (1) There is a clear statement of the study by a properly authorized officer objectives of the investigation and a or employee of the Department of summary of the proposed or actual Health and Human Services or refuses methods of analysis in the protocol for to submit reserve samples of the drug the study and in the report of its re- products used in the study when results. In addition, the protocol should quested by FDA. contain a description of the proposed (18) For a new drug, the application methods of analysis, and the study re- failed to contain the patent informa- port should contain a description of the tion required by section 505(b)(1) of the methods of analysis ultimately used. If act. 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 treatments are parallel, sequential, or FR 41524, Oct. 21, 1988; 57 FR 17991, Apr. 28, crossover, and whether the sample size 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. is predetermined or based upon some 5, 1999; 73 FR 39610, July 10, 2008; 74 FR 9766, interim analysis. Generally, the fol- Mar. 6, 2009] lowing types of control are recognized: § 314.126 Adequate and well-controlled (i) Placebo concurrent control. The test studies. drug is compared with an inactive 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

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treatment would be contrary to the in- ment is by randomization, with or terest of the patient. An active treat- without stratification. ment study may include additional (5) Adequate measures are taken to treatment groups, however, such as a minimize bias on the part of the sub- placebo control or a dose-comparison jects, observers, and analysts of the control. Active treatment trials usu- data. The protocol and report of the ally include randomization and blind- study should describe the procedures ing of patients or investigators, or used to accomplish this, such as blind- both. If the intent of the trial is to ing. show similarity of the test and control (6) The methods of assessment of sub- drugs, the report of the study should jects’ response are well-defined and re- 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.

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(e) Uncontrolled studies or partially ingredient different from the reference controlled studies are not acceptable as listed drug: the sole basis for the approval of (A) Information submitted with the claims of effectiveness. Such studies abbreviated new drug application is in- carefully conducted and documented, sufficient to show: may provide corroborative support of (1) That the other active ingredients well-controlled studies regarding effi- are the same as the active ingredients cacy and may yield valuable data re- of the reference listed drug; or garding safety of the test drug. Such (2) That the different active ingre- studies will be considered on their mer- dient is an active ingredient of a listed its in the light of the principles listed drug or a drug that does not meet the here, with the exception of the require- requirements of section 201(p) of the ment for the comparison of the treated act; or subjects with controls. Isolated case re- (B) No petition to submit an abbre- ports, random experience, and reports viated application for the drug product lacking the details which permit sci- with the different active ingredient entific evaluation will not be consid- was approved under § 314.93. ered. (4)(i) If the abbreviated new drug application is for a drug product whose [50 FR 7493, Feb. 22, 1985, as amended at 50 route of administration, dosage form, FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, or strength purports to be the same as 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. 4, 2002] that of the listed drug referred to in the abbreviated new drug application, § 314.127 Refusal to approve an abbre- information submitted in the abbreviated new drug application. viated new drug application is insufficient to show that the route of admin- (a) FDA will refuse to approve an ab- istration, dosage form, or strength is breviated application for a new drug the same as that of the reference listed under section 505(j) of the act for any drug; or of the following reasons: (ii) If the abbreviated new drug appli- (1) The methods used in, or the facili- cation is for a drug product whose ties and controls used for, the manu- route of administration, dosage form, facture, processing, and packing of the or strength is different from that of the drug product are inadequate to ensure listed drug referred to in the applica- and preserve its identity, strength, tion, no petition to submit an abbre- quality, and purity. viated new drug application for the (2) Information submitted with the drug product with the different route abbreviated new drug application is in- of administration, dosage form, or sufficient to show that each of the pro- strength was approved under § 314.93. posed conditions of use has been pre- (5) If the abbreviated new drug appli- viously approved for the listed drug re- cation was submitted under the ap- ferred to in the application. proval of a petition under § 314.93, the (3)(i) If the reference listed drug has abbreviated new drug application did only one active ingredient, information not contain the information required submitted with the abbreviated new by FDA with respect to the active in- drug application is insufficient to show gredient, route of administration, dos- that the active ingredient is the same age form, or strength that is not the as that of the reference listed drug; same as that of the reference listed (ii) If the reference listed drug has drug. more than one active ingredient, infor- (6)(i) Information submitted in the mation submitted with the abbreviated abbreviated new drug application is in- new drug application is insufficient to sufficient to show that the drug prod- show that the active ingredients are uct is bioequivalent to the listed drug the same as the active ingredients of referred to in the abbreviated new drug the reference listed drug; or application; or (iii) If the reference listed drug has (ii) If the abbreviated new drug appli- more than one active ingredient and if cation was submitted under a petition the abbreviated new drug application is approved under § 314.93, information for a drug product that has an active submitted in the abbreviated new drug

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application is insufficient to show that From its experience with reviewing in- the active ingredients of the drug prod- active ingredients, and from other in- uct are of the same pharmacological or formation available to it, FDA may therapeutic class as those of the ref- identify changes in inactive ingredi- erence listed drug and that the drug ents or composition that may ad- product can be expected to have the versely affect a drug product’s safety same therapeutic effect as the ref- or efficacy. The inactive ingredients or erence listed drug when administered composition of a proposed drug product to patients for each condition of use will be considered to raise serious ques- approved for the reference listed drug. tions of safety or efficacy if the prod- (7) Information submitted in the ab- uct incorporates one or more of these breviated new drug application is insuf- changes. Examples of the changes that ficient to show that the labeling pro- may raise serious questions of safety or posed for the drug is the same as the efficacy include, but are not limited to, labeling approved for the listed drug the following: referred to in the abbreviated new drug (1) A change in an inactive ingredient application except for changes required so that the product does not comply because of differences approved in a pe- with an official compendium. tition under § 314.93 or because the drug (2) A change in composition to in- product and the reference listed drug clude an inactive ingredient that has are produced or distributed by different not been previously approved in a drug manufacturers or because aspects of product for human use by the same the listed drug’s labeling are protected route of administration. by patent, or by exclusivity, and such (3) A change in the composition of a differences do not render the proposed parenteral drug product to include an drug product less safe or effective than inactive ingredient that has not been the listed drug for all remaining, non- previously approved in a parenteral protected conditions of use. drug product. (8)(i) Information submitted in the (4) A change in composition of a drug abbreviated new drug application of product for ophthalmic use to include any other information available to an inactive ingredient that has not 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 abbreviated new drug application gredient in, or the composition of, a under paragraph (a)(8)(i) of this section drug product intended for parenteral if, on the basis of information available use to be unsafe and will refuse to ap- to the agency, there is a reasonable prove the abbreviated new drug appli- basis to conclude that one or more of cation unless it contains the same in- the inactive ingredients of the pro- active ingredients, other than preserv- posed drug or its composition raises se- atives, buffers, and antioxidants, in the rious questions of safety or efficacy. same concentration as the listed drug,

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and, if it differs from the listed drug in (13) The abbreviated new drug appli- a preservative, buffer, or antioxidant, cation contains an untrue statement of the application contains sufficient in- material fact. formation to demonstrate that the dif- (b) FDA may refuse to approve an ab- ference does not affect the safety or ef- breviated application for a new drug if ficacy of the drug product. the applicant or contract research or- (C) FDA will consider an inactive in- ganization that conducted a bio- gredient in, or the composition of, a availability or bioequivalence study drug product intended for ophthalmic described in § 320.63 of this chapter that or otic use unsafe and will refuse to ap- is contained in the abbreviated new prove the abbreviated new drug appli- drug application refuses to permit an cation unless it contains the same in- inspection of facilities or records rel- active ingredients, other than preserv- evant to the study by a properly au- atives, buffers, substances to adjust to- thorized officer of employee of the De- nicity, or thickening agents, in the partment of Health and Human Serv- same concentration as the listed drug, ices or refuses to submit reserve sam- and if it differs from the listed drug in ples of the drug products used in the a preservative, buffer, substance to ad- study when requested by FDA. just tonicity, or thickening agent, the [57 FR 17991, Apr. 28, 1992; 57 FR 29353, July application contains sufficient infor- 1, 1992, as amended at 58 FR 25927, Apr. 28, mation to demonstrate that the dif- 1993; 67 FR 77672, Dec. 19, 2002] ference does not affect the safety or efficacy of the drug product and the la- § 314.150 Withdrawal of approval of an beling does not claim any therapeutic application or abbreviated applica- advantage over or difference from the tion. listed drug. (a) The Food and Drug Administra- (9) Approval of the listed drug re- tion will notify the applicant, and, if ferred to in the abbreviated new drug appropriate, all other persons who application has been withdrawn or sus- manufacture or distribute identical, re- pended for grounds described in lated, or similar drug products as de- § 314.150(a) or FDA has published a no- fined in §§ 310.6 and 314.151(a) of this tice of opportunity for hearing to with- chapter and for a new drug afford an draw approval of the reference listed opportunity for a hearing on a proposal drug under § 314.150(a). to withdraw approval of the applica- (10) Approval of the listed drug re- tion or abbreviated new drug applica- ferred to in the abbreviated new drug tion under section 505(e) of the act and application has been withdrawn under under the procedure in § 314.200, if any § 314.151 or FDA has proposed to with- of the following apply: draw approval of the reference listed (1) The Secretary of Health and drug under § 314.151(a). Human Services has suspended the ap- (11) FDA has determined that the ref- proval of the application or abbre- erence listed drug has been withdrawn viated application for a new drug on a from sale for safety or effectiveness finding that there is an imminent haz- reasons under § 314.161, or the reference ard to the public health. FDA will listed drug has been voluntarily with- promptly afford the applicant an expe- drawn from sale and the agency has dited hearing following summary sus- not determined whether the with- pension on a finding of imminent haz- drawal is for safety or effectiveness ard to health. reasons, or approval of the reference (2) FDA finds: listed drug has been suspended under (i) That clinical or other experience, § 314.153, or the agency has issued an tests, or other scientific data show initial decision proposing to suspend that the drug is unsafe for use under the reference listed drug under the conditions of use upon the basis of § 314.153(a)(1). which the application or abbreviated (12) The abbreviated new drug appli- application was approved; or cation does not meet any other re- (ii) That new evidence of clinical ex- quirement under section 505(j)(2)(A) of perience, not contained in the applica- the act. tion or not available to FDA until after

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the application or abbreviated applica- application or abbreviated application tion was approved, or tests by new was approved, the methods used in, or methods, or tests by methods not the facilities and controls used for, the deemed reasonably applicable when the manufacture, processing, and packing application or abbreviated application of the drug are inadequate to ensure was approved, evaluated together with and preserve its identity, strength, the evidence available when the appli- quality, and purity and were not made cation or abbreviated application was adequate within a reasonable time approved, reveal that the drug is not after receipt of written notice from the shown to be safe for use under the con- agency. ditions of use upon the basis of which (3) That on the basis of new informa- the application or abbreviated application before FDA, evaluated together tion was approved; or with the evidence available when the (iii) Upon the basis of new informa- application or abbreviated application tion before FDA with respect to the was approved, the labeling of the drug, 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 (7) That any nonclinical laboratory afford an opportunity for a hearing on study that is described in the applica- a proposal to withdraw approval of the tion or abbreviated application and application or abbreviated new drug that is essential to show that the drug application under section 505(e) of the is safe for use under the conditions pre- act and under the procedure in § 314.200, scribed, recommended, or suggested in if the agency finds: its labeling was not conducted in com- (1) That the applicant has failed to pliance with the good laboratory prac- establish a system for maintaining re- tice regulations in part 58 of this chap- quired records, or has repeatedly or deter and no reason for the noncompli- liberately failed to maintain required ance was provided or, if it was, the dif- records or to make required reports ferences between the practices used in under section 505(k) or 507(g) of the act conducting the study and the good lab- and § 314.80, § 314.81, or § 314.98, or that oratory practice regulations do not the applicant has refused to permit ac- support the validity of the study. cess to, or copying or verification of, (8) Any clinical investigation involv- its records. ing human subjects described in the ap- (2) That on the basis of new informa- plication or abbreviated application, tion before FDA, evaluated together subject to the institutional review with the evidence available when the board regulations in part 56 of this

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chapter or informed consent regula- the market and may ask the applicant tions in part 50 of this chapter, was not to waive the opportunity for hearing conducted in compliance with those otherwise provided for under this sec- regulations such that the rights or tion, to permit FDA to withdraw ap- safety of human subjects were not ade- proval of the application or abbre- quately protected. viated application for the product, and (9) That the applicant or contract re- to remove voluntarily the product from search organization that conducted a the market. If the applicant agrees, the bioavailability or bioequivalence study agency will not make a finding under described in § 320.38 or § 320.63 of this paragraph (b) of this section, but will chapter that is contained in the appli- withdraw approval of the application cation or abbreviated application re- or abbreviated application in a notice fuses to permit an inspection of facili- published in the FEDERAL REGISTER ties or records relevant to the study by that contains a brief summary of the 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 [57 FR 17993, Apr. 28, 1992, as amended at 58 reserve samples of the drug products 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 § 314.105(d) may be withdrawn when the new drug application, except for dif- agency withdraws approval, under ferences approved in the abbreviated § 314.150(a) or under this section, of the new drug application or those dif- approved drug referred to in the abbre- ferences resulting from: viated new drug application. If the (i) A patent on the listed drug issued agency proposed to withdraw approval after approval of the abbreviated new of a listed drug under § 314.150(a), the drug application; or holder of an approved application for (ii) Exclusivity accorded to the listed the listed drug has a right to notice drug after approval of the abbreviated and opportunity for hearing. The pub- new drug application that do not lished notice of opportunity for hearing render the drug product less safe or ef- will identify all drug products approved fective than the listed drug for any re- under § 314.105(d) whose applications maining, nonprotected condition(s) of are subject to withdrawal under this use. section if the listed drug is withdrawn, (c) FDA will withdraw approval of an and will propose to withdraw such application or abbreviated application drugs. Holders of approved applications if the applicant requests its withdrawal for the identified drug products will be because the drug subject to the appli- provided notice and an opportunity to cation or abbreviated application is no respond to the proposed withdrawal of longer being marketed, provided none their applications as described in para- of the conditions listed in paragraphs graphs (b) and (c) of this section. (a) and (b) of this section applies to the (b)(1) The published notice of oppor- drug. FDA will consider a written re- tunity for hearing on the withdrawal of quest for a withdrawal under this para- the listed drug will serve as notice to graph to be a waiver of an opportunity holders of identified abbreviated new for hearing otherwise provided for in drug applications of the grounds for this section. Withdrawal of approval of the proposed withdrawal. an application or abbreviated applica- (2) Holders of applications for drug tion under this paragraph is without products identified in the notice of op- prejudice to refiling. portunity for hearing may submit writ- (d) FDA may notify an applicant that ten comments on the notice of oppor- it believes a potential problem associ- tunity for hearing issued on the pro- ated with a drug is sufficiently serious posed withdrawal of the listed drug. If that the drug should be removed from an abbreviated new drug application

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holder submits comments on the notice which the agency shall make a final of opportunity for hearing and a hear- decision. ing is granted, the abbreviated new (7) Except as provided in paragraph drug application holder may partici- (d) of this section, any abbreviated new pate in the hearing as a nonparty par- drug application whose holder sub- ticipant as provided for in § 12.89 of this mitted comments on the notice of op- chapter. portunity for hearing shall be with- (3) Except as provided in paragraphs drawn upon the issuance of a final deci- (c) and (d) of this section, the approval sion concluding that the listed drug of an abbreviated new drug application should be withdrawn for grounds as de- for a drug product identified in the no- scribed in § 314.150(a). The final decision tice of opportunity for hearing on the shall be in writing and shall constitute withdrawal of a listed drug will be 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. (2) Abbreviated new drug application for such drug is not withdrawn. holders to whom the initial decision [57 FR 17994, Apr. 28, 1992] was sent may, within 30 days of the issuance of the initial decision, submit § 314.152 Notice of withdrawal of ap- written objections. proval of an application or abbre- (3) The agency may, at its discretion, viated application for a new drug. hold a limited oral hearing to resolve If the Food and Drug Administration dispositive factual issues that cannot withdraws approval of an application be resolved on the basis of written sub- or abbreviated application for a new missions. drug, FDA will publish a notice in the (4) If there are no timely objections FEDERAL REGISTER announcing the to the initial decision, it will become withdrawal of approval. If the applica- final at the expiration of 30 days. tion or abbreviated application was (5) If timely objections are submitted, they will be reviewed and re- withdrawn for grounds described in sponded to in a final decision. § 314.150(a) or § 314.151, the notice will (6) The written comments received, announce the removal of the drug from the initial decision, the evidence relied the list of approved drugs published on in the comments and in the initial under section 505(j)(6) of the act and decision, the objections to the initial shall satisfy the requirement of decision, and, if a limited oral hearing § 314.162(b). has been held, the transcript of that [57 FR 17994, Apr. 28, 1992] hearing and any documents submitted therein, shall form the record upon

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§ 314.153 Suspension of approval of an Dockets Management (HFA–305), Food abbreviated new drug application. and Drug Administration, room 1–23, (a) Suspension of approval. The ap- 12420 Parklawn Dr., Rockville, MD proval of an abbreviated new drug ap- 20857. plication approved under § 314.105(d) (2) Each abbreviated new drug appli- shall be suspended for the period stated cation holder will have 30 days from when: the issuance of the initial decision to (1) The Secretary of the Department present, in writing, comments and in- of Health and Human Services, under formation bearing on the initial deci- the imminent hazard authority of sec- sion. If no comments or information is tion 505(e) of the act or the authority received, the initial decision will be- of this paragraph, suspends approval of come final at the expiration of 30 days. a listed drug referred to in the abbre- (3) Comments and information re- viated new drug application, for the pe- ceived within 30 days of the issuance of riod of the suspension; the initial decision will be considered (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

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will be placed on public display in the (d) If the agency determines under Division of Dockets Management (ad- paragraph (a) of this section that a dress in paragraph (b)(1) of this sec- listed drug is withdrawn from sale for tion) promptly upon receipt in that of- safety and effectiveness reasons and fice. there are approved abbreviated new [57 FR 17995, Apr. 28, 1992] drug applications that are subject to suspension under section 505(j)(5) of the § 314.160 Approval of an application or act, FDA will initiate a proceeding in abbreviated application for which accordance with § 314.153(b). approval was previously refused, (e) A drug that the agency deter- suspended, or withdrawn. mines is withdrawn for safety or effec- Upon the Food and Drug Administra- tiveness reasons will be removed from tion’s own initiative or upon request of the list, under § 314.162. The drug may an applicant, FDA may, on the basis of be relisted if the agency has evidence 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: proval of all suspended abbreviated new (1) Prior to approving an abbreviated drug applications that referred to the new drug application that refers to the listed drug. listed drug; (2) Whenever a listed drug is volun- [57 FR 17995, Apr. 28, 1992] tarily withdrawn from sale and abbre- § 314.162 Removal of a drug product viated new drug applications that re- from the list. ferred to the listed drug have been approved; 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 for the period stated when: of this chapter. (1) The agency withdraws or suspends (b) Any person may petition under approval of a new drug application or §§ 10.25(a) and 10.30 of this chapter for a an abbreviated new drug application determination whether a listed drug under § 314.150(a) or § 314.151 or under has been voluntarily withdrawn for the imminent hazard authority of sec- safety or effectiveness reasons. Any tion 505(e) of the act, for the same pe- such petition must contain all evidence riod as the withdrawal or suspension of available to the petitioner concerning the application; or the reason that the drug is withdrawn (2) The agency, in accordance with from sale. the procedures in § 314.153(b) or § 314.161, (c) If the agency determines that a issues a final decision stating that the listed drug is withdrawn from sale for listed drug was withdrawn from sale safety or effectiveness reasons, the for safety or effectiveness reasons, or agency will, except as provided in para- suspended under § 314.153(b), until the graph (d) of this section, publish a no- agency determines that the withdrawal tice of the determination in the FED- from the market has ceased or is not ERAL REGISTER. for safety or effectiveness reasons.

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(b) FDA will publish in the FEDERAL notice) or specific (that is, either refer- REGISTER a notice announcing the re- ring to specific requirements in the moval of a drug from the list. statute and regulations with which (c) At the end of the period specified there is a lack of compliance, or pro- in paragraph (a)(1) or (a)(2) of this sec- viding a detailed description and anal- tion, FDA will relist a drug that has ysis of the specific facts resulting in been removed from the list. The agency the notice). will publish in the FEDERAL REGISTER a (2) FDA will publish the notice in the notice announcing the relisting of the FEDERAL REGISTER and will state that drug. the applicant, and other persons sub- [57 FR 17996, Apr. 28, 1992] ject to the notice under § 310.6, who wishes to participate in a hearing, has § 314.170 Adulteration and mis- 30 days after the date of publication of branding of an approved drug. the notice to file a written notice of All drugs, including those the Food participation and request for hearing. and Drug Administration approves The applicant, or other persons subject under section 505 of the act and this to the notice under § 310.6, who fails to part, are subject to the adulteration file a written notice of participation and misbranding provisions in sections and request for hearing within 30 days, 501, 502, and 503 of the act. FDA is au- waives the opportunity for a hearing. thorized to regulate approved new (3) It is the responsibility of every drugs by regulations issued through in- manufacturer and distributor of a drug formal rulemaking under sections 501, product to review every notice of op- 502, and 503 of the act. portunity for a hearing published in the FEDERAL REGISTER to determine [50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992, and amended at 64 FR whether it covers any drug product 402, Jan. 5, 1999] that person manufactures or distrib- utes. Any person may request an opinion of the applicability of a notice to a Subpart E—Hearing Procedures for specific product that may be identical, New Drugs related, or similar to a product listed in a notice by writing to the Division SOURCE: 50 FR 7493, Feb. 22, 1985, unless of New Drugs and Labeling Compli- otherwise noted. Redesignated at 57 FR 17983, ance, Office of Compliance, Center for Apr. 28, 1992. Drug Evaluation and Research, Food § 314.200 Notice of opportunity for and Drug Administration, 10903 New hearing; notice of participation and Hampshire Ave., Silver Spring, MD request for hearing; grant or denial 20993–0002. A person shall request an of hearing. opinion within 30 days of the date of (a) Notice of opportunity for hearing. publication of the notice to be eligible The Director of the Center for Drug for an opportunity for a hearing under Evaluation and Research, Food and the notice. If a person requests an opin- Drug Administration, will give the ap- ion, that person’s time for filing an applicant, and all other persons who man- pearance and request for a hearing and ufacture or distribute identical, re- supporting studies and analyses begins lated, or similar drug products as de- on the date the person receives the fined in § 310.6 of this chapter, notice opinion from FDA. and an opportunity for a hearing on the (b) FDA will provide the notice of op- Center’s proposal to refuse to approve portunity for a hearing to applicants an application or to withdraw the ap- and to other persons subject to the no- proval of an application or abbreviated tice under § 310.6, as follows: application under section 505(e) of the (1) To any person who has submitted act. The notice will state the reasons an application or abbreviated applica- for the action and the proposed tion, by delivering the notice in person grounds for the order. or by sending it by registered or cer- (1) The notice may be general (that tified mail to the last address shown in is, simply summarizing in a general the application or abbreviated applica- way the information resulting in the tion.

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(2) To any person who has not sub- comments on the proposal to withdraw mitted an application or abbreviated approval of the application or abbre- application but who is subject to the viated application. The comments are notice under § 310.6 of this chapter, by requested to be submitted within the publication of the notice in the FED- time and under the conditions specified ERAL REGISTER. in this section. (c)(1) Notice of participation and re- (d) The person requesting a hearing is quest for a hearing, and submission of required to submit under paragraph studies and comments. The applicant, or (c)(1)(ii) of this section the studies (in- any other person subject to the notice cluding all protocols and underlying under § 310.6, who wishes to participate raw data) on which the person relies to in a hearing, shall file with the Divi- justify a hearing with respect to the sion of Dockets Management (HFA– drug product. Except, a person who re- 305), Food and Drug Administration, quests a hearing on the refusal to ap- 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 stud- (2) The submission is required to in- ies were not available within 60 days clude a factual analysis of all the stud- after the date of publication of the no- ies submitted. If the grounds for FDA’s tice. Nevertheless, FDA may consider proposed action concern the effective- other studies on the basis of a showing ness of the drug, the analysis is re- by the person requesting a hearing of quired to specify how each study ac- inadvertent omission and hardship. cords, on a point-by-point basis, with The person requesting a hearing shall each criterion required for an adequate list in the request for hearing all stud- well-controlled clinical investigation ies in progress, the results of which the established under § 314.126 and, if the person intends later to submit in sup- product is a combination drug product, port of the request for a hearing. The with each of the requirements for a person shall submit under paragraph combination drug established in (c)(1)(ii) of this section a copy of the § 300.50, or the study is required to be complete protocol, a list of the partici- accompanied by an appropriate waiver pating investigators, and a brief status previously granted by FDA. If a study report of the studies. concerns a drug or dosage form or con- (3) Any other interested person who dition of use or mode of administration is not subject to the notice of oppor- other than the one in question, that tunity for a hearing may also submit fact is required to be clearly stated.

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Any study conducted on the final mar- III. A summary of the data and views set- keted form of the drug product is re- ting forth the medical rationale and purpose quired to be clearly identified. for the drug and its ingredients and the scientific basis for the conclusion that the drug (3) Each person requesting a hearing and its ingredients have been proven safe shall submit an analysis of the data and/or effective for the intended use. If there upon which the person relies, except is an absence of controlled studies in the ma- that the required information relating terial submitted or the requirements of any either to safety or to effectiveness may element of § 300.50 or § 314.126 have not been be omitted if the notice of opportunity fully met, that fact is required to be stated for hearing does not raise any issue clearly and a waiver obtained under § 314.126 is required to be submitted. with respect to that aspect of the drug; IV. A statement signed by the person re- information on compliance with § 300.50 sponsible for such submission that it in- may be omitted if the drug product is cludes in full (or incorporates by reference as 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 under section 107(c) of the Drug may influence a determination about the Amendments of 1962, or for any other safety of each individual active component. 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 ure of any person subject to a notice of may influence a determination about the opportunity for a hearing, including safety of each individual active component. any person who manufactures or dis- II. Effectiveness data. 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 com- contentions not raised. ponents. (1) A contention that a drug product 1. Controlled studies with an analysis is generally recognized as safe and ef- showing clearly how each study satisfies on 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

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that is required to obtain approval of date, nature, and rationale for each dis- an application for the product, unless continuance or change and a copy of each FDA has waived a requirement for ef- pertinent document or record to establish fectiveness (under § 314.126) or safety, each such discontinuance or change should be submitted, including, but not limited to, or both. The submission should be in the labeling which resulted from each such the format and with the analyses re- discontinuance or change. If no such dis- quired under paragraph (d) of this sec- continuance or change has been made, a copy tion. A person who fails to submit the of representative documents or records show- required scientific evidence required ing labeling at representative points in time under paragraph (d) waives the conten- should be submitted to support the state- tion. General recognition of safety and ment. effectiveness shall ordinarily be based III. Marketing. A. A copy of each pertinent document or upon published studies which may be record to establish the exact date the drug corroborated by unpublished studies was initially marketed. and other data and information. B. A statement whether such marketing (2) A contention that a drug product has at any subsequent time been discon- is exempt from part or all of the new tinued. If such marketing has been discon- drug provisions of the act under the ex- tinued, the exact date of each such dis- emption for products marketed before continuance should be submitted, together with a copy of each pertinent document or June 25, 1938, contained in section record to establish each such date. 201(p) of the act, or under section 107(c) IV. Verification. of the Drug Amendments of 1962, is re- A statement signed by the person respon- quired to be supported by evidence of sible for such submission, that all appro- past and present quantitative for- priate records have been searched and to the mulas, labeling, and evidence of mar- best of that person’s knowledge and belief it keting. A person who makes such a includes a true and accurate presentation of contention should submit the formulas, the facts. labeling, and evidence of marketing in (WARNING: A willfully false statement is a the following format. criminal offense, 18 U.S.C. 1001.) (3) The Food and Drug Administra- I. Formulation. A. A copy of each pertinent document or tion will not find a drug product, in- record to establish the exact quantitative cluding any active ingredient, which is formulation of the drug (both active and in- identical, related, or similar, as de- active ingredients) on the date of initial scribed in § 310.6, to a drug product, in- marketing of the drug. cluding any active ingredient for which B. A statement whether such formulation an application is or at any time has has at any subsequent time been changed in been effective or deemed approved, or any manner. If any such change has been approved under section 505 of the act, made, the exact date, nature, and rationale for each change in formulation, including to be exempt from part or all of the any deletion or change in the concentration new drug provisions of the act. of any active ingredient and/or inactive in- (4) A contention that a drug product gredient, should be stated, together with a is not a new drug for any other reason copy of each pertinent document or record to is required to be supported by submis- establish the date and nature of each such sion of the factual records, data, and change, including, but not limited to, the information that are necessary and ap- formula which resulted from each such propriate to support the contention. change. If no such change has been made, a copy of representative documents or records (5) It is the responsibility of every showing the formula at representative points person who manufactures or distrib- in time should be submitted to support the utes a drug product in reliance upon a statement. ‘‘grandfather’’ provision of the act to II. Labeling. maintain files that contain the data A. A copy of each pertinent document or and information necessary fully to doc- record to establish the identity of each item ument and support that status. of written, printed, or graphic matter used (f) Separation of functions. Separation as labeling on the date the drug was initially of functions commences upon receipt of marketed. B. A statement whether such labeling has a request for hearing. The Director of at any subsequent time been discontinued or the Center for Drug Evaluation and Re- changed in any manner. If such discontinu- search, Food and Drug Administration, ance or change has been made, the exact will prepare an analysis of the request

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and a proposed order ruling on the judgment against a person who re- matter. The analysis and proposed quests a hearing, making findings and order, the request for hearing, and any conclusions, denying a hearing, if it proposed order denying a hearing and conclusively appears from the face of response under paragraph (g) (2) or (3) the data, information, and factual of this section will be submitted to the analyses in the request for the hearing Office of the Commissioner of Food and that there is no genuine and substan- Drugs for review and decision. When tial issue of fact which precludes the the Center for Drug Evaluation and Re- refusal to approve the application or search recommends denial of a hearing abbreviated application or the with- 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 of fact which justifies a hearing. resumes upon issuance of a notice of (3) When following a general or spe- hearing. The Office of the General cific notice of opportunity for a hear- Counsel, Department of Health and ing a person requesting a hearing sub- Human Services, will observe the same mits data or information of a type re- separation of functions. quired by the statute and regulations, (g) Summary judgment. A person who and the Director of the Center for Drug requests a hearing may not rely upon Evaluation and Research concludes allegations or denials but is required to that summary judgment against the set forth specific facts showing that person should be considered, the Direc- there is a genuine and substantial issue tor will serve upon the person by reg- of fact that requires a hearing with re- istered mail a proposed order denying a spect to a particular drug product spec- hearing. The person has 60 days after ified in the request for hearing. receipt of the proposed order to re- (1) Where a specific notice of oppor- spond with sufficient data, informa- tunity for hearing (as defined in para- tion, and analyses to demonstrate that graph (a)(1) of this section) is used, the there is a genuine and substantial issue Commissioner will enter summary of fact which justifies a hearing.

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(4) If review of the data, information, § 314.201 Procedure for hearings. and analyses submitted show that the Parts 10 through 16 apply to hearings grounds cited in the notice are not relating to new drugs under section 505 valid, for example, that substantial (d) and (e) of the act. evidence of effectiveness exists, the Commissioner will enter summary § 314.235 Judicial review. judgment for the person requesting the (a) The Commissioner of Food and hearing, and rescind the notice of op- Drugs will certify the transcript and portunity for hearing. record. In any case in which the Com- (5) If the Commissioner grants a missioner enters an order without a hearing, it will begin within 90 days hearing under § 314.200(g), the record after the expiration of the time for re- certified by the Commissioner is requesting the hearing unless the parties quired to include the requests for hear- otherwise agree in the case of denial of ing together with the data and infor- approval, and as soon as practicable in mation submitted and the Commis- the case of withdrawal of approval. sioner’s findings and conclusion. (6) The Commissioner will grant a (b) A manufacturer or distributor of hearing if there exists a genuine and an identical, related, or similar drug substantial issue of fact or if the Com- product under § 310.6 may seek judicial missioner concludes that a hearing review of an order withdrawing approval of a new drug application, would otherwise be in the public inter- whether or not a hearing has been held, est. in a United States court of appeals (7) If the manufacturer or distributor under section 505(h) of the act. of an identical, related, or similar drug product requests and is granted a hear- Subpart F Reserved ing, the hearing may consider whether [ ] the product is in fact identical, related, or similar to the drug product named Subpart G—Miscellaneous in the notice of opportunity for a hear- Provisions ing. (8) A request for a hearing, and any SOURCE: 50 FR 7493, Feb. 22, 1985, unless subsequent grant or denial of a hear- otherwise noted. Redesignated at 57 FR 17983, Apr. 28, 1992. ing, applies only to the drug products named in such documents. § 314.410 Imports and exports of new (h) FDA will issue a notice with- drugs. drawing approval and declaring all (a) Imports. (1) A new drug may be im- products unlawful for drug products ported into the United States if: (i) It subject to a notice of opportunity for a is the subject of an approved applica- hearing, including any identical, re- tion under this part; or (ii) it complies lated, or similar drug product under with the regulations pertaining to in- § 310.6, for which an opportunity for a vestigational new drugs under part 312; hearing is waived or for which a hear- and it complies with the general regu- ing is denied. The Commissioner may lations pertaining to imports under defer or stay the action pending a rul- subpart E of part 1. ing 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, (b) Exports. (1) A new drug may be ex- 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, ported if it is the subject of an ap- Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 68 FR proved application under this part or it 24879, May 9, 2003; 69 FR 48775, Aug. 11, 2004; complies with the regulations per- 74 FR 13113, Mar. 26, 2009] taining to investigational new drugs under part 312.

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(2) A new drug substance that is cov- (5) FDA-accepted reference informa- ered by an application approved under tion. (A person wishing to submit in- this part for use in the manufacture of formation and supporting data in a an approved drug product may be ex- drug master file (DMF) that is not cov- ported by the applicant or any person ered by Types II through IV DMF’s listed as a supplier in the approved ap- must first submit a letter of intent to plication, provided the drug substance the Drug Master File Staff, Food and intended for export meets the speci- Drug Administration, 5901–B fication of, and is shipped with a copy Ammendale Rd., Beltsville, MD 20705– of the labeling required for, the ap- 1266.) FDA will then contact the person proved drug product. to discuss the proposed submission. (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 the requirements of section 801(e)(1) of plement may incorporate by reference the act. all or part of the contents of any drug master file in support of the submis- [50 FR 7493, Feb. 22, 1985, unless otherwise sion if the holder authorizes the incor- noted. Redesignated at 57 FR 17983, Apr. 28, poration in writing. Each incorpora- 1992, and amended at 64 FR 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 infor- and to describe by name, reference mation to the person. FDA ordinarily number, volume, and page number the neither independently reviews drug information affected in the drug mas- master files nor approves or dis- ter file. approves submissions to a drug master (d) The drug master file is required to file. Instead, the agency customarily contain a complete list of each person reviews the information only in the currently authorized to incorporate by context of an application under part reference any information in the file, 312 or this part. A drug master file may 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

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information in the file to a person au- the agency sends an approval letter, thorized to reference the file, is deter- but the Commissioner may, in his or mined under part 20 and § 314.430. her discretion, disclose a summary of selected portions of the safety and ef- [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 53 FR 33122, Aug. 30, fectiveness data that are appropriate 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, for public consideration of a specific Jan. 12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR pending issue; for example, for consid- 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004] eration of an open session of an FDA advisory committee. § 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 set forth in § 20.81 and a summary or previously publicly disclosed or ac- summaries of the safety and effective- knowledged. ness data and information submitted (c) If the existence of an unapproved with or incorporated by reference in application or abbreviated application the application. The summaries do not has not been publicly disclosed or ac- constitute the full reports of investiga- knowledged, no data or information in tions under section 505(b)(1) of the act the application or abbreviated applica- (21 U.S.C. 355(b)(1)) on which the safety tion is available for public disclosure. or effectiveness of the drug may be ap- (d)(1) If the existence of an applica- proved. The summaries consist of the tion or abbreviated application has following: been publicly disclosed or acknowl- (i) For an application approved be- edged before the agency sends an ap- fore July 1, 1975, internal agency proval letter to the applicant, no data records that describe safety and effec- or information contained in the appli- tiveness data and information, for ex- cation or abbreviated application is ample, a summary of the basis for ap- available for public disclosure before proval or internal reviews of the data

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and information, after deletion of the (f) All safety and effectiveness data following: and information which have been sub- (a) Names and any information that mitted in an application and which would identify patients or test subjects have not previously been disclosed to or investigators. the public are available to the public, (b) Any inappropriate gratuitous upon request, at the time any one of comments unnecessary to an objective the following events occurs unless ex- analysis of the data and information. traordinary circumstances are shown: (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 ex- proval of an abbreviated application emption established for trade secrets under section 505(j) of the act which re- and confidential commercial informa- fers to such drug could be made effec- tion in § 20.61. tive if such an abbreviated application (4) Adverse reaction reports, product had been submitted. experience reports, consumer com- (6) For abbreviated applications sub- plaints, and other similar data and in- mitted under section 505(j) of the act, formation after deletion of the fol- when FDA sends an approval letter to lowing: the applicant. (i) Names and any information that (g) The following data and informa- would identify the person using the tion in an application or abbreviated product. application are not available for public (ii) Names and any information that disclosure unless they have been pre- would identify any third party involved viously disclosed to the public as set with the report, such as a physician or forth in § 20.81 of this chapter or they hospital or other institution. relate to a product or ingredient that (5) A list of all active ingredients and has been abandoned and they do not any inactive ingredients previously represent a trade secret or confidential disclosed to the public as set forth in commercial or financial information § 20.81. under § 20.61 of this chapter: (6) An assay procedure or other ana- (1) Manufacturing methods or proc- lytical procedure, unless it serves no esses, including quality control proce- regulatory or compliance purpose and dures. is shown to fall within the exemption (2) Production, sales distribution, established for trade secrets and con- and similar data and information, ex- fidential commercial information in cept that any compilation of that data § 20.61. and information aggregated and pre- (7) All correspondence and written pared in a way that does not reveal summaries of oral discussions between data or information which is not avail- FDA and the applicant relating to the able for public disclosure under this application, under the provisions of provision is available for public disclo- part 20. sure.

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(3) Quantitative or semiquantitative Center for Drug Evaluation and Re- formulas. search, Food and Drug Administration, (h) The compilations of information Attn: [insert name of person], Metro specified in § 20.117 are available for Park North II, HFD–[insert mail code public disclosure. of office or division], 7500 Standish [50 FR 7493, Feb. 22, 1985, as amended at 50 Place, rm. 150, Rockville, MD 20855. FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, The mail code for the Office of Generic 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Drugs is HFD–600, the mail codes for Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR the Divisions of Chemistry I, II, and III 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68 are HFD–620, HFD–640, and HFD–630, FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, 2004; 73 FR 39610, July 10, 2008] respectively, and the mail code for the Division of Bioequivalence is HFD–650. § 314.440 Addresses for applications (3) A request for an opportunity for a and abbreviated applications. hearing under § 314.110 on the question (a) Applicants shall send applica- of whether there are grounds for deny- tions, abbreviated applications, and ing approval of an application, except other correspondence relating to mat- an application under paragraph (b) of ters covered by this part, except for this section, should be directed to the products listed in paragraph (b) of this Associate Director for Policy (HFD–5). section, to the appropriate office iden- (4) The field copy of an application, tified below: an abbreviated application, amend- (1) Except as provided in paragraph ments, supplements, resubmissions, re- (a)(4) of this section, an application quests for waivers, and other cor- under § 314.50 or § 314.54 submitted for respondence about an application and filing should be directed to the Central an abbreviated application shall be Document Room, 5901–B Ammendale sent to the applicant’s home FDA dis- Rd., Beltsville, MD 20705–1266. Appli- trict office, except that a foreign applicants may obtain information about folders for binding applications on the cant shall send the field copy to the ap- Internet at http://www.fda.gov/cder/ propriate address identified in para- ddms/binders.htm. After FDA has filed graphs (a)(1) and (a)(2) of this section. the application, the agency will inform (b) Applicants shall send applications the applicant which division is respon- and other correspondence relating to sible for the application. Amendments, matters covered by this part for the supplements, resubmissions, requests drug products listed below to the Docu- for waivers, and other correspondence ment Control Center (HFM–99), Center about an application that has been for Biologics Evaluation and Research, filed should be addressed to 5901–B 1401 Rockville Pike, suite 200N, Rock- Ammendale Rd., Beltsville, MD 20705– ville, MD 20852–1448, except applicants 1266, to the attention of the appro- shall send a request for an opportunity priate division. for a hearing under § 314.110 on the (2) Except as provided in paragraph question of whether there are grounds (a)(4) of this section, an abbreviated ap- for denying approval of an application plication under § 314.94, and amend- to the Director, Center for Biologics ments, supplements, and resubmissions Evaluation and Research (HFM–1), at should be directed to the Office of Ge- the same address. neric Drugs (HFD–600), Center for Drug (1) Ingredients packaged together Evaluation and Research, Food and with containers intended for the collec- Drug Administration, Metro Park North VII, 7620 Standish Pl., Rockville, tion, processing, or storage of blood MD 20855. This includes items sent by and blood components; parcel post or overnight courier serv- (2) Plasma volume expanders and hy- ice. Correspondence not associated droxyethyl starch for leukapheresis; with an abbreviated application should (3) Blood component processing solu- be addressed specifically to the in- tions and shelf life extenders; and tended office or division and to the person as follows: Office of Generic Drugs,

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(4) Oxygen carriers. adequate and well-controlled clinical trials establishing that the drug prod- [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 FR 11581, Mar. 29, uct has an effect on a surrogate end- 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, point that is reasonably likely, based Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR on epidemiologic, therapeutic, patho- 13473, Mar. 23, 2004; 70 FR 14981, Mar. 24, 2005; physiologic, or other evidence, to pre- 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. dict clinical benefit or on the basis of 26, 2009; 75 FR 37295, June 29, 2010] an effect on a clinical endpoint other than survival or irreversible morbidity. § 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 and Drug Administration, 10903 New assure safe use. Hampshire Ave., Silver Spring, MD (a) If FDA concludes that a drug 20993–0002. product shown to be effective can be [65 FR 56480, Sept. 19, 2000, as amended at 74 safely used only if distribution or use FR 13113, Mar. 26, 2009] is restricted, FDA will require such postmarketing restrictions as are need- Subpart H—Accelerated Approval ed to assure safe use of the drug product, 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;

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(4) The applicant fails to adhere to tation. No other person attending the the postmarketing restrictions agreed hearing may question a person making upon; 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 Commis- use. sioner’s decision constitutes final (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 letter, will state generally the reasons [57 FR 58958, Dec. 11, 1992, as amended at 64 for the action and the proposed FR 402, Jan. 5, 1999] grounds for the order. (c) Submission of data and information. § 314.540 Postmarketing safety report- (1) If the applicant fails to file a writing. ten request for a hearing within 15 days Drug products approved under this of receipt of the notice, the applicant program are subject to the post- waives the opportunity for a hearing. marketing recordkeeping and safety (2) If the applicant files a timely re- reporting applicable to all approved quest for a hearing, the agency will drug products, as provided in §§ 314.80 publish a notice of hearing in the FED- and 314.81. ERAL REGISTER in accordance with §§ 12.32(e) and 15.20 of this chapter. § 314.550 Promotional materials. (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 held under this section will be con- proval, unless otherwise informed by ducted in accordance with the provi- the agency, the applicant must submit sions of part 15 of this chapter, with promotional materials at least 30 days the following modifications: prior to the intended time of initial (1) An advisory committee duly con- dissemination of the labeling or initial stituted under part 14 of this chapter publication of the advertisement. will be present at the hearing. The § 314.560 Termination of requirements. committee will be asked to review the issues involved and to provide advice If FDA determines after approval and recommendations to the Commis- that the requirements established in sioner of Food and Drugs. § 314.520, § 314.530, or § 314.550 are no (2) The presiding officer, the advisory longer necessary for the safe and effec- committee members, up to three rep- tive use of a drug product, it will so no- resentatives of the applicant, and up to tify the applicant. Ordinarily, for drug three representatives of the Center products approved under § 314.510, these may question any person during or at requirements will no longer apply when the conclusion of the person’s presen- FDA determines that the required

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postmarketing study verifies and de- met based on adequate and well-con- scribes the drug product’s clinical ben- trolled animal studies when the results efit and the drug product would be ap- of those animal studies establish that propriate for approval under tradi- the drug product is reasonably likely tional procedures. For drug products to produce clinical benefit in humans. approved under § 314.520, the restric- In assessing the sufficiency of animal tions would no longer apply when FDA data, the agency may take into ac- determines that safe use of the drug count other data, including human product can be assured through appro- data, available to the agency. FDA will priate labeling. FDA also retains the rely on the evidence from studies in 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 more than one animal species expected SOURCE: 67 FR 37995, May 31, 2002, unless 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 indicated when such studies are fea- regulations (e.g., accelerated approval sible and ethical. Such postmarketing based on surrogate markers or clinical studies would not be feasible until an endpoints other than survival or irre- exigency arises. When such studies are versible morbidity), nor does it address feasible, the applicant must conduct the safety evaluation for the products such studies with due diligence. Appli- to which it does apply. cants must include as part of their application a plan or approach to post- § 314.610 Approval based on evidence marketing study commitments in the of effectiveness from studies in ani- event such studies become ethical and mals. feasible. (a) FDA may grant marketing ap- (2) Approval with restrictions to ensure proval for a new drug product for which safe use. If FDA concludes that a drug safety has been established and for product shown to be effective under which the requirements of § 314.600 are this subpart can be safely used only if

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distribution or use is restricted, FDA (6) Other evidence demonstrates that will require such postmarketing re- the drug product is not shown to be strictions as are needed to ensure safe safe or effective under its conditions of use of the drug product, commensurate use. with the specific safety concerns pre- (b) Notice of opportunity for a hearing. sented by the drug product, such as: The Director of the Center for Drug (i) Distribution restricted to certain Evaluation and Research (CDER) will facilities or health care practitioners give the applicant notice of an oppor- with special training or experience; tunity for a hearing on CDER’s pro- (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 administration), contraindications, a descrip- (3) An applicant who requests a hear- tion of any reasonably foreseeable ing under this section must, within 30 risks, adverse reactions, anticipated days of receipt of the notice of oppor- benefits, drug interactions, and any tunity for a hearing, submit the data other relevant information required by and information upon which the appli- FDA at the time of approval. The pa- cant intends to rely at the hearing. tient labeling must be available with (d) Separation of functions. Separation the product to be provided to patients of functions (as specified in § 10.55 of prior to administration or dispensing this chapter) will not apply at any of the drug product for the use appoint in withdrawal proceedings under proved under this subpart, if possible. this section. (e) Procedures for hearings. Hearings § 314.620 Withdrawal procedures. held under this section will be con- (a) Reasons to withdraw approval. For ducted in accordance with the provi- new drugs approved under this subpart, sions of part 15 of this chapter, with FDA may withdraw approval, following the following modifications: a hearing as provided in part 15 of this (1) An advisory committee duly con- chapter, as modified by this section, if: stituted under part 14 of this chapter (1) A postmarketing clinical study will be present at the hearing. The fails to verify clinical benefit; committee will be asked to review the (2) The applicant fails to perform the issues involved and to provide advice postmarketing study with due dili- and recommendations to the Commis- gence; sioner of Food and Drugs. (3) Use after marketing demonstrates (2) The presiding officer, the advisory that postmarketing restrictions are in- committee members, up to three rep- adequate to ensure safe use of the drug resentatives of the applicant, and up to product; three representatives of CDER may (4) The applicant fails to adhere to question any person during or at the the postmarketing restrictions applied conclusion of the person’s presen- at the time of approval under this sub- tation. No other person attending the part; hearing may question a person making (5) The promotional materials are a presentation. The presiding officer false or misleading; or may, as a matter of discretion, permit

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

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(a) The proposed use of the diagnostic in identifying or characterizing the dis- radiopharmaceutical in the practice of ease or pathology. medicine, (4) The claim of diagnostic or thera- (b) The pharmacological and toxi- peutic patient management is estab- cological activity of the diagnostic lished by demonstrating in a defined radiopharmaceutical (including any clinical setting that the test is useful 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 disease-specific information, the proposed § 315.6 Evaluation of safety. 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: § 315.5 Evaluation of effectiveness. (1) The radiation dose; (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 of this evaluation varies depending (4) The adverse reaction profile of the upon the proposed indication(s) and drug; may use one or more of the following (5) Results of human experience with criteria: the radiopharmaceutical for other uses; (1) The claim of structure delineation and is established by demonstrating in a (6) Results of any previous human ex- defined clinical setting the ability to perience with the carrier or ligand of locate anatomical structures and to the radiopharmaceutical when the characterize their anatomy. same chemical entity as the carrier or (2) The claim of functional, physio- ligand has been used in a previously logical, or biochemical assessment is studied product. established by demonstrating in a de- (b) The assessment of the adverse re- fined clinical setting reliable measure- action profile includes, but is not lim- ment of function(s) or physiological, ited to, an evaluation of the potential biochemical, or molecular process(es). of the diagnostic radiopharmaceutical, (3) The claim of disease or pathology including the carrier or ligand, to elic- detection or assessment is established it the following: by demonstrating in a defined clinical (1) Allergic or hypersensitivity re- setting that the diagnostic radio- sponses, pharmaceutical has sufficient accuracy (2) Immunologic responses,

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(3) Changes in the physiologic or bio- Subpart B—Written Recommendations for chemical function of the target and Investigations of Orphan Drugs nontarget tissues, and 316.10 Content and format of a request for (4) Clinically detectable signs or written recommendations. symptoms. 316.12 Providing written recommendations. (c)(1) To establish the safety of a di- 316.14 Refusal to provide written rec- agnostic radiopharmaceutical, FDA ommendations. may require, among other information, the following types of data: Subpart C—Designation of an Orphan (i) Pharmacology data, Drug (ii) Toxicology data, 316.20 Content and format of a request for (iii) Clinical adverse event data, and orphan-drug designation. (iv) Radiation safety assessment. 316.21 Verification of orphan-drug status. (2) The amount of new safety data re- 316.22 Permanent-resident agent for foreign quired will depend on the characteris- sponsor. tics of the product and available infor- 316.23 Timing of requests for orphan-drug mation regarding the safety of the di- designation; designation of already ap- agnostic radiopharmaceutical, and its proved drugs. 316.24 Granting orphan-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 designa- dose, route of administration, fre- tion. quency of use, half-life of the ligand or 316.27 Change in ownership of orphan-drug carrier, half-life of the radionuclide, designation. and results of clinical and preclinical 316.28 Publication of orphan-drug designa- studies. FDA will establish categories tions. of diagnostic radiopharmaceuticals 316.29 Revocation of orphan-drug designa- based on defined characteristics rel- tion. evant to risk and will specify the 316.30 Annual reports of holder of orphan- amount and type of safety data that drug designation. are appropriate for each category (e.g., Subpart D—Orphan-drug Exclusive required safety data may be limited for Approval diagnostic radiopharmaceuticals with a well established, low-risk profile). 316.31 Scope of orphan-drug exclusive ap- Upon reviewing the relevant product proval. characteristics and safety information, 316.34 FDA recognition of exclusive ap- FDA will place each diagnostic radio- proval. pharmaceutical into the appropriate 316.36 Insufficient quantities of orphan drugs. safety risk category. (d) Radiation safety assessment. The Subpart E—Open Protocols for radiation safety assessment must es- Investigations tablish the radiation dose of a diagnostic radiopharmaceutical by radi- 316.40 Treatment use of a designated orphan ation dosimetry evaluations in humans drug. and appropriate animal models. The Subpart F—Availability of Information maximum tolerated dose need not be established. 316.50 Guidance documents. 316.52 Availability for public disclosure of PART 316—ORPHAN DRUGS data and information in requests and applications.

Subpart A—General Provisions AUTHORITY: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371. Sec. 316.1 Scope of this part. SOURCE: 57 FR 62085, Dec. 29, 1992, unless 316.2 Purpose. otherwise noted. 316.3 Definitions. EDITORIAL NOTE: Nomenclature changes to 316.4 Address for submissions. part 316 appear at 69 FR 13717, Mar. 24, 2004.

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Subpart A—General Provisions (2) Active moiety means the molecule or ion, excluding those appended por- § 316.1 Scope of this part. tions of the molecule that cause the (a) This part implements sections 525, drug to be an ester, salt (including a 526, 527, and 528 of the act and provides salt with hydrogen or coordination procedures to encourage and facilitate bonds), or other noncovalent derivative the development of drugs for rare dis- (such as a complex, chelate, or clath- eases or conditions, including biologi- rate) of the molecule, responsible for cal products and antibiotics. This part the physiological or pharmacological sets forth the procedures and require- action of the drug substance. ments for: (3) Clinically superior means that a (1) Submissions to FDA of: drug is shown to provide a significant (i) Requests for recommendations for therapeutic advantage over and above investigations of drugs for rare dis- that provided by an approved orphan eases or conditions; drug (that is otherwise the same drug) (ii) Requests for designation of a drug in one or more of the following ways: for a rare disease or condition; and (i) Greater effectiveness than an ap- (iii) Requests for gaining exclusive proved orphan drug (as assessed by ef- approval for a drug product for a rare fect on a clinically meaningful end- disease or condition. point in adequate and well controlled (2) Allowing a sponsor to provide an clinical trials). Generally, this would investigational drug product under a represent the same kind of evidence treatment protocol to patients who needed to support a comparative effec- need the drug for treatment of a rare tiveness claim for two different drugs; disease or condition. in most cases, direct comparative clin- (b) This part does not apply to food, ical trials would be necessary; or medical devices, or drugs for veteri- (ii) Greater safety in a substantial nary use. portion of the target populations, for (c) References in this part to regu- example, by the elimination of an in- latory sections of the Code of Federal gredient or contaminant that is associ- Regulations are to chapter I of title 21, ated with relatively frequent adverse unless otherwise noted. 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 inves- (5) FDA means the Food and Drug tigational orphan drugs. This part is Administration. also intended to satisfy Congress’ re- (6) Holder means the sponsor in whose quirements that FDA promulgate pro- name an orphan drug is designated and cedures for the implementation of sec- approved. tions 525(a) and 526(a) of the act. (7) IND means an investigational new drug application under part 312 of this § 316.3 Definitions. chapter. (a) The definitions and interpreta- (8) Manufacturer means any person or tions contained in section 201 of the act agency engaged in the manufacture of apply to those terms when used in this a drug that is subject to investigation part. and approval under the act or the bio- (b) The following definitions of terms logics provisions of the Public Health apply to this part: Service Act (42 U.S.C. 262–263). (1) Act means the Federal Food, Drug, (9) Marketing application means an ap- and Cosmetic Act as amended by sec- plication for approval of a new drug tion 2 of the Orphan Drug Act (sections filed under section 505(b) of the act or 525–528 (21 U.S.C. 360aa–360dd)). an application for a biologics license

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submitted under section 351 of the Pub- differences were shown to be clinically lic Health Service Act (42 U.S.C. 262). superior. (10) Orphan drug means a drug in- (B) Two polysaccharide drugs would tended for use in a rare disease or con- be considered the same if they had dition as defined in section 526 of the identical saccharide repeating units, act. even if the number of units were to (11) Orphan-drug designation means vary and even if there were postpolym- FDA’s act of granting a request for des- erization modifications, unless the sub- ignation under section 526 of the act. sequent drug could be shown to be (12) Orphan-drug exclusive approval or clinically superior. exclusive approval means that, effective on the date of FDA approval as stated (C) Two polynucleotide drugs con- in the approval letter of a marketing sisting of two or more distinct nucleo- application for a sponsor of a des- tides would be considered the same if ignated orphan drug, no approval will they had an identical sequence of pu- be given to a subsequent sponsor of the rine and pyrimidine bases (or their de- same drug product for the same indica- rivatives) bound to an identical sugar tion for 7 years, except as otherwise backbone (ribose, deoxyribose, or modi- provided by law or in this part. fications of these sugars), unless the (13) Same drug means: subsequent drug were shown to be (i) If it is a drug composed of small clinically superior. molecules, a drug that contains the (D) Closely related, complex partly same active moiety as a previously ap- definable drugs with similar thera- proved drug and is intended for the peutic intent, such as two live viral same use as the previously approved vaccines for the same indication, would drug, even if the particular ester or be considered the same unless the sub- salt (including a salt with hydrogen or sequent drug was shown to be clini- coordination bonds) or other noncovalent derivative such as a com- cally superior. plex, chelate or clathrate has not been (14) Sponsor means the entity that as- previously approved, except that if the sumes responsibility for a clinical or subsequent drug can be shown to be nonclinical investigation of a drug, in- clinically superior to the first drug, it cluding the responsibility for compli- will not be considered to be the same ance with applicable provisions of the drug. act and regulations. A sponsor may be (ii) If it is a drug composed of large an individual, partnership, corporation, molecules (macromolecules), a drug or Government agency and may be a that contains the same principal mo- manufacturer, scientific institution, or lecular structural features (but not an investigator regularly and lawfully necessarily all of the same structural engaged in the investigation of drugs. features) and is intended for the same For purposes of the Orphan Drug Act, use as a previously approved drug, ex- FDA considers the real party or parties cept that, if the subsequent drug can be in interest to be a sponsor. shown to be clinically superior, it will not be considered to be the same drug. [57 FR 62085, Dec. 29, 1992, as amended at 64 This criterion will be applied as follows FR 402, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999] to different kinds of macromolecules: (A) Two protein drugs would be con- § 316.4 Address for submissions. sidered the same if the only differences All correspondence and requests for in structure between them were due to FDA action pursuant to the provisions post-translational events or infidelity of this rule should be addressed as fol- of translation or transcription or were lows: Office of Orphan Products Devel- minor differences in amino acid se- opment (HF–35), Food and Drug Admin- quence; other potentially important istration, 5600 Fishers Lane, Rockville, differences, such as different glycosyl- MD 20857. ation patterns or different tertiary structures, would not cause the drugs to be considered different unless the

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Subpart B—Written Recommenda- (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 re- (iv) All adverse regulatory actions quest for written recommendations. taken by the United States or foreign (a) A sponsor’s request for written authorities. recommendations from FDA con- (8) The basis for concluding that the cerning the nonclinical and clinical in- drug is for a disease or condition that vestigations necessary for approval of a is rare in the United States, including marketing application shall be sub- the following: mitted in the form and contain the in- (i) The size and other known demo- formation required in this section. graphic characteristics of the patient FDA may require the sponsor to subpopulation affected and the source of mit information in addition to that this information. specified in paragraph (b) of this sec- (ii) For drugs intended for diseases or tion if FDA determines that the spon- conditions affecting 200,000 or more sor’s initial request does not contain people in the United States, or for a adequate information on which to base vaccine, diagnostic drug, or preventive recommendations. drug that would be given to 200,000 or (b) A sponsor shall submit two copies more persons per year, a summary of of a completed, dated, and signed re- the sponsor’s basis for believing that quest for written recommendations the disease or condition described in that contains the following: paragraph (b)(6) of this section occurs (1) The sponsor’s name and address. so infrequently that there is no reason- (2) A statement that the sponsor is able expectation that the costs of drug requesting written recommendations development and marketing will be re- on orphan-drug development under sec- covered in future sales of the drug in tion 525 of the act. the United States. The estimated costs (3) The name of the sponsor’s pri- and sales data should be submitted as mary contact person and/or resident provided for in § 316.21(c). agent, and the person’s title, address, (9) A summary and analysis of avail- and telephone number. able data on the pharmacologic effects (4) The generic name and trade name, of the drug. if any, of the drug and a list of the drug (10) A summary and analysis of avail- product’s components or description of able nonclinical and clinical data perti- the drug product’s formulation, and nent to the drug and the disease to be chemical and physical properties. studied including copies of pertinent (5) The proposed dosage form and published reports. When a drug pro- route of administration. posed for orphan drug designation is in- (6) A description of the disease or tended to treat a life-threatening or se- condition for which the drug is pro- verely debilitating illness, especially posed to be investigated and the pro- where no satisfactory alternative ther- posed indication or indications for use apy exists, the sponsor may wish vol- for such disease or condition. untarily to provide this information. A (7) Current regulatory and marketing sponsor of such a drug may be entitled status and history of the drug product, to expeditious development, evalua- including: tion, and marketing under 21 CFR part (i) Whether the product is the subject 312, subpart E. of an IND or a marketing application (11) An explanation of how the data (if the product is the subject of an IND summarized and analyzed under para- or a marketing application, the IND or graphs (b)(9) and (b)(10) of this section marketing application numbers should support the rationale for use of the be stated and the investigational or ap- drug in the rare disease or condition. proved indication or indications for use (12) A definition of the population specified); from which subjects will be identified (ii) Known marketing experience or for clinical trials, if known. investigational status outside the (13) A detailed outline of any proto- United States; cols under which the drug has been or

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is being studied for the rare disease or (2) There is insufficient information condition and a summary and analysis about: of any available data from such stud- (i) The drug to identify the active ies. moiety and its physical and chemical (14) The sponsor’s proposal as to the properties, if these characteristics can scope of nonclinical and clinical inves- be determined; or tigations needed to establish the safety (ii) The disease or condition to deter- and effectiveness of the drug. mine that the disease or condition is (15) Detailed protocols for each pro- rare in the United States; or posed United States or foreign clinical (iii) The reasons for believing that investigation, if available. the drug may be useful for treating the (16) Specific questions to be ad- rare disease or condition with that dressed by FDA in its recommenda- drug; or tions for nonclinical laboratory studies (iv) The regulatory and marketing and clinical investigations. 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 response may be limited to written rec- in the United States. ommendations concerning only non- (5) On the basis of the information clinical laboratory studies, or only cer- submitted and on other information tain of the clinical studies (e.g., Phase available to the agency, FDA deter- 1 studies as described in § 312.21 of this mines that there is an inadequate basis chapter). Prior to providing written for permitting investigational use of recommendations for the clinical in- the drug under part 312 of this chapter vestigations required to achieve mar- for the rare disease or condition. keting approval, FDA may require that (6) The request for information con- the results of the nonclinical labora- tains an untrue statement of material tory studies or completed early clinical fact. studies be submitted to FDA for agen- (b) A refusal to provide written rec- cy review. ommendations will be in writing and will include a statement of the reason § 316.14 Refusal to provide written rec- for FDA’s refusal. Where practicable, ommendations. FDA will describe the information or (a) FDA may refuse to provide writ- material it requires or the conditions ten recommendations concerning the the sponsor must meet for FDA to pro- nonclinical laboratory studies and clin- vide recommendations. ical investigations necessary for ap- (c) Within 90 days after the date of a proval of a marketing application for letter from FDA requesting additional any of the following reasons: information or material or setting (1) The information required to be forth the conditions that the sponsor is submitted by § 316.10(b) has not been asked to meet, the sponsor shall either: submitted, or the information sub- (1) Provide the information or mate- mitted is incomplete. rial or amend the request for written

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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 in- recommendations. FDA will consider a dication or indications for use of the sponsor’s failure to respond within 90 drug, and the reasons why such therapy days to an FDA letter requesting infor- is needed. mation or material or setting forth (4) A description of the drug and a conditions to be met to be a with- discussion of the scientific rationale drawal of the request for written rec- for the use of the drug for the rare dis- ommendations. ease or condition, including all data from nonclinical laboratory studies, Subpart C—Designation of an clinical investigations, and other rel- Orphan Drug evant data that are available to the sponsor, whether positive, negative, or § 316.20 Content and format of a re- inconclusive. Copies of pertinent un- quest for orphan-drug designation. published and published papers are also required. (a) A sponsor that submits a request for orphan-drug designation of a drug (5) Where the sponsor of a drug that for a specified rare disease or condition is otherwise the same drug as an al- shall submit each request in the form ready-approved orphan drug seeks or- and containing the information re- phan-drug designation for the subse- quired in paragraph (b) of this section. quent drug for the same rare disease or A sponsor may request orphan-drug condition, an explanation of why the designation of a previously unapproved proposed variation may be clinically drug, or of a new orphan indication for superior to the first drug. an already marketed drug. In addition, (6) Where a drug is under develop- a sponsor of a drug that is otherwise ment for only a subset of persons with the same drug as an already approved a particular disease or condition, a orphan drug may seek and obtain or- demonstration that the subset is medi- phan-drug designation for the subse- cally plausible. quent drug for the same rare disease or (7) A summary of the regulatory sta- condition if it can present a plausible tus and marketing history of the drug hypothesis that its drug may be clini- in the United States and in foreign cally superior to the first drug. More countries, e.g., IND and marketing ap- than one sponsor may receive orphan- plication status and dispositions, what drug designation of the same drug for uses are under investigation and in the same rare disease or condition, but what countries; for what indication is each sponsor seeking orphan-drug des- the drug approved in foreign countries; ignation must file a complete request what adverse regulatory actions have for designation as provided in para- been taken against the drug in any graph (b) of this section. country. (b) A sponsor shall submit two copies (8) Documentation, with appended of a completed, dated, and signed re- authoritative references, to dem- quest for designation that contains the onstrate that: following: (i) The disease or condition for which (1) A statement that the sponsor re- the drug is intended affects fewer than quests orphan-drug designation for a 200,000 people in the United States or, rare disease or condition, which shall if the drug is a vaccine, diagnostic be identified with specificity. drug, or preventive drug, the persons to (2) The name and address of the spon- whom the drug will be administered in sor; the name of the sponsor’s primary the United States are fewer than 200,000 contact person and/or resident agent per year as specified in § 316.21(b), or including title, address, and telephone (ii) For a drug intended for diseases number; the generic and trade name, if or conditions affecting 200,000 or more any, of the drug or drug product; and people, or for a vaccine, diagnostic the name and address of the source of drug, or preventive drug to be adminis- the drug if it is not manufactured by tered to 200,000 or more persons per the sponsor. year in the United States, there is no

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reasonable expectation that costs of re- mation provided and literature cita- search and development of the drug for tions) for the estimate; the indication can be recovered by (2) Upon request by FDA, the esti- sales of the drug in the United States mated prevalence of any other disease as specified in § 316.21(c). or condition for which the drug has al- (9) A statement as to whether the ready been approved or for which the sponsor submitting the request is the drug is currently being developed, to- real party in interest of the develop- gether with an explanation of the bases ment and the intended or actual proof these estimates; and duction and sales of the product. (3) The estimated number of people (c) Any of the information previously to whom the drug will be administered provided by the sponsor to FDA under annually if the drug is a vaccine or is subpart B of this part may be ref- a drug intended for diagnosis or pre- erenced by specific page or location if vention of a rare disease or condition, it duplicates information required else- together with an explanation of the where in this section. 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 These costs shall include, but are not product is indicated is fewer than limited to, nonclinical laboratory stud- 200,000 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 expectation that the sales of the drug designation request, IND/marketing ap- will be sufficient to offset the costs of developing the drug for the U.S. mar- plication preparation, distribution of ket and the costs of making the drug the drug under a ‘‘treatment’’ protocol, available in the United States. licensing costs, liability insurance, and (b) For the purpose of documenting overhead and depreciation. Further- that the number of people affected by more, the sponsor shall demonstrate the disease or condition for which the the reasonableness of the cost data. drug product is indicated is less than For example, if the sponsor has in- 200,000 persons, ‘‘prevalence’’ is defined curred costs for clinical investigations, as the number of persons in the United the sponsor shall provide information States who have been diagnosed as hav- on the number of investigations, the ing the disease or condition at the time years in which they took place, and on of the submission of the request for or- the scope, duration, and number of pa- phan-drug designation. To document tients that were involved in each inves- the number of persons in the United tigation. States who have the disease or condi- (2) If the drug was developed wholly tion for which the drug is to be indi- or in part outside the United States, in cated, the sponsor shall submit to FDA addition to the documentation listed in evidence showing: paragraph (c)(1) of this section: (1) The estimated prevalence of the (i) Data on and justification for all disease or condition for which the drug costs that the sponsor has incurred is being developed, together with a list outside of the United States in the of the sources (including dates of infor- course of developing the drug for the

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U.S. market. The justification, in addi- that the drug will be used to treat. The tion to demonstrating the reasonable- justification should include: ness of the cost data, must also explain (i) An estimate of the expected mar- the method that was used to determine ket share of the drug in each of the which portion of the foreign develop- first 7 years that it is marketed, to- ment costs should be applied to the gether with an explanation of the basis U.S. market, and what percent these for that estimate; costs are of total worldwide develop- (ii) A projection of and justification ment costs. Any data submitted to for- for the price at which the drug will be eign government authorities to support sold; and drug pricing determinations must be (iii) Comparisons with sales of simi- included with this information. larly situated drugs, where available. (ii) Data that show which foreign de- (7) The name of each country where velopment costs were recovered the drug has already been approved for through cost recovery procedures that marketing for any indication, the dates are allowed during drug development in of approval, the indication for which some foreign countries. For example, if the drug is approved, and the annual the sponsor charged patients for the sales and number of prescriptions in drug during clinical investigations, the each country since the first approval revenues collected by the sponsor must date. be reported to FDA. (8) A report of an independent cer- (3) In cases where the drug has al- tified public accountant in accordance ready been approved for marketing for with Statement on Standards for At- any indication or in cases where the testation established by the American drug is currently under investigation Institute of Certified Public Account- for one or more other indications (in ants on agreed upon procedures per- addition to the indication for which or- formed with respect to the data estimates 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 cases where the extent of these future FDA-designated personnel to examine development costs are not clear, the at reasonable times and in a reasonable sponsor should request FDA’s advice manner all relevant financial records and assistance in estimating the scope and sales data of the sponsor and man- of nonclinical laboratory studies and ufacturer. clinical investigations and other data that are needed to support marketing § 316.22 Permanent-resident agent for approval. Based on these recommenda- foreign sponsor. tions, a cost estimate should be pre- Every foreign sponsor that seeks or- pared. phan-drug designation shall name a (5) A statement of and justification permanent resident of the United for production and marketing costs States as the sponsor’s agent upon that the sponsor has incurred in the whom service of all processes, notices, past and expects to incur during the orders, decisions, requirements, and first 7 years that the drug is marketed. other communications may be made on (6) An estimate of and justification behalf of the sponsor. Notifications of for the expected revenues from sales of changes in such agents or changes of the drug in the United States during address of agents should preferably be its first 7 years of marketing. The jus- provided in advance, but not later than tification should assume that the total 60 days after the effective date of such market for the drug is equal to the changes. The permanent-resident agent prevalence of the disease or condition may be an individual, firm, or domestic

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corporation and may represent any will be recovered from sales of the drug number of sponsors. The name of the for the orphan indication in the United permanent-resident agent shall be pro- States. A sponsor’s failure to comply vided to: Office of Orphan Products De- with § 316.21 shall constitute a failure velopment (HF–35), Food and Drug Ad- to make the demonstration required in ministration, 5600 Fishers Lane, Rock- this paragraph. ville, MD 20857. (2) There is insufficient information about the drug, or the disease or condi- § 316.23 Timing of requests for orphan- drug designation; designation of al- tion for which it is intended, to estab- ready approved drugs. lish a medically plausible basis for ex- pecting the drug to be effective in the (a) A sponsor may request orphan- prevention, diagnosis, or treatment of drug designation at any time in the that disease or condition. drug development process prior to the submission of a marketing application (3) A drug that is otherwise the same for the drug product for the orphan in- drug as one that already has orphan- dication. drug exclusive approval for the same (b) A sponsor may request orphan- rare disease or condition and the spon- drug designation of an already ap- sor has not submitted a medically proved drug product for an unapproved plausible hypothesis for the possible use without regard to whether the clinical superiority of the subsequent prior marketing approval was for an drug. orphan-drug indication. (b) FDA may refuse to grant a request for orphan-drug designation if § 316.24 Granting orphan-drug des- the request for designation contains an ignation. untrue statement of material fact or (a) FDA will grant the request for or- omits material information. phan-drug designation if none of the reasons described in § 316.25 for requir- § 316.26 Amendment to orphan-drug ing or permitting refusal to grant such designation. a request applies. (a) At any time prior to approval of a (b) When a request for orphan-drug marketing application for a designated designation is granted, FDA will notify orphan drug, the sponsor holding des- the sponsor in writing and will pub- ignation may apply for an amendment licize the orphan-drug designation in to the indication stated in the orphan- accordance with § 316.28. drug designation if the proposed § 316.25 Refusal to grant orphan-drug change is due to new and unexpected designation. findings in research on the drugs, information arising from FDA recommenda- (a) FDA will refuse to grant a request tions, or unforeseen developments in for orphan-drug designation if any of the following reasons apply: treatment or diagnosis of the disease (1) The drug is not intended for a rare or condition. disease or condition because: (b) FDA will grant the amendment if (i) There is insufficient evidence to it finds that the initial designation re- support the estimate that the drug is quest was made in good faith and that intended for treatment of a disease or the amendment is intended to conform condition in fewer than 200,000 people the orphan-drug designation indication in the United States, or that the drug to the results of unanticipated research is intended for use in prevention or in findings, to unforeseen developments diagnosis in fewer than 200,000 people in the treatment or diagnosis of the annually in the United States; or disease or condition, or to changes (ii) Where the drug is intended for based on FDA recommendations, and prevention, diagnosis, or treatment of that, as of the date of the submission a disease or condition affecting 200,000 of the amendment request, the amend- or more people in the United States, ment would not result in exceeding the the sponsor has failed to demonstrate prevalence or cost recovery thresholds that there is no reasonable expectation in § 316.21 (a)(1) or (a)(2) upon which the that development and production costs drug was originally designated.

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§ 316.27 Change in ownership of or- § 316.28 Publication of orphan-drug phan-drug designation. designations. (a) A sponsor may transfer ownership Each month FDA will update a pub- of or any beneficial interest in the or- lically available list of drugs des- phan-drug designation of a drug to a ignated as orphan drugs. A cumulative, new sponsor. At the time of the trans- updated list of all designated drugs will fer, the new and former owners are re- be provided annually. These will be quired to submit the following infor- placed on file at the FDA Division of mation to FDA: Dockets Management, and will contain (1) The former owner or assignor of rights shall submit a letter or other the following information: document that states that all or some (a) The name and address of the man- rights to the orphan-drug designation ufacturer and sponsor; of the drug have been transferred to (b) The generic name and trade name, the new owner or assignee and that a if any, of the drug and the date of the complete copy of the request for or- granting of orphan-drug designation; phan-drug designation, including any (c) The rare disease or condition for amendments to the request, supple- which orphan-drug designation was ments to the granted request, and cor- granted; and respondence relevant to the orphan- (d) The proposed indication for use of drug designation, has been provided to the drug. the new owner or assignee. (2) The new owner or assignee of § 316.29 Revocation of orphan-drug rights shall submit a statement accept- designation. ing orphan-drug designation and a letter or other document containing the (a) FDA may revoke orphan-drug des- following: ignation for any drug if the agency (i) The date that the change in own- finds that: ership or assignment of rights is effec- (1) The request for designation con- tive; tained an untrue statement of material (ii) A statement that the new owner fact; or has a complete copy of the request for (2) The request for designation omit- orphan-drug designation including any ted material information required by amendments to the request, supple- this part; or ments to the granted request, and cor- (3) FDA subsequently finds that the respondence relevant to the orphan- drug in fact had not been eligible for drug designation; and orphan-drug designation at the time of (iii) A specific description of the submission of the request therefor. rights that have been assigned and (b) For an approved drug, revocation those that have been reserved. This may be satisfied by the submission of of orphan-drug designation also sus- either a list of rights assigned and re- pends or withdraws the sponsor’s exclu- served or copies of all relevant agree- sive marketing rights for the drug but ments between assignors and assignees; not the approval of the drug’s mar- and keting application. (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. [57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]

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§ 316.30 Annual reports of holder of or- (3) Consent by the holder of exclusive phan-drug designation. approval to permit another marketing Within 14 months after the date on application to gain approval; or which a drug was designated as an or- (4) Failure of the holder of exclusive phan drug and annually thereafter approval to assure a sufficient quantity until marketing approval, the sponsor of the drug under section 527 of the act of a designated drug shall submit a and § 316.36. brief progress report to the FDA Office (b) If a sponsor’s marketing applica- of Orphan Products Development on tion for a drug product is determined the drug that includes: not to be approvable because approval (a) A short account of the progress of is barred under section 527 of the act drug development including a review of until the expiration of the period of ex- preclinical and clinical studies initi- clusive marketing of another drug ated, ongoing, and completed and a product, FDA will so notify the sponsor short summary of the status or results in writing. of such studies. § 316.34 FDA recognition of exclusive (b) A description of the investiga- approval. tional plan for the coming year, as well as any anticipated difficulties in devel- (a) FDA will send the sponsor (or, the opment, testing, and marketing; and permanent-resident agent, if applica- (c) A brief discussion of any changes ble) timely written notice recognizing that may affect the orphan-drug status exclusive approval once the marketing of the product. For example, for prod- application for a designated orphan- ucts nearing the end of the approval drug product has been approved. The process, sponsors should discuss any written notice will inform the sponsor disparity between the probable mar- of the requirements for maintaining or- keting indication and the designated phan-drug exclusive approval for the indication as related to the need for an full 7-year term of exclusive approval. amendment to the orphan-drug des- (b) When a marketing application is ignation pursuant to § 316.26. approved for a designated orphan drug that qualifies for exclusive approval, FDA will publish in its publication en- Subpart D—Orphan-drug titled ‘‘Approved Drug Products with Exclusive Approval Therapeutic Equivalence Evaluations’’ information identifying the sponsor, § 316.31 Scope of orphan-drug exclu- the drug, and the date of termination sive approval. of the orphan-drug exclusive approval. (a) After approval of a sponsor’s mar- A subscription to this publication and keting application for a designated or- its monthly cumulative supplements is phan-drug product for treatment of the available from the Superintendent of rare disease or condition concerning Documents, Government Printing Of- which orphan-drug designation was fice, Washington, DC 20402–9325. granted, FDA will not approve another sponsor’s marketing application for the § 316.36 Insufficient quantities of or- same drug before the expiration of 7 phan drugs. years from the date of such approval as (a) Under section 527 of the act, stated in the approval letter from FDA, whenever the Director has reason to except that such a marketing applica- believe that the holder of exclusive ap- tion can be approved sooner if, and proval cannot assure the availability of such time as, any of the following oc- sufficient quantities of an orphan drug curs: to meet the needs of patients with the (1) Withdrawal of exclusive approval disease or condition for which the drug or revocation of orphan-drug designa- was designated, the Director will so no- tion by FDA under any provision of tify the holder of this possible insuffi- this part; or ciency and will offer the holder one of (2) Withdrawal for any reason of the the following options, which must be marketing application for the drug in exercised by a time that the Director question; or specifies:

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(1) Provide the Director in writing, or tained on the Internet and is published orally, or both, at the Director’s dis- annually in the FEDERAL REGISTER. A cretion, views and data as to how the request for a copy of the list should be holder can assure the availability of directed to the Office of Orphan Prod- sufficient quantities of the orphan drug ucts Development (HF–35), Food and within a reasonable time to meet the Drug Administration, 5600 Fishers needs of patients with the disease or Lane, Rockville, MD 20857. condition for which the drug was designated; or [65 FR 56480, Sept. 19, 2000] (2) Provide the Director in writing the holder’s consent for the approval of § 316.52 Availability for public disclo- other marketing applications for the sure of data and information in re- same drug before the expiration of the quests and applications. 7-year period of exclusive approval. (a) FDA will not publicly disclose the (b) If, within the time that the Direc- existence of a request for orphan-drug tor specifies, the holder fails to consent designation under section 526 of the act to the approval of other marketing ap- prior to final FDA action on the re- plications and if the Director finds that quest unless the existence of the re- the holder has not shown that it can quest has been previously publicly dis- assure the availability of sufficient closed or acknowledged. quantities of the orphan drug to meet (b) Whether or not the existence of a the needs of patients with the disease pending request for designation has or condition for which the drug was been publicly disclosed or acknowl- designated, the Director will issue a edged, no data or information in the re- written order withdrawing the drug quest are available for public disclo- product’s exclusive approval. This sure prior to final FDA action on the order will embody the Director’s find- request. ings and conclusions and will constitute final agency action. An order (c) Upon final FDA action on a re- withdrawing the sponsor’s exclusive quest for designation, FDA will deter- marketing rights may issue whether or mine the public availability of data not there are other sponsors that can and information in the request in ac- assure the availability of alternative cordance with part 20 and § 314.430 of sources of supply. Once withdrawn this chapter and other applicable stat- under this section, exclusive approval utes and regulations. may not be reinstated for that drug. (d) In accordance with § 316.28, FDA will make a cumulative list of all or- Subpart E—Open Protocols for phan drug designations available to the Investigations public and update such list monthly. (e) FDA will not publicly disclose the § 316.40 Treatment use of a designated existence of a pending marketing appli- orphan drug. cation for a designated orphan drug for Prospective investigators seeking to the use for which the drug was des- obtain treatment use of designated or- ignated unless the existence of the ap- phan drugs may do so as provided in plication has been previously publicly subpart I of this chapter. disclosed or acknowledged. [74 FR 40945, Aug. 13, 2009] (f) FDA will determine the public availability of data and information Subpart F—Availability of contained in pending and approved Information marketing applications for a designated orphan drug for the use for § 316.50 Guidance documents. which the drug was designated in accordance with part 20 and § 314.430 of FDA’s Office of Orphan Products De- velopment will maintain and make this chapter and other applicable stat- publicly available a list of guidance utes and regulations. documents that apply to the regulations in this part. The list is main-

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PART 320—BIOAVAILABILITY AND into the bloodstream, bioavailability BIOEQUIVALENCE REQUIREMENTS may be assessed by measurements intended to reflect the rate and extent to Subpart A—General Provisions which the active ingredient or active moiety becomes available at the site of Sec. action. 320.1 Definitions. (b) Drug product means a finished dos- Subpart B—Procedures for Determining the age form, e.g., tablet, capsule, or solu- Bioavailability or Bioequivalence of tion, that contains the active drug in- Drug Products gredient, generally, but not necessarily, in association with inactive 320.21 Requirements for submission of bio- ingredients. availability and bioequivalence data. 320.22 Criteria for waiver of evidence of in (c) Pharmaceutical equivalents means vivo bioavailability or bioequivalence. drug products in identical dosage forms 320.23 Basis for measuring in vivo bio- that contain identical amounts of the availability or demonstrating bioequiva- identical active drug ingredient, i.e., lence. the same salt or ester of the same 320.24 Types of evidence to measure bio- therapeutic moiety, or, in the case of availability or establish bioequivalence. 320.25 Guidelines for the conduct of an in modified release dosage forms that re- vivo bioavailability study. quire a reservoir or overage or such 320.26 Guidelines on the design of a single- forms as prefilled syringes where resid- dose in vivo bioavailability or bioequiva- ual volume may vary, that deliver lence study. identical amounts of the active drug 320.27 Guidelines on the design of a multiple-dose in vivo bioavailability study. ingredient over the identical dosing pe- 320.28 Correlation of bioavailability with an riod; do not necessarily contain the acute pharmacological effect or clinical same inactive ingredients; and meet evidence. the identical compendial or other ap- 320.29 Analytical methods for an in vivo plicable standard of identity, strength, bioavailability or bioequivalence study. quality, and purity, including potency 320.30 Inquiries regarding bioavailability and bioequivalence requirements and re- and, where applicable, content uni- view of protocols by the Food and Drug formity, disintegration times, and/or Administration. dissolution rates. 320.31 Applicability of requirements regard- (d) Pharmaceutical alternatives means ing an ‘‘Investigational New Drug Appli- drug products that contain the iden- cation.’’ tical therapeutic moiety, or its pre- 320.32 Procedures for establishing or amending a bioequivalence requirement. cursor, but not necessarily in the same 320.33 Criteria and evidence to assess actual amount or dosage form or as the same or potential bioequivalence problems. salt or ester. Each such drug product 320.34 Requirements for batch testing and individually meets either the identical certification by the Food and Drug Ad- or its own respective compendial or ministration. other applicable standard of identity, 320.35 Requirements for in vitro testing of each batch. strength, quality, and purity, including 320.36 Requirements for maintenance of potency and, where applicable, content records of bioequivalence testing. uniformity, disintegration times and/or 320.38 Retention of bioavailability samples. dissolution rates. 320.63 Retention of bioequivalence samples. (e) Bioequivalence means the absence AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. of a significant difference in the rate and extent to which the active ingre- Subpart A—General Provisions dient or active moiety in pharmaceutical equivalents or pharmaceutical § 320.1 Definitions. alternatives becomes available at the (a) Bioavailability means the rate and site of drug action when administered extent to which the active ingredient at the same molar dose under similar or active moiety is absorbed from a conditions in an appropriately designed drug product and becomes available at study. Where there is an intentional the site of action. For drug products difference in rate (e.g., in certain ex- that are not intended to be absorbed tended release dosage forms), certain

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pharmaceutical equivalents or alter- (1) Evidence demonstrating that the natives may be considered bioequiva- drug product that is the subject of the lent if there is no significant difference abbreviated new drug application is in the extent to which the active ingre- bioequivalent to the reference listed dient or moiety from each product be- drug (defined in § 314.3(b) of this chap- comes available at the site of drug ac- ter). A complete study report must be tion. This applies only if the difference submitted for the bioequivalence study in the rate at which the active ingre- upon which the applicant relies for ap- dient or moiety becomes available at proval. For all other bioequivalence the site of drug action is intentional studies conducted on the same drug and is reflected in the proposed label- product formulation, the applicant ing, is not essential to the attainment must submit either a complete or sum- of effective body drug concentrations mary report. If a summary report of a on chronic use, and is considered medi- bioequivalence study is submitted and cally insignificant for the drug. FDA determines that there may be bio- (f) Bioequivalence requirement means a equivalence issues or concerns with the requirement imposed by the Food and product, FDA may require that the ap- Drug Administration for in vitro and/or plicant submit a complete report of the in vivo testing of specified drug prod- bioequivalence study to FDA; or ucts which must be satisfied as a condi- (2) Information to show that the drug tion of marketing. product is bioequivalent to the ref- (g) Same drug product formulation erence listed drug which would permit means the formulation of the drug FDA to waive the submission of evi- product submitted for approval and dence demonstrating in vivo bioequiva- any formulations that have minor dif- lence as provided in paragraph (f) of ferences in composition or method of this section. manufacture from the formulation sub- (c) Any person submitting a supple- mitted for approval, but are similar mental application to FDA shall in- enough to be relevant to the agency’s clude in the supplemental application determination of bioequivalence. the evidence or information set forth [42 FR 1634, Jan. 7, 1977, as amended at 42 FR in paragraphs (a) and (b) of this section 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67 if the supplemental application pro- FR 77672, Dec. 19, 2002; 74 FR 2861, Jan. 16, poses any of the following changes: 2009] (1) A change in the manufacturing site or a change in the manufacturing 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 otherwise noted. drug product, if clinical studies are required 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.

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(1) The application is otherwise ap- § 320.22 Criteria for waiver of evidence provable. of in vivo bioavailability or bio- (2) The application agrees to submit, equivalence. within the time specified by FDA, ei- (a) Any person submitting a full or ther: abbreviated new drug application, or a (i) Evidence measuring the in vivo supplemental application proposing bioavailability and demonstrating the any of the changes set forth in in vivo bioequivalence of the drug § 320.21(c), may request FDA to waive product that is the subject of the appli- the requirement for the submission of cation; or evidence measuring the in vivo bio- (ii) Information to permit FDA to availability or demonstrating the in waive measurement of in vivo bio- vivo bioequivalence of the drug product availability. that is the subject of the application. (e) Evidence measuring the in vivo An applicant shall submit a request for bioavailability and demonstrating the waiver with the application. Except as in vivo bioequivalence of a drug prod- provided in paragraph (f) of this sec- uct shall be obtained using one of the tion, FDA shall waive the requirement approaches for determining bio- for the submission of evidence of in availability set forth in § 320.24. vivo bioavailability or bioequivalence (f) Information to permit FDA to if the drug product meets any of the waive the submission of evidence meas- provisions of paragraphs (b), (c), (d), or uring the in vivo bioavailability or (e) of this section. demonstrating the in vivo bioequiva- (b) For certain drug products, the in lence shall meet the criteria set forth vivo bioavailability or bioequivalence in § 320.22. of the drug product may be self-evi- (g) Any person holding an approved dent. FDA shall waive the requirement full or abbreviated new drug applica- for the submission of evidence obtained tion shall submit to FDA a supple- in vivo measuring the bioavailability mental application containing new evi- or demonstrating the bioequivalence of dence measuring the in vivo bio- these drug products. A drug product’s availability or demonstrating the in in vivo bioavailability or bioequiva- vivo bioequivalence of the drug product lence may be considered self-evident that is the subject of the application if based on other data in the application notified by FDA that: if the product meets one of the fol- (1) There are data demonstrating lowing criteria: that the dosage regimen in the labeling (1) The drug product: is based on incorrect assumptions or (i) Is a parenteral solution intended facts regarding the pharmacokinetics solely for administration by injection, of the drug product and that following or an ophthalmic or otic solution; and this dosage regimen could potentially (ii) Contains the same active and in- result in subtherapeutic or toxic levels; active ingredients in the same con- or centration as a drug product that is the (2) There are data measuring signifi- subject of an approved full new drug cant intra-batch and batch-to-batch application or abbreviated new drug variability, e.g., plus or minus 25 per- application. cent, in the bioavailability of the drug (2) The drug product: product. (i) Is administered by inhalation as a (h) The requirements of this section gas, e.g., a medicinal or an inhalation regarding the submission of evidence anesthetic; and measuring the in vivo bioavailability (ii) Contains an active ingredient in or demonstrating the in vivo bio- the same dosage form as a drug product equivalence apply only to a full or ab- that is the subject of an approved full breviated new drug application or a new drug application or abbreviated supplemental application for a finished new drug application. dosage formulation. (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

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or nebulization, a nasal solution, or another drug product for which the similar other solubilized form; and same manufacturer has obtained ap- (ii) Contains an active drug ingre- proval and the conditions in para- dient in the same concentration and graphs (d)(2)(i) through (d)(2)(iii) of dosage form as a drug product that is this section are met: the subject of an approved full new (i) The bioavailability of this other drug application or abbreviated new drug product has been measured; drug application; and (ii) Both drug products meet an ap- (iii) Contains no inactive ingredient propriate in vitro test approved by or other change in formulation from FDA; and the drug product that is the subject of (iii) The applicant submits evidence the approved full new drug application showing that both drug products are or abbreviated new drug application proportionally similar in their active that may significantly affect absorp- and inactive ingredients. tion of the active drug ingredient or active moiety for products that are (iv) Paragraph (d) of this section does systemically absorbed, or that may sig- not apply to delayed release or ex- nificantly affect systemic or local tended release products. availability for products intended to (3) The drug product is, on the basis act locally. of scientific evidence submitted in the (c) FDA shall waive the requirement application, shown to meet an in vitro for the submission of evidence meas- test that has been correlated with in uring the in vivo bioavailability or vivo data. demonstrating the in vivo bioequiva- (4) The drug product is a reformu- lence of a solid oral dosage form (other lated product that is identical, except than a delayed release or extended re- for a different color, flavor, or preserv- lease dosage form) of a drug product ative that could not affect the bio- determined to be effective for at least availability of the reformulated prod- one indication in a Drug Efficacy uct, to another drug product for which Study Implementation notice or which the same manufacturer has obtained is identical, related, or similar to such approval and the following conditions a drug product under § 310.6 of this are met: chapter unless FDA has evaluated the (i) The bioavailability of the other drug product under the criteria set product has been measured; and 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] (2) The drug product is in the same availability or bioequivalence of the dosage form, but in a different drug product. strength, and is proportionally similar [57 FR 17998, Apr. 28, 1992, as amended at 67 in its active and inactive ingredients to FR 77673, Dec. 19, 2002]

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§ 320.23 Basis for measuring in vivo ered medically insignificant for the bioavailability or demonstrating particular drug product studied. bioequivalence. [57 FR 17999, Apr. 28, 1992, as amended at 67 (a)(1) The in vivo bioavailability of a FR 77673, Dec. 19, 2002] drug product is measured if the product’s rate and extent of absorption, as § 320.24 Types of evidence to measure determined by comparison of measured bioavailability or establish bio- parameters, e.g., concentration of the equivalence. active drug ingredient in the blood, (a) Bioavailability may be measured urinary excretion rates, or pharma- or bioequivalence may be dem- cological effects, do not indicate a sig- onstrated by several in vivo and in nificant difference from the reference vitro methods. FDA may require in material’s rate and extent of absorp- vivo or in vitro testing, or both, to tion. For drug products that are not in- measure the bioavailability of a drug tended to be absorbed into the blood- product or establish the bioequivalence stream, bioavailability may be as- of specific drug products. Information sessed by measurements intended to re- on bioequivalence requirements for flect the rate and extent to which the specific products is included in the cur- active ingredient or active moiety be- rent edition of FDA’s publication ‘‘Ap- comes available at the site of action. proved Drug Products with Thera- (2) Statistical techniques used shall peutic Equivalence Evaluations’’ and be of sufficient sensitivity to detect any current supplement to the publica- differences in rate and extent of ab- tion. The selection of the method used sorption that are not attributable to to meet an in vivo or in vitro testing subject variability. requirement depends upon the purpose (3) A drug product that differs from of the study, the analytical methods the reference material in its rate of ab- available, and the nature of the drug sorption, but not in its extent of ab- product. Applicants shall conduct bio- sorption, may be considered to be bioavailability and bioequivalence testing available if the difference in the rate of using the most accurate, sensitive, and reproducible approach available among absorption is intentional, is appro- those set forth in paragraph (b) of this priately reflected in the labeling, is not section. The method used must be ca- essential to the attainment of effective pable of measuring bioavailability or body drug concentrations on chronic establishing bioequivalence, as appro- use, and is considered medically insig- priate, for the product being tested. nificant for the drug product. (b) The following in vivo and in vitro (b) Two drug products will be consid- approaches, in descending order of ac- ered bioequivalent drug products if curacy, sensitivity, and reproduc- they are pharmaceutical equivalents or ibility, are acceptable for determining pharmaceutical alternatives whose the bioavailability or bioequivalence of rate and extent of absorption do not a drug product. show a significant difference when ad- (1)(i) An in vivo test in humans in ministered at the same molar dose of which the concentration of the active the active moiety under similar experi- ingredient or active moiety, and, when mental conditions, either single dose or appropriate, its active metabolite(s), in multiple dose. Some pharmaceutical whole blood, plasma, serum, or other equivalents or pharmaceutical alter- appropriate biological fluid is meas- natives may be equivalent in the ex- ured as a function of time. This ap- tent of their absorption but not in proach is particularly applicable to their rate of absorption and yet may be dosage forms intended to deliver the considered bioequivalent because such active moiety to the bloodstream for differences in the rate of absorption are systemic distribution within the body; intentional and are reflected in the la- or beling, are not essential to the attain- (ii) An in vitro test that has been ment of effective body drug concentra- correlated with and is predictive of tions on chronic use, and are consid- human in vivo bioavailability data; or

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(2) An in vivo test in humans in (b)(1)(ii), (b)(1)(iii), and (b)(3) of this which the urinary excretion of the ac- section are not available. This ap- tive moiety, and, when appropriate, its proach may also be considered suffi- active metabolite(s), are measured as a ciently accurate for measuring bio- function of time. The intervals at availability or demonstrating bio- which measurements are taken should equivalence of dosage forms intended ordinarily be as short as possible so to deliver the active moiety locally, that the measure of the rate of elimi- e.g., topical preparations for the skin, nation is as accurate as possible. De- eye, and mucous membranes; oral dos- pending on the nature of the drug prod- age forms not intended to be absorbed, uct, this approach may be applicable to e.g., an antacid or radiopaque medium; the category of dosage forms described and bronchodilators administered by in paragraph (b)(1)(i) of this section. inhalation if the onset and duration of This method is not appropriate where pharmacological activity are defined. urinary excretion is not a significant (5) A currently available in vitro test mechanism of elimination. acceptable to FDA (usually a dissolu- (3) An in vivo test in humans in tion rate test) that ensures human in which an appropriate acute pharma- vivo bioavailability. cological effect of the active moiety, (6) Any other approach deemed ade- and, when appropriate, its active me- quate by FDA to measure bio- tabolite(s), are measured as a function availability or establish bioequiva- of time if such effect can be measured lence. with sufficient accuracy, sensitivity, (c) FDA may, notwithstanding prior and reproducibility. This approach is requirements for measuring bio- applicable to the category of dosage availability or establishing bioequiva- forms described in paragraph (b)(1)(i) of lence, require in vivo testing in hu- this section only when appropriate mans of a product at any time if the methods are not available for measure- agency has evidence that the product: ment of the concentration of the moi- (1) May not produce therapeutic ef- ety, and, when appropriate, its active fects comparable to a pharmaceutical metabolite(s), in biological fluids or ex- equivalent or alternative with which it cretory products but a method is avail- is intended to be used interchangeably; able for the measurement of an appro- (2) May not be bioequivalent to a priate acute pharmacological effect. pharmaceutical equivalent or alter- This approach may be particularly ap- native with which it is intended to be plicable to dosage forms that are not used interchangeably; or intended to deliver the active moiety (3) Has greater than anticipated po- to the bloodstream for systemic dis- tential toxicity related to pharmaco- tribution. kinetic or other characteristics. (4) Well-controlled clinical trials that 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 bioequivalence. This approach is the an in vivo bioavailability study. 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

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physician determines that there is a tion, it may be necessary to compare potential benefit to the patient. the oral dosage form proposed for mar- (b) Basic design. The basic design of keting with the active drug ingredient an in vivo bioavailability study is de- or therapeutic moiety administered in termined by the following: solution both orally and intravenously. (1) The scientific questions to be an- (e) New formulations of active drug in- swered. gredients or therapeutic moieties approved (2) The nature of the reference mate- for marketing. (1) An in vivo bio- rial and the dosage form to be tested. availability study involving a drug (3) The availability of analytical product that is a new dosage form, or a methods. new salt or ester of an active drug in- (4) Benefit-risk considerations in re- gredient or therapeutic moiety that gard to testing in humans. has been approved for marketing can (c) Comparison to a reference material. be used to: In vivo bioavailability testing of a drug (i) Measure the bioavailability of the product shall be in comparison to an new formulation, new dosage form, or appropriate reference material unless new salt or ester relative to an appro- some other approach is more appropriate reference material; and priate for valid scientific reasons. (ii) Define the pharmacokinetic pa- (d) Previously unmarketed active drug rameters of the new formulation, new ingredients or therapeutic moieties. (1) An dosage form, or new salt or ester to es- in vivo bioavailability study involving tablish dosage recommendation. a drug product containing an active (2) The selection of the reference ma- drug ingredient or therapeutic moiety terial(s) in such a bioavailability study that has not been approved for mar- depends upon the scientific questions keting can be used to measure the fol- to be answered, the data needed to es- lowing pharmacokinetic data: tablish comparability to a currently (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 labeling claims made in relation to the after multiple-dose administration. drug product that is the subject of an This characterization is a necessary approved new drug application. part of the investigation of the drug to (f) Extended release formulations. (1) support drug labeling. The purpose of an in vivo bio- (2) The reference material in such a availability study involving a drug bioavailability study should be a solu- product for which an extended release tion or suspension containing the same claim is made is to determine if all of quantity of the active drug ingredient the following conditions are met: or therapeutic moiety as the formula- (i) The drug product meets the ex- tion proposed for marketing. tended release claims made for it. (3) The reference material should be (ii) The bioavailability profile estab- administered by the same route as the lished for the drug product rules out formulation proposed for marketing the occurrence of any dose dumping. unless an alternative or additional (iii) The drug product’s steady-state route is necessary to answer the sci- performance is equivalent to a cur- entific question under study. For ex- rently marketed nonextended release ample, in the case of an active drug in- or extended release drug product that gredient or therapeutic moiety that is contains the same active drug ingre- poorly absorbed after oral administra- dient or therapeutic moiety and that is

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subject to an approved full new drug (3) The Food and Drug Administra- application. tion may permit a bioavailability (iv) The drug product’s formulation study involving a combination drug provides consistent pharmacokinetic product to determine the rate and ex- performance between individual dosage tent of absorption of selected, but not units. all, active drug ingredients or thera- (2) The reference material(s) for such peutic moieties in the combination a bioavailability study shall be chosen drug product. The Food and Drug Ad- to permit an appropriate scientific ministration may permit this deter- evaluation of the extended release mination if the pharmacokinetics and claims made for the drug product. The the interactions of the active drug in- reference material shall be one of the gredients or therapeutic moieties in following or any combination thereof: the combination drug product are well (i) A solution or suspension of the ac- known and the therapeutic activity of tive drug ingredient or therapeutic the combination drug product is gen- moiety. erally recognized to reside in only one (ii) A currently marketed noncon- of the active drug ingredients or thera- trolled release drug product containing peutic moieties, e.g., ampicillin in an the same active drug ingredient or ampicillin-probenecid combination therapeutic moiety and administered drug product. according to the dosage recommenda- (h) Use of a placebo as the reference tions in the labeling of the noncon- material. Where appropriate or where trolled release drug product. necessary to demonstrate the sensi- (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 more currently marketed, single-ingre- [42 FR 1648, Jan. 7, 1977, as amended at 67 FR dient drug products each of which con- 77674, Dec. 19, 2002] tains one of the active drug ingredients or therapeutic moieties in the com- § 320.26 Guidelines on the design of a bination drug product. The Food and single-dose in vivo bioavailability Drug Administration may, for valid or bioequivalence study. scientific reasons, specify that the ref- (a) Basic principles. (1) An in vivo bio- erence material shall be a combination availability or bioequivalence study drug product that is the subject of an should be a single-dose comparison of approved new drug application. the drug product to be tested and the

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appropriate reference material con- times should be based on valid sci- ducted in normal adults. entific reasons. (2) The test product and the reference (d) Collection of urine samples. When material should be administered to comparison of the test product and the subjects in the fasting state, unless reference material is to be based on cu- some other approach is more appro- mulative urinary excretion-time priate for valid scientific reasons. curves, unless some other approach is (b) Study design. (1) A single-dose more appropriate for valid scientific study should be crossover in design, reasons, samples of the urine should be unless a parallel design or other design collected with sufficient frequency to is more appropriate for valid scientific permit an estimate of the rate and ex- reasons, and should provide for a drug tent of urinary excretion of the active elimination period. drug ingredient or therapeutic moiety, (2) Unless some other approach is ap- or its metabolite(s), measured. propriate for valid scientific reasons, (e) Measurement of an acute pharma- the drug elimination period should be cological effect. (1) When comparison of either: the test product and the reference ma- (i) At least three times the half-life terial is to be based on acute pharma- of the active drug ingredient or thera- cological effect-time curves, measure- peutic moiety, or its metabolite(s), ments of this effect should be made measured in the blood or urine; or with sufficient frequency to permit a reasonable estimate of the total area (ii) At least three times the half-life under the curve for a time period at of decay of the acute pharmacological least three times the half-life of decay effect. of the pharmacological effect, unless (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 (ii) The total area under the curve for 77674, Dec. 19, 2002] 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: (2) The test product and the reference (i) The distribution and elimination material should be administered to phase of the intravenous dosage form; subjects in the fasting or nonfasting and state, depending upon the conditions (ii) The absorption and elimination reflected in the proposed labeling of phase of the oral dosage form. the test product. (4) In a study comparing drug deliv- (3) A multiple-dose study may be re- ery systems other than oral or intra- quired to determine the bioavailability venous dosage forms with an appro- of a drug product in the following cir- priate reference standard, the sampling cumstances:

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(i) There is a difference in the rate of (2) Whenever comparison of the test absorption but not in the extent of ab- product and the reference material is sorption. to be based on cumulative urinary ex- (ii) There is excessive variability in cretion-time curves at steady state, ap- bioavailability from subject to subject. propriate dosage administration and (iii) The concentration of the active sampling should be carried out to docu- drug ingredient or therapeutic moiety, ment attainment of steady state. or its metabolite(s), in the blood re- (3) A more complete characterization sulting from a single dose is too low for of the blood concentration or urinary accurate determination by the analyt- excretion rate during the absorption ical method. and elimination phases of a single dose (iv) The drug product is an extended administered at steady-state is encour- release dosage form. aged to permit estimation of the total (b) Study design. (1) A multiple-dose area under concentration-time curves study should be crossover in design, or cumulative urinary excretion-time unless a parallel design or other design curves and to obtain pharmacokinetic is more appropriate for valid scientific information, e.g., half-life or blood reasons, and should provide for a drug clearance, that is essential in pre- elimination period if steady-state con- paring adequate labeling for the drug ditions are not achieved. product. (2) A multiple-dose study is not re- (e) Steady-state parameters. (1) In cer- quired to be of crossover design if the tain instances, e.g., in a study involv- study is to establish dose proportion- ing a new drug entity, blood clearances ality under a multiple-dose regimen or at steady-state obtained in a multiple- to establish the pharmacokinetic profile of a new drug product, a new drug dose study should be compared to blood delivery system, or an extended release clearances obtained in a single-dose dosage form. study to support adequate dosage rec- (3) If a drug elimination period is re- ommendations. quired, unless some other approach is (2) In a linear system, the area under more appropriate for valid scientific the blood concentration-time curve reasons, the drug elimination period during a dosing interval in a multiple- should be either: dose steady-state study is directly pro- (i) At least five times the half-life of portional to the fraction of the dose ab- the active drug ingredient or thera- sorbed and is equal to the cor- peutic moiety, or its active metabo- responding ‘‘zero to infinity’’ area lite(s), measured in the blood or urine; under the curve for a single-dose study. or Therefore, when steady-state condi- (ii) At least five times the half-life of tions are achieved, a comparison of decay of the acute pharmacological ef- blood concentrations during a dosing fect. interval may be used to define the frac- (c) Achievement of steady-state condition of the active drug ingredient or tions. Whenever a multiple-dose study therapeutic moiety absorbed. is conducted, unless some other ap- (3) Other methods based on valid sci- proach is more appropriate for valid entific reasons should be used to deter- scientific reasons, sufficient doses of mine the bioavailability of a drug prod- the test product and reference material uct having dose-dependent kinetics should be administered in accordance (non-linear system). with the labeling to achieve steady- (f) Measurement of an acute pharma- state conditions. cological effect. When comparison of the (d) Collection of blood or urine samples. test product and the reference material (1) Whenever comparison of the test is to be based on acute pharma- product and the reference material is cological effect-time curves, measure- to be based on blood concentration- ments of this effect should be made time curves at steady state, appropriate dosage administration and sam- with sufficient frequency to dem- pling should be carried out to docu- onstrate a maximum effect and a lack ment attainment of steady state. of significant difference between the

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test product and the reference mate- person planning to conduct a bio- rial. availability or bioequivalence study submit the proposed protocol for the [42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002] study to FDA for review prior to the initiation of the study. § 320.28 Correlation of bioavailability (b) FDA may review a proposed pro- with an acute pharmacological ef- tocol for a bioavailability or bioequiva- fect or clinical evidence. lence study and will offer advice with Correlation of in vivo bioavailability respect to whether the following condi- data with an acute pharmacological ef- tions are met: fect or clinical evidence of safety and (1) The design of the proposed bio- effectiveness may be required if needed availability or bioequivalence study is to establish the clinical significance of appropriate. a special claim, e.g., in the case of an (2) The reference material to be used extended release preparation. in the bioavailability or bioequivalence [42 FR 1648, Jan. 7, 1977, as amended at 67 FR study is appropriate. 77674, Dec. 19, 2002] (3) The proposed chemical and statistical analytical methods are adequate. § 320.29 Analytical methods for an in (c)(1) General inquiries relating to in vivo bioavailability or bioequiva- vivo bioavailability requirements and lence study. methodology shall be submitted to the (a) The analytical method used in an Food and Drug Administration, Center in vivo bioavailability or bioequiva- for Drug Evaluation and Research, Of- lence study to measure the concentra- fice of Clinical Pharmacology, 10903 tion of the active drug ingredient or New Hampshire Ave., Silver Spring, therapeutic moiety, or its active me- MD 20993–0002. tabolite(s), in body fluids or excretory (2) General inquiries relating to bio- products, or the method used to meas- equivalence requirements and method- ure an acute pharmacological effect ology shall be submitted to the Food shall be demonstrated to be accurate and Drug Administration, Center for and of sufficient sensitivity to meas- Drug Evaluation and Research, Divi- ure, with appropriate precision, the ac- sion of Bioequivalence (HFD–650), 7500 tual concentration of the active drug Standish Pl., Rockville, MD 20855–2773. ingredient or therapeutic moiety, or its active metabolite(s), achieved in the [57 FR 18000, Apr. 28, 1992, as amended at 67 body. FR 77674, Dec. 19, 2002; 74 FR 13114, Mar. 26, (b) When the analytical method is 2009] not sensitive enough to measure accu- § 320.31 Applicability of requirements rately the concentration of the active regarding an ‘‘Investigational New drug ingredient or therapeutic moiety, Drug Application.’’ or its active metabolite(s), in body 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 chemical entity as defined in [42 FR 1648, Jan. 7, 1977, as amended at 67 FR § 314.108(a) of this chapter; or 77674, Dec. 19, 2002] (2) The study involves a radioactively § 320.30 Inquiries regarding bio- labeled drug product; or availability and bioequivalence re- (3) The study involves a cytotoxic quirements and review of protocols drug product. by the Food and Drug Administra- (b) Any person planning to conduct a tion. bioavailability or bioequivalence study (a) The Commissioner of Food and in humans using a drug product that Drugs strongly recommends that, to contains an already approved, non-new avoid the conduct of an improper study chemical entity shall submit an IND if and unnecessary human research, any the study is one of the following:

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(1) A single-dose study in normal sub- submission (e.g., method of trans- jects or patients where either the max- mission, media, file formats, prepara- imum single or total daily dose exceeds tion and organization of files). Each re- that specified in the labeling of the port must bear prominent identifica- drug product that is the subject of an tion of its contents, i.e., ‘‘bio- approved new drug application or ab- availability/bioequivalence safety re- breviated new drug application. port.’’ The person conducting the (2) A multiple-dose study in normal study, including any contract research subjects or patients where either the organization, must also notify FDA of single or total daily dose exceeds that any fatal or life-threatening adverse specified in the labeling of the drug event from the study as soon as pos- product that is the subject of an ap- sible but in no case later than 7 cal- proved new drug application or abbre- endar days after becoming aware of its viated new drug application. occurrence. Each notification under (3) A multiple-dose study on an ex- this paragraph must be submitted to tended release product on which no sin- the Director, Office of Generic Drugs in gle-dose study has been completed. the Center for Drug Evaluation and Re- (c) The provisions of parts 50, 56, and search at FDA. Relevant followup in- 312 of this chapter are applicable to formation to a bioavailability/bio- any bioavailability or bioequivalence equivalence safety report must be sub- study in humans conducted under an mitted as soon as the information is IND. available and must be identified as (d) A bioavailability or bioequiva- such, i.e., ‘‘Followup bioavailability/ lence study in humans other than one bioequivalence safety report.’’ Upon re- described in paragraphs (a) through (c) quest from FDA, the person conducting 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 [57 FR 18000, Apr. 28, 1992, as amended at 58 and reference standard used in the FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, study and release the reserve samples 2002; 75 FR 59963, Sept. 29, 2010] to FDA upon request, in accordance with, and for the period specified in, § 320.32 Procedures for establishing or § 320.38; amending a bioequivalence require- (2) An in vivo bioavailability or bio- ment. equivalence study in humans must be (a) The Food and Drug Administra- conducted in compliance with the re- tion, on its own initiative or in requirements for institutional review set sponse to a petition by an interested forth in part 56 of this chapter, and in- person, may propose and promulgate a formed consent set forth in part 50 of regulation to establish a bioequiva- this chapter; and lence requirement for a product not (3) The person conducting the study, subject to section 505(j) of the act if it including any contract research orga- finds there is well-documented evi- nization, must notify FDA and all par- dence that specific pharmaceutical ticipating investigators of any serious equivalents or pharmaceutical alter- adverse event, as defined in § 312.32(a), natives intended to be used inter- observed during the conduct of the changeably for the same therapeutic study as soon as possible but in no case effect: later than 15 calendar days after be- (1) Are not bioequivalent drug prod- coming aware of its occurrence. Each ucts; or report must be submitted on FDA (2) May not be bioequivalent drug Form 3500A or in an electronic format products based on the criteria set forth that FDA can process, review, and ar- in § 320.33; or chive. FDA will periodically issue guid- (3) May not be bioequivalent drug ance on how to provide the electronic products because they are members of

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a class of drug products that have close (d) Competent medical determination structural similarity and similar phys- that a lack of bioequivalence would icochemical or pharmacokinetic prop- have a serious adverse effect in the erties to other drug products in the treatment or prevention of a serious same class that FDA finds are not bio- disease or condition. equivalent drug products. (e) Physicochemical evidence that: (b) FDA shall include in a proposed (1) The active drug ingredient has a rule to establish a bioequivalence re- low solubility in water, e.g., less than 5 quirement the evidence and criteria set milligrams per 1 milliliter, or, if dis- forth in § 320.33 that are to be consid- solution in the stomach is critical to ered in determining whether to issue absorption, the volume of gastric fluids the proposal. If the rulemaking is pro- required to dissolve the recommended posed in response to a petition, FDA dose far exceeds the volume of fluids shall include in the proposal a sum- present in the stomach (taken to be 100 mary and analysis of the relevant in- milliliters for adults and prorated for formation that was submitted in the infants and children). petition as well as other available in- (2) The dissolution rate of one or formation to support the establishment more such products is slow, e.g., less of a bioequivalence requirement. than 50 percent in 30 minutes when (c) FDA, on its own initiative or in tested using either a general method response to a petition by an interested specified in an official compendium or person, may propose and promulgate a paddle method at 50 revolutions per 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 dif- (1) The active drug ingredient, thera- ference in median lethal dose (LD50) peutic moiety, or its precursor is ab- and median effective dose (ED50) val- sorbed in large part in a particular seg- ues, or have less than a 2-fold dif- ment of the gastrointestinal tract or is ference in the minimum toxic con- absorbed from a localized site. centrations and minimum effective (2) The degree of absorption of the ac- concentrations in the blood, and safe tive drug ingredient, therapeutic moi- and effective use of the drug products ety, or its precursor is poor, e.g., less requires careful dosage titration and than 50 percent, ordinarily in compari- patient monitoring. son to an intravenous dose, even when

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it is administered in pure form, e.g., in § 320.35 Requirements for in vitro test- solution. ing of each batch. (3) There is rapid metabolism of the If a bioequivalence requirement therapeutic moiety in the intestinal specifies a currently available in vitro wall or liver during the process of ab- test or an in vitro bioequivalence sorption (first-class metabolism) so the standard comparing the drug product therapeutic effect and/or toxicity of to a reference standard, the manufac- such drug product is determined by the turer shall conduct the test on a sam- rate as well as the degree of absorp- ple of each batch of the drug product to tion. assure batch-to-batch uniformity. (4) The therapeutic moiety is rapidly metabolized or excreted so that rapid [42 FR 1635, Jan. 7, 1977. Redesignated at 57 dissolution and absorption are required FR 18001, Apr. 28, 1992] for effectiveness. (5) The active drug ingredient or § 320.36 Requirements for mainte- therapeutic moiety is unstable in spe- nance of records of bioequivalence cific portions of the gastrointestinal testing. tract and requires special coatings or (a) All records of in vivo or in vitro formulations, e.g., buffers, enteric tests conducted on any marketed batch coatings, and film coatings, to assure of a drug product to assure that the adequate absorption. product meets a bioequivalence re- (6) The drug product is subject to quirement shall be maintained by the dose dependent kinetics in or near the manufacturer for at least 2 years after therapeutic range, and the rate and ex- the expiration date of the batch and tent of absorption are important to submitted to the Food and Drug Ad- bioequivalence. ministration on request. [42 FR 1635, Jan. 7, 1977. Redesignated and (b) Any person who contracts with amended at 57 FR 18001, Apr. 28, 1992] 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 [42 FR 1635, Jan. 7, 1977. Redesignated at 57 and Drug Administration and found to 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

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under section 505 of the Federal Food, (d) Each reserve sample shall be ade- Drug, and Cosmetic Act, or, if bio- quately identified so that the reserve availability testing was performed sample can be positively identified as under contract, the contract research having come from the same sample as organization shall retain an appro- used in the specific bioavailability priately identified reserve sample of study. the drug product for which the appli- (e) Each reserve sample shall be cant is seeking approval (test article) stored under conditions consistent and of the reference standard used to with product labeling and in an area perform an in vivo bioavailability segregated from the area where testing study in accordance with and for the is conducted and with access limited to studies described in paragraph (b) of authorized personnel. Each reserve this section that is representative of sample shall be retained for a period of each sample of the test article and ref- at least 5 years following the date on erence standard provided by the appli- which the application or supplemental cant for the testing. application is approved, or, if such ap- (b) Reserve samples shall be retained plication or supplemental application for the following test articles and ref- is not approved, at least 5 years fol- erence standards and for the studies de- lowing the date of completion of the scribed: bioavailability study in which the sam- (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 sample or remaining sample for the 5- bioequivalence study comparing the year period specified in paragraph (e) test article to the formulation(s) (ref- of this section. erence standard) used in the clinical (g) Upon release of the reserve sam- studies. ples to FDA, the applicant or contract (3) For a new formulation, new dos- research organization shall provide a age form, or a new salt or ester of an written assurance that, to the best active drug ingredient or therapeutic knowledge and belief of the individual moiety that has been approved for mar- executing the assurance, the reserve keting, a reserve sample of the test ar- samples came from the same samples ticle and of the reference standard used as used in the specific bioavailability to conduct an in vivo bioequivalence or bioequivalence study identified by study comparing the test article to a the agency. The assurance shall be exe- marketed product (reference standard) cuted by an individual authorized to that contains the same active drug in- act for the applicant or contract re- gredient or therapeutic moiety. search organization in releasing the re- (c) Each reserve sample shall consist serve samples to FDA. of a sufficient quantity to permit FDA (h) A contract research organization to perform five times all of the release may contract with an appropriate, tests required in the application or independent third party to provide supplemental application. storage of reserve samples provided

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that the sponsor of the study has been Subpart C—Labeling notified in writing of the name and ad- 328.50 Principal display panel of all OTC dress of the facility at which the re- drug products intended for oral ingestion serve samples will be stored. that contain alcohol. (i) If a contract research organization AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, conducting a bioavailability or bio- 701 of the Federal Food, Drug, and Cosmetic equivalence study that requires reserve Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371). sample retention under this section or § 320.63 goes out of business, it shall SOURCE: 60 FR 13595, Mar. 13, 1995, unless otherwise noted. transfer its reserve samples to an appropriate, independent third party, and EDITORIAL NOTE: Nomenclature changes to shall notify in writing the sponsor of part 328 appear at 69 FR 13717, Mar. 24, 2004. the study of the transfer and provide the study sponsor with the name and Subpart A—General Provisions address of the facility to which the re- § 328.1 Scope. serve samples have been transferred. Reference in this part to regulatory [58 FR 25927, Apr. 28, 1993, as amended at 64 sections of the Code of Federal Regula- FR 402, Jan. 5, 1999] tions are to chapter I of title 21 unless otherwise noted. § 320.63 Retention of bioequivalence samples. § 328.3 Definitions. The applicant of an abbreviated ap- As used in this part: plication or a supplemental application (a) Alcohol means the substance submitted under section 505 of the Fed- known as ethanol, ethyl alcohol, or Al- eral Food, Drug, and Cosmetic Act, or, cohol, USP. if bioequivalence testing was per- (b) Inactive ingredient means any com- formed under contract, the contract re- ponent of a product other than an ac- search organization shall retain re- tive ingredient as defined in § 210.3(b)(7) serve samples of any test article and of this chapter. 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 of age and over, the amount of alcohol DRUG PRODUCTS INTENDED FOR 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 of age, the amount of alcohol in the Sec. product shall not exceed 5 percent. 328.1 Scope. (d) For any OTC drug product in- 328.3 Definitions. tended for oral ingestion and labeled Subpart B—Ingredients for use by children under 6 years of age, the amount of alcohol in the prod- 328.10 Alcohol. uct shall not exceed 0.5 percent.

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(e) The Food and Drug Administra- percentage of alcohol present in the tion will grant an exemption from product shall also appear on the imme- paragraphs (b), (c), and (d) of this sec- diate container label; it may appear tion where appropriate, upon petition anywhere on that label in accord with under the provisions of § 10.30 of this section 502(e) of the Federal Food, chapter. Appropriate cause, such as a Drug, and Cosmetic Act. specific solubility or manufacturing (d) The statement expressing the problem, must be adequately docu- amount (percentage) of alcohol present mented in the petition. Decisions with in the product shall be in a size reason- respect to requests for exemption shall ably related to the most prominent be maintained in a permanent file for printed matter on the panel or label on public review by the Division of Dock- which it appears, and shall be in lines ets Management (HFA–305), Food and generally parallel to the base on which Drug Administration, 5630 Fishers the package rests as it is designed to be Lane, rm. 1061, Rockville, MD 20852. displayed. (f) Ipecac syrup is exempt from the (e) For a product to state in its label- provisions of paragraph (d) of this sec- ing that it is ‘‘alcohol free,’’ it must tion. contain no alcohol (0 percent). (g) The following drugs are temporarily exempt from the provisions of (f) For any OTC drug product in- paragraphs (b), (c), and (d) of this sec- tended for oral ingestion containing tion: over 5 percent alcohol and labeled for (1) Aromatic Cascara Fluidextract. use by adults and children 12 years of (2) Cascara Sagrada Fluidextract. age and over, the labeling shall contain (3) Orally ingested homeopathic drug the following statement in the direc- products. tions section: ‘‘Consult a physician for use in children under 12 years of age.’’ [60 FR 13595, Mar. 13, 1995, as amended at 61 (g) For any OTC drug product in- FR 58630, Nov. 18, 1996; 68 FR 24879, May 9, 2003] tended for oral ingestion containing 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 § 328.50 Principal display panel of all following statement in the directions OTC drug products intended for section: ‘‘Consult a physician for use in oral ingestion that contain alcohol. children under 6 years of age.’’ (a) The amount (percentage) of alco- (h) When the direction regarding age hol present in a product shall be stated in paragraph (e) or (f) of this section in terms of percent volume of absolute differs from an age-limiting direction alcohol at 60 °F (15.56 °C) in accordance contained in any OTC drug monograph with § 201.10(d)(2) of this chapter. in this chapter, the direction con- (b) A statement expressing the taining the more stringent age limita- amount (percentage) of alcohol present tion shall be used. in a product shall appear prominently and conspicuously on the ‘‘principal PART 330—OVER-THE-COUNTER display panel,’’ as defined in § 201.60 of (OTC) HUMAN DRUGS WHICH this chapter. For products whose prin- ARE GENERALLY RECOGNIZED cipal display panel is on the immediate container label and that are not mar- AS SAFE AND EFFECTIVE AND keted in another retail package (e.g., NOT MISBRANDED an outer box), the statement of the percentage of alcohol present in the prod- Subpart A—General Provisions uct shall appear prominently and con- Sec. spicuously on the ‘‘principal display 330.1 General conditions for general rec- panel’’ of the immediate container ognition as safe, effective and not mis- label. branded. (c) For products whose principal dis- 330.2 Pregnancy-nursing warning. play panel is on the retail package and 330.3 Imprinting of solid oral dosage form the retail package is not the imme- drug products. diate container, the statement of the 330.5 Drug categories.

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Subpart B—Administrative Procedures quirements in § 201.66 of this chapter. An OTC drug product that is not in 330.10 Procedures for classifying OTC drugs compliance with chapter V and sub- as generally recognized as safe and effective and not misbranded, and for estab- chapter C, including § 201.66 of this lishing monographs. chapter, is subject to regulatory ac- 330.11 NDA deviations from applicable tion. For purposes of § 201.61(b) of this monograph. chapter, the statement of identity of 330.12 Status of over-the-counter (OTC) the product shall be the term or phrase drugs previously reviewed under the used in the applicable OTC drug mono- Drug Efficacy Study (DESI). 330.13 Conditions for marketing ingredients graph established in this part. recommended for over-the-counter (OTC) (2) The ‘‘Uses’’ section of the label use under the OTC drug review. and labeling of the product shall con- 330.14 Additional criteria and procedures for tain the labeling describing the ‘‘Indi- classifying OTC drugs as generally recog- cations’’ that have been established in nized as safe and effective and not mis- an applicable OTC drug monograph or branded. alternative truthful and nonmisleading AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, statements describing only those indi- 360, 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 Food, Drug, and Cosmetic Act (the act) type]. The labeling of drugs shall also and subchapter C et seq. of this chapter, state as follows: For drugs used by oral including the format and content re- administration, ‘‘In case of overdose,

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get medical help or contact a Poison (14) ‘‘Clean’’ or ‘‘cleanse’’. Control Center right away’’; for drugs (15) ‘‘Consulting’’ or ‘‘advising’’. used topically, rectally, or vaginally (16) ‘‘Continue(s)’’ or ‘‘persist(s)’’ or and not intended for oral ingestion, ‘‘If ‘‘is persistent’’ or ‘‘do(es) not go away’’ swallowed, get medical help or contact or ‘‘last(s)’’. a Poison Control Center right away’’; (17) ‘‘Daily’’ or ‘‘every day’’. and for drugs used topically and in- (18) ‘‘Develop(s)’’ or ‘‘begin(s)’’ or tended for oral use, ‘‘If more than used ‘‘occur(s)’’. for’’ (insert intended use, e.g., pain) ‘‘is (19) ‘‘Difficulty’’ or ‘‘trouble’’. accidentally swallowed, get medical (20) ‘‘Difficulty in urination’’ or help or contact a Poison Control Cen- ‘‘trouble urinating’’. ter right away.’’ The Food and Drug (21) ‘‘Discard’’ or ‘‘throw away’’. Administration will grant an exemp- (22) ‘‘Discontinue’’ or ‘‘stop’’ or tion from these general warnings where ‘‘quit’’. appropriate upon petition, which shall (23) ‘‘Doctor’’ or ‘‘physician’’. be maintained in a permanent file for (24) ‘‘Drowsiness’’ or ‘‘the drowsiness public review by the Division of Dock- effect’’. ets Management, Food and Drug Ad- (25) ‘‘Drowsiness may occur’’ or ‘‘you ministration, 5630 Fishers Lane, rm. may get drowsy’’. 1061, Rockville, MD 20852. (26) ‘‘Enlargement of the’’ or ‘‘an en- (h) Where no maximum daily dosage larged’’. limit for an active ingredient is estab- (27) ‘‘Especially in children’’ or espe- lished in this part, it is used in a prod- cially children’’. uct at a level that does not exceed the (28) ‘‘Exceed’’ or ‘‘use more than’’ or amount reasonably required to achieve ‘‘go beyond’’. its intended effect. (29) ‘‘Exceed recommended dosage’’ (i) The following terms may be used or ‘‘use more than directed’’. interchangeably in the labeling of OTC (30) ‘‘Excessive’’ or ‘‘too much’’. drug products, provided such use does (31) ‘‘Excitability may occur’’ or not alter the meaning of the labeling ‘‘you may get excited’’. that has been established and identi- (32) ‘‘Experience’’ or ‘‘feel’’. fied in an applicable monograph or by (33) ‘‘For relief of’’ or ‘‘relieves’’. regulation. The following terms shall (34) ‘‘For temporary reduction of’’ or not be used to change in any way the ‘‘temporarily reduces’’. title, headings, and subheadings re- (35) ‘‘For the temporary relief of’’ or quired under § 201.66(c)(1) through (c)(9) ‘‘temporarily relieves’’. of this chapter: (36) ‘‘For the treatment of’’ or (1) ‘‘Abdominal’’ or ‘‘stomach’’ (in ‘‘treats’’. context only). (37) ‘‘Frequently’’ or ‘‘often’’. (2) ‘‘Administer’’ or ‘‘give’’. (38) ‘‘Give to’’ or ‘‘use in’’. (3) ‘‘Aggravate(s)’’ or ‘‘make(s) (39) ‘‘Immediately’’ or ‘‘right away’’ worse’’. 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’’. (12) ‘‘Before a doctor is consulted’’ or (49) ‘‘Is (are) accompanied by’’ or ‘‘without first consulting your doctor’’ ‘‘you also have’’ (in context only) or or ‘‘consult your doctor before’’. ‘‘(optional: that) occur(s) with’’. (13) ‘‘Beverages’’ or ‘‘drinks’’. (50) ‘‘Longer’’ or ‘‘more’’.

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(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’’. ‘‘right away’’. (18) ‘‘This product’’. (63) ‘‘Reduce’’ or ‘‘minimize’’. (19) ‘‘Unless directed by a doctor’’. (64) ‘‘Referred to as’’ or ‘‘of’’. (20) ‘‘While taking this product’’ or (65) ‘‘Sensation’’ or ‘‘feeling’’. ‘‘before taking this product’’. (66) ‘‘Solution’’ or ‘‘liquid’’. (21) ‘‘Within’’. (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 back’’. 16266, May 1, 1986; 55 FR 11581, Mar. 29, 1990; 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’’). (76) ‘‘You also have’’ or ‘‘occurs A requirement to imprint an identi- with’’. fication code on solid oral dosage form (77) ‘‘When practical’’ or ‘‘if pos- drug products is set forth under part sible’’. 206 of this chapter. (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. shall not be used to change in any way (c) Antidiarrheal products. the specific title, headings, and sub- (d) Emetics. headings required under § 201.66(c)(1) (e) Antiemetics. through (c)(9) of this chapter: (f) Antiperspirants.

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(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 mis- tent that the person submitting it branded, and for establishing mono- demonstrates that it still falls within graphs. 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 la- I. Label(s) and all labeling (preferably beling, and to advise him on the pro- 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. III. Animal safety data. sory review panel shall be established A. Individual active components. for each designated category of OTC 1. Controlled studies. drugs and every OTC drug category 2. Partially controlled or uncontrolled will be considered by a panel. The studies. members of a panel shall be qualified B. Combinations of the individual active experts (appointed by the Commis- components. sioner) and may include persons from 1. Controlled studies.

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2. Partially controlled or uncontrolled C. Finished drug product. studies. 1. Controlled studies. C. Finished drug product. 2. Partially controlled or uncontrolled 1. Controlled studies. studies. 2. Partially controlled or uncontrolled 3. Documented case reports. Identify ex- studies. pected or frequently reported side effects. IV. Human safety data. 4. Pertinent marketing experiences that A. Individual active components. may influence a determination on the effi- 1. Controlled studies. cacy of the finished drug product. 2. Partially controlled or uncontrolled 5. Pertinent medical and scientific lit- studies. erature. 3. Documented case reports. Identify ex- 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 studies. its conclusions and recommendations 3. Documented case reports. Identify ex- to the Commissioner with respect to pected 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. B. Combinations of the individual active oral views to the panel; such request components. may be granted or denied by the panel. 1. Controlled studies. Such requests for oral presentations 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 4. Pertinent marketing experiences that views which shall be considered by the may influence a determination on the efficacy of combinations of the individual active panel. This information shall be pre- components. sented to the panel in the format set 5. Pertinent medical and scientific lit- forth in paragraph (a)(2) of this section erature. and within the time period established

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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 be based upon published studies which verse reactions in such terms as to may be corroborated by unpublished render them likely to be read and un- studies and other data. derstood by the ordinary individual, in- (ii) Effectiveness means a reasonable cluding individuals of low comprehen- expectation that, in a significant pro- sion, under customary conditions of portion of the target population, the purchase and use. pharmacological effect of the drug, (vi) A drug shall be permitted for when used under adequate directions OTC sale and use by the laity unless, for use and warnings against unsafe because of its toxicity or other poten- use, will provide clinically significant tial for harmful effect or because of the relief of the type claimed. Proof of ef- method or collateral measures nec- fectiveness shall consist of controlled essary to its use, it may safely be sold clinical investigations as defined in and used only under the supervision of § 314.126(b) of this chapter, unless this a practitioner licensed by law to ad- requirement is waived on the basis of a minister such drugs. showing that it is not reasonably appli- (5) Advisory review panel report to the cable to the drug or essential to the va- Commissioner. An advisory review panel lidity of the investigation and that an may submit to the Commissioner a re- alternative method of investigation is port containing its conclusions and adequate to substantiate effectiveness. recommendations with respect to the Investigations may be corroborated by conditions under which OTC drugs fall- partially controlled or uncontrolled ing within the category covered by the studies, documented clinical studies by panel are generally recognized as safe qualified experts, and reports of signifi- and effective and not misbranded. In- cant human experience during mar- cluded within this report shall be: keting. Isolated case reports, random (i) A recommended monograph or experience, and reports lacking the de- monographs covering the category of tails which permit scientific evalua- OTC drugs and establishing conditions tion will not be considered. General under which the drugs involved are

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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 at the office of the Division of Dockets and excluded from the monograph on Management between the hours of 9 the basis of the panel’s determination a.m. and 4 p.m., Monday through Fri- that the available data are insufficient day. Within 30 days after the final day to classify such condition under either for submission of comments, reply paragraph (a)(5) (i) or (ii) of this sec- comments may be filed with the Divi- tion and for which further testing is sion of Dockets Management; these therefore required (Category III). The comments shall be utilized to reply to report may recommend the type of fur- comments made by other interested ther testing required and the time pe- persons and not to reiterate a position. riod within which it might reasonably The Commissioner may satisfy this re- be concluded. quirement by publishing in the FED- (6) Proposed monograph. After review- ERAL REGISTER a proposed order sum- ing the conclusions and recommenda- marizing the full report of the advisory tions of the advisory review panel, the review panel, containing its conclu- Commissioner shall publish in the FED- sions and recommendations, to obtain ERAL REGISTER a proposed order con- full public comment before under- taining: taking his own evaluation and decision (i) A monograph or monographs es- on the matters involved. tablishing conditions under which a (7) Tentative final monograph. (i) After category of OTC drugs or a specific or reviewing all comments, reply com- specific OTC drugs are generally recog- ments, and any new data and informa- nized as safe and effective and not mis- tion or, alternatively, after reviewing a branded (Category I). panel’s recommendations, the Commis- (ii) A statement of the conditions ex- sioner shall publish in the FEDERAL cluded from the monograph on the REGISTER a tentative order containing basis of the Commissioner’s determina- a monograph establishing conditions tion that they would result in the under which a category of OTC drugs drug’s not being generally recognized or specific OTC drugs are generally rec- as safe and effective or would result in ognized as safe and effective and not misbranding (Category II). misbranded. Within 90 days, any inter- (iii) A statement of the conditions ested person may file with the Division excluded from the monograph on the of Dockets Management, Food and basis of the Commissioner’s determina- Drug Administration, written com- tion that the available data are insuffi- ments or written objections specifying cient to classify such conditions under with particularity the omissions or ad- either paragraph (a)(6)(i) or (ii) of this ditions requested. These objections are section (Category III). to be supported by a brief statement of

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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 data and information were received by (9) Final monograph. After reviewing the Food and Drug Administration the objections, the entire administra- under paragraph (a)(6)(iv) of this sec- tive record including all new data and tion or when the Commissioner has information and comments, and consid- evaluated and concurs with a panel’s ering the arguments made at any oral recommendation that a condition be hearing, the Commissioner shall pub- excluded from the monograph. Within lish in the FEDERAL REGISTER a final 90 days, any interested person may file order containing a monograph estab- with the Division of Dockets Manage- lishing conditions under which a cat- ment, Food and Drug Administration, egory of OTC drugs or a specific or spe- written objections specifying with par- cific OTC drugs are generally recog- ticularity the provision of the ten- nized as safe and effective and not mis- tative order to which objection is branded. The monograph shall become made. These objections are to be sup- effective as specified in the order. ported by a brief statement of the (10) Administrative record. (i) All data grounds therefor. A request for an oral and information to be considered in hearing may accompany such objec- any proceeding pursuant to this sections. tion shall be submitted in response to (iii) Within 12 months after pub- the request for data and views pursu- lishing a tentative order pursuant to ant to paragraph (a)(2) of this section, paragraph (a)(7)(i) of this section, any in response to any other notice pub- interested person may file with the Di- lished in the FEDERAL REGISTER, or ac- vision of Dockets Management, Food cepted by the panel during its delibera- and Drug Administration, new data tions pursuant to paragraph (a)(3) of and information to support a condition this section or submitted to the Divi- excluded from the monograph in the sion of Dockets Management as part of tentative order. the comments during the 90-day period (iv) Within 60 days after the final day for submission of new data and infor- and 30-day rebuttal comment period mation, comments on the new data and permitted pursuant to paragraph (a)(6) information may be filed with the Divi- of this section or submitted to the Di- sion of Dockets Management, Food and vision of Dockets Management during Drug Administration. the 12-month period or as part of the (v) New data and information sub- comments during the 60-day period permitted after the time specified in this mitted pursuant to paragraph (a)(7) of paragraph but prior to the establish- this section. ment of a final monograph will be con- (ii) The Commissioner shall make all sidered as a petition to amend the decisions and issue all orders pursuant monograph and will be considered by to this section solely on the basis of the Commissioner only after a final the administrative record, and shall monograph has been published in the not consider data or information not FEDERAL REGISTER unless the included as part of the administrative Commisisoner finds that good cause record.

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(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 adminis- the drug product with the condition trative record as part of the basis for that is the subject of the new drug ap- the Commissioner’s decision. plication has not been marketed on an (11) Court appeal. The monograph interim basis (such as under the provi- contained in the final order constitutes sions of paragraph (a)(6)(iii) of this sec- final agency action from which appeal tion), all clinical testing has been con- lies to the courts. The Food and Drug ducted pursuant to a new drug applica- Administration will request consolidation plan, and no marketing of the tion of all appeals in a single court. product with the condition for which Upon court appeal, the Commissioner approval is sought is undertaken prior may, at his discretion, stay the effec- to approval of the new drug applica- tive date for part or all of the mono- tion. The Food and Drug Administra- graph pending appeal and final court tion shall handle a new drug applica- adjudication. tion as a petition for amendment of a (12) Amendment of monographs. (i) The monograph, and shall review it on that Commissioner may propose on the basis, if the provisions of this para- Commissioner’s own initiative to graph preclude approval of a new drug amend or repeal any monograph estab- application but permit the granting of lished pursuant to this section. Any in- such a petition. terested person may petition the Com- (b) Regulatory action. Any product missioner for such proposal pursuant which fails to conform to an applicable to § 10.30 of this chapter. The Commis- monograph after its effective date is sioner may deny the petition if the liable to regulatory action. Commissioner finds a lack of safety or (c) Information and data submitted effectiveness employing the standards under this section shall include, with in paragraph (a)(4) of this section (in respect to each nonclinical laboratory which case the appeal provisions of study contained in the application, ei- paragraph (a)(11) of this section shall ther a statement that the study was apply), or the Commissioner may pub- conducted in compliance with the good lish a proposed amendment or repeal in laboratory practice regulations set

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forth in part 58 of this chapter, or, if review of drugs introduced to the mar- the study was not conducted in compli- ket through new drug procedures be- ance with such regulations, a brief tween 1938 and 1962). A careful review statement of the reason for the non- has been made of the reports on these compliance. drugs to determine those drugs for (d) [Reserved] which implementation may be deferred (e) Institutional review and informed without significant risk to the public consent. Information and data sub- health, pending review by appropriate mitted under this section after July 27, OTC drug advisory review panels and 1981, shall include statements regard- promulgation of a monograph. ing each clinical investigation involv- (b) On and after April 20, 1972, a num- ing human subjects, from which the in- ber of notices were published in the formation and data are derived, that it FEDERAL REGISTER concerning pre- either was conducted in compliance viously unpublished OTC drugs re- with the requirements for institutional viewed by the National Academy of review set forth in part 56 of this chap- Sciences-National Research Council ter, or was not subject to such require- Drug Efficacy Study Group. Only the ments in accordance with §§ 56.104 or evaluations and comments of the pan- 56.105, and that it was conducted in els were published, with no conclusions compliance with the requirements for of the Commissioner of Food and informed consent set forth in part 50 of Drugs. Those publications were for the this chapter. purpose of giving interested persons (f) Financial certification or disclosure the benefit of the Academy’s opinions. statement. Any clinical data submitted For those products, and also for OTC under this section must be accom- drug products previously published panied by financial certifications or with the Commissioner’s conclusions disclosure statements or both as re- (except for the products listed in para- quired by part 54 of this chapter. graphs (b) (1) and (2) of this section, all requests for data, revised labeling, re- [39 FR 11741, Mar. 29, 1974, as amended at 39 quests for new drug applications, ab- FR 39556, Nov. 8, 1974; 42 FR 19141, Apr. 12, 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, breviated new drug applications, updat- 8955, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; ing supplements, data to support less 46 FR 21360, Apr. 10, 1981; 46 FR 47738, Sept. than effective claims, if any, etc., are 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, deferred, and such OTC drug products Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR are instead subject to the OTC drug re- 3073, Jan. 23, 2002] view in their appropriate classes pursuant to the procedures established in § 330.11 NDA deviations from applica- this subpart. ble monograph. (1) The requirements of the following A new drug application requesting DESI announcements are not deferred approval of an OTC drug deviating in (the reference document may also per- any respect from a monograph that has tain to prescription drugs): become final shall be in the form re- (i) Certain Surgical Sutures (DESI quired by § 314.50 of this chapter, but 4725), published in the FEDERAL REG- shall include a statement that the ISTER of November 11, 1971 (36 FR product meets all conditions of the ap- 21612). plicable monograph except for the devi- (ii) Absorbable Dusting Powder ation for which approval is requested (DESI 6264), published in the FEDERAL and may omit all information except REGISTER of May 25, 1971 (36 FR 9475). that pertinent to the deviation. (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). (iv) Sulfo-Van Ointment (DESI 2230), § 330.12 Status of over-the-counter published in the FEDERAL REGISTER of (OTC) drugs previously reviewed October 8, 1970 (35 FR 15860). under the Drug Efficacy Study (v) Antiperspirants and Deodorants (DESI). Containing Neomycin Sulfate (DESI (a) There were 420 OTC drugs re- 11048) for which an order revoking pro- viewed in the Drug Efficacy Study (a visions for certification or release was

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published in the FEDERAL REGISTER of (b) Zirnox Topical Lotion, containing December 5, 1972 (37 FR 25820) and has phenyitoloxamine citrate and zir- been stayed by the filing of objections. conium oxide. (vi) Thorexin Cough Medicine (DESI (iv) Menacyl Tablets, containing as- 11160) for which a notice of opportunity pirin, menadione, and ascorbic acid for hearing was published in the FED- (DESI 6363), for which notice of with- ERAL REGISTER of February 2, 1973 (38 drawal of approval of the new drug ap- FR 3210). plication was published in the FEDERAL (vii) Antibiotic susceptibility discs REGISTER of July 23, 1970 (35 FR 11827). (DESI 90235) for which an order pro- (v) Curad Medicated Adhesive Ban- dage containing sulfathiazole (DESI viding for certain discs to be certified 4964), for which notice of withdrawal of and removing provisions for certifi- approval of the new drug application cation of other discs was published in was published in the FEDERAL REG- the FEDERAL REGISTER of September ISTER of December 31, 1969 (34 FR 20441). 30, 1972 (37 FR 20525) and has been (vi) Drugs Containing Rutin, Quer- stayed by the filing of objections no- cetin, Hesperidin, or any Bioflavonoids tice of which was published in the FED- (DESI 5960), for which notice of with- ERAL REGISTER of March 15, 1973 (38 FR drawal of approval of new drug applica- 7007). tions was published in the FEDERAL (2) Deferral of requirements is not ap- REGISTER of July 3, 1970 (35 FR 10872, propriate when an announcement has 10873) and October 17, 1970 (35 FR 16332). been published and has been followed A further notice of opportunity for by a final order classifying a drug ei- hearing with respect to the drugs cov- ther as lacking substantial evidence of ered by the October 17, 1970 FEDERAL effectiveness or as not shown to be REGISTER notice will be published at a safe. These products will be removed later date. from the market, if they have not al- (vii) Antibiotics in Combination with ready been removed. Regulatory action Other Drugs for Nasal Use (DESI 7561), will also be undertaken against iden- for which an order revoking provision tical, similar and related products (21 for certification was published in the CFR 310.6). Deferral of requirements is FEDERAL REGISTER of August 6, 1971 (36 not appropriate for the following (the FR 14469) and confirmed in the FED- referenced document may also pertain ERAL REGISTER of October 28, 1971 (36 to prescription drugs): FR 20686). (i) Certain Sulfonamide-Deconges- (viii) Antibiotic Troches (DESI 8328), tant Nasal Preparation (DESI 4850), for for which an order revoking provision which notice of withdrawal of approval for certification was published in the of new drug applications was published FEDERAL REGISTER of July 14, 1971 (36 FR 13089) and confirmed in the FED- in the FEDERAL REGISTER of October 24, 1970 (35 FR 16605, 16606). ERAL REGISTER of October 9, 1971 (36 FR 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 published in the FEDERAL REGISTER of 5294), and confirmed in the FEDERAL August 28, 1971 (36 FR 17368): REGISTER of July 6, 1972 (37 FR 13254). (a) Rhulitol Solution, containing tan- (xi) Candette Cough Gel (DESI 11562), nic acid, chlorobutanol, phenol, cam- for which notice of withdrawal of ap- phor, alum, and isopropyl alcohol. proval of the new drug application was

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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 changes, the Food and Drug Adminis- the meaning of section 201(p) of the act tration will not take legal action for which an approved new drug appli- against any OTC drug, other than those cation is required. not deferred, based on a charge that (b)(1) An OTC drug product that con- the product is a new drug and not tains: (i) An active ingredient limited,

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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 recommendation and may instead adopt a (2) An active ingredient at a dosage different position that may require re- level higher than that available in any labeling, recall, or other regulatory ac- OTC drug product on December 4, 1975, tion. The Commissioner may state which ingredient and/or dosage level is such position at any time by notice in classified by the panel in category III (conditions subject to § 330.10(a)(6)(iii)), the FEDERAL REGISTER, either separately or as part of another document; may be marketed only after: appropriate regulatory action will (i) The Center for Drug Evaluation commence immediately and will not and Research or the Commissioner ten- await publication of a final monograph. tatively determines that the ingredient Marketing of such a product with a for- is generally recognized as safe and ef- mulation or labeling not in accord with fective, and the Commissioner states a proposed monograph or tentative by notice in the FEDERAL REGISTER final monograph also may result in (separately or as part of another docu- regulatory action against the product, ment) that marketing under specified the marketer, or both. conditions will be permitted; (c) An OTC drug product that con- (ii) The ingredient is determined by tains: (1) An active ingredient limited, the Commissioner to be generally recon or after May 11, 1972, to prescription ognized as safe and effective and is in- use for the indication and route of ad- cluded in the appropriate published ministration under consideration by an OTC drug final monograph; or OTC advisory review panel, and not (iii) A new drug application for the thereafter exempted from such limita- product has been approved. tion pursuant to § 310.200 of this chap- (e) This section applies only to condi- ter, or tions under consideration as part of the (2) An active ingredient at a dosage OTC drug review initiated on May 11, level higher than that available in any 1972, and evaluated under the proce- OTC drug product on December 4, 1975, dures set forth in § 330.10. Section which ingredient and/or dosage level is 330.14(h) applies to the marketing of all classified by the panel in category II conditions under consideration and

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evaluated using the criteria and proce- in sufficient quantity, as determined in dures set forth in § 330.14. paragraphs (c)(2)(ii), (c)(2)(iii), and (c)(2)(iv) of this section. Depending on [41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 FR 8996, Mar. 6, the condition’s extent of marketing in 1985; 55 FR 11581, Mar. 29, 1990; 67 FR 3074, only one country with 5 continuous Jan. 23, 2002] years of marketing, marketing in more than one country may be necessary. § 330.14 Additional criteria and proce- (c) Time and extent application. Cer- dures for classifying OTC drugs as tain information must be provided generally recognized as safe and ef- when requesting that a condition sub- fective and not misbranded. ject to this section be considered for (a) Introduction. This section sets inclusion in the OTC drug monograph forth additional criteria and proce- system. The following information dures by which over the counter (OTC) must be provided in the format of a drugs initially marketed in the United time and extent application (TEA): States after the OTC drug review began (1) Basic information about the con- in 1972 and OTC drugs without any U.S. dition that includes a description of marketing experience can be consid- the active ingredient(s) or botanical ered in the OTC drug monograph sys- drug substance(s), pharmacologic tem. This section also addresses condi- class(es), intended OTC use(s), OTC tions regulated as a cosmetic or die- strength(s) and dosage form(s), route(s) tary supplement in a foreign country of administration, directions for use, that would be regulated as OTC drugs and the applicable existing OTC drug in the United States. For purposes of monograph(s) under which the condi- this section, ‘‘condition’’ means an action would be marketed or the request tive ingredient or botanical drug sub- and rationale for creation of a new OTC stance (or a combination of active in- drug monograph(s). gredients or botanical drug sub- (i) A detailed chemical description of stances), dosage form, dosage strength, the active ingredient(s) that includes a or route of administration, marketed full description of the drug substance, for a specific OTC use, except as ex- including its physical and chemical cluded in paragraph (b)(2) of this sec- characteristics, the method of syn- tion. For purposes of this part, ‘‘botan- thesis (or isolation) and purification of ical drug substance’’ means a drug sub- the drug substance, and any specifica- stance derived from one or more tions and analytical methods necessary plants, algae, or macroscopic fungi, but to ensure the identity, strength, qual- does not include a highly purified or ity, and purity of the drug substance. chemically modified substance derived (ii) For a botanical drug substance(s), from such a source. a detailed description of the botanical (b) Criteria. To be considered for in- ingredient (including proper identifica- clusion in the OTC drug monograph tion of the plant, plant part(s), alga, or system, the condition must meet the macroscopic fungus used; a certificate following criteria: of authenticity; and information on the (1) The condition must be marketed grower/supplier, growing conditions, for OTC purchase by consumers. If the harvest location and harvest time); a condition is marketed in another coun- qualitative description (including the try in a class of OTC drug products name, appearance, physical/chemical that may be sold only in a pharmacy, properties, chemical constituents, ac- with or without the personal involve- tive constituent(s) (if known), and bio- ment of a pharmacist, it must be estab- logical activity (if known)); a quan- lished that this marketing restriction titative description of the chemical does not indicate safety concerns about constituents, including the active con- the condition’s toxicity or other poten- stituent(s) or other chemical marker(s) tiality for harmful effect, the method (if known and measurable); the type of of its use, or the collateral measures manufacturing process (e.g., aqueous necessary to its use. extraction, pulverization); and infor- (2) The condition must have been mation on any further processing of marketed OTC for a minimum of 5 con- the botanical substance (e.g., addition tinuous years in the same country and of excipients or blending).

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(iii) Reference to the current edition tries based on the condition’s pack- of the U.S. Pharmacopeia (USP)–Na- aging and labeling, or changes in use tional Formulary (NF) or foreign com- pattern have occurred over time in one pendiums may help satisfy the require- or more countries, describe the use pat- ments in this section. tern for each country and explain why (2) A list of all countries in which the there are differences or changes. condition has been marketed. Include (v) A description of the country’s sys- the following information for each tem for identifying adverse drug expe- country. (For a condition that has been riences, especially those found in OTC marketed OTC in 5 or more countries marketing experience, including meth- with a minimum of 5 continuous years od of collection if applicable. of marketing in at least one country, (3) A statement of how long the con- the sponsor may submit information in dition has been marketed in each coun- accordance with paragraph (c)(4) of this try and how long the current product section): labeling has been in use, accompanied (i) How the condition has been mar- by a copy of the current product label- keted (e.g., OTC general sales direct- ing. All labeling that is not in English to-consumer; sold only in a pharmacy, must be translated to English in ac- with or without the personal involve- cordance with § 10.20(c)(2) of this chap- ment of a pharmacist; dietary supple- ter. State whether the current product ment; or cosmetic). If the condition has labeling has or has not been author- been marketed as a nonprescription ized, accepted, or approved by a regu- pharmacy-only product, establish that latory body in each country where the this marketing restriction does not in- condition is marketed. dicate safety concerns about its tox- (4) For a condition that has been icity or other potentiality for harmful marketed OTC in five or more coun- effect, the method of its use, or the col- tries with a minimum of 5 continuous lateral measures necessary to its use. years of marketing in at least one (ii) The cumulative total number of country, the sponsor may select at dosage units (e.g., tablets, capsules, least five of these countries from which ounces) sold for each dosage form of to submit information in accord with the condition. Manufacturers or sup- paragraphs (c)(2)(i) through (c)(2)(iv) of pliers of OTC active ingredients may this section. Selected countries must provide dosage unit information as the include the country with a minimum of total weight of active ingredient sold. 5 continuous years of OTC marketing, List the various package sizes for each countries that have the longest dura- dosage form in which the condition is tion of marketing, and countries hav- marketed OTC. Provide an estimate of ing the most support for extent of mar- the minimum number of potential con- keting, i.e., a large volume of sales sumer exposures to the condition using with cultural diversity among users of one of the following calculations: the product. If the condition meets (A) Divide the total number of dosage these criteria in countries listed in sec- units sold by the number of dosage tion 802(b)(1)(A) of the Federal Food, units in the largest package size mar- Drug, and Cosmetic Act, some of these keted, or countries should be included among the (B) Divide the total weight of the ac- five selected. Sponsors should provide tive ingredient sold by the total weight information from more than five coun- of the active ingredient in the largest tries if they believe that it is needed to package size marketed. support eligibility. Sponsors should ex- (iii) A description of the population plain the basis for the countries se- demographics (percentage of various lected in the TEA. racial/ethnic groups) and the source(s) (5) A list of all countries where the from which this information has been condition is marketed only as a pre- compiled, to ensure that the condi- scription drug and the reasons why its tion’s use(s) can be reasonably extrapo- marketing is restricted to prescription lated to the U.S. population. in these countries. (iv) If the use pattern (i.e., how often (6) A list of all countries in which the it is to be used (according to the label) condition has been withdrawn from and for how long) varies between coun- marketing or in which an application

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for OTC marketing approval has been tion for its intended OTC use(s). These denied. Include the reasons for such data shall be submitted to a docket es- withdrawal or application denial. tablished in the Division of Dockets (7) The information requested in Management and shall be publicly paragraphs (c)(2), (c)(2)(i) through available for viewing at that office, ex- (c)(2)(iv), and (c)(3) of this section must cept data deemed confidential under 18 be provided in a table format. The la- U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. beling required by paragraph (c)(3) of 331(j). Data considered confidential this section must be attached to the under these provisions must be clearly table. identified. Any proposed compendial (8) For OTC drugs that have been standards for the condition shall not be marketed for more than 5 years in the considered confidential. The safety and United States under a new drug appli- effectiveness submissions shall include cation, the information requested in the following: paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), (1) All data and information listed in (c)(3), and (c)(5) of this section need not § 330.10(a)(2) under the outline ‘‘OTC be provided. Drug Review Information,’’ items III (d) Submission of information; confiden- through VII. tiality. The sponsor must submit three (2) All serious adverse drug experi- copies of the TEA to the Central Docu- ences as defined in §§ 310.305 and 314.80 ment Room, 5630 Fishers Lane, rm. of this chapter, from each country 1061, Rockville, MD 20852. The Food and where the condition has been or is cur- Drug Administration will handle the rently marketed as a prescription drug TEA as confidential until such time as or as an OTC drug or product. Provide a decision is made on the eligibility of individual adverse drug experience re- the condition for consideration in the ports (FDA Form 3500A or equivalent) OTC drug monograph system. If the along with a summary of all serious ad- condition is found eligible, the TEA verse drug experiences and expected or will be placed on public display in the frequently reported side effects for the Division of Dockets Management after condition. Individual reports that are deletion of information deemed con- not in English must be translated to fidential under 18 U.S.C. 1905, 5 U.S.C. English in accordance with § 10.20(c)(2) 552(b), or 21 U.S.C. 331(j). Sponsors of this chapter. must identify information that is con- (g) Administrative procedures. The sidered confidential under these statu- agency may use an advisory review tory provisions. If the condition is not panel to evaluate the safety and effec- found eligible, the TEA will not be tiveness data in accord with the provi- placed on public display, but a letter sions of § 330.10(a)(3). Alternatively, the from the agency to the sponsor stating agency may evaluate the data in con- why the condition was not found ac- junction with the advisory review ceptable will be placed on public dis- panel or on its own without using an play in the Division of Dockets Man- advisory review panel. The agency will agement. use the safety, effectiveness, and label- (e) Notice of eligibility. If the condition ing standards in § 330.10(a)(4)(i) through is found eligible, the agency will pub- (a)(4)(vi) in evaluating the data. lish a notice of eligibility in the FED- (1) If the agency uses an advisory re- ERAL REGISTER and provide the sponsor view panel to evaluate the data, the and other interested parties an oppor- panel may submit its recommendations tunity to submit data to demonstrate in its official minutes of meeting(s) or safety and effectiveness. When the no- by a report under the provisions of tice of eligibility is published, the § 330.10(a)(5). agency will place the TEA on public (2) The agency may act on an advi- display in the Division of Dockets Man- sory review panel’s recommendations agement. using the procedures in §§ 330.10(a)(2) (f) Request for data and views. The no- and 330.10(a)(6) through (a)(10). tice of eligibility shall request inter- (3) If the condition is initially deter- ested persons to submit published and mined to be generally recognized as unpublished data to demonstrate the safe and effective for OTC use in the safety and effectiveness of the condi- United States, the agency will propose

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to include it in an appropriate OTC official USP-NF drug monograph that drug monograph(s), either by amending sets forth its standards of identity, an existing monograph(s) or estab- strength, quality, and purity. Sponsors lishing a new monograph(s), if nec- must include an official or proposed essary. compendial monograph as part of the (4) If the condition is initially deter- safety and effectiveness data submis- mined not to be generally recognized as sion listed in § 330.10(a)(2) under item safe and effective for OTC use in the VII of the outline entitled ‘‘OTC DRUG United States, the agency will inform REVIEW INFORMATION.’’ the sponsor and other interested par- [67 FR 3074, Jan. 23, 2002] ties who have submitted data of its determination by letter, a copy of which will be placed on public display in the PART 331—ANTACID PRODUCTS docket established in the Division of FOR OVER-THE-COUNTER (OTC) Dockets Management. The agency will HUMAN USE publish a notice of proposed rulemaking to include the condition in Subpart A—General Provisions § 310.502 of this chapter. Sec. (5) Interested parties will have an op- 331.1 Scope. portunity to submit comments and new data. The agency will subsequently Subpart B—Active Ingredients publish a final rule (or reproposal if necessary) in the FEDERAL REGISTER. 331.10 Antacid active ingredients. (h) Marketing. A condition submitted 331.11 Listing of specific active ingredients. under this section for consideration in 331.15 Combination with nonantacid active ingredients. the OTC drug monograph system may be marketed in accordance with an ap- Subpart C—Testing Procedures plicable final OTC drug monograph(s) only after the agency determines that 331.20 Determination of percent contribu- the condition is generally recognized as tion of active ingredients. safe and effective and includes it in the 331.21 Test Modifications. appropriate OTC drug final mono- Subpart D—Labeling graph(s), and the condition complies with paragraph (i) of this section. 331.30 Labeling of antacid products. When an OTC drug monograph has not 331.80 Professional labeling. been finalized and finalization is not AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, imminent, after the agency has evalu- 360, 371. ated the comments to a proposed rule SOURCE: 39 FR 19874, June 4, 1974, unless to include a new condition in a ten- otherwise noted. tative final monograph as generally recognized as safe and effective and the agency has not changed its position as Subpart A—General Provisions a result of the comments, and the con- § 331.1 Scope. dition complies with paragraph (i) of this section, the agency may publish a An over-the-counter antacid product notice of enforcement policy that al- in a form suitable for oral administra- lows marketing to begin pending com- tion is generally recognized as safe and pletion of the final monograph subject effective and is not misbranded if it to the risk that the agency may, prior meets each of the following conditions to or in the final monograph, adopt a and each of the general conditions es- different position that could require re- tablished in § 330.1 of this chapter. labeling, recall, or other regulatory action. Subpart B—Active Ingredients (i) Compendial monograph. Any active ingredient or botanical drug substance § 331.10 Antacid active ingredients. included in a final OTC drug mono- (a) The active antacid ingredients of graph or the subject of an enforcement the product consist of one or more of notice described in paragraph (h) of the ingredients permitted in § 331.11 this section must be recognized in an within any maximum daily dosage

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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 determine the percent contribution of (3) Magnesium aluminosilicates. each antacid active ingredient. (4) Magnesium carbonate. (b) This section does not apply to an (5) Magnesium glycinate. antacid ingredient specifically added as (6) Magnesium hydroxide. a corrective to prevent a laxative or (7) Magnesium oxide. constipating effect. (8) Magnesium trisilicate. [39 FR 19874, June 4, 1974, as amended at 61 (h) Milk solids, dried. FR 4822, Feb. 8, 1996] (i) Phosphate-containing active ingredients: § 331.11 Listing of specific active in- (1) Aluminum phosphate; maximum gredients. daily dosage limit 8 grams. (a) Aluminum-containing active in- (2) Mono or dibasic calcium salt; gredients: maximum daily dosage limit 2 grams. (1) Basic aluminum carbonate gel. (3) Tricalcium phosphate; maximum (2) Aluminum hydroxide (or as alu- daily dosage limit 24 grams. minum hydroxide-hexitol stabilized (j) Potassium-containing active in- polymer, aluminum hydroxide-magne- gredients: sium carbonate codried gel, aluminum hydroxide-magnesium trisilicate (1) Potassium bicarbonate (or car- codried gel, aluminum-hydroxide su- bonate when used as a component of an crose powder hydrated). effervescent preparation); maximum (3) Dihydroxyaluminum amino- daily dosage limit 200 mEq. of bicar- acetate and dihydroxyaluminum ami- bonate ion for persons up to 60 years noacetic acid. old and 100 mEq. of bicarbonate ion for (4) Aluminum phosphate gel when persons 60 years or older. used as part of an antacid combination (2) Sodium potassium tartrate. product and contributing at least 25 (k) Sodium-containing active ingre- percent of the total acid neutralizing dients: capacity; maximum daily dosage limit (1) Sodium bicarbonate (or carbonate is 8 grams. when used as a component of an effer- (5) Dihydroxyaluminum sodium car- vescent preparation); maximum daily bonate. dosage limit 200 mEq. of sodium for (b) Bicarbonate-containing active in- persons up to 60 years old and 100 mEq. gredients: Bicarbonate ion; maximum of sodium for persons 60 years or older, daily dosage limit 200 mEq. for persons and 200 mEq. of bicarbonate ion for per- up to 60 years old and 100 mEq. for persons up to 60 years old and 100 mEq. of sons 60 years or older. bicarbonate ion for persons 60 years or (c) Bismuth-containing active ingre- older. That part of the warning re- dients: quired by § 330.1(g), which states, ‘‘Keep (1) Bismuth aluminate. this and all drugs out of the reach of (2) Bismuth carbonate. children’’ is not required on a product (3) Bismuth subcarbonate. (4) Bismuth subgallate. which contains only sodium bicarbon- (5) Bismuth subnitrate. ate powder and which is intended pri- (d) Calcium-containing active ingre- marily for other than drug uses. dients: Calcium, as carbonate or phos- (2) Sodium potassium tartrate. phate; maximum daily dosage limit 160 (l) Silicates: mEq. calcium (e.g., 8 grams calcium (1) Magnesium aluminosilicates. carbonate). (2) Magnesium trisilicate.

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(m) Tartrate-containing active ingre- § 331.21 Test modifications. dients. Tartaric acid or its salts; max- The formulation or mode of adminis- imum daily dosage limit 200 mEq. (15 tration of certain products may require grams) of tartrate. a modification of the United States [39 FR 19874, June 4, 1974, as amended at 51 Pharmacopeia 23/National Formulary FR 27763, Aug. 1, 1986; 55 FR 19859, May 11, 18 acid neutralizing capacity test. Any 1990] proposed modification and the data to support it shall be submitted as a peti- § 331.15 Combination with nonantacid tion under the rules established in active ingredients. § 10.30 of this chapter. All information (a) An antacid may contain any gen- submitted will be subject to the disclo- erally recognized as safe and effective sure rules in part 20 of this chapter. nonantacid laxative ingredient to correct for constipation caused by the ant- [61 FR 4823, Feb. 8, 1996] acid. No labeling claim of the laxative effect may be used for such a product. Subpart D—Labeling (b) An antacid may contain any gen- § 331.30 Labeling of antacid products. erally recognized as safe and effective analgesic ingredient(s), if it is indi- (a) Statement of identity. The labeling cated for use solely for the concurrent of the product contains the established symptoms involved, e.g., headache and name of the drug, if any, and identifies acid indigestion, and is marketed in a the product as an ‘‘antacid.’’ form intended for ingestion as a solu- (b) Indications. The labeling of the tion. product states, under the heading ‘‘In- (c) An antacid may contain any gen- dications,’’ the following: ‘‘For the re- erally recognized as safe and effective lief of’’ (optional, any or all of the fol- antiflatulent ingredient if it is indi- lowing:) ‘‘heartburn,’’ ‘‘sour stomach,’’ cated for use solely for the concurrent and/or ‘‘acid indigestion’’ (which may symptoms of gas associated with heart- be followed by the optional statement:) burn, sour stomach or acid indigestion. ‘‘and upset stomach associated with’’ (optional, as appropriate) ‘‘this symp- Subpart C—Testing Procedures tom’’ or ‘‘these symptoms.’’ Other truthful and nonmisleading state- § 331.20 Determination of percent con- ments, describing only the indications tribution of active ingredients. for use that have been established and listed in this paragraph (b), may also To determine the percent contribu- be used, as provided in § 330.1(c)(2) of tion of an antacid active ingredient, this chapter, subject to the provisions place an accurately weighed amount of of section 502 of the act relating to the antacid active ingredient equal to misbranding and the prohibition in sec- the amount present in a unit dose of tion 301(d) of the act against the intro- the product into a 250-milliliter (mL) duction or delivery for introduction beaker. If wetting is desired, add not into interstate commerce of unap- more than 5 mL of alcohol (neutralized proved new drugs in violation of sec- to an apparent pH of 3.5), and mix to tion 505(a) of the act. wet the sample thoroughly. Add 70 mL (c) Warnings. The labeling of the of water, and mix on a magnetic stirrer product contains the following warn- at 300 ±30 r.p.m. for 1 minute. Analyze ings, under the heading ‘‘Warnings’’, the acid neutralizing capacity of the which may be combined but not rear- sample according to the procedure pro- ranged to eliminate duplicative words vided in the United States Pharma- or phrases if the resulting warning is copeia 23/National Formulary 18 and clear and understandable: calculate the percent contribution of (1) ‘‘Do not take more than (max- the antacid active ingredient in the imum recommended daily dosage, bro- total product as follows: ken down by age groups if appropriate, Percent contribution =(Total mEq. expressed in units such as tablets or Antacid Active Ingredient×100)/(Total teaspoonfuls) in a 24–hour period, or mEq. Antacid Product). use the maximum dosage of this prod- [61 FR 4823, Feb. 8, 1996] uct for more than 2 weeks, except

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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 tion of sodium bicarbonate powder aluminum are absorbed from the gas- products identified in § 331.11(k)(1), the trointestinal tract and renal excretion labeling must continue to bear the first of aluminum is impaired in renal fail- part of the general warning in § 330.1(g) ure. Aluminum is not well removed by of this chapter, which states, ‘‘Keep dialysis because it is bound to albumin this and all drugs out of the reach of and transferrin, which do not cross di- children.’’ alysis membranes. As a result, aluminum is deposited in bone, and dialy- 1 See § 201.66(b)(4) of this chapter. sis osteomalacia may develop when

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

Sec. Subpart C—Labeling 332.1 Scope. 332.3 Definitions. § 332.30 Labeling of antiflatulent drug products. Subpart B—Active Ingredients (a) Statement of identity. The labeling 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 active ingredients. the product as an ‘‘antiflatulent,’’ ‘‘antigas,’’ or ‘‘antiflatulent (antigas).’’ Subpart C—Labeling (b) Indications. The labeling of the 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 appro- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, priate. Other truthful and nonmis- 360, 371. leading statements, describing only the 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 safe and effective and is not mis- of unapproved new drugs in violation of branded if it meets each of the fol- section 505(a) of the act. lowing conditions and each of the gen- (1) (Select one of the following: ‘‘Al- eral conditions established in § 330.1 of leviates or Relieves’’) ‘‘the symptoms this chapter. referred to as gas.’’

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(2) (Select one of the following: ‘‘Al- 333.150 Labeling of first aid antibiotic drug leviates’’ or ‘‘Relieves’’) (select one or products. more of the following: ‘‘bloating,’’ 333.160 Labeling of permitted combinations 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. taining simethicone identified in 333.203 Definitions. 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 SOURCE: 52 FR 47322, Dec. 11, 1987, unless all drugs out of the reach of children.’’ otherwise noted. [39 FR 19877, June 4, 1974, as amended at 40 FR 11719, Mar. 13, 1975; 51 FR 16266, May 1, Subpart A [Reserved] 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, 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 pro- § 333.101 Scope. vided to health professionals (but not (a) An over-the-counter first aid anti- to the general public) may contain as biotic drug product in a form suitable additional indications postoperative for topical administration is generally gas pain or for use in endoscopic exam- recognized as safe and effective and is ination. not misbranded if it meets each of the (b) Professional labeling for an anti- conditions in this subpart and each of flatulent-antacid combination may the general conditions established in contain information allowed for health § 330.1. professionals for antacids and anti- (b) References in this subpart to reg- flatulents. ulatory sections of the Code of Federal Regulations are to chapter I of title 21 PART 333—TOPICAL ANTI- unless otherwise noted. MICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER § 333.103 Definitions. HUMAN USE As used in this subpart: First aid antibiotic. An antibiotic-con- Subpart A [Reserved] taining drug product applied topically to the skin to help prevent infection in Subpart B—First Aid Antibiotic Drug minor cuts, scrapes, and burns. Products [52 FR 47322, Dec. 11, 1987, as amended at 64 FR 403, Jan. 5, 1999] Sec. 333.101 Scope. § 333.110 First aid antibiotic active in- 333.103 Definitions. gredients. 333.110 First aid antibiotic active ingredients. The product consists of any of the 333.120 Permitted combinations of active in- following active ingredients within the gredients. specified concentration established for

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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 hicle, packaged in a pressurized con- units of polymyxin B with a suitable tainer with suitable inert gases. filler. (4) Bacitracin zinc-neomycin sulfate (b) Combinations of first aid antibiotic ointment containing, in each gram, 500 active ingredients and local anesthetic ac- units of bacitracin and 3.5 milligrams tive ingredients. (1) Bacitracin ointment

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containing, in each gram, 500 units of (5) Bacitracin zinc-polymyxin B sul- bacitracin and any single generally fate ointment containing, in each recognized as safe and effective amine gram, 500 units of bacitracin, 10,000 or ‘‘caine’’-type local anesthetic active units of polymyxin B, and any single ingredient in a suitable ointment base. generally recognized as safe and effec- (2) Bacitracin-neomycin sulfate-poly- tive amine or ‘‘caine’’-type local anes- myxin B sulfate ointment containing, thetic active ingredient in a suitable in each gram, in a suitable ointment ointment base. base the following: (6) Neomycin sulfate-polymyxin B (i) 500 units of bacitracin, 3.5 milli- sulfate cream containing, in each grams of neomycin, 5,000 units of poly- gram, 3.5 milligrams of neomycin, myxin B, and any single generally rec- 10,000 units of polymyxin B, and any ognized as safe and effective amine or single generally recognized as safe and ‘‘caine’’-type local anesthetic active effective amine or ‘‘caine’’-type local ingredient; or anesthetic active ingredient in a suit- (ii) 400 units of bacitracin, 3.5 milli- able vehicle. grams of neomycin, 5,000 units of poly- [52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. myxin B, and any single generally rec- 24, 1987, as amended at 53 FR 18838, May 25, ognized as safe and effective amine or 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, ‘‘caine’’-type local anesthetic active Oct. 3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR ingredient. 403, Jan. 5, 1999] (3) Bacitracin-polymyxin B sulfate topical aerosol containing, in each § 333.150 Labeling of first aid anti- gram, 500 units of bacitracin and 5,000 biotic drug products. units of polymyxin B and any single (a) Statement of identity. The labeling generally recognized as safe and effec- of the product contains the established tive amine or ‘‘caine’’-type local anes- name of the drug, if any, and identifies thetic active ingredient in a suitable the product as a ‘‘first aid antibiotic.’’ vehicle, packaged in a pressurized con- (b) Indications. The labeling of the tainer with suitable inert gases. product states, under the heading ‘‘In- (4) Bacitracin zinc-neomycin sulfate- dications,’’ the following: ‘‘First aid to polymyxin B sulfate ointment con- help’’ [select one of the following: taining, in each gram, in a suitable ‘‘prevent,’’ (‘‘decrease’’ (‘‘the risk of’’ ointment base the following: or ‘‘the chance of’’)), (‘‘reduce’’ (‘‘the (i) 400 units of bacitracin, 3 milli- risk of’’ or ‘‘the chance of’’)), ‘‘guard grams of neomycin, 8,000 units of poly- against,’’ or ‘‘protect against’’] [select myxin B, and any single generally rec- one of the following: ‘‘infection,’’ ognized as safe and effective amine or ‘‘bacterial contamination,’’ or ‘‘skin ‘‘caine’’-type local anesthetic active infection’’] ‘‘in minor cuts, scrapes, ingredient; or and burns.’’ Other truthful and nonmis- (ii) 400 units of bacitracin, 3.5 milli- leading statements describing only the grams of neomycin, 5,000 units of poly- indications for use that have been es- myxin B, and any single generally rec- tablished and listed in this paragraph ognized as safe and effective amine or (b), may also be used, as provided in ‘‘caine’’-type local anesthetic active § 330.1(c)(2), subject to the provisions of ingredient; or section 502 of the act relating to mis- (iii) 500 units of bacitracin, 3.5 milli- branding and the prohibition in section grams of neomycin, 5,000 units of poly- 301(d) of the act against the introduc- myxin B, and any single generally rection or delivery for introduction into ognized as safe and effective amine or interstate commerce of unapproved ‘‘caine’’-type local anesthetic active new drugs in violation of section 505(a) ingredient; or of the act. (iv) 500 units of bacitracin, 3.5 milli- (c) Warnings. The labeling of the grams of neomycin, 10,000 units of poly- product contains the following warn- myxin B, and any single generally rec- ings under the heading ‘‘Warnings’’: ognized as safe and effective amine or (1) ‘‘For external use only. Do not use ‘‘caine’’-type local anesthetic active in the eyes or apply over large areas of ingredient; the body. In case of deep or puncture

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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. section 502 of the act relating to mis- May be covered with a sterile ban- branding and the prohibition in section dage.’’ (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 tablished name, the labeling of the the directions established for each in- product states the established name of gredient in the directions sections of the combination drug product, followed the applicable OTC drug monographs.

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

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

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(e) The word ‘‘physician’’ may be sub- (f) Whitehead. A condition of the skin stituted for the word ‘‘doctor’’ in any that occurs in acne and is character- of the labeling statements in this sec- ized by a small, firm, whitish elevation tion. of the skin.

[58 FR 49898, Sept. 23, 1993, as amended at 65 § 333.310 Acne active ingredients. FR 52305, Aug. 29, 2000] The active ingredient of the product § 333.280 Professional labeling. consists of any of the following: The labeling provided to health pro- (a) Benzoyl peroxide, 2.5 to 10 per- fessionals (but not to the general pub- cent. lic) may contain the following addi- (b) Resorcinol, 2 percent, when com- tional indication: bined with sulfur in accordance with (a) For products containing haloprogin § 333.320(a). or miconazole nitrate identified in (c) Resorcinol monoacetate, 3 per- § 333.210 (a) and (c). ‘‘For the treatment cent, when combined with sulfur in ac- of superficial skin infections caused by cordance with § 333.320(b). yeast (Candida albicans).’’ (d) Salicylic acid, 0.5 to 2 percent. (b) [Reserved] (e) Sulfur, 3 to 10 percent. (f) Sulfur, 3 to 8 percent, when combined with resorcinol or resorcinol Subpart D—Topical Acne Drug monoacetate in accordance with Products § 333.320. [75 FR 9776, Mar. 4, 2010] SOURCE: 56 FR 41019, Aug. 16, 1991, unless otherwise noted. § 333.320 Permitted combinations of § 333.301 Scope. active ingredients. (a) An over-the-counter acne drug (a) Resorcinol identified in § 333.310(b) product in a form suitable for topical may be combined with sulfur identified application is generally recognized as in § 333.310(f). safe and effective and is not mis- (b) Resorcinol monoacetate identified branded if it meets each of the condi- in § 333.310(c) may be combined with tions in this subpart and each general sulfur identified in § 333.310(f). condition established in § 330.1 of this [75 FR 9776, Mar. 4, 2010] chapter. (b) References in this subpart to reg- § 333.350 Labeling of acne drug prod- ulatory sections of the Code of Federal ucts. Regulations are to chapter I of title 21 (a) Statement of identity. The labeling unless otherwise noted. of the product contains the established name of the drug, if any, and identifies § 333.303 Definitions. the product as an ‘‘acne medication,’’ As used in this subpart: ‘‘acne treatment,’’ ‘‘acne medication’’ (a) Acne. A disease involving the oil (insert dosage form, e.g., ‘‘cream,’’ glands and hair follicles of the skin ‘‘gel,’’ ‘‘lotion,’’ or ‘‘ointment’’), or which is manifested by blackheads, ‘‘acne treatment’’ (insert dosage form, whiteheads, acne pimples, and acne e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or blemishes. ‘‘ointment’’). (b) Acne blemish. A flaw in the skin (b) Indications. The labeling of the resulting from acne. product states, under the heading ‘‘In- (c) Acne drug product. A drug product dications,’’ the phrase listed in para- used to reduce the number of acne graph (b)(1) of this section and may blemishes, acne pimples, blackheads, contain any of the additional phrases and whiteheads. listed in paragraph (b)(2) of this sec- (d) Acne pimple. A small, prominent, tion. Other truthful and nonmisleading inflamed elevation of the skin result- statements, describing only the indica- ing from acne. tions for use that have been established (e) Blackhead. A condition of the skin and listed in paragraph (b) of this sec- that occurs in acne and is character- tion, may also be used, as provided in ized by a black tip. § 330.1(c)(2) of this chapter, subject to

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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 up,’’ ‘‘Reduces the number of,’’ or ‘‘Re- oxide identified in § 333.310(a). duces the severity of’’) (select one or (i) The labeling states ‘‘Do not use if more of the following: ‘‘acne blem- you [bullet] have very sensitive skin ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ [bullet] are sensitive to benzoyl per- or ‘‘whiteheads’’) which may be fol- oxide.’’ lowed by ‘‘and allows skin to heal.’’ (ii) The labeling states ‘‘When using (ii) ‘‘Penetrates pores to’’ (select one this product [bullet] avoid unnecessary of the following: ‘‘eliminate most,’’ sun exposure and use a sunscreen [bul- ‘‘control,’’ ‘‘clear most,’’ or ‘‘reduce let] avoid contact with the eyes, lips, the number of’’) (select one or more of and mouth [bullet] avoid contact with the following: ‘‘acne blemishes,’’ ‘‘acne hair and dyed fabrics, which may be pimples,’’ ‘‘blackheads,’’ or bleached by this product [bullet] skin ‘‘whiteheads’’). irritation may occur, characterized by (iii) ‘‘Helps keep skin clear of new’’ redness, burning, itching, peeling, or (select one or more of the following: possibly swelling. Irritation may be re- ‘‘acne blemishes,’’ ‘‘acne pimples,’’ duced by using the product less fre- ‘‘blackheads,’’ or ‘‘whiteheads’’). quently or in a lower concentration.’’ (iv) ‘‘Helps prevent new’’ (select one (iii) The labeling states ‘‘Stop use or more of the following: ‘‘acne blem- and ask a doctor if [bullet] irritation ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ becomes severe.’’ or ‘‘whiteheads’’) which may be fol- (d) Directions. The labeling of the lowed by ‘‘from forming.’’ product contains the following infor- (v) ‘‘Helps prevent the development mation under the heading ‘‘Direc- of new’’ (select one or more of the fol- tions’’: lowing: ‘‘acne blemishes,’’ ‘‘acne pim- (1) For products applied containing any ples,’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). ingredient identified in § 333.310. The la- (c) Warnings. The labeling of the beling states ‘‘[bullet] clean the skin product contains the following warn- thoroughly before applying this prod- ings under the heading ‘‘Warnings’’: uct [bullet] cover the entire affected (1) For products containing any ingredi- area with a thin layer one to three ents identified in § 330.310. times daily [bullet] because excessive (i) The labeling states ‘‘For external drying of the skin may occur, start use only.’’ with one application daily, then gradu- (ii) The labeling states ‘‘When using ally increase to two or three times this product [bullet] skin irritation and daily if needed or as directed by a doc- dryness is more likely to occur if you tor [bullet] if bothersome dryness or use another topical acne medication at peeling occurs, reduce application to the same time. If irritation occurs, once a day or every other day.’’

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

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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 ance with § 201.66(c)(5)(ii) of this chap- grams] ‘‘in 24 hours [bullet] children ter. under 12 years of age: ask a doctor’’. (A) The Reye’s syndrome warning in (e) Products that meet the criteria es- § 201.314(h) of this chapter. tablished in § 201.66(d)(10) of this chapter.

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

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

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of the labeling statements in this sec- § 338.3 Definition. tion. As used in this part: [52 FR 15892, Apr. 30, 1987, as amended at 53 Nighttime sleep-aid. A drug that is use- FR 35809, Sept. 15, 1988; 59 FR 16982, Apr. 11, ful for the relief of occasional sleep- 1994; 67 FR 72559, Dec. 6, 2003] lessness 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 Subpart A—General Provisions name of the drug, if any, and identifies Sec. the product as a ‘‘nighttime sleep-aid.’’ 338.1 Scope. (b) Indications. The labeling of the 338.3 Definition. product states, under the heading ‘‘In- dications,’’ one or more of the phrases Subpart B—Active Ingredients listed in this paragraph. Other truthful 338.10 Nighttime sleep-aid active ingredi- and nonmisleading statements, de- ents. scribing only the indications for use that have been established and listed in Subpart C—Labeling this paragraph (b), may also be used, as 338.50 Labeling of nighttime sleep-aid drug provided in § 330.1(c)(2) of this chapter, products. subject to the provisions of section 502 AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, of the act relating to misbranding and 360, 371. the prohibition in section 301(d) of the act against the introduction or deliv- SOURCE: 54 FR 6826, Feb. 14, 1989, unless otherwise noted. ery for introduction into interstate commerce of unapproved new drugs in Subpart A—General Provisions violation of section 505(a) of the act. (1) (‘‘Helps you’’ or ‘‘Reduces time § 338.1 Scope. to’’) ‘‘fall asleep if you have difficulty falling asleep.’’ (a) An over-the-counter nighttime sleep-aid drug product in a form suit- (2) ‘‘For relief of occasional sleepless- able for oral administration is gen- ness.’’ erally recognized as safe and effective (3) ‘‘Helps to reduce difficulty falling and is not misbranded if it meets each asleep.’’ condition in this part and each general (c) Warnings. The labeling of the condition established in § 330.1 of this product contains the following warn- chapter. ings under the heading ‘‘Warnings’’: (b) References in this part to regu- (1) ‘‘Do not give to children under 12 latory sections of the Code of Federal years of age.’’ Regulations are to chapter I of title 21 (2) ‘‘If sleeplessness persists continu- unless otherwise noted. ously for more than 2 weeks, consult

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your doctor. Insomnia may be a symp- Subpart C—Labeling tom of serious underlying medical illness.’’ 340.50 Labeling of stimulant drug products. (3) ‘‘Do not take this product, unless AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, directed by a doctor, if you have a 360, 371. breathing problem such as emphysema SOURCE: 53 FR 6105, Feb. 29, 1988, unless or chronic bronchitis, or if you have otherwise noted. glaucoma or difficulty in urination due to enlargement of the prostate gland.’’ Subpart A—General Provisions (4) ‘‘Avoid alcoholic beverages while taking this product. Do not take this § 340.1 Scope. product if you are taking sedatives or (a) An over-the-counter stimulant tranquilizers, without first consulting drug product in a form suitable for oral your doctor.’’ administration is generally recognized 1 (5) ‘‘Do not use [bullet] with any as safe and effective and is not mis- other product containing branded if it meets each of the condi- diphenhydramine, even one used on tions in this part and each of the gen- skin’’. eral conditions established in § 330.1. (d) Directions. The labeling of the (b) References in this part to regu- product contains the following infor- latory sections of the Code of Federal mation under the heading ‘‘Direc- Regulations are to chapter I of title 21 tions’’: unless otherwise noted. (1) For products containing diphenhydramine hydrochloride identified § 340.3 Definition. in § 338.10(a). Adults and children 12 As used in this part: years of age and over: Oral dosage is 50 Stimulant. A drug which helps restore milligrams at bedtime if needed, or as mental alertness or wakefulness during directed by a doctor. fatigue or drowsiness. (2) For products containing diphenhydramine citrate identified in § 338.10(b). Adults and children 12 years Subpart B—Active Ingredient of age and over: Oral dosage is 76 milligrams at bedtime if needed, or as di- § 340.10 Stimulant active ingredient. rected by a doctor. The active ingredient of the product (e) The word ‘‘physician’’ may be sub- consists of caffeine when used within stituted for the word ‘‘doctor’’ in any the dosage limits established in of the labeling statements in this sec- § 340.50(d). tion. [54 FR 6826, Feb. 14, 1989, as amended at 59 Subpart C—Labeling FR 16983, Apr. 11, 1994; 67 FR 72559, Dec. 6, 2002] § 340.50 Labeling of stimulant drug products. PART 340—STIMULANT DRUG (a) Statement of identity. The labeling 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 Sec. product states, under the heading ‘‘In- 340.1 Scope. dications,’’ the following: ‘‘Helps re- 340.3 Definition. store mental alertness or wakefulness 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 chamber only) [bullet] breathe in the be repeated every hour as needed or as medicated vapors [bullet] use up to directed by a doctor. Children under 2 three times daily or as directed by a years of age: Consult a doctor. doctor [bullet] children under 2 years (iv) For products containing camphor of age: Ask a doctor. identified in § 341.14(b)(1) for steam inha- (e) The word ‘‘physician’’ may be sub- lation use. The product contains 6.2 per- stituted for the word ‘‘doctor’’ in any cent camphor. ‘‘[bullet] see important of the labeling statements in this sec- warnings under ‘When using this prod- tion. uct’ ’’ [appears as the first statement (f) Exemption from the general acci- under the heading ‘‘Directions’’ and is dental overdose warning. The labeling highlighted in bold type] [bullet] for antitussive drug products con- adults and children 2 years and older: taining the active ingredient identified (select one of the following, as appro- in § 341.14(b)(2) marketed in accordance priate: For products formulated to be with § 341.74(d)(2)(iii) is exempt from added directly to cold water inside a hot the requirement in § 330.1(g) of this steam vaporizer. [bullet] use 1 table- chapter that the labeling bear the gen- spoonful of solution for each quart of eral warning statement ‘‘In case of ac- water or 11⁄2 teaspoonsful of solution cidental overdose, seek professional as- for each pint of water [bullet] add solu- sistance or contact a poison control tion directly to cold water only in a center immediately.’’ The labeling hot steam vaporizer [bullet] follow must continue to bear the first part of manufacturer’s directions for using va- the general warning in § 330.1(g) of this porizer or For products formulated to be chapter, which states, ‘‘Keep this and placed in the medication chamber of a hot all drugs out of the reach of children.’’ steam vaporizer. [bullet] place water in the vaporizer and follow manufactur- [52 FR 30055, Aug. 12, 1987; 52 FR 35610, Sept. 22, 1987; 53 FR 35809, Sept. 15, 1988; 55 FR er’s directions for using vaporizer [bul- 27808, July 6, 1990; 55 FR 40383, Oct. 3, 1990; 58 let] place solution in the medication FR 54236, Oct. 20, 1993; 59 FR 29174, June 3, chamber only) [bullet] breathe in the 1994; 59 FR 36051, July 15, 1994; 64 FR 13295, medicated vapors [bullet] use up to Mar. 17, 1999; 65 FR 8, Jan. 3, 2000; 65 FR three times daily or as directed by a 46867, Aug. 1, 2000; 67 FR 72559, Dec. 6, 2002] doctor [bullet] children under 2 years of age: Ask a doctor. § 341.76 Labeling of bronchodilator (v) For products containing menthol drug products. identified in § 341.14(b)(2) for steam inha- (a) Statement of identity. The labeling lation use. The product contains 3.2 per- of the product contains the established cent menthol. ‘‘[bullet] see important name of the drug, if any, and identifies warnings under ‘When using this prod- the product as a ‘‘bronchodilator.’’ uct’ ’’[appears as the first statement (b) Indications. The labeling of the under the heading ‘‘Directions’’ and is product states, under the heading ‘‘In- highlighted in bold type] [bullet] dications,’’ the phrase listed in para- adults and children 2 years and older: graph (b)(1) of this section. Other (select one of the following, as appro- truthful and nonmisleading state- priate: For products formulated to be ments, describing only the indications added directly to cold water inside a hot for use that have been established and

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listed in this paragraph (b), may also diately if symptoms are not relieved be used, as provided in § 330.1(c)(2), sub- within 1 hour or become worse.’’ ject to the provisions of section 502 of (ii) ‘‘Some users of this product may the act relating to misbranding and the experience nervousness, tremor, sleep- prohibition in section 301(d) of the act lessness, nausea, and loss of appetite. If against the introduction or delivery for these symptoms persist or become introduction into interstate commerce worse, consult your doctor.’’ of unapproved new drugs in violation of (6) For products containing epineph- section 505(a) of the act. rine, epinephrine bitartrate, or (1) ‘‘For temporary relief of shortness racepinephrine hydrochloride identified in of breath, tightness of chest, and § 341.16 (d), (e), and (g). (i) ‘‘Do not use wheezing due to bronchial asthma.’’ this product more frequently or at (2) In addition to the required infor- higher doses than recommended unless mation identified in paragraph (b)(1) of directed by a doctor. [first sentence in this section, the labeling of the product boldface type] Excessive use may cause may contain one or more of the fol- nervousness and rapid heart beat, and, lowing statements: possibly, adverse effects on the heart.’’ (i) ‘‘For the’’ (select one of the fol- (ii) ‘‘Do not continue to use this lowing: ‘‘temporary relief’’ or ‘‘symp- product, but seek medical assistance tomatic control’’) ‘‘of bronchial asthma.’’ immediately if symptoms are not relieved within 20 minutes or become (ii) ‘‘Eases breathing for asthma patients’’ (which may be followed by: ‘‘by worse.’’ [sentence in boldface type] reducing spasms of bronchial mus- (iii) For products intended for use in a cles’’). hand-held rubber bulb nebulizer. ‘‘Do not (c) Warnings. The labeling of the use this product if it is brown in color product contains the following warn- or cloudy.’’ ings under the heading ‘‘Warnings’’: (d) Directions. The labeling of the (1) ‘‘Do not use this product unless a product contains the following infor- diagnosis of asthma has been made by mation under the heading ‘‘Direc- a doctor.’’ tions’’: (2) ‘‘Do not use this product if you (1) For products containing ephedrine, have heart disease, high blood pressure, ephedrine hydrochloride, ephedrine sul- thyroid disease, diabetes, or difficulty fate, or racephedrine hydrochloride iden- in urination due to enlargement of the tified in § 341.16 (a), (b), (c), and (f). prostate gland unless directed by a doc- Adults and children 12 years of age and tor.’’ over: Oral dosage is 12.5 to 25 milli- (3) ‘‘Do not use this product if you grams every 4 hours, not to exceed 150 have ever been hospitalized for asthma milligrams in 24 hours, or as directed or if you are taking any prescription by a doctor. Do not exceed rec- drug for asthma unless directed by a ommended dose unless directed by a doctor.’’ doctor. Children under 12 years of age: (4) Drug interaction precaution. ‘‘Do Consult a doctor. not use if you are now taking a pre- (2) For products containing epineph- scription monoamine oxidase inhibitor rine, epinephrine bitartrate, and (MAOI) (certain drugs for depression, racepinephrine hydrochloride identified in psychiatric, or emotional conditions, § 341.16(d), (e), and (g) for use in a hand- or Parkinson’s disease), or for 2 weeks held rubber bulb nebulizer. The ingre- after stopping the MAOI drug. If you do dient is used in an aqueous solution at not know if your prescription drug con- a concentration equivalent to 1 percent tains an MAOI, ask a doctor or pharmacist before taking this product.’’ epinephrine. Inhalation dosage for adults, children 12 years of age and (5) For products containing ephedrine, ephedrine hydrochloride, ephedrine sul- over, and children 4 to under 12 years fate, or racephedrine hydrochloride iden- of age: 1 to 3 inhalations not more tified in § 341.16 (a), (b), (c), and (f). (i) often than every 3 hours. The use of ‘‘Do not continue to use this product, but seek medical assistance imme-

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this product by children should be su- sistent or chronic cough such as occurs pervised by an adult. Children under 4 with asthma or if cough is accom- years of age: Consult a doctor. panied by excessive phlegm (mucus) (Collection of information requirement ap- unless directed by a doctor.’’ proved by the Office of Management and (d) Directions. The labeling of the Budget under control number 0910–0237) product contains the following infor- [51 FR 35339, Oct. 2, 1986, as amended at 52 FR mation under the heading ‘‘Directions’’ 7126, Mar. 9, 1987; 52 FR 7830, Mar. 13, 1987; 53 for products containing guaifenesin FR 35810, Sept. 15, 1988; 58 FR 54242, Oct. 20, identified in § 341.18: Adults and chil- 1993; 61 FR 25146, May 20, 1996; 62 FR 9684, dren 12 years of age and over: oral dos- Mar. 4, 1997; 64 FR 13295, Mar. 17, 1999] age is 200 to 400 milligrams every 4 hours not to exceed 2,400 milligrams in § 341.78 Labeling of expectorant drug 24 hours. Children 6 to under 12 years of products. age: oral dosage is 100 to 200 milligrams (a) Statement of identity. The labeling every 4 hours not to exceed 1,200 milli- of the product contains the established grams in 24 hours. Children 2 to under name of the drug, if any, and identifies 6 years of age: oral dosage is 50 to 100 the product as an ‘‘expectorant.’’ milligrams every 4 hours not to exceed (b) Indications. The labeling of the 600 milligrams in 24 hours. Children product states, under the heading ‘‘In- under 2 years of age: consult a doctor. dications,’’ the following: ‘‘Helps loos- (e) The word ‘‘physician’’ may be sub- en phlegm (mucus) and thin bronchial stituted for the word ‘‘doctor’’ in any secretions to’’ (select one or more of of the labeling statements in this sec- the following: ‘‘rid the bronchial pas- tion. sageways of bothersome mucus,’’ ‘‘drain bronchial tubes,’’ and ‘‘make [54 FR 8509, Feb. 28, 1989, as amended at 57 coughs more productive’’). Other truth- FR 29177, June 30, 1992] ful and nonmisleading statements, de- § 341.80 Labeling of nasal deconges- scribing only the indications for use tant drug products. that have been established and listed in this paragraph (b), may also be used, as (a) Statement of identity. The labeling provided in § 330.1(c)(2) of this chapter, of the product contains the established subject to the provisions of section 502 name of the drug, if any, and identifies of the act relating to misbranding and the product as a ‘‘nasal decongestant.’’ the prohibition in section 301(d) of the (b) Indications. The labeling of the act against the introduction or deliv- product states, under the heading ‘‘In- ery for introduction into interstate dications,’’ the phrase listed in para- commerce of unapproved new drugs in graph (b)(1) of this section, as appro- violation of section 505(a) of the act. priate, and may contain any additional (c) Warnings. The labeling of the phrases listed in paragraph (b)(2) of product contains the following warn- this section. Other truthful and non- ings, under the heading ‘‘Warnings’’: misleading statements, describing only (1) ‘‘A persistent cough may be a sign the indications for use that have been of a serious condition. If cough persists established and listed in paragraphs for more than 1 week, tends to recur, (b)(1) and (b)(2) of this section, may or is accompanied by a fever, rash, or also be used, as provided in § 330.1(c)(2) persistent headache, consult a doctor.’’ of this chapter, subject to the provi- (2) For expectorant drug products la- sions of section 502 of the Federal beled for adults or for adults and children Food, Drug, and Cosmetic Act (the act) under 12 years of age. ‘‘Do not take this relating to misbranding and the prohi- product for persistent or chronic cough bition in section 301(d) of the act such as occurs with smoking, asthma, against the introduction or delivery for chronic bronchitis, or emphysema, or introduction into interstate commerce where cough is accompanied by exces- of unapproved new drugs in violation of sive phlegm (mucus) unless directed by section 505(a) of the act. a doctor.’’ (1) (Select one of the following: ‘‘For (3) For expectorant drug products la- the temporary relief of nasal conges- beled only for children under 12 years of tion’’ or ‘‘Temporarily relieves nasal age. ‘‘Do not give this product for per- congestion’’) (which may be followed

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by any of the following in paragraphs scription monoamine oxidase inhibitor (b)(1) (i), (ii), and (iii) of this section): (MAOI) (certain drugs for depression, (i) ‘‘due to’’ (select one of the fol- psychiatric, or emotional conditions, lowing: ‘‘the common cold’’ or ‘‘a or Parkinson’s disease), or for 2 weeks cold’’). after stopping the MAOI drug. If you do (ii) ‘‘due to’’ (select one of the fol- not know if your prescription drug con- lowing: ‘‘hay fever,’’ ‘‘hay fever (aller- tains an MAOI, ask a doctor or phar- gic rhinitis),’’ ‘‘hay fever or other macist before taking this product.’’ upper respiratory allergies,’’ or ‘‘hay (ii) For products containing phenyl- fever or other upper respiratory aller- ephrine hydrochloride, pseudoephedrine gies (allergic rhinitis)’’). hydrochloride, pseudoephedrine sulfate, (2) In addition to the information or phenylephrine bitartrate identified in identified in paragraph (b)(1) of this § 341.20 (a)(1) through (a)(4) when labeled section, the labeling of the product for children under 12 years of age. (A) may contain any (one or more) of the ‘‘Do not exceed recommended dosage. following statements: [first sentence in boldface type] If (i) (Select one of the following: ‘‘For nervousness, dizziness, or sleeplessness the temporary relief of’’ or ‘‘Tempo- occur, discontinue use and consult a rarily relieves’’) (select one of the fol- doctor.’’ lowing: ‘‘stuffy nose,’’ ‘‘stopped up (B) ‘‘If symptoms do not improve nose,’’ ‘‘nasal stuffiness,’’ or ‘‘clogged within 7 days or are accompanied by up nose.’’) fever, consult a doctor.’’ (ii) (Select one of the following: ‘‘Re- (C) ‘‘Do not give this product to a duces swelling of,’’ ‘‘Decongests,’’ or child who has heart disease, high blood ‘‘Helps clear’’) ‘‘nasal passages; shrinks pressure, thyroid disease, or diabetes swollen membranes.’’ unless directed by a doctor.’’ (iii) ‘‘Temporarily restores freer (D) Drug interaction precaution. ‘‘Do breathing through the nose.’’ not use in a child who is taking a pre- (iv) ‘‘Helps decongest sinus openings scription monoamine oxidase inhibitor and passages; temporarily relieves (MAOI) (certain drugs for depression, sinus congestion and pressure.’’ psychiatric, or emotional conditions, (v) ‘‘Promotes nasal and/or sinus or Parkinson’s disease), or for 2 weeks drainage; temporarily relieves sinus after stopping the MAOI drug. If you do congestion and pressure.’’ not know if your child’s prescription (c) Warnings. The labeling of the drug contains an MAOI, ask a doctor or product contains the following warn- pharmacist before giving this product.’’ ings under the heading ‘‘Warnings’’: (iii) For oral nasal decongestant prod- (1) Oral nasal decongestants—(i) For ucts labeled for both adults and children products containing phenylephrine hydro- under 12 years of age. The labeling of chloride, pseudoephedrine hydrochloride, the product contains the warnings 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.

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‘‘Do not use this product for more than oxymetazoline hydrochloride, phenyl- 7 days. Use only as directed. Frequent ephrine hydrochloride, or xylometazoline or prolonged use may cause nasal con- hydrochloride identified in § 341.20(b)(2), gestion to recur or worsen. If symp- (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and toms persist, ask a doctor.’’ (b)(10) when used as nasal sprays, drops, (iii) For products containing ephedrine, or jellies and when labeled for children ephedrine hydrochloride, ephedrine sul- under 12 years of age. (A) ‘‘Do not use fate, naphazoline hydrochloride, this product for more than 3 days. Use oxymetazoline hydrochloride, phenyl- only as directed. Frequent or prolonged ephrine hydrochloride, or xylometazoline use may cause nasal congestion to hydrochloride identified in § 341.20 (b)(2), recur or worsen. If symptoms persist, (b)(3), (b)(4), (b)(6), (b)(7), (b)(8), and consult a doctor.’’ (b)(10) when used as nasal sprays, drops, (B) ‘‘Do not use this product in a or jellies and when labeled for adults. (A) child who has heart disease, high blood ‘‘Do not use this product for more than pressure, thyroid disease, or diabetes 3 days. Use only as directed. Frequent unless directed by a doctor.’’ or prolonged use may cause nasal con- (ix) For products containing gestion to recur or worsen. If symp- propylhexedrine identified in § 341.20(b)(9) toms persist, consult a doctor.’’ when used in an inhalant dosage form (B) ‘‘Do not use this product if you and when labeled for children under 12 have heart disease, high blood pressure, years of age. ‘‘Do not use this product thyroid disease, diabetes, or difficulty for more than 3 days. Use only as di- in urination due to enlargement of the rected. Frequent or prolonged use may prostate gland unless directed by a doc- cause nasal congestion to recur or tor.’’ worsen. If symptoms persist, consult a (iv) For products containing naphazo- doctor.’’ line hydrochloride identified in (x) For topical nasal decongestant prod- § 341.20(b)(6) at a concentration of 0.05 ucts labeled for both adults and for chil- percent. ‘‘Do not use this product in dren under 12 years of age. The labeling children under 12 years of age because of the product contains the applicable it may cause sedation if swallowed.’’ warnings identified in paragraphs (v) For products containing (c)(2)(i), (c)(2)(ii), (c)(2)(iii), and (c)(2)(v) propylhexedrine identified in § 341.20(b)(9) of this section. when used in an inhalant dosage form (d) Directions. The labeling of the and when labeled for adults. ‘‘Do not use product contains the following infor- this product for more than 3 days. Use mation under the heading ‘‘Direc- only as directed. Frequent or prolonged tions’’: use may cause nasal congestion to (1) Oral nasal decongestants—(i) For recur or worsen. If symptoms persist, products containing phenylephrine hydro- consult a doctor.’’ chloride identified in § 341.20(a)(1). (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

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milligrams in 24 hours. Children 2 to § 341.20(b)(6)—(A) Nasal drops or sprays— under 6 years of age: 15 milligrams (1) For a 0.05-percent aqueous solution. every 4 to 6 hours not to exceed 60 mil- Adults and children 12 years of age and ligrams in 24 hours. Children under 2 over: 1 or 2 drops or sprays in each nos- years of age: consult a doctor. tril not more often than every 6 hours. (iii) For products containing phenyl- Do not give to children under 12 years ephrine bitartrate identified in of age unless directed by a doctor. § 341.20(a)(4). Include information on (2) For a 0.025-percent aqueous solution. the number of dosage units and the Children 6 to under 12 years of age quantity of water the dosage units are (with adult supervision): 1 or 2 drops or to be dissolved in prior to administra- sprays in each nostril not more often tion as shown in the following table: than every 6 hours. Children under 6 years of age: consult a doctor. Age 1 Dose 1 (B) Nasal jelly—(1) For a 0.05-percent Adults and children 15.6 milligrams every 4 hours not water-based jelly. Adults and children 12 12 years of age to exceed 62.4 milligrams in 24 years of age and over: place a small and over hours amount in each nostril and inhale well Children 6 to under 7.8 milligrams every 4 hours not to back into the nasal passages. Use not 12 years of age exceed 31.2 milligrams in 24 more often than every 6 hours. Do not hours give to children under 12 years of age Children under 6 Ask a doctor unless directed by a doctor. years of age (2) For a 0.025-percent water-based 1Headings are not required to appear in the product’s jelly. Children 6 to under 12 years of age labeling (with adult supervision): place a small (2) Topical nasal decongestants—(i) For amount in each nostril and inhale well products containing levmetamfetamine back into the nasal passages. Use not identified in § 341.20(b)(1) when used in an more often than every 6 hours. Chil- inhalant dosage form. The product deliv- dren under 6 years of age: consult a ers in each 800 milliliters of air 0.04 to doctor. 0.150 milligrams of levmetamfetamine. (iv) For products containing Adults: 2 inhalations in each nostril oxymetazoline hydrochloride identified in not more often than every 2 hours. § 341.20(b)(7)—(A) Nasal drops or sprays— Children 6 to under 12 years of age (1) For a 0.05-percent aqueous solution. (with adult supervision): 1 inhalation Adults and children 6 to under 12 years in each nostril not more often than of age (with adult supervision): 2 or 3 every 2 hours. Children under 6 years of drops or sprays in each nostril not age: ask a doctor. more often than every 10 to 12 hours. (ii) For products containing ephedrine, Do not exceed 2 doses in any 24-hour ephedrine hydrochloride, or ephedrine period. Children under 6 years of age: sulfate identified in § 341.20(b) (2), (3), consult a doctor. 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

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the nasal passages. Use not more often hale well back into the nasal passages. than every 10 to 12 hours. Do not ex- Use not more often than every 4 hours. ceed 2 doses in any 24-hour period. Chil- Children under 6 years of age: consult a dren under 6 years of age: consult a doctor. doctor. (vi) For products containing (v) For products containing phenyl- propylhexedrine identified in § 341.20(b)(9) ephrine hydrochloride identified in when used in an inhalant dosage form. § 341.20(b)(8)—(A) Nasal drops or sprays— The product delivers in each 800 milli- (1) For a 1-percent aqueous solution. liters of air 0.40 to 0.50 milligrams of Adults and children 12 years of age and propylhexedrine. Adults and children 6 over: 2 or 3 drops or sprays in each nos- to under 12 years of age (with adult su- tril not more often than every 4 hours. pervision): 2 inhalations in each nostril Do not give to children under 12 years not more often than every 2 hours. of age unless directed by a doctor. Children under 6 years of age: consult a (2) For a 0.5-percent aqueous solution. doctor. Adults and children 12 years of age and (vii) For products containing over: 2 or 3 drops or sprays in each nos- xylometazoline hydrochloride identified in tril not more often than every 4 hours. § 341.20(b)(10)—(A) Nasal drops or Do not give to children under 12 years sprays—(1) For a 0.1-percent aqueous so- of age unless directed by a doctor. lution. Adults and children 12 years of (3) For a 0.25-percent aqueous solution. age and over: 2 or 3 drops or sprays in Adults and children 6 to under 12 years each nostril not more often than every of age (with adult supervision): 2 or 3 8 to 10 hours. Do not give to children drops or sprays in each nostril not under 12 years of age unless directed by more often than every 4 hours. Chil- a doctor. dren under 6 years of age: consult a (2) A 0.05-percent aqueous solution in a doctor. container having either a calibrated drop- (4) A 0.125-percent aqueous solution in per or a metered-dose spray that delivers a container having either a calibrated no more than 0.054 milligrams of dropper or a metered-dose spray that de- xylometazoline per three drops or three livers no more than 0.135 milligrams of sprays. Children 6 to under 12 years of phenylephrine per three drops or three age (with adult supervision): 2 or 3 sprays. Children 2 to under 6 years of drops or sprays in each nostril not age (with adult supervision): 2 or 3 more often than every 8 to 10 hours. drops or sprays in each nostril not Children 2 to under 6 years of age (with more often than every 4 hours. Use adult supervision): 2 or 3 drops or only recommended amount. [previous sprays in each nostril not more often sentence in boldface type] Children than every 8 to 10 hours. Use only rec- under 2 years of age: consult a doctor. ommended amount. Do not exceed 3 (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.

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(viii) Other required statements—For (b). Other truthful and nonmisleading products containing levmetamfetamine or statements, describing only the indica- propylhexedrine identified in § 341.20(b)(1) tions for use that have been established or (b)(9) when used in an inhalant dosage and listed in the applicable OTC drug form. (A) ‘‘This inhaler is effective for a monographs or listed in this paragraph minimum of 3 months after first use.’’ (b), may also be used, as provided in (B) ‘‘Keep inhaler tightly closed.’’ § 330.1(c)(2) of this chapter, subject to [59 FR 43409, Aug. 23, 1994, as amended at 63 the provisions of section 502 of the Fed- FR 40650, July 30, 1998; 64 FR 13295, Mar. 17, eral Food, Drug, and Cosmetic Act (the 1999; 65 FR 8, Jan. 3, 2000; 70 FR 58977, Oct. 11, act) relating to misbranding and the 2005; 71 FR 43362, Aug. 1, 2006] prohibition in section 301(d) of the act against the introduction or delivery for § 341.85 Labeling of permitted com- introduction into interstate commerce binations of active ingredients. of unapproved new drugs in violation of The statements of identity, indica- section 505(a) of the act. tions, warnings, and directions for use, (1) For permitted combinations con- respectively, applicable to each ingre- taining an analgesic-antipyretic active in- dient in the product may be combined gredient identified in § 341.40(a), (c), (f). to eliminate duplicative words or (g), (l), (m), (n), (o), (q), and (r) when la- phrases so that the resulting informa- beled for relief of general cough-cold tion is clear and understandable. symptoms and/or the common cold. (i) The (a) Statement of identity. For a com- labeling for the analgesic-antipyretic bination drug product that has an es- ingredients states ‘‘[bullet] tempo- tablished name, the labeling of the rarily relieves [bullet] minor aches and product states the established name of pains [bullet] headache’’ and ‘‘[bullet] the combination drug product, followed temporarily reduces fever’’. by the statement of identity for each (ii) The labeling for the cough-cold ingredient in the combination, as es- ingredient(s) may follow a separate tablished in the statement of identity bullet(s) or may be combined with the sections of the applicable OTC drug relieves part of the indication in para- monographs. If there is no established graph (b)(1)(i) of this section. name, the labeling of the product (2) For permitted combinations con- states the statement of identity for taining an analgesic-antipyretic active in- each ingredient in the combination, as gredient identified in § 341.40(a), (c), (f), established in the statement of iden- (g), (m), (q), and (r) when labeled for re- tity sections of the applicable OTC lief of hay fever/allergic rhinitis and/or drug monographs, unless otherwise nasal congestion symptoms. (i) The label- stated in this paragraph (a). ing for the analgesic-antipyretic ingre- (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

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states both indications in paragraphs (ii) For products labeled only for chil- (b)(1) and (b)(2) of this section. dren under 12 years of age. The following (4) For permitted combinations con- warning should be used instead of the taining an oral anesthetic-analgesic ac- warnings in § 341.74(c)(3) and part 343 of tive ingredient identified in § 341.40(k), (s), this chapter: ‘‘Stop use and ask a doc- (t), (z), (aa), and (bb). The labeling for tor if [in bold type] [bullet] pain or the anesthetic-analgesic ingredients in cough gets worse or lasts more than 5 part 356 of this chapter should be used. days [bullet] fever gets worse or lasts (5) For permitted combinations con- more than 3 days [bullet] redness or taining camphor, menthol, and euca- swelling is present [bullet] new symp- lyptus oil identified in § 341.40(u). The la- toms occur [bullet] cough comes back beling for antitussive ingredients in or occurs with rash or headache that § 341.74(b) should be used. lasts. These could be signs of a serious (6) For permitted combinations con- condition.’’ taining levmetamfetamine with aromatics (iii) For products labeled for both identified in § 341.40(v). The labeling for adults and for children under 12 years of nasal decongestant ingredients in age. The following warning should be § 341.80(b) should be used. used instead of the warnings in § 341.74(c)(2) and part 343 of this chap- (7) Other allowable statements. In addi- ter: ‘‘Stop use and ask a doctor if [in tion to the required information identi- bold type] [bullet] pain or cough gets fied in paragraph (b) of this section, worse or lasts more than 5 days (chil- the labeling of the combination drug dren) or 7 days (adults) [bullet] fever product may contain any of the ‘‘other gets worse or lasts more than 3 days allowable statements’’ (if any), that [bullet] redness or swelling is present are identified in the applicable OTC [bullet] new symptoms occur [bullet] drug monographs, provided such state- cough comes back or occurs with rash ments are neither placed in direct con- or headache that lasts. These could be junction with information required to signs of a serious condition.’’ appear in the labeling nor occupy la- (2) For permitted combinations con- beling space with greater prominence taining an expectorant and an analgesic- or conspicuousness than the required antipyretic identified in § 341.40(o). The information. labeling states the following warnings: (c) Warnings. The labeling of the (i) For products labeled only for adults. product states, under the heading The warning in paragraph (c)(1)(i) of ‘‘Warnings,’’ the warning(s) for each in- this section should be used instead of gredient in the combination, as estab- the warnings in § 341.78(c)(3) and part lished in the warnings sections of the 343 of this chapter. 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

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chapter: ‘‘Stop use and ask a doctor if states the warnings for topical nasal [in bold type] [bullet] pain or nasal decongestant ingredients in congestion gets worse or lasts more § 341.80(c)(2). than 7 days [bullet] fever gets worse or (d) Directions. The labeling of the lasts more than 3 days [bullet] redness product states, under the heading ‘‘Di- or swelling is present [bullet] new rections,’’ directions that conform to symptoms occur’’. the directions established for each in- (ii) For products labeled for only chil- gredient in the directions sections of dren under 12 years of age. The following the applicable OTC drug monographs, warning should be used instead of the unless otherwise stated in paragraph warnings in § 341.80(c)(1)(ii)(B) and part (d) of this section. When the time in- 343 of this chapter: ‘‘Stop use and ask a tervals or age limitations for adminis- doctor if [in bold type] [bullet] pain or tration of the individual ingredients nasal congestion gets worse or lasts differ, the directions for the combina- more than 5 days [bullet] fever gets tion product may not exceed any max- worse or lasts more than 3 days [bullet] imum dosage limits established for the redness or swelling is present [bullet] individual ingredients in the applicable new symptoms occur’’. OTC drug monograph. (iii) For products labeled for both (1) For permitted combinations con- adults and children under 12 years of age. taining an anesthetic/analgesic and/or a The following warning should be used demulcent in a liquid dosage form identi- instead of the warnings in fied in § 341.40(k), (s), (t), (w), (x), (y), (z), § 341.80(c)(1)(iii) and part 343 of this (aa), and (bb). The labeling states ‘‘[op- chapter: ‘‘Stop use and ask a doctor if tional, bullet] gargle, swish around, or [in bold type] [bullet] pain or nasal keep in the mouth for at least 1 minute congestion gets worse or lasts more and then swallow. Do not spit out.’’ than 5 days (children) or 7 days (adults) (2) For permitted combinations con- [bullet] fever gets worse or lasts more taining camphor, menthol, and euca- than 3 days [bullet] redness or swelling lyptus oil identified in § 341.40(u). The la- is present [bullet] new symptoms beling states the directions for topical occur’’. antitussive ingredients in § 341.74(d). (4) For permitted combinations con- (3) For permitted combinations containing an antihistamine combined with taining levmetamfetamine with aromatics an oral antitussive. The labeling states identified in § 341.40(v). The labeling the warning ‘‘When using this product states the directions for topical nasal [in bold type] [bullet] may cause decongestant ingredients in marked drowsiness.’’ The word § 341.80(d)(2)(i) and (d)(2)(viii). ‘‘marked’’ may be deleted from the warning upon petition under the provi- [67 FR 78170, Dec. 23, 2002, as amended at 70 sions of § 10.30 of this chapter provided FR 58977, Oct. 11, 2005; 71 FR 43362, Aug. 1, adequate data are submitted to dem- 2006] onstrate that the combination product does not cause a significant increase in § 341.90 Professional labeling. drowsiness as compared with each ac- The labeling of the product provided tive ingredient when tested alone. The to health professionals (but not to the petition and the data it contains will general public) may contain the fol- be maintained in a permanent file for lowing additional dosage information public review in the Division of Dock- for products containing the active in- ets Management (HFA–305), Food and gredients identified below: Drug Administration, 5630 Fishers (a) For products containing ephedrine, Lane, rm. 1061, Rockville, MD 20852. ephedrine hydrochloride, ephedrine sul- (5) For permitted combinations con- fate, or racephedrine hydrochloride iden- taining camphor, menthol, and euca- tified in § 341.16 (a), (b), (c), and (f). Chil- lyptus oil identified in § 341.40(u). The la- dren 6 to under 12 years of age: oral beling states the warnings for topical dosage is 6.25 to 12.5 milligrams every 4 antitussive ingredients in § 341.74(c). hours, not to exceed 75 milligrams in 24 (6) For permitted combinations con- hours. Children 2 to under 6 years of taining levmetamfetamine with aromatics age: oral dosage is 0.3 to 0.5 milligram identified in § 341.40(v). The labeling per kilogram of body weight every 4

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hours, not to exceed 2 milligrams per sant effects of codeine, including res- kilogram of body weight in 24 hours. piratory arrest, coma, and death. (b) For products containing (d) The following labeling indication chlophedianol hydrochloride identified in may be used for products containing 341.14(a)(1). Children 2 to under 6 years guaifenesin identified in § 341.18 when of age: oral dosage is 12.5 milligrams used as a single ingredient product. every 6 to 8 hours, not to exceed 50 mil- ‘‘Helps loosen phlegm and thin bron- ligrams in 24 hours. chial secretions in patients with stable (c) For products containing codeine in- chronic bronchitis.’’ gredients identified in § 341.14(a)(2). (1) (e) For products containing Children 2 to under 6 years of age: Oral brompheniramine maleate identified in dosage is 1 milligram per kilogram § 341.12(a). Children 2 to under 6 years body weight per day administered in of age: oral dosage is 1 milligram every four equal divided doses. The average 4 to 6 hours, not to exceed 6 milligrams body weight for each age may also be in 24 hours. used to determine dosage as follows: (f) For products containing For children 2 years of age (average chlorcyclizine hydrochloride identified in body weight, 12 kilograms), the oral § 341.12(b). Children 6 to under 12 years dosage is 3 milligrams every 4 to 6 of age: oral dosage is 12.5 milligrams hours, not to exceed 12 milligrams in 24 every 6 to 8 hours, not to exceed 37.5 hours; for children 3 years of age (aver- milligrams in 24 hours. Children 2 to age body weight, 14 kilograms), the under 6 years of age: oral dosage is 6.25 oral dosage is 3.5 milligrams every 4 to milligrams every 6 to 8 hours, not to 6 hours, not to exceed 14 milligrams in exceed 18.75 milligrams in 24 hours. 24 hours; for children 4 years of age (av- (g) For products containing erage body weight, 16 kilograms), the chlorpheniramine maleate identified in oral dosage is 4 milligrams every 4 to 6 § 341.12(c). Children 2 to under 6 years of hours, not to exceed 16 milligrams in 24 age: oral dosage is 1 milligram every 4 hours: for children 5 years of age (aver- to 6 hours, not to exceed 6 milligrams age body weight, 18 kilograms), the in 24 hours. oral dosage is 4.5 milligrams every 4 to (h) For products containing 6 hours, not to exceed 18 milligrams in dexbrompheniramine maleate identified in 24 hours. The manufacturer must re- § 341.12(d). Children 2 to under 6 years late these dosages for its specific prod- of age: oral dosage is 0.5 milligram uct dosages for its specific product to every 4 to 6 hours, not to exceed 3 mil- the use of the calibrated measuring de- ligrams in 24 hours. vice discussed in paragraph (c)(3) of (i) For products containing this section. If age is used to determine dexchlorpheniramine maleate identified in the dose, the directions must include § 341.12(e). Children 2 to under 6 years: instructions to reduce the dose for low- oral dosage is 0.5 milligram every 4 to weight children. 6 hours, not to exceed 3 milligrams in (2) Parents should be instructed to 24 hours. obtain and use a calibrated measuring (j) For products containing device for administering the drug to diphenhydramine citrate identified in the child, to use extreme care in meas- § 341.12(f). Children 2 to under 6 years of uring the dosage, and not exceed the age: oral dosage is 9.5 milligrams every recommended daily dosage. 4 to 6 hours, not to exceed 57 milli- (3) A dispensing device (such as a grams in 24 hours. dropper calibrated for age or weight) (k) For products containing should be dispensed along with the diphenhydramine hydrochloride identified product when it is intended for use in in § 341.12(g). Children 2 to under 6 years children 2 to under 6 years of age to of age: oral dosage is 6.25 milligrams prevent possible overdose due to im- every 4 to 6 hours, not to exceed 37.5 proper measuring of the dose. mg in 24 hours. (4) Codeine is not recommended for (l) For products containing doxylamine use in children under 2 years of age. succinate identified in § 341.12(h). Chil- Children under 2 years may be more dren 2 to under 6 years of age: oral dos- susceptible to the respiratory depres- age is 1.9 to 3.125 milligrams every 4 to

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6 hours, not to exceed 18.75 milligrams PART 343—INTERNAL ANALGESIC, in 24 hours. ANTIPYRETIC, AND (m) For products containing ANTIRHEUMATIC DRUG PROD- phenindamine tartrate identified in UCTS FOR OVER-THE-COUNTER § 341.12(i). Children 2 to under 6 years of HUMAN USE age: oral dosage is 6.25 milligrams every 4 to 6 hours, not to exceed 37.5 Subpart A—General Provisions milligrams in 24 hours. (n) For products containing Sec. pheniramine maleate identified in 343.1 Scope. 343.3 Definitions. § 341.12(j). Children 2 to under 6 years of age: oral dosage is 3.125 to 6.25 milli- Subpart B—Active Ingredients grams every 4 to 6 hours, not to exceed 37.5 milligrams in 24 hours. 343.10 [Reserved] 343.12 Cardiovascular active ingredients. (o) For products containing pyrilamine 343.13 Rheumatologic active ingredients. maleate identified in § 341.12(k). Children 343.20 [Reserved] 2 to under 6 years of age: oral dosage is 343.22 Permitted combinations of active in- 6.25 to 12.5 milligrams every 6 to 8 gredients for cardiovascular- hours, not to exceed 50 milligrams in 24 rheumatologic use. hours. Subpart C—Labeling (p) For products containing thonzylamine hydrochloride identified in 343.50–343.60 [Reserved] § 341.12(l). Children 2 to under 6 years of 343.80 Professional labeling. age: oral dosage is 12.5 to 25 milligrams Subpart D—Testing Procedures every 4 to 6 hours, not to exceed 150 milligrams in 24 hours. 343.90 Dissolution and drug release testing. (q) For products containing triprolidine AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, hydrochloride identified in § 341.12(m). 360, 371. Children 4 to under 6 years of age: oral SOURCE: 63 FR 56814, Oct. 23, 1998, unless dosage is 0.938 milligram every 4 to 6 otherwise noted. hours, not to exceed 3.744 milligrams in 24 hours. Children 2 to under 4 years of Subpart A—General Provisions age: oral dosage is 0.625 milligram every 4 to 6 hours, not to exceed 2.5 § 343.1 Scope. milligrams in 24 hours. Infants 4 (a) An over-the-counter analgesic- months to under 2 years of age: oral antipyretic drug product in a form dosage is 0.313 milligram every 4 to 6 suitable for oral administration is gen- 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 § 343.3 Definitions. in § 341.14(a)(6). Children 2 to under 6 As used in this part: years of age: oral dosage is 6.25 milli- Analgesic—antipyretic drug. An agent grams every 4 hours, not to exceed 37.5 used to alleviate pain and to reduce milligrams in 24 hours. fever. [51 FR 35339, Oct. 2, 1986, as amended at 52 FR Cardiovascular drug. An agent used to 30057, Aug. 12, 1987; 54 FR 8509, Feb. 28, 1989; prevent ischemic events. 57 FR 58376, Dec. 9, 1992; 59 FR 4218, Jan. 28, Rheumatologic drug. An agent used for 1994; 59 FR 29174, June 3, 1994; 59 FR 36051, the treatment of rheumatologic dis- July 15, 1994] orders.

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Subpart B—Active Ingredients Subpart C—Labeling

§ 343.10 [Reserved] §§ 343.50–343.60 [Reserved]

§ 343.12 Cardiovascular active ingredi- § 343.80 Professional labeling. ents. The labeling of an over-the-counter (a) Aspirin. drug product written for health profes- (b) Buffered aspirin. Aspirin identi- sionals (but not for the general public) fied in paragraph (a) of this section shall consist of the following: may be buffered with any antacid in- (a) For products containing aspirin gredient(s) identified in § 331.11 of this identified in §§ 343.12 and 343.13 or per- chapter provided that the finished mitted combinations identified in § 343.22. product contains at least 1.9 milli- (These products must meet United States Pharmacopeia (USP) standards equivalents of acid-neutralizing capac- for dissolution or drug release in ity per 325 milligrams of aspirin as § 343.90.) measured by the procedure provided in (1) The labeling contains the fol- the United States Pharmacopeia 23/Na- lowing prescribing information under tional Formulary 18. the heading ‘‘Comprehensive Pre- scribing Information’’ and the sub- § 343.13 Rheumatologic active ingredi- headings ‘‘Description,’’ ‘‘Clinical ents. Pharmacology,’’ ‘‘Clinical Studies,’’ (a) Aspirin. ‘‘Animal Toxicology,’’ ‘‘Indications and (b) Buffered aspirin. Aspirin identi- Usage,’’ ‘‘Contraindications,’’ ‘‘Warn- fied in paragraph (a) of this section ings,’’ ‘‘Precautions,’’ ‘‘Adverse Reac- may be buffered with any antacid in- tions,’’ ‘‘Drug Abuse and Dependence,’’ gredient(s) identified in § 331.11 of this ‘‘Overdosage,’’ ‘‘Dosage and Adminis- chapter provided that the finished tration,’’ and ‘‘How Supplied’’ in the product contains at least 1.9 milli- exact language and the exact order pro- equivalents of acid-neutralizing capac- vided as follows: ity per 325 milligrams of aspirin as COMPREHENSIVE PRESCRIBING measured by the procedure provided in INFORMATION the United States Pharmacopeia 23/Na- tional Formulary 18. DESCRIPTION (Insert the proprietary name and the estab- § 343.20 [Reserved] lished name (if any) of the drug, type of dosage form (followed by the phrase ‘‘for oral adminis- § 343.22 Permitted combinations of ac- tration’’), the established name(s) and quantity tive ingredients for cardiovascular- of the active ingredient(s) per dosage unit, the rheumatologic use. total sodium content in milligrams per dosage unit if the sodium content of a single rec- Combinations containing aspirin ommended dose is 5 milligrams or more, the es- must meet the standards of an accept- tablished name(s) (in alphabetical order) of any able dissolution test, as set forth in inactive ingredient(s) which may cause an aller- § 343.90. The following combinations are gic hypersensitivity reaction, the pharma- permitted: Aspirin identified in §§ 343.12 cological or therapeutic class of the drug, and the chemical name(s) and structural formula(s) and 343.13 may be combined with any of the drug.) Aspirin is an odorless white, antacid ingredient identified in § 331.11 needle-like crystalline or powdery substance. of this chapter or any combination of When exposed to moisture, aspirin antacids permitted in accordance with hydrolyzes into salicylic and acetic acids, § 331.10(a) of this chapter provided that and gives off a vinegary-odor. It is highly the finished product meets the require- lipid soluble and slightly soluble in water. ments of § 331.10 of this chapter and is CLINICAL PHARMACOLOGY marketed in a form intended for inges- Mechanism of Action: Aspirin is a more po- tion as a solution. tent inhibitor of both prostaglandin synthesis and platelet aggregation than other salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on

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the aspirin molecule. This acetyl group is recent as salicyluric acid, and 10 percent phe- sponsible for the inactivation of cyclo- nolic and 5 percent acyl glucuronides of sali- oxygenase via acetylation. cylic acid. Pharmacodynamics Aspirin affects platelet PHARMACOKINETICS aggregation by irreversibly inhibiting Absorption: In general, immediate release prostaglandin cyclo-oxygenase. This effect aspirin is well and completely absorbed from lasts for the life of the platelet and prevents the gastrointestinal (GI) tract. Following ab- the formation of the platelet aggregating sorption, aspirin is hydrolyzed to salicylic factor thromboxane A2. Nonacetylated acid with peak plasma levels of salicylic acid salicylates do not inhibit this enzyme and occurring within 1–2 hours of dosing (see have no effect on platelet aggregation. At PHARMACOKINETICS—Metabolism). The rate of somewhat higher doses, aspirin reversibly in- absorption from the GI tract is dependent hibits the formation of prostaglandin I2 upon the dosage form, the presence or ab- (prostacyclin), which is an arterial vaso- sence of food, gastric pH (the presence or ab- dilator and inhibits platelet aggregation. sence of GI antacids or buffering agents), and At higher doses aspirin is an effective anti- other physiologic factors. Enteric coated as- inflammatory agent, partially due to inhibi- pirin products are erratically absorbed from tion of inflammatory mediators via cyclo- the GI tract. oxygenase inhibition in peripheral tissues. In Distribution: Salicylic acid is widely dis- vitro studies suggest that other mediators of tributed to all tissues and fluids in the body inflammation may also be suppressed by as- including the central nervous system (CNS), pirin administration, although the precise breast milk, and fetal tissues. The highest mechanism of action has not been eluci- concentrations are found in the plasma, dated. It is this nonspecific suppression of liver, renal cortex, heart, and lungs. The pro- cyclo-oxygenase activity in peripheral tis- tein binding of salicylate is concentration- sues following large doses that leads to its dependent, i.e., nonlinear. At low concentra- primary side effect of gastric irritation. (See tions (< 100 micrograms/milliliter (μg/mL)), ADVERSE REACTIONS.) approximately 90 percent of plasma salicylate is bound to albumin while at higher con- CLINICAL STUDIES centrations (> 400 μg/mL), only about 75 per- Ischemic Stroke and Transient Ischemic At- cent is bound. The early signs of salicylic tack (TIA): In clinical trials of subjects with overdose (salicylism), including tinnitus TIA’s due to fibrin platelet emboli or (ringing in the ears), occur at plasma con- ischemic stroke, aspirin has been shown to centrations approximating 200 μg/mL. Severe significantly reduce the risk of the combined toxic effects are associated with levels > 400 endpoint of stroke or death and the com- μg/mL. (See ADVERSE REACTIONS and OVER- bined endpoint of TIA, stroke, or death by DOSAGE.) Metabolism: Aspirin is rapidly hydrolyzed about 13–18 percent. in the plasma to salicylic acid such that Suspected Acute Myocardial Infarction (MI): plasma levels of aspirin are essentially In a large, multi-center study of aspirin, undetectable 1–2 hours after dosing. Salicylic streptokinase, and the combination of aspi- acid is primarily conjugated in the liver to rin and streptokinase in 17,187 patients with form salicyluric acid, a phenolic glu- suspected acute MI, aspirin treatment pro- curonide, an acyl glucuronide, and a number duced a 23-percent reduction in the risk of of minor metabolites. Salicylic acid has a vascular mortality. Aspirin was also shown plasma half-life of approximately 6 hours. to have an additional benefit in patients Salicylate metabolism is saturable and total given a thrombolytic agent. body clearance decreases at higher serum Prevention of Recurrent MI and Unstable An- concentrations due to the limited ability of gina Pectoris: These indications are supported the liver to form both salicyluric acid and by the results of six large, randomized, phenolic glucuronide. Following toxic doses multi-center, placebo-controlled trials of (10–20 grams (g)), the plasma half-life may be predominantly male post-MI subjects and increased to over 20 hours. one randomized placebo-controlled study of Elimination: The elimination of salicylic men with unstable angina pectoris. Aspirin acid follows zero order pharmacokinetics; therapy in MI subjects was associated with a (i.e., the rate of drug elimination is constant significant reduction (about 20 percent) in in relation to plasma concentration). Renal the risk of the combined endpoint of subse- excretion of unchanged drug depends upon quent death and/or nonfatal reinfarction in urine pH. As urinary pH rises above 6.5, the these patients. In aspirin-treated unstable renal clearance of free salicylate increases angina patients the event rate was reduced from < 5 percent to > 80 percent. to 5 percent from the 10 percent rate in the Alkalinization of the urine is a key concept placebo group. in the management of salicylate overdose. Chronic Stable Angina Pectoris: In a random- (See OVERDOSAGE.) Following therapeutic ized, multi-center, double-blind trial de- doses, approximately 10 percent is found ex- signed to assess the role of aspirin for pre- creted in the urine as salicylic acid, 75 per- vention of MI in patients with chronic stable

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angina pectoris, aspirin significantly re- Spondyloarthropathies, Osteoarthritis, and the duced the primary combined endpoint of Arthritis and Pleurisy of Systemic Lupus nonfatal MI, fatal MI, and sudden death by 34 Erythematosus (SLE)): Aspirin is indicated for percent. The secondary endpoint for vascular the relief of the signs and symptoms of rheu- events (first occurrence of MI, stroke, or vas- matoid arthritis, juvenile rheumatoid arthri- cular death) was also significantly reduced tis, osteoarthritis, spondyloarthropathies, (32 percent). and arthritis and pleurisy associated with Revascularization Procedures: Most patients SLE. who undergo coronary artery revascularization procedures have already CONTRAINDICATIONS had symptomatic coronary artery disease for which aspirin is indicated. Similarly, pa- Allergy: Aspirin is contraindicated in patients with lesions of the carotid bifurcation tients with known allergy to nonsteroidal sufficient to require carotid endarterectomy anti-inflammatory drug products and in pa- are likely to have had a precedent event. As- tients with the syndrome of asthma, rhinitis, pirin is recommended for patients who un- and nasal polyps. Aspirin may cause severe dergo revascularization procedures if there is urticaria, angioedema, or bronchospasm a preexisting condition for which aspirin is (asthma). already indicated. Reye’s Syndrome: Aspirin should not be used Rheumatologic Diseases: In clinical studies in children or teenagers for viral infections, in patients with rheumatoid arthritis, juve- with or without fever, because of the risk of nile rheumatoid arthritis, ankylosing spon- Reye’s syndrome with concomitant use of as- dylitis and osteoarthritis, aspirin has been pirin in certain viral illnesses. shown to be effective in controlling various indices of clinical disease activity. WARNINGS Alcohol Warning: Patients who consume ANIMAL TOXICOLOGY three or more alcoholic drinks every day The acute oral 50 percent lethal dose in should be counseled about the bleeding risks rats is about 1.5 g/kilogram (kg) and in mice involved with chronic, heavy alcohol use 1.1 g/kg. Renal papillary necrosis and de- while taking aspirin. creased urinary concentrating ability occur Coagulation Abnormalities: Even low doses in rodents chronically administered high of aspirin can inhibit platelet function lead- doses. Dose-dependent gastric mucosal in- ing to an increase in bleeding time. This can jury occurs in rats and humans. Mammals adversely affect patients with inherited (he- may develop aspirin toxicosis associated mophilia) or acquired (liver disease or vita- with GI symptoms, circulatory effects, and min K deficiency) bleeding disorders. central nervous system depression. (See GI Side Effects: GI side effects include OVERDOSAGE.) stomach pain, heartburn, nausea, vomiting, INDICATIONS AND USAGE and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are com- Vascular Indications (Ischemic Stroke, TIA, mon and can occur anytime during therapy, Acute MI, Prevention of Recurrent MI, Unstable physicians should remain alert for signs of Angina Pectoris, and Chronic Stable Angina ulceration and bleeding, even in the absence Pectoris): Aspirin is indicated to: (1) Reduce of previous GI symptoms. Physicians should the combined risk of death and nonfatal inform patients about the signs and symp- stroke in patients who have had ischemic toms of GI side effects and what steps to stroke or transient ischemia of the brain due take if they occur. to fibrin platelet emboli, (2) reduce the risk Peptic Ulcer Disease: Patients with a his- of vascular mortality in patients with a sus- tory of active peptic ulcer disease should pected acute MI, (3) reduce the combined avoid using aspirin, which can cause gastric risk of death and nonfatal MI in patients mucosal irritation and bleeding. with a previous MI or unstable angina pectoris, and (4) reduce the combined risk of MI PRECAUTIONS and sudden death in patients with chronic stable angina pectoris. General Revascularization Procedures (Coronary Ar- tery Bypass Graft (CABG), Percutaneous Renal Failure: Avoid aspirin in patients Transluminal Coronary Angioplasty (PTCA), with severe renal failure (glomerular filtra- and Carotid Endarterectomy): Aspirin is indi- tion rate less than 10 mL/minute). cated in patients who have undergone Hepatic Insufficiency: Avoid aspirin in pa- revascularization procedures (i.e., CABG, tients with severe hepatic insufficiency. PTCA, or carotid endarterectomy) when Sodium Restricted Diets: Patients with so- there is a preexisting condition for which as- dium-retaining states, such as congestive pirin is already indicated. heart failure or renal failure, should avoid Rheumatologic Disease Indications (Rheu- sodium-containing buffered aspirin prepara- matoid Arthritis, Juvenile Rheumatoid Arthritis, tions because of their high sodium content.

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Laboratory Tests assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations Aspirin has been associated with elevated in cultured human fibroblasts. Aspirin inhib- hepatic enzymes, blood urea nitrogen and its ovulation in rats. (See Pregnancy.) serum creatinine, hyperkalemia, proteinuria, and prolonged bleeding time. Pregnancy: Pregnant women should only take aspirin if clearly needed. Because of the Drug Interactions known effects of NSAID’s on the fetal cardiovascular system (closure of the ductus Angiotensin Converting Enzyme (ACE) Inhibi- arteriosus), use during the third trimester of tors: The hyponatremic and hypotensive ef- pregnancy should be avoided. Salicylate fects of ACE inhibitors may be diminished by products have also been associated with al- the concomitant administration of aspirin terations in maternal and neonatal hemo- due to its indirect effect on the renin- stasis mechanisms, decreased birth weight, angiotensin conversion pathway. and with perinatal mortality. Acetazolamide: Concurrent use of aspirin Labor and Delivery: Aspirin should be and acetazolamide can lead to high serum avoided 1 week prior to and during labor and concentrations of acetazolamide (and tox- delivery because it can result in excessive icity) due to competition at the renal tubule blood loss at delivery. Prolonged gestation for secretion. and prolonged labor due to prostaglandin in- Anticoagulant Therapy (Heparin and War- hibition have been reported. farin): Patients on anticoagulation therapy Nursing Mothers: Nursing mothers should are at increased risk for bleeding because of avoid using aspirin because salicylate is ex- drug-drug interactions and the effect on creted in breast milk. Use of high doses may platelets. Aspirin can displace warfarin from lead to rashes, platelet abnormalities, and protein binding sites, leading to prolonga- bleeding in nursing infants. tion of both the prothrombin time and the Pediatric Use: Pediatric dosing rec- bleeding time. Aspirin can increase the anti- ommendations for juvenile rheumatoid ar- coagulant activity of heparin, increasing thritis are based on well-controlled clinical bleeding risk. studies. An initial dose of 90–130 mg/kg/day Anticonvulsants: Salicylate can displace in divided doses, with an increase as needed protein-bound phenytoin and valproic acid, for anti-inflammatory efficacy (target plas- leading to a decrease in the total concentra- ma salicylate levels of 150–300 μg/mL) are ef- tion of phenytoin and an increase in serum fective. At high doses (i.e., plasma levels of valproic acid levels. greater than 200 μg/mL), the incidence of tox- Beta Blockers: The hypotensive effects of icity increases. beta blockers may be diminished by the concomitant administration of aspirin due to in- ADVERSE REACTIONS hibition of renal prostaglandins, leading to decreased renal blood flow, and salt and fluid Many adverse reactions due to aspirin in- retention. gestion are dose-related. The following is a Diuretics: The effectiveness of diuretics in list of adverse reactions that have been re- patients with underlying renal or cardio- ported in the literature. (See WARNINGS.) vascular disease may be diminished by the Body as a Whole: Fever, hypothermia, concomitant administration of aspirin due to thirst. inhibition of renal prostaglandins, leading to Cardiovascular: Dysrhythmias, hypo- decreased renal blood flow and salt and fluid tension, tachycardia. retention. Central Nervous System: Agitation, cerebral Methotrexate: Salicylate can inhibit renal edema, coma, confusion, dizziness, headache, clearance of methotrexate, leading to bone subdural or intracranial hemorrhage, leth- marrow toxicity, especially in the elderly or argy, seizures. renal impaired. Fluid and Electrolyte: Dehydration, hyper- Nonsteroidal Anti-inflammatory Drugs kalemia, metabolic acidosis, respiratory (NSAID’s): The concurrent use of aspirin with alkalosis. other NSAID’s should be avoided because Gastrointestinal: Dyspepsia, GI bleeding, ul- this may increase bleeding or lead to de- ceration and perforation, nausea, vomiting, creased renal function. transient elevations of hepatic enzymes, hep- Oral Hypoglycemics: Moderate doses of aspi- atitis, Reye’s Syndrome, pancreatitis. rin may increase the effectiveness of oral Hematologic: Prolongation of the pro- hypoglycemic drugs, leading to hypo- thrombin time, disseminated intravascular glycemia. coagulation, coagulopathy, Uricosuric Agents (Probenecid and thrombocytopenia. Sulfinpyrazone): Salicylates antagonize the Hypersensitivity: Acute anaphylaxis, uricosuric action of uricosuric agents. angioedema, asthma, bronchospasm, laryn- Carcinogenesis, Mutagenesis, Impairment of geal edema, urticaria. Fertility: Administration of aspirin for 68 Musculoskeletal: Rhabdomyolysis. weeks at 0.5 percent in the feed of rats was Metabolism: Hypoglycemia (in children), not carcinogenic. In the Ames Salmonella hyperglycemia.

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Reproductive: Prolonged pregnancy and electrolytes and pH should be monitored to labor, stillbirths, lower birth weight infants, promote alkaline diuresis of salicylate if antepartum and postpartum bleeding. renal function is normal. Infusion of glucose Respiratory: Hyperpnea, pulmonary edema, may be required to control hypoglycemia. tachypnea. Hemodialysis and peritoneal dialysis can Special Senses: Hearing loss, tinnitus. Pa- be performed to reduce the body drug con- tients with high frequency hearing loss may tent. In patients with renal insufficiency or have difficulty perceiving tinnitus. In these in cases of life-threatening intoxication, di- patients, tinnitus cannot be used as a clin- alysis is usually required. Exchange trans- ical indicator of salicylism. fusion may be indicated in infants and young Urogenital: Interstitial nephritis, papillary children. necrosis, proteinuria, renal insufficiency and failure. DOSAGE AND ADMINISTRATION Each dose of aspirin should be taken with DRUG ABUSE AND DEPENDENCE a full glass of water unless patient is fluid Aspirin is nonnarcotic. There is no known restricted. Anti-inflammatory and analgesic potential for addiction associated with the dosages should be individualized. When aspi- use of aspirin. rin is used in high doses, the development of tinnitus may be used as a clinical sign of ele- OVERDOSAGE vated plasma salicylate levels except in pa- Salicylate toxicity may result from acute tients with high frequency hearing loss. Ischemic Stroke and TIA: 50–325 mg once a ingestion (overdose) or chronic intoxication. day. Continue therapy indefinitely. The early signs of salicylic overdose Suspected Acute MI: The initial dose of 160– (salicylism), including tinnitus (ringing in 162.5 mg is administered as soon as an MI is the ears), occur at plasma concentrations ap- suspected. The maintenance dose of 160–162.5 proaching 200 μg/mL. Plasma concentrations mg a day is continued for 30 days post-infarc- of aspirin above 300 μg/mL are clearly toxic. tion. After 30 days, consider further therapy Severe toxic effects are associated with lev- μ based on dosage and administration for pre- els above 400 g/mL. (See CLINICAL PHARMA- vention of recurrent MI. COLOGY.) A single lethal dose of aspirin in Prevention of Recurrent MI: 75–325 mg once adults is not known with certainty but death a day. Continue therapy indefinitely. may be expected at 30 g. For real or sus- Unstable Angina Pectoris: 75–325 mg once a pected overdose, a Poison Control Center day. Continue therapy indefinitely. should be contacted immediately. Careful Chronic Stable Angina Pectoris: 75–325 mg medical management is essential. once a day. Continue therapy indefinitely. Signs and Symptoms: In acute overdose, se- CABG: 325 mg daily starting 6 hours post- vere acid-base and electrolyte disturbances procedure. Continue therapy for 1 year post- may occur and are complicated by procedure. hyperthermia and dehydration. Respiratory PTCA: The initial dose of 325 mg should be alkalosis occurs early while given 2 hours pre-surgery. Maintenance dose hyperventilation is present, but is quickly is 160–325 mg daily. Continue therapy indefi- followed by metabolic acidosis. nitely. Treatment: Treatment consists primarily of Carotid Endarterectomy: Doses of 80 mg once supporting vital functions, increasing salicy- daily to 650 mg twice daily, started late elimination, and correcting the acid- presurgery, are recommended. Continue base disturbance. Gastric emptying and/or therapy indefinitely. lavage is recommended as soon as possible Rheumatoid Arthritis: The initial dose is 3 g after ingestion, even if the patient has vom- a day in divided doses. Increase as needed for ited spontaneously. After lavage and/or anti-inflammatory efficacy with target plas- emesis, administration of activated char- ma salicylate levels of 150–300 μg/mL. At high coal, as a slurry, is beneficial, if less than 3 doses (i.e., plasma levels of greater than 200 hours have passed since ingestion. Charcoal μg/mL), the incidence of toxicity increases. adsorption should not be employed prior to Juvenile Rheumatoid Arthritis: Initial dose is emesis and lavage. 90–130 mg/kg/day in divided doses. Increase as Severity of aspirin intoxication is deter- needed for anti-inflammatory efficacy with mined by measuring the blood salicylate target plasma salicylate levels of 150–300 μg/ level. Acid-base status should be closely fol- mL. At high doses (i.e., plasma levels of lowed with serial blood gas and serum pH greater than 200 μg/mL), the incidence of tox- measurements. Fluid and electrolyte balance icity increases. should also be maintained. Spondyloarthropathies: Up to 4 g per day in In severe cases, hyperthermia and divided doses. hypovolemia are the major immediate Osteoarthritis: Up to 3 g per day in divided threats to life. Children should be sponged doses. with tepid water. Replacement fluid should Arthritis and Pleurisy of SLE: The initial be administered intravenously and aug- dose is 3 g a day in divided doses. Increase as mented with correction of acidosis. Plasma needed for anti-inflammatory efficacy with

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target plasma salicylate levels of 150–300 μg/ REV: October 23, 1998. mL. At high doses (i.e., plasma levels of (2) In addition to, and immediately greater than 200 mμ/mL), the incidence of toxicity increases. preceding, the labeling required under paragraph (a)(1) of this section, the HOW SUPPLIED professional labeling may contain the (Insert specific information regarding, following highlights of prescribing in- strength of dosage form, units in which the dos- formation in the exact language and age form is generally available, and information exact format provided, but only when to facilitate identification of the dosage form as accompanied by the comprehensive required under § 201.57(k)(1), (k)(2), and (k)(3).) Store in a tight container at 25 °C (77 °F); ex- prescribing information required in cursions permitted to 15–30 °C (59–86 °F). 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 344.3 Definitions. § 343.90 Dissolution and drug release Subpart B—Active Ingredients testing. 344.10 Earwax removal aid active ingre- (a) [Reserved] dient. (b) Aspirin capsules. Aspirin capsules 344.12 Ear drying aid active ingredient. must meet the dissolution standard for aspirin capsules as contained in the Subpart C—Labeling United States Pharmacopeia (USP) 23 at page 132. 344.50 Labeling of earwax removal aid drug (c) Aspirin delayed-release capsules and products. aspirin delayed-release tablets. Aspirin 344.52 Labeling of ear drying aid drug prod- delayed-release capsules and aspirin ucts. delayed-release tablets must meet the AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, drug release standard for aspirin de- 360, 371. layed-release capsules and aspirin de- SOURCE: 51 FR 28660, Aug. 8, 1986, unless layed-release tablets as contained in otherwise noted: USP 23 at pages 133 and 136 respectively. (d) Aspirin tablets. Aspirin tablets Subpart A—General Provisions must meet the dissolution standard for § 344.1 Scope. aspirin tablets as contained in USP 23 at page 134. (a) An over-the-counter topical otic (e) Aspirin, alumina, and magnesia tab- drug product in a form suitable for top- lets. Aspirin in combination with alu- ical administration is generally recog- mina and magnesia in a tablet dosage nized as safe and effective and is not form must meet the dissolution stand- misbranded if it meets each of the con- ard for aspirin, alumina, and magnesia ditions in this part in addition to each tablets as contained in USP 23 at page of the general conditions established in 138. § 330.1. (f) Aspirin, alumina, and magnesium (b) References in this part to regu- oxide tablets. Aspirin in combination latory sections of the Code of Federal with alumina, and magnesium oxide in Regulations are to chapter I of title 21 a tablet dosage form must meet the unless otherwise noted. dissolution standard for aspirin, alumina, and magnesium tablets as con- § 344.3 Definitions. tained in USP 23 at page 139. (g) Aspirin effervescent tablets for oral As used in this part: solution. Aspirin effervescent tablets (a) Anhydrous glycerin. An ingredient for oral solution must meet the dis- that may be prepared by heating glyc- solution standard for aspirin effer- erin U.S.P. at 150 °C for 2 hours to drive vescent tablets for oral solution as con- off the moisture content. tained in USP 23 at page 137. (b) Earwax removal aid. A drug used in (h) Buffered aspirin tablets. Buffered the external ear canal that aids in the aspirin tablets must meet the dissolu- removal of excessive earwax. tion standard for buffered aspirin tab- (c) Water-clogged ears. The retention lets as contained in USP 23 at page 135. of water in the external ear canal, thereby causing discomfort and a sen- PART 344—TOPICAL OTIC DRUG sation of fullness or hearing impair- PRODUCTS FOR OVER-THE- ment. COUNTER HUMAN USE (d) Ear drying aid. A drug used in the external ear canal to help dry water- Subpart A—General Provisions clogged ears. Sec. [51 FR 28660, Aug. 8, 1986, as amended at 65 344.1 Scope. FR 48905, Aug. 10, 2000]

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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. indication identified in paragraph (b)(1) (A) ‘‘For the temporary relief of’’ (se- of this section, the labeling of the prod- lect one or both of the following: uct intended for external or intrarectal ‘‘pain’’ or ‘‘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, may also be used, as provided in (2) [Reserved] § 330.1(c)(2) of this chapter, subject to (e) The word ‘‘physician’’ may be sub- 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 section 505(a) of the act. COUNTER HUMAN USE (1) For products containing any ingredient identified in § 348.10(a). (i) ‘‘Helps Subpart A—General Provisions 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 one of the following: ‘‘retarding the 349.10 Ophthalmic astringent. onset of,’’ ‘‘slowing the onset of,’’ or 349.12 Ophthalmic demulcents. ‘‘prolonging the time until’’) followed 349.14 Ophthalmic emollients. by ‘‘ejaculation.’’ 349.16 Ophthalmic hypertonicity agent. (iv) ‘‘For reducing oversensitivity in 349.18 Ophthalmic vasoconstrictors. the male in advance of intercourse.’’ 349.20 Eyewashes. (2) [Reserved] 349.30 Permitted combinations of active in- (c) Warnings. The labeling of the gredients. product contains the following warnings under the heading ‘‘Warnings’’: Subpart C—Labeling (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 (ii) ‘‘Avoid contact with the eyes.’’ drug products. (iii) ‘‘If you or your partner develop a 349.70 Labeling of ophthalmic hypertonicity rash or irritation, such as burning or drug products. itching, discontinue use. If symptoms 349.75 Labeling of ophthalmic vasocon- persist, consult a doctor.’’ strictor drug products. (2) [Reserved] 349.78 Labeling of eyewash drug products. (d) Directions. The labeling of the 349.79 Labeling of permitted combinations product contains the following infor- of active ingredients. mation under the heading ‘‘Direc- 349.80 Professional labeling. tions’’: AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (1) For products containing any ingre- 360, 371. dient identified in § 348.10(a)—(i) For products containing benzocaine identified SOURCE: 53 FR 7090, Mar. 4, 1988, unless oth- in § 348.10(a)(1). ‘‘Apply a small amount erwise noted. 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 para- (4) For products in an aerosolized dos- graphs (b)(2) through (b)(5) of this sec- age form. (i) ‘‘When using this product tion, as appropriate. Other truthful and [bullet] 1 keep away from face and nonmisleading statements, describing mouth to avoid breathing it’’. only the uses that have been established 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 EFFECTIVE DATE NOTE: At 69 FR 61149, Oct. introduction or delivery for introduc- 15, 2004, the limitation of the enhanced duration into interstate commerce of unap- tion claim to 24 hours (21 CFR 350.50 (b)(3) proved new drugs in violation of sec- and (b) (5)) was stayed until further notice. tion 505(a) of the act. (1) For any product, the labeling Subpart D—Guidelines for states [select one of the following: Effectiveness Testing ‘‘decreases,’’ ‘‘lessens,’’ or ‘‘reduces’’] ‘‘underarm’’ [select one of the fol- § 350.60 Guidelines for effectiveness lowing: ‘‘dampness,’’ ‘‘perspiration,’’ testing of antiperspirant drug prod- ‘‘sweat,’’ ‘‘sweating,’’ or ‘‘wetness’’]. ucts. (2) The labeling may state ‘‘also [se- An antiperspirant in finished dosage lect one of the following: ‘decreases,’ form may vary in degree of effective- ‘lessens,’ or ‘reduces’] underarm [select ness because of minor variations in for- one of the following: ‘dampness,’ ‘per- mulation. To assure the effectiveness spiration,’ ‘sweat,’ ‘sweating,’ or ‘wet- of an antiperspirant, the Food and ness’] due to stress’’. (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 These guidelines are available on the extra effectiveness (30 percent sweat FDA’s Web site at http://www.fda.gov/ reduction), the labeling may state cder/otc/index.htm or on request for a ‘‘extra effective’’. nominal charge by submitting a Free- (5) Products that demonstrate extra dom of Information (FOI) request in effectiveness (30 percent sweat reduc- writing to FDA’s FOI Staff (HFI–35), tion) sustained over a 24-hour period 5600 Fishers Lane, rm. 12A–16, Rock- may state the claims in paragraphs ville, MD 20857. (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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PART 352—SUNSCREEN DRUG required to produce the first percep- PRODUCTS FOR OVER-THE- tible, redness reaction with clearly defined 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 indi- Sec. vidual’s complexion (pigmentation) 352.1 Scope. and desired response to ultraviolet 352.3 Definitions. (UV) radiation. (1) Minimal sun protection product. A Subpart B—Active Ingredients sunscreen product that provides a sun 352.10 Sunscreen active ingredients. protection factor (SPF) value of 2 to 352.20 Permitted combinations of active in- under 12. gredients. (2) Moderate sun protection product. A sunscreen product that provides an Subpart C—Labeling SPF value of 12 to under 30. 352.50 Principal display panel of all sun- (3) High sun protection product. A sunscreen drug products. screen product that provides an SPF 352.52 Labeling of sunscreen drug products. value of 30 or above. 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 290 352.70 Standard sunscreen. to 400 nanometers. 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. 352.77 Test modifications. on unprotected skin, which may also be defined by the following ratio: SPF AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, value =MED (protected skin (PS))/MED 360, 371. (unprotected skin (US)), where MED SOURCE: 64 FR 27687, May 21, 1999, unless (PS) is the minimal erythema dose for otherwise noted. protected skin after application of 2 EFFECTIVE DATE NOTE: At 68 FR 33381, June milligrams per square centimeter of 4, 2003, part 352 was stayed until further no- the final formulation of the sunscreen tice, effective June 4, 2004. product, and MED (US) is the minimal erythema dose for unprotected skin, Subpart A—General Provisions i.e., skin to which no sunscreen product has been applied. In effect, the SPF § 352.1 Scope. value is the reciprocal of the effective (a) An over-the-counter sunscreen transmission of the product viewed as a drug product in a form suitable for top- 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 than 2 as measured by the testing pro- § 352.3 Definitions. cedures established in subpart D of this As used in this part: part: (a) Minimal erythema dose (MED). The (a) Aminobenzoic acid (PABA) up to quantity of erythema-effective energy 15 percent. (expressed as Joules per square meter) (b) Avobenzone up to 3 percent.

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

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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 sunscreen drug products. applicable to the product and may contain 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 statement tion 505(a) of the act. accompanying the marketed product (1) For products containing any ingre- that states a specific SPF value above dient in § 352.10. (i) ‘‘[bullet] 1 helps pre- 30 or similar language indicating a per- vent sunburn [bullet] higher SPF gives son can stay in the sun more than 30 more sunburn protection’’. times longer than without sunscreen (ii) For products that satisfy the water will cause the product to be mis- resistant testing procedures identified in branded under section 502 of the Fed- § 352.76. ‘‘[bullet] retains SPF after 40 eral Food, Drug, and Cosmetic Act (the minutes of’’ (select one or more of the act). following: ‘‘activity in the water,’’ (b) For products that satisfy the water ‘‘sweating,’’ or ‘‘perspiring’’). resistant sunscreen product testing proce- (iii) For products that satisfy the very dures in § 352.76. (1) (Select one of the water resistant testing procedures identi- following: ‘‘Water,’’ ‘‘Water/Sweat,’’ or fied in § 352.76. ‘‘[bullet] retains SPF ‘‘Water/Perspiration’’) ‘‘Resistant.’’ after 80 minutes of’’ (select one or more (2) ‘‘SPF (insert SPF value of the of the following: ‘‘activity in the product, as stated in paragraph (a)(1) water,’’ ‘‘sweating,’’ or ‘‘perspiring’’). or (a)(2) of this section, after it has been tested using the water resistant 1 See § 201.66(b)(4) of this chapter.

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(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 ing ‘‘Directions.’’ More detailed direc- variation of this statement will cause tions applicable to a particular product the product to be misbranded under formulation (e.g., cream, gel, lotion, section 502 of the act. oil, spray, etc.) may also be included. (f) Products labeled for use only on spe- (1) For products containing any ingre- cific small areas of the face (e.g., lips, dient in § 352.10. (i) ‘‘[bullet] apply’’ (se- nose, ears, and/or around eyes) and that lect one or more of the following, as meet the criteria established in applicable: ‘‘liberally,’’ ‘‘generously,’’ § 201.66(d)(10) of this chapter. The title, ‘‘smoothly,’’ or ‘‘evenly’’) ‘‘(insert ap- headings, subheadings, and information

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described in § 201.66(c) of this chapter to eliminate duplicative words or shall be printed in accordance with the phrases so that the resulting informa- following specifications: tion is clear and understandable. (1) The labeling shall meet the re- (a) Statement of identity. For a com- quirements of § 201.66(c) of this chapter bination drug product that has an es- except that the title, headings, and in- tablished name, the labeling of the formation described in § 201.66(c)(1), product states the established name of (c)(3), and (c)(7) may be omitted, and the combination drug product, followed the headings, subheadings, and infor- by the statement of identity for each mation described in § 201.66(c)(2), (c)(4), ingredient in the combination, as es- (c)(5), and (c)(6) may be presented as tablished in the statement of identity follows: sections of the applicable OTC drug (i) The active ingredients monographs. For a combination drug (§ 201.66(c)(2) of this chapter) shall be product that does not have an estab- listed in alphabetical order. lished name, the labeling of the prod- (ii) The heading and the indication uct states the statement of identity for required by § 201.66(c)(4) of this chapter each ingredient in the combination, as may be limited to: ‘‘Use [in bold type] established in the statement of iden- helps protect against sunburn.’’ For a tity sections of the applicable OTC lip protectant product, the heading and drug monographs. the indication required by § 201.66(c)(4) (b) Indications. The labeling of the may be limited to: ‘‘Use [in bold type] product states, under the heading helps protect against sunburn and chapped lips.’’ ‘‘Uses,’’ the indication(s) for each in- (iii) The ‘‘external use only’’ warning gredient in the combination as estab- in § 201.66(c)(5)(i) of this chapter may be lished in the indications sections of the omitted. applicable OTC drug monographs, un- (iv) The subheadings in less otherwise stated in this paragraph. § 201.66(c)(5)(iii) through (c)(5)(vii) of Other truthful and nonmisleading this chapter may be omitted, provided statements, describing only the indica- the information after the heading tions for use that have been established ‘‘Warnings’’ states: ‘‘Keep out of eyes.’’ in the applicable OTC drug monographs and ‘‘Stop use if skin rash occurs.’’ or listed in this paragraph (b), may (v) The warning in § 201.66(c)(5)(x) of also be used, as provided by § 330.1(c)(2) this chapter may be limited to the fol- of this chapter, subject to the provi- lowing: ‘‘Keep out of reach of chil- sions of section 502 of the Federal dren.’’ Food, Drug, and Cosmetic Act (the act) (vi) For a lip protectant product or relating to misbranding and the prohi- lipstick, the warnings ‘‘Keep out of bition in section 301(d) of the act eyes’’ in § 352.52(f)(1)(iv) and ‘‘Keep out against the introduction or delivery for of reach of children’’ in § 352.52(f)(1)(v) introduction into interstate commerce and the directions in § 352.52(d) may be of unapproved new drugs in violation of omitted. section 505(a) of the act. (2) The labeling shall be printed in (1) In addition, the labeling of the accordance with the requirements of product may contain any of the ‘‘other § 201.66(d) of this chapter except that allowable statements’’ that are identi- any requirements related to fied in the applicable monographs. § 201.66(c)(1), (c)(3), and (c)(7), and the (2) For permitted combinations con- horizontal barlines and hairlines de- taining a sunscreen and a skin protect- scribed in § 201.66(d)(8), may be omitted. ant identified in § 352.20(b), any or all of [64 FR 27687, May 21, 1999, as amended at 68 the applicable indications for sun- FR 33380, June 4, 2003] screens in § 352.52(b) and the indication for skin protectants in § 347.50(b)(2)(i) of § 352.60 Labeling of permitted com- this chapter should be used. For prod- binations of active ingredients. ucts marketed as a lip protectant, the Statements of identity, indications, indication in § 352.52(f)(1)(ii) should be warnings, and directions for use, re- used. spectively, applicable to each ingre- (c) Warnings. The labeling of the dient in the product may be combined product states, under the heading

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‘‘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,’’ Ingredients Percent by weight which may be omitted), and (f)(1)(vi) 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 Preparation B gredient in the directions sections of 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 Purified water U.S.P ...... 74.30 limitations for administration of the 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 homosalate sunscreen preparation by or lipstick, § 352.52(d)(4) applies. 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 mining the SPF value of a sunscreen preparation. Accurately weigh 1 gram of drug product to ensure the uniform the standard homosalate sunscreen evaluation of sunscreen drug products. preparation into a 100-milliliter volu- The standard sunscreen shall be an 8- metric flask. Add 50 milliliters of the percent homosalate preparation with a assay solvent. Heat on a steam bath mean SPF value of 4.47 (standard devi- and mix well. Cool the solution to ation =1.279). In order for the SPF de- room temperature (15 to 30 °C). Then termination of a test product to be dilute the solution to volume with the considered valid, the SPF of the stand- assay solvent and mix well to make a ard sunscreen must fall within the 1-percent solution. standard deviation range of the ex- (3) Preparation of the test solution (1:50 pected SPF (i.e., 4.47 ±1.279) and the 95- dilution of the 1-percent solution). Filter

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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 Skin Type and Sunburn and Tanning History tion of the 1-percent solution). (Based on first 30 to 45 minutes sun exposure (4) Spectrophotometric determination. after a winter season of no sun exposure.) The absorbance of the test solution is I—Always burns easily; never tans (sen- measured in a suitable double beam sitive). spectrophotometer with the assay sol- II—Always burns easily; tans minimally vent and reference beam at a wave- (sensitive). length near 306 nanometers. III—Burns moderately; tans gradually (light (5) Calculation of the concentration of brown) (normal). IV—Burns minimally; always tans well homosalate. The concentration of (moderate brown) (normal). homosalate is determined by the fol- V—Rarely burns; tans profusely (dark lowing formula which takes into con- brown) (insensitive). sideration the absorbance of the sam- VI—Never burns; deeply pigmented (insensi- ple of the test solution, the dilution of tive). the 1-percent solution (1:50), the weight (2) A medical history shall be ob- of the sample of the standard tained from all subjects with emphasis homosalate sunscreen preparation (1 on the effects of sunlight on their skin. gram), and the standard absorbance Ascertain the general health of the in- value (172) of homosalate as deter- dividual, the individual’s skin type (I, mined by averaging the absorbance of a II, or III), whether the individual is large number of batches of raw taking medication (topical or sys- homosalate: temic) that is known to produce abnor- Concentration of homosalate mal sunlight responses, and whether =absorbance × 50 × 100 × 172 =percent the individual is subject to any abnor- concentration by weight. mal responses to sunlight, such as a phototoxic or photoallergic response. § 352.71 Light source (solar simulator). (b) Test site inspection. The physical A solar simulator used for deter- examination shall determine the pres- mining the SPF of a sunscreen drug ence of sunburn, suntan, scars, active product should be filtered so that it dermal lesions, and uneven skin tones provides a continuous emission spec- on the areas of the back to be tested. trum from 290 to 400 nanometers simi- The presence of nevi, blemishes, or lar to sunlight at sea level from the moles will be acceptable if in the phy- sun at a zenith angle of 10° it has less sician’s judgment they will not inter- than 1 percent of its total energy out- fere with the study results. Excess hair put contributed by nonsolar wave- on the back is acceptable if the hair is lengths shorter than 290 nanometers; clipped or shaved. and it has not more than 5 percent of (c) Informed consent. Legally effective its total energy output contributed by written informed consent must be ob- wavelengths longer than 400 nano- tained from all individuals. meters. In addition, a solar simulator (d) Test site delineation—(1) Test site should have no significant time-related area. A test site area serves as an area fluctuations in radiation emissions for determining the subject’s MED after an appropriate warmup time, and after application of either the sun- it should have good beam uniformity screen standard or the test sunscreen (within 10 percent) in the exposure product, or for determining the sub- plane. To ensure that the solar simu- ject’s MED when the skin is unpro- lator delivers the appropriate spectrum tected (control site). The area to be of UV radiation, it must be measured tested shall be the back between the periodically with an accurately-cali- beltline and the shoulder blade

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(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 posi- (h) Response criteria. In order that the tion, the lines shall be drawn on the person who evaluates the MED re- skin with the subject upright. If the sponses does not know which sunscreen subject is to be tested while prone, the formulation was applied to which site markings shall be made with the sub- or what doses of UV radiation were ad- ject prone. ministered, he/she must not be the (2) Test subsite area. Each test site same person who applied the sunscreen area shall be divided into at least three drug product to the test site or admin- test subsite areas that are at least 1 istered the doses of UV radiation. After square centimeter. Usually four or five UV radiation exposure from the solar subsites are employed. Each test simulator is completed, all immediate subsite within a test site area is sub- responses shall be recorded. These in- jected to a specified dosage of UV radi- clude several types of typical responses ation, in a series of UV radiation expo- such as the following: An immediate sures, in which the test site area is ex- darkening or tanning, typically greyish posed for the determination of the or purplish in color, fading in 30 to 60 MED. minutes, and attributed to photo-oxi- (e) Application of test materials. To ensure 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 being evaluated at the same time, the range of 450 to 550 lux, and the test sub- test products and the standard sun- ject should be in the same position screen, as specified in § 352.70, should be used when the test site was irradiated. applied in a blinded, randomized man- Testing depends upon determining the ner. If only one sunscreen drug product smallest dose of energy that produces is being tested, the testing subsites redness reaching the borders of the ex- should be exposed to the varying doses posure site at 22 to 24 hours of UV radiation in a randomized man- postexposure for each series of expo- ner. sures. To determine the MED, some- (f) Waiting period. Before exposing the what more intense erythemas must test site areas after applying a product, also be produced. The goal is to have a waiting period of at least 15 minutes some exposures that produce abso- is required. lutely no effect, and of those exposures

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that produce an effect, the maximal ex- § 352.73 Determination of SPF value. posure should be no more than twice (a)(1) The following erythema action the total energy of the minimal exposure. spectrum shall be used to calculate the (i) Rejection of test data. Test data erythema effective exposure of a solar shall be rejected if the exposure series simulator: fails to elicit an MED response on ei- Vi (λ)=1.0 (250 < λ < 298 nm) 0.094 (298 - λ ther the treated or unprotected skin Vi (λ)=1.0 ) (298 < λ < 328 sites, or if the responses on the treated nanometers) 0.015 (139 - λ sites are randomly absent (which indi- Vi (λ)=1.0 ) (328 < λ < 400 cates the product was not spread even- nanometers) ly), or if the subject was noncompliant (2) The data contained in this action (e.g., subject withdraws from the test spectrum are to be used as spectral due to illness or work conflicts, subject weighting factors to calculate the ery- does not shield the exposed testing thema effective exposure of a solar sites from further UV radiation until simulator as follows: the MED is read, etc.).

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

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(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. Sixth shall consist of a geometric series of and last, the drug product is classified five exposures, where the middle expo- into a PCD as follows: if 30 + A < x¯ , the sure is placed to yield the expected PCD is High; if 12 + A < x¯ < 30 + A, the SPF plus two other exposures placed PCD is Moderate; if 2 + A < x¯ < 12 + A, symmetrically around the middle expo- the PCD is Minimal; if x¯ < 2 + A, the sure. The exact series of exposures to be given to the protected skin shall be product shall not be labeled as a sun- determined by the previously estab- screen drug product and shall not dis- lished MED(US) and the expected SPF play an SPF value. of the test sunscreen. For products § 352.76 Determination if a product is with an expected SPF less than 8, the water resistant or very water resist- exposures shall be the MED(US) times ant. 0.64X, 0.80X, 0.90X, 1.00X, 1.10X, 1.25X, and 1.56X, where X equals the expected The general testing procedures in SPF of the test product. For products § 352.72 shall be used as part of the fol- with an expected SPF between 8 and 15, lowing tests, except where modified in the exposures shall be the MED(US) this section. An indoor fresh water times 0.69X, 0.83X, 0.91X, 1.00X, 1.09X, pool, whirlpool, and/or jacuzzi main- 1.20X, and 1.44X, where X equals the ex- tained at 23 to 32 °C shall be used in pected SPF of the test product. For these testing procedures. Fresh water products with an expected SPF greater is clean drinking water that meets the that 15, the exposures shall be the standards in 40 CFR part 141. The pool MED(US) times 0.76X, 0.87X, 0.93X, and air temperature and the relative 1.00X, 1.07X, 1.15X, and 1.32X, where X humidity shall be recorded. equals the expected SPF of the test (a) Procedure for testing the water re- product. The MED is the quantity of sistance of a sunscreen product. For sun- erythema-effective energy required to screen products making the claim of produce the first perceptible, unambig- ‘‘water resistant,’’ the label SPF shall uous redness reaction with clearly de- be the label SPF value determined fined borders at 22 to 24 hours after 40 minutes of water immersion postexposure. The SPF value of the using the following procedure for the test sunscreen is then calculated from water resistance test: the dose of UV radiation required to (1) Apply sunscreen product (followed produce the MED of the protected skin by the waiting period after application and from the dose of UV radiation re- of the sunscreen product indicated on quired to produce the MED of the un- the product labeling). protected skin (control site) as follows: (2) 20 minutes moderate activity in SPF value =the ratio of erythema effective exposure (Joules per square water. meter) (MED(PS)) to the erythema ef- (3) 20-minute rest period (do not fective exposure (Joules per square towel test sites). meter) (MED(US)). (4) 20 minutes moderate activity in (d) Determination of the test product’s water. SPF value and PCD. Use data from at (5) Conclude water test (air dry test least 20 test subjects with n rep- sites without toweling). resenting the number of subjects used. (6) Begin solar simulator exposure to First, for each subject, compute the test site areas as described in § 352.73.

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(b) Procedure for testing a very water PART 355—ANTICARIES DRUG resistant sunscreen product. For sun- PRODUCTS FOR OVER-THE- screen products making the claim of COUNTER HUMAN USE ‘‘very water resistant,’’ the label SPF shall be the label SPF value deter- Subpart A—General Provisions mined after 80 minutes of water immersion using the following procedure for Sec. 355.1 Scope. the very water resistant test: 355.3 Definitions. (1) Apply sunscreen product (followed by the waiting period after application Subpart B—Active Ingredients of the sunscreen product indicated on 355.10 Anticaries active ingredients. the product labeling). 355.20 Packaging conditions. (2) 20 minutes moderate activity in water. Subpart C—Labeling (3) 20-minute rest period (do not 355.50 Labeling of anticaries drug products. towel test sites). 355.55 Principal display panel of all fluoride (4) 20 minutes moderate activity in rinse drug products. water. 335.60 Professional labeling. (5) 20-minute rest period (do not Subpart D—Testing Procedures towel test sites). (6) 20 minutes moderate activity in 355.70 Testing procedures for fluoride den- water. tifrice drug products. (7) 20-minute rest period (do not AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, towel test sites). 360, 371. (8) 20 minutes moderate activity in SOURCE: 60 FR 52507, Oct. 6, 1995, unless water. otherwise noted. (9) Conclude water test (air dry test EDITORIAL NOTE: Nomenclature changes to sites without toweling). part 355 appear at 69 FR 13717, Mar. 24, 2004. (10) Begin solar simulator exposure to test site areas as described in Subpart A—General Provisions § 352.73. § 355.1 Scope. § 352.77 Test modifications. (a) An over-the-counter anticaries The formulation or mode of adminis- drug product in a form suitable for top- tration of certain products may require ical administration to the teeth is gen- modification of the testing procedures erally recognized as safe and effective in this subpart. In addition, alternative and is not misbranded if it meets each methods (including automated or in condition in this part and each general vitro procedures) employing the same condition established in § 330.1 of this basic procedures as those described in chapter. this subpart may be used. Any proposed (b) References in this part to regulatory sections of the Code of Federal modification or alternative procedure Regulations are to chapter I of title 21 shall be submitted as a petition in ac- unless otherwise noted. cord with § 10.30 of this chapter. The petition should contain data to support § 355.3 Definitions. the modification or data dem- As used in this part: onstrating that an alternative proce- (a) Abrasive. Solid materials that are dure provides results of equivalent ac- added to dentifrices to facilitate me- curacy. All information submitted will chanical removal of dental plaque, de- be subject to the disclosure rules in bris, and stain from tooth surfaces. part 20 of this chapter. (b) Anhydrous glycerin. An ingredient that may be prepared by heating glycerin U.S.P. at 150 –C for 2 hours to drive off the moisture content. (c) Anticaries drug. A drug that aids 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 312

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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, April 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] 337

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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—500)

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 100—199) II Office of Management and Budget Circulars and Guidance (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) VIII Department of Veterans Affairs (Parts 800—899) IX Department of Energy (Parts 900—999) 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 1880— 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 Housing and Urban Development (Parts 2400—2499) XXV National Science Foundation (Parts 2500—2599) XXVI National Archives and Records Administration (Parts 2600—2699) XXVII Small Business Administration (Parts 2700—2799) XXVIII Department of Justice (Parts 2800—2899) XXX Department of Homeland Security (Parts 3000—3099)

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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) XXXV Export-Import Bank of the United States (Parts 3500—3599) XXXVII Peace Corps (Parts 3700—3799) LVIII Election Assistance Commission (Parts 5800—5899)

Title 3—The President

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

Title 4—Accounts

I Government Accountability Office (Parts 1—99) II Recovery Accountability and Transparency Board (Parts 200— 299)

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) 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) XV Office of Administration, Executive Office of the President (Parts 2500—2599) 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) 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)

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XXXV Office of Personnel Management (Parts 4500—4599) 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) LXXI Consumer Product Safety Commission (Parts 8100—8199) LXXII Special Inspector General for Iraq Reconstruction (Parts 8200— 8299) LXXIII Department of Agriculture (Parts 8300—8399) 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 8700—8799) LXXXII Special Inspector General for Iraq Reconstruction (Parts 9200— 9299) XCVII Department of Homeland Security Human Resources Manage- ment System (Department of Homeland Security—Office of Personnel Management) (Parts 9700—9799)

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XCIX Department of Defense Human Resources Management and Labor Relations Systems (Department of Defense—Office of Personnel Management) (Parts 9900—9999)

Title 6—Domestic Security

I Department of Homeland Security, Office of the Secretary (Parts 0—99)

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) 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)

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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) L Rural Business-Cooperative Service, Rurual Housing Service, and Rural Utilities Service, Department of Agriculture (Parts 5000—5099)

Title 8—Aliens and Nationality

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)

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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 1303—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) XI Federal Financial Institutions Examination Council (Parts 1100—1199) XII Federal Housing Finance Agency (Parts 1200—1299) XIV Farm Credit System Insurance Corporation (Parts 1400—1499) XV Department of the Treasury (Parts 1500—1599) 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)

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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—499) 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) XI Technology Administration, Department of Commerce (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)

Title 16—Commercial Practices

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

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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)

Title 20—Employees’ Benefits

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

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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 Millenium 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) 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 HousingCommissioner, Department of Housing and Urban De- velopment (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)

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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) XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Parts 3200—3899) XXIV Board of Directors of the HOPE for Homeowners Program (Parts 4000—4099) 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—799) V Bureau of Indian Affairs, Department of the Interior, and Indian Health Service, Department of Health and Human Services (Part 900) 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)

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I Internal Revenue Service, Department of the Treasury (Parts 1— 899)

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)

Title 29—Labor

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)

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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 Ocean Energy Management, Regulation, and Enforce- ment, Department of the Interior (Parts 200—299) IV Geological Survey, Department of the Interior (Parts 400—499) 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) 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 International Investment, 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, Departmnent 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)

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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 (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) 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 Vocational and Adult Education, Department of Edu- cation (Parts 400—499) V Office of Bilingual Education and Minority Languages Affairs, Department of Education (Parts 500—599) VI Office of Postsecondary Education, Department of Education (Parts 600—699) VII Office of Educational Research and Improvmeent, Department of Education [Reserved] XI National Institute for Literacy (Parts 1100—1199) SUBTITLE C—REGULATIONS RELATING TO EDUCATION 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)

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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 Copyright Office, Library of Congress (Parts 200—299) III Copyright Royalty Board, Library of Congress (Parts 301—399) IV Assistant Secretary for Technology Policy, Department of Com- merce (Parts 400—499) V Under Secretary for Technology, Department of Commerce (Parts 500—599)

Title 38—Pensions, Bonuses, and Veterans’ Relief

I Department of Veterans Affairs (Parts 0—99) II Armed Forces Retirement Home

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)

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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] 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) IV Centers for Medicare & Medicaid Services, Department of Health and Human Services (Parts 400—499) V Office of Inspector General-Health Care, Department of Health and Human Services (Parts 1000—1999)

Title 43—Public Lands: Interior

SUBTITLE A—OFFICE OF THE SECRETARY OF THE INTERIOR (PARTS 1—199) SUBTITLE B—REGULATIONS RELATING TO PUBLIC LANDS

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I Bureau of Reclamation, Department of the Interior (Parts 200— 499) 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) 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) [Reserved] 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 Office of Human Development Services, 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 on Fine Arts (Parts 2100—2199) XXIII Arctic Research Commission (Part 2301) XXIV James Madison Memorial Fellowship Foundation (Parts 2400— 2499)

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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) IV National Telecommunications and Information Administration, Department of Commerce, and National Highway Traffic Safe- ty Administration, Department of Transportation (Parts 400— 499)

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 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)

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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 [Reserved] 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) 63 Department of Transportation Board of Contract Appeals (Parts 6300—6399) 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)

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X Surface Transportation Board, Department of Transportation (Parts 1000—1399) XI Research and Innovative Technology Administration, Depart- ment of Transportation [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) VI Fishery Conservation and Management, National Oceanic and Atmospheric Administration, Department of Commerce (Parts 600—699)

CFR Index and Finding Aids

Subject/Agency Index List of Agency Prepared Indexes Parallel Tables of Statutory Authorities and Rules List of CFR Titles, Chapters, Subchapters, and Parts Alphabetical List of Agencies Appearing in the CFR

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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 Advanced Research Projects Agency 32, I Advisory Council on Historic Preservation 36, VIII African Development Foundation 22, XV Federal Acquisition Regulation 48, 57 Agency for International Development 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 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, L Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV, L Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII, L 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 Animal and Plant Health Inspection Service 7, III; 9, I Appalachian Regional Commission 5, IX

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2001 21 CFR—Continued 67 FR Page 21 CFR 66 FR Chapter I—Continued Page 312.47 OMB number ...... 9586 Chapter I 312.53 OMB number ...... 9586 310 Technical correction ...... 53088 312.55 OMB number ...... 9586 310.545 (a)(6)(iv)(D) and (d)(33) 312.56 OMB number ...... 9586 added; (d) introductory text re- 312.57 OMB number ...... 9586 vised...... 49277 312.59 OMB number ...... 9586 314.81 Regulation at 65 FR 64617 312.62 OMB number ...... 9586 eff. Date delayed to 4-30-01...... 10815 312.64 OMB number ...... 9586 314.430 (f)(6) amended ...... 1832 312.66 OMB number ...... 9586 341 Policy statement ...... 49276 312.70 OMB number ...... 9586 352 Stayed ...... 67485 312.110 OMB number ...... 9586 312.120 OMB number ...... 9586 2002 312.140 OMB number ...... 9586 21 CFR 67 FR 312.160 OMB number ...... 9586 Page 314.50 OMB number ...... 9586 Chapter I 314.70 OMB number ...... 9586 310.103 (a)(3)(i) amended...... 4907 314.71 OMB number ...... 9586 310.305 OMB number ...... 9585 314.72 OMB number ...... 9586 310.500 Removed ...... 42997 314.80 OMB number ...... 9586 310.545 (a)(28)(i) heading added; 314.90 OMB number ...... 9586 (a)(28)(ii) and (d)(34) through 314.94 (a)(9)(ii), (iii) and (iv) (36) added; (d)(28) revised...... 31125 amended; (a)(9)(v) revised ...... 77672 (a)(12)(iv)(C) and (d)(30) added...... 31127 314.126 OMB number ...... 9586 312.7 OMB number ...... 9585 314.127 (a)(8)(ii)(A) introductory 312.10 OMB number ...... 9585 text, (B) and (C) amended ...... 77672 312.23 OMB number ...... 9585 314.200 OMB number ...... 9586 312.30 OMB number ...... 9585 314.420 OMB number ...... 9586 312.31 OMB number ...... 9585 314.600—314.650 (Subpart I) 312.32 OMB number ...... 9585 Added ...... 37995 312.33 OMB number ...... 9585 320.1 (c) revised; (e) amended...... 77672 312.35 OMB number ...... 9585 320.21 (d)(1) removed; (d)(2) and (3) 312.36 OMB number ...... 9585 redesignated as (d)(1) and (2); 312.38 OMB number ...... 9586 (a)(1), (2), (b)(1), (2), (c)(1), new 312.41 OMB number ...... 9586 (d)(2)(i), new (ii), (e), (f), (g) in- 312.44 OMB number ...... 9586 troductory text, (2) and (h) re- 312.45 OMB number ...... 9586 vised...... 77672

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21 CFR—Continued 67 FR 2003 Page 21 CFR 68 FR Chapter I—Continued Page 320.22 (a), (b)(1)(ii), (2)(ii), (3)(i), Chapter I (ii), (iii), (c), (d) introductory text, (2)(i), (iv) and (4)(i) re- 310.518 Revised ...... 59715 vised; (b) introductory text and 310.538 (a) amended; (e) added...... 24348 (e) amended ...... 77673 310.545 (a)(3)(i) heading, (ii) and (d)(17) added; (d)(1) revised; eff. 320.23 Heading revised; (a)(1) 4–19–04 ...... 18881 amended...... 77673 (a)(18)(i), (v), (vi), and (d)(1) re- 320.24 Heading, (b)(5), (6) and (c) vised; (d)(32) added; eff. 6–4–04 introductory text revised; (a) ...... 33376 and (b)(4) amended ...... 77673 (a)(4) redesignated as (a)(4)(i); 320.25 (a)(2) removed; (a)(3) redes- new (a)(4)(i) heading, (ii) and ignated as (a)(2); new (a)(2), (d)(34) added; (d)(1) revised; eff. (d)(1), (e)(1) introductory text, 12–9–04...... 34291 (i) and (f) heading revised; (f) (a)(26)(xi) and (d)(37) added; (d) amended...... 77674 introductory text and (13) re- 320.26 Heading and (a)(1) revised ...... 51170 vised...... 77674 (d)(1) corrected; eff. 4–19–04 ...... 37963 320.27 (a)(3)(iv), (d)(1) and (2) re- 312 Nomenclature change ...... 24879 vised; (b)(2) and (3)(i) amend- 314 Nomenclature change ...... 24879 ed ...... 77674 314.50 (l)(1) revised; (l)(4) heading 320.28 Amended...... 77674 added; (l)(2) and (3) amended; 320.29 Heading and (a) revised; (b) (l)(5) added; eff. 6–8–04...... 69019 amended...... 77674 314.52 (a)(3) redesignated as (a)(4); 320.30 (c) revised ...... 77674 new (a)(3) added ...... 36703 314.53 (b), (c)(1), (2) and (3) re- 320.31 (b) introductory text and vised...... 36703 (3) amended ...... 77674 314.65 Amended...... 25287 329 Removed ...... 4907 314.72 (a)(2)(iii) amended...... 25287 330 Compliance date extension...... 16304 314.81 (b)(2)(iii) revised; eff. 6–8– 330.10 Amended ...... 3073 04...... 69019 330.13 (e) added...... 3074 314.94 (d)(1) revised; eff. 6–8–04 ...... 69019 330.14 Added ...... 3074 314.95 (a)(3) redesignated as (a)(4); 331 Compliance date extension...... 16304 new (a)(3) added ...... 36705 333 Technical correction...... 11571 328 Nomenclature change ...... 24879 333.210 (g) added...... 5943 330 Nomenclature change ...... 24879 336.50 (c)(8) added; eff. 12–8–03 ...... 72559 335 Added; eff. 4–19–04...... 18881 341.40 Corrected; eff. 12–23–04...... 17881 338.50 (c)(5) added; eff. 12–8–03 ...... 72559 341.70 (b) corrected; eff. 12–23– 341 Compliance date extension...... 16304 04...... 17881 341.14 (a)(2) amended...... 4907 347.1—347.50 (Subpart A) Heading 341.40 Added; eff. 12–23–04 ...... 78168 revised; eff. 6–4–04 ...... 33376 341.70 (b) added; eff. 12–23–04 ...... 78170 347.3 Revised; eff. 6–4–04 ...... 33376 341.72 (c)(6)(iv) and (7) added; eff. 347.10—347.20 (Subpart B) Des- 12–8–03 ...... 72559 ignation and heading added; 341.74 (c)(4)(viii)(C) and (ix)(C) eff. 6–4–04 ...... 33377 added; eff. 12–8–03 ...... 72559 347.10 Redesignated as 347.12; new 341.85 Added; eff. 12–23–04 ...... 78170 347.10 added; eff. 6–4–04...... 33377 346 Compliance date extension...... 16304 347.12 Redesignated from 347.10; 352.10 (f) through (n) revised...... 41823 eff. 6–4–04 ...... 33377 347.20 Added; (d) suspended; eff. 6– 352.20 (a)(1) and (2) revised...... 41823 4–04...... 33377 355 Compliance date extension...... 16304 347.50—347.60 (Subpart C) Des- 358 Compliance date extension...... 16304 ignation and heading added; 361.1 (f)(1) amended...... 4907 eff. 6–4–04 ...... 33377 369 Compliance date extension...... 16304 347.50 Redesignated as 347.52; new 369.22 Removed ...... 4907 347.50 added; eff. 6–4–04...... 33377

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21 CFR—Continued 68 FR 21 CFR—Continued 69 FR Page Page Chapter I—Continued Chapter I—Continued (b)(2), (e)(1)(ii) and (f)(1)(ii) re- 314.95 (a)(3) removed; (a)(4) redes- vised; eff. 6–4–04 ...... 68511 ignated as (a)(3) ...... 11310 347.52 Redesignated from 347.50; 314.200 (a)(3) amended ...... 48775 eff. 6–4–04 ...... 33377 314.410 (b)(2) amended ...... 18766 (c)(4) and (e) added; (d)(1)(i), (ii) 314.420 (a)(5) amended ...... 13473 and (3) revised ...... 35293 314.430 (e)(6) amended ...... 18766 Regulation at 68 FR 35293 con- 314.440 (a)(1) amended ...... 13473 firmed...... 58273 316 Nomenclature change ...... 13717 347.60 Added; eff. 6–4–04 ...... 33377 328 Nomenclature change ...... 13717 349.12 (a)(3) amended...... 32982 330 Nomenclature change ...... 13717 349.20 Revised ...... 7921 331.30 (c)(4) and (5) removed; (c)(6) 349.78 (a) revised...... 7921 redesignated as new (c)(4); eff. 350 Added; eff. 12–9–04...... 34291 4–23–04 ...... 13734 352 Regulation at 66 FR 67485 rein- 335.3 (c) added ...... 26302 stated; eff. 6–4–04...... 33380 335.50 (b)(1) revised ...... 26302 Suspended; eff. 6–4–04 ...... 33381 341 Nomenclature change ...... 13717 347 Technical correction ...... 3005 352.20 (b) added; eff. 6–4–04 ...... 33380 350.50 Regulation at 68 FR 34291 352.52 (c)(2) heading, (d)(4) head- stayed in part ...... 61148 ing, (f)(1)(ii) and (vi) revised; 355 Nomenclature change ...... 13717 eff. 6–4–04 ...... 33380 369 Nomenclature change ...... 13717 352.60 (b)(2), (c) and (d) revised; eff. 6–4–04 ...... 33380 355 Nomenclature change ...... 24879 2005 358.301—358.350 (Subpart D) 21 CFR 70 FR Added ...... 24348 Page 358.650 Revised; eff. 6–30–05...... 75417 Chapter I 369.20 Amended; eff. 4–19–04 ...... 18882 310.4 (b) amended ...... 14981 Amended; eff. 12–9–04...... 34293 310.545 (a)(6)(ii)(C) added; eff. 4– 11–07 ...... 58977 2004 312 Authority citation revised ...... 70729 312.110 (b) revised; (c) and (d) 21 CFR 69 FR Page added...... 70729 312.140 Revised ...... 14981 Chapter I 314.440 (b) revised...... 14981 310.545 (a)(18)(v)(A) and (vi)(A) 341.80 (b)(1)(iii) removed; eff. 4– headings, (d)(1) and (d)(11) re- 11–07 ...... 58977 vised...... 51362 341.85 (b)(2) heading, (ii) and (3) 312 Nomenclature change ...... 13717 heading amended; eff. 4–11– 312.36 Revised ...... 17927 07...... 58977 312.140 (a) amended ...... 13473 314 Nomenclature change ...... 13717 314.3 (b) amended ...... 18763 2006 314.50 (d)(1)(i), (ii), (a), (b), (v), 21 CFR 71 FR (3)(i), (ii), (4)(iv), (e)(1) intro- Page ductory text and (2)(i) amend- Chapter I ed ...... 18763 314.70 (b)(2)(v)(B) amended; 314.52 (a)(3) removed; (a)(4) redes- (b)(2)(v)(C) added; (c)(6)(iii) in- ignated as (a)(3) ...... 11310 troductory text and (d)(2)(x) 314.53 (d)(4) amended...... 13473 revised; eff. 6-30-06 ...... 3997 314.60 (c) amended...... 18764 341.3 (i) added...... 43362 314.70 Revised ...... 18764 341.20 (a)(4) added...... 43362 314.80 (c) introductory text 341.80 (c)(1)(i) heading and (ii) amended...... 13473 heading revised; (d)(1)(iii) 314.81 (b)(1)(ii) amended...... 18766 added...... 43362 (b)(3)(iii)(b) amended ...... 48775 341.85 (b)(2) and (3) headings re- 314.94 (d)(2) amended...... 18766 vised...... 43362

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2007 21 CFR—Continued 73 FR Page 21 CFR 72 FR Chapter I—Continued Page 314.120 Removed ...... 39610 Chapter I 314.125 (a)(1) amended ...... 39610 310.200 (a), (b) and (e) amended...... 15043 314.430 (b) amended ...... 39610 310.201 (a) amended ...... 15043 314.440 (a)(1), (3) and (b) introduc- 310.201 (a)(20) removed ...... 67640 tory text amended; (a)(2) re- 310.545 (d)(3) revised; eff. 4–5–07 ...... 9852 vised...... 39610 (a)(12)(i) redesignated as 347.50 (a) and (e)(1)(iii) revised ...... 6017 (a)(12)(i)(A); (a)(12)(i)(B) and (d)(38) added; (d) introductory 2009 text and (1) revised; eff. 10–1–07 ...... 14674 21 CFR 74 FR 312.6 (c) added; interim ...... 73599 Page 314 Authority citation revised ...... 58999 Chapter I 314.70 (a)(1) revised; interim...... 73600 310.6 (e) amended ...... 13113 314.81 (b)(3)(iii) redesignated as 310.305 (c) amended; (d)(4) re- (b)(3)(iv); new (b)(3)(iii) added; vised...... 13113 new (b)(3)(iv)(c) amended ...... 58999 310.501 (e) amended ...... 13113 314.91 Added ...... 58999 310.515 (d) amended ...... 13113 341.40 Transferred from Subpart 310.545 (a)(18)(ii) amended; (d) in- C to Subpart B...... 12730 troductory text and (11) re- 358.720 Revised; eff. 4–5–07...... 9852 vised; (d)(39) added ...... 9764 358.760 Added; eff. 4–5–07 ...... 9852 312 Authority citation revised ...... 40942 369.21 Amended...... 67640 312.7 Heading revised; (d) removed ...... 40899 2008 312.8 Added ...... 40899 312.30 (c) revised ...... 40942 21 CFR 73 FR 312.34 Removed...... 40942 Page 312.35 Removed...... 40942 Chapter I 312.36 Removed...... 40942 312.3 (b) amended ...... 22815 312.42 (b)(3) revised ...... 40942 312.84 (c) amended...... 39607 312.140 (b) amended ...... 13113 312.120 Revised ...... 22815 (a)(1) revised ...... 55771 314 Authority citation revised ...... 39607 312.145 (b) amended ...... 13113 314.3 (b) amended ...... 39607, 49609, 56491 312.300—312.320 (Subpart I) 314.50 (d)(5)(vi)(b) amended ...... 39608 Added ...... 40942 314.60 (b) and (c) redesignated as 314.3 Regulation at 73 FR 56491 new (c) and (d); new (b) added; withdrawn ...... 6541 heading, (a), new (c)(1)(iii) and (b) amended ...... 37167 (iv) revised; new (c)(2) amend- 314.52 (a)(2) amended ...... 9766, 36605 ed ...... 39608 314.53 (f) amended...... 9766, 36605 314.65 Amended...... 39609 314.80 (d)(2) amended; (f)(3)(ii) and 314.70 (c)(6)(iii) introductory text (4) revised ...... 13113 and (A) revised...... 49609 314.81 Regulation at 73 FR 56491 314.71 (c) amended...... 39609 withdrawn ...... 6541 314.81 (b)(2)(ii) redesignated as (b)(3)(i) amended ...... 13113 (b)(2)(ii)(a); (b)(2)(ii)(b) (b)(2)(ii) redesignated as added...... 56491 (b)(2)(ii)(a); (b)(2)(ii)(b) added 314.96 (a)(2) revised; (a)(3) re- ...... 37167 moved ...... 39609 314.94 (a)(7)(i) revised; eff. 7–15– 314.100 Revised ...... 39609 09 ...... 2861 314.101 (f)(1)(ii) revised; (f)(2) 314.95 (a)(2) amended ...... 9766, 36605 amended...... 39609 314.96 (a)(1) amended; eff. 7–15– 314.102 (b) amended; (d) revised...... 39609 09 ...... 2861 314.103 (c)(1) amended ...... 39609 314.98 (b) amended ...... 13113 314.105 (b) amended ...... 39609 314.107 (e) and (f)(2)(iv) amend- 314.107 (b)(3)(v) amended ...... 39609 ed...... 9766 314.110 Revised ...... 39609 314.125 (b)(16) amended ...... 9766

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21 CFR—Continued 74 FR 21 CFR—Continued 75 FR Page Page Chapter I—Continued 312.64 (b) revised ...... 59963 314.200 (a)(3) amended ...... 13113 312.140 (a)(1) amended ...... 37295 314.440 (a) introductory text and 312.310 (d)(1) revised...... 32659 (1) revised ...... 13113 314.440 (a)(2) amended ...... 37295 314.445 (b) amended ...... 13113 316.40 Revised ...... 40945 320.31 (d)(1) and (2) amended; 320.1 (g) added; eff. 7–15–09...... 2861 (d)(3) added ...... 59963 320.21 Heading and (b)(1) revised; 333.310 Revised; eff. 3–4–11...... 9776 eff. 7–15–09 ...... 2862 333.320 Revised; eff. 3–4–11...... 9776 320.30 (c)(1) amended...... 13114 333.350 (c) and (d) revised; (e) re- 347.20 (b), (c) and (d) redesignated moved; eff. 3–4–11...... 9776 as (c), (d) and (e); new (b) added ...... 9765 2011 347.52 (a), (b)(1) heading, (c) and (d)(1) revised; (d)(4) added ...... 9765 (Regulations published from January 1, 2011 through April 1, 2011)

2010 21 CFR 76 FR Page 21 CFR 75 FR Page 312.83 Amended...... 13880 312.32 Revised ...... 59961 314.94 (a)(8)(iv) amended ...... 13880 Æ

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