Food and Drugs

21 Parts 300 to 499 Revised as of April 1, 2004

Food and Drugs

Containing a codification of documents of general applicability and future effect

As of April 1, 2004

With Ancillaries

Published by Office of the Federal Register National Archives and Records Administration

A Special Edition of the Federal Register

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For sale by the Superintendent of Documents, U.S. Government Printing Office Internet: bookstore.gpo.gov Phone: toll free (866) 512-1800; DC area (202) 512-1800 Fax: (202) 512-2250 Mail: Stop SSOP, Washington, DC 20402–0001

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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:

Material Approved for Incorporation by Reference ...... 335

Table of CFR Titles and Chapters ...... 337

Alphabetical List of Agencies Appearing in the CFR ...... 355

List of CFR Sections Affected ...... 365

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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, 2004), 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<24>2004 15:46 Apr 22, 2004 Jkt 203068 PO 00000 Frm 00005 Fmt 8008 Sfmt 8092 Y:\SGML\203068F.XXX 203068F 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 January 1, 2001, consult either the List of CFR Sections Affected, 1949–1963, 1964–1972, 1973–1985, or 1986–2000, published in 11 separate volumes. For the period beginning January 1, 2001, a ‘‘List of CFR Sections Affected’’ is published at the end of each CFR volume. 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. Properly approved incorporations by reference in this volume are listed in the Finding Aids at the end of this volume. What if the material incorporated by reference cannot be found? If you have any problem locating or obtaining a copy of material listed in the Finding Aids of this volume 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, Washington DC 20408, 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 Statutory Authorities and Agency Rules (Table I). A list of CFR titles, chapters, 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. 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.

VerDate mar<24>2004 15:46 Apr 22, 2004 Jkt 203068 PO 00000 Frm 00006 Fmt 8008 Sfmt 8092 Y:\SGML\203068F.XXX 203068F 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, Washington, DC 20408 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 202–512–2250, 24 hours a day. For payment by check, write to the Superintendent of Documents, Attn: New Orders, P.O. Box 371954, Pittsburgh, PA 15250–7954. For GPO Customer Serv- ice call 202–512–1803. ELECTRONIC SERVICES The full text of the Code of Federal Regulations, The United States Govern- ment Manual, the Federal Register, Public Laws, Public Papers, Weekly Compila- tion of Presidential Documents and the Privacy Act Compilation are available in electronic format at www.gpoaccess.gov/nara. For more information, contact Electronic Information Dissemination Services, U.S. Government Printing Office. Phone 202–512–1530, or 888–293–6498 (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/federallregister. The NARA site also contains links to GPO Access.

RAYMOND A. MOSLEY, Director, Office of the Federal Register. April 1, 2004.

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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–end. The first eight volumes, containing parts 1–1299, comprise Chapter I—Food and Drug Administration, Department of Health and Human Services. The ninth volume, containing part 1300 to end, includes Chapter II—Drug Enforcement Administration, Department of Justice, 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, 2004.

For this volume, Bonnie Fritts was Chief Editor. The Code of Federal Regula- tions publication program is under the direction of Frances D. McDonald, assisted by Alomha S. Morris.

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VerDate mar<24>2004 15:46 Apr 22, 2004 Jkt 203068 PO 00000 Frm 00010 Fmt 8092 Sfmt 8092 Y:\SGML\203068F.XXX 203068F CFRORDR.FRM Title 21—Food and Drugs

(This book contains parts 300 to 499)

Part

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

CROSS REFERENCES: Food Safety and Inspection Service, Department of Agriculture: See 9 CFR chapter III. Federal Trade Commission: See Commercial Practices, 16 CFR chapter I. United States Customs Service, Department of the Treasury: See Customs Duties, 19 CFR chapter I. Internal Revenue Service, Department of the Treasury: See Internal Revenue, 26 CFR chapter I. Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury: See Alcohol, To- bacco Products and Firearms, 27 CFR chapter I.

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(Parts 300 to 499)

EDITORIAL NOTE: For nomenclature changes to chapter I see 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 ...... 51 314 Applications for FDA approval to market a new drug ...... 88 315 Diagnostic radiopharmaceuticals...... 171 316 Orphan drugs...... 173 320 Bioavailability and bioequivalence requirements ... 185 328 Over-the-counter drug products intended for oral ingestion that contain alcohol ...... 199 330 Over-the-counter (OTC) human drugs which are generally recognized as safe and effective and not misbranded ...... 201 331 Antacid products for over-the-counter (OTC) human use ...... 218 332 Antiflatulent products for over-the-counter human use ...... 221 333 Topical antimicrobial drug products for over-the- counter human use ...... 222 335 Antidiarrheal drug products for over-the-counter human use ...... 230 336 Antiemetic drug products for over-the-counter human use ...... 232 338 Nighttime sleep-aid drug products for over-the- counter human use ...... 234 340 Stimulant drug products for over-the-counter human use ...... 235 3

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Part Page 341 Cold, cough, allergy, bronchodilator, and antiasthmatic drug products for over-the-counter human use ...... 236 343 Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use .... 259 344 Topical OTIC drug products for over-the-counter human use ...... 266 346 Anorectal drug products for over-the-counter human use ...... 268 347 Skin protectant drug products for over–the– counter human use ...... 273 348 External analgesic drug products for over–the– counter human use ...... 282 349 Ophthalmic drug products for over-the-counter human use ...... 283 350 Antiperspirant drug products for over-the-counter human use ...... 289 352 Sunscreen drug products for over-the-counter human use [stayed indefinitely] ...... 291 355 Anticaries drug products for over-the-counter human use ...... 302 357 Miscellaneous internal drug products for over-the- counter human use ...... 306 358 Miscellaneous external drug products for over-the- counter human use ...... 310 361 Prescription drugs for human use generally recognized as safe and effective and not misbranded: Drugs used in research ...... 320 369 Interpretative statements re warnings on drugs and devices for over-the-counter sale ...... 325 370–499 [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 ornuclide (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(b) of branding) of the act. this chapter. (b)(1) An identical, related, or similar drug includes other brands, potencies, [64 FR 56448, Oct. 20, 1999] dosage forms, salts, and esters of the § 310.6 Applicability of ‘‘new drug’’ or same drug moiety as well as of any safety or effectiveness findings in drug moiety related in chemical struc- drug efficacy study implementation ture or known pharmacological prop- notices and notices of opportunity erties. for hearing to identical, related, (2) Where experts qualified by sci- and similar drug products. entific training and experience to (a) The Food and Drug Administra- evaluate the safety and effectiveness of tion’s conclusions on the effectiveness drugs would conclude that the findings of drugs are currently being published and conclusions, stated in a drug effi- in the FEDERAL REGISTER as Drug Effi- cacy notice or notice of opportunity for 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 notices. All persons with an interest in (c) Manufacturers and distributors of a product that is identical, related, or drugs should review their products as similar to a drug listed in a drug effi- drug efficacy notices are published and cacy notice or a notice of opportunity assure that identical, related, or simi- for a hearing will be given the same op- lar products comply with all applicable portunity 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- drug application is withdrawn under tle and not readily recognized, the pur- provisions of section 505(e) of the Fed- chasing agent may request an opinion eral Food, Drug, and Cosmetic Act, a by writing to the Food and Drug Ad- drug generally recognized as safe may ministration at the address shown in become a ‘‘new drug’’ within the mean- paragraph (e) of this section. ing of section 201(p) of said act as (e) Interested parties may submit to amended by the Kefauver-Harris Act on the Food and Drug Administration, October 10, 1962. This is of special im- Center for Drug Evaluation and Re- portance by reason of proposed actions search, Office of Compliance, HFD–300, to withdraw approval of new drug ap- 5600 Fishers Lane, Rockville, MD 20857, plications for lack of substantial evi- the names of drug products, and of dence of effectiveness as a result of re- their manufacturers or distributors, ports of the National Academy of that should be the subject of the same Sciences—National Research Council purchasing and regulatory policies as on its review of drug effectiveness; for those reviewed by the Drug Efficacy example, see the notice published in Study Group. Appropriate action, in- the FEDERAL REGISTER of January 23, cluding referral to purchasing officials 1968 (33 FR 818), regarding rutin, quer- of various government agencies, will be cetin, et al. taken. (c) Any marketed drug is a ‘‘new (f) This regulation does not apply to drug’’ if any labeling change made OTC drugs identical, similar, or related after October 9, 1962, recommends or to a drug in the Drug Efficacy Study suggests new conditions of use under unless there has been or is notification which the drug is not generally recog- in the FEDERAL REGISTER that a drug nized as safe and effective by qualified will not be subject to an OTC panel re- experts. Undisclosed or unreported side view pursuant to §§ 330.10, 330.11, and effects as well as the emergence of new 330.5 of this chapter. knowledge presenting questions with respect to the safety or effectiveness of [39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 FR 8996, Mar. 6, 1985; a drug may result in its becoming a 55 FR 11578, Mar. 29, 1990] ‘‘new drug’’ even though it was previously considered ‘‘not a new drug.’’ Subpart B—Specific Administrative Any previously given informal advice that an article is ‘‘not a new drug’’ Rulings and Decisions does not apply to such an article if it § 310.100 New drug status opinions; has been changed in formulation, man- statement of policy. ufacture control, or labeling in a way that may significantly affect the safety (a) Over the years since 1938 the Food and Drug Administration has given in- of the drug. (d) For these reasons, all opinions formal advice to inquirers as to the new drug status of preparations. These previously given by the Food and Drug drugs have sometimes been identified Administration to the effect that an only by general statements of composi- article is ‘‘not a new drug’’ or is ‘‘no tion. Generally, such informal opinions longer a new drug’’ are hereby revoked. were incorporated in letters that did This does not mean that all articles not explicitly relate all of the nec- that were the subjects of such prior essary conditions and qualifications opinions will be regarded as new drugs. such as the quantitative formula for The prior opinions will be replaced by the drug and the conditions under opinions of the Food and Drug Admin- which it was prescribed, recommended, istration that are qualified and current or suggested. This has contributed to on when an article is ‘‘not a new drug,’’ misunderstanding and misinterpreta- as set forth in this subchapter. tion of such opinions. [39 FR 11680, Mar. 29, 1974] (b) These informal opinions that an article is ‘‘not a new drug’’ or ‘‘no § 310.103 New drug substances in- longer a new drug’’ require reexamina- tended for hypersensitivity testing. tion under the Kefauver-Harris Act (a) The Food and Drug Administra- (Public Law 87–781; 76 Stat. 788–89). In tion is aware of the need in the prac- particular, when approval of a new tice of medicine for the ingredients of

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a new drug to be available for tests of 1944, as amended. (See subchapter F— hypersensitivity to such ingredients Biologics, of this chapter.) and therefore will not object to the [39 FR 11680, Mar. 29, 1974, as amended at 55 shipment of a new drug substance, as FR 11578, Mar. 29, 1990; 67 FR 4907, Feb. 1, defined in § 310.3(g), for such purpose if 2002] all of the following conditions are met: (1) The shipment is made as a result Subpart C—New Drugs Exempted of a specific request made to the manu- From Prescription-Dispensing facturer or distributor by a practi- Requirements tioner licensed by law to administer such drugs, and the use of such drugs § 310.200 Prescription-exemption pro- for patch testing is not promoted by cedure. the manufacturer or distributor. (a) Duration of prescription require- (2) The new drug substance requested ment. Any drug limited to prescription is an ingredient in a marketed new use under section 503(b)(1)(C) of the act drug and is not one that is an ingre- remains so limited until it is exempted dient solely in a new drug that is le- as provided in paragraph (b) or (e) of gally available only under the inves- this section. tigational drug provisions of this part. (b) Prescription-exemption procedure for (3) The label bears the following drugs limited by a new drug application. prominently placed statements in lieu Any drug limited to prescription use of adequate directions for use and in under section 503(b)(1)(C) of the act addition to complying with the other shall be exempted from prescription- labeling provisions of the act: dispensing requirements when the (i) ‘‘Rx only’’; and Commissioner finds such requirements (ii) ‘‘For use only in patch testing’’. are not necessary for the protection of (4) The quantity shipped is limited to the public health by reason of the an amount reasonable for the purpose drug’s toxicity or other potentiality of patch testing in the normal course for harmful effect, or the method of its of the practice of medicine and is used use, or the collateral measures nec- solely for such patch testing. essary to its use, and he finds that the (5) The new drug substance is manu- drug is safe and effective for use in factured by the same procedures and self-medication as directed in proposed meets the same specifications as the labeling. A proposal to exempt a drug component used in the finished dosage from the prescription-dispensing re- form. quirements of section 503(b)(1)(C) of the 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. (c) This section does not apply to (d) Prescription legend not allowed on drugs or their components that are exempted drugs. The use of the prescrip- subject to the licensing requirements tion caution statement quoted in sec- of the Public Health Service Act of tion 503(b) (4) of the act, in the labeling

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of a drug exempted under the provi- grams (40 grains) per 24-hour period: for sions of this section, constitutes mis- children 6 to 12 years of age, one-half of branding. Any other statement or sug- the maximum adult dose or dosage; for gestion in the labeling of a drug ex- children 3 to 6 years of age, one-fifth of empted under this section, that such the maximum adult dose or dosage. drug is limited to prescription use, (vii) The labeling bears, in juxtaposi- may constitute misbranding. tion with the dosage recommendations, (e) Prescription-exemption procedure of a clear warning statement against ad- OTC drug review. A drug limited to pre- ministration of the drug to children scription use under section 503(b)(1)(C) under 3 years of age and against use of of the act may also be exempted from the drug for more than 10 days, unless prescription-dispensing requirements such uses are directed by a physician. by the procedure set forth in § 330.13 of (viii) If the article is offered for use this chapter. in arthritis or rheumatism, the labeling prominently bears a statement [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 FR 4714, Jan. 25, that the beneficial effects claimed are 1977; 42 FR 15674, Mar. 22, 1977] limited to the temporary relief of minor aches and pains of arthritis and § 310.201 Exemption for certain drugs rheumatism and, in juxtaposition with limited by new-drug applications to directions for use in such conditions, a prescription sale. conspicuous warning statement, such (a) The prescription-dispensing re- as ‘‘Caution: If pain persists for more quirements of section 503(b)(1)(C) of the than 10 days, or redness is present, or Federal Food, Drug, and Cosmetic Act in conditions affecting children under are not necessary for the protection of 12 years of age, consult a physician im- the public health with respect to the mediately’’. following drugs subject to new drug ap- (2) Sodium gentisate (sodium-2, 5-di- plications: hydroxybenzoate) preparations meet- (1) N-Acetyl-p-aminophenol (acetami- ing all the following conditions: nophen, p-hydroxy-acetanilid) prepara- (i) The sodium gentisate is prepared, tions meeting all the following condi- with or without other drugs, in tablet tions: or other dosage form suitable for oral (i) The N-acetyl-p-aminophenol is use in self-medication, and containing prepared, with or without other drugs, no drug limited to prescription sale in tablet or other dosage form suitable under the provisions of section 503(b)(1) for oral use in self-medication, and of the act. containing no drug limited to prescrip- (ii) The sodium gentisate and all tion sale under the provisions of sec- other components of the preparation tion 503(b)(1) of the act. meet their professed standards of iden- (ii) The N-acetyl-p-aminophenol and tity, strength, quality, and purity. all other components of the prepara- (iii) If the preparation is a new drug, tion meet their professed standards of an application pursuant to section identity, strength, quality, and purity. 505(b) of the act is approved for it. (iii) If the preparation is a new drug, (iv) The preparation contains not an application pursuant to section 505 more than 0.5 gram (7.7 grains) of anhy- (b) of the act is approved for it. drous sodium gentisate per dosage (iv) The preparation contains not unit. more than 0.325 gram (5 grains) of N- (v) The preparation is labeled with acetyl-p-aminophenol per dosage unit, adequate directions for use in minor or if it is in liquid form not more than conditions as a simple analgesic. 100 milligrams of N-acetyl-p-amino- (vi) The dosages of sodium gentisate phenol per milliliter. recommended or suggested in the label- (v) The preparation is labeled with ing do not exceed: For adults, 0.5 gram adequate directions for use in minor (7.7 grains) per dose of 2.0 grams (31 conditions as a simple analgesic. grains) per 24-hour period; for children (vi) The dosages of N-acetyl-p-amino- 6 to 12 years of age, one-half of the phenol recommended or suggested in maximum adult dose or dosage. the labeling do not exceed: For adults, (vii) The labeling bears, in juxtaposi- 0.65 gram (10 grains) per dose or 2.6 tion with the dosage recommendations,

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a clear warning statement against ad- form suitable for oral use in self-medi- ministration of the drug to children cation, and containing no drug limited under 6 years of age and against use of to prescription sale under the provi- the drug for a prolonged period, except sions of section 503(b)(1) of the act. as such uses may be directed by a phy- (ii) The phenyltoloxamine dihydro- sician. gen citrate and all other components of (3) Isoamylhydrocupreine and zola- the preparation meet their professed mine hydrochloride (N, N-dimethyl-N′- standards of identity, strength, qual- 2-thiazolyl-N′-p-methoxybenzyl-ethyl- ity, and purity. enediamine 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 isoamylhydrocupreine and zo- (iv) The preparation contains not lamine hydrochloride are prepared in more than 88 milligrams of phenyl- dosage form suitable for self-medica- toloxamine dihydrogen citrate (equiva- tion as rectal suppositories or as an lent to 50 milligrams of phenyltolox- ointment and containing no drug lim- amine) per dosage unit. ited to prescription sale under the pro- (v) The preparation is labeled with visions of section 503(b)(1) of the act. 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. case of rectal bleeding, as this may in- (5)–(7) [Reserved] dicate serious disease. (8) Dicyclomine hydrochloride (1- (4) Phenyltoloxamine dihydrogen cit- cyclohexylhexahydrobenzoic acid. b-di- rate (N,N-dimethyl-(a-phenyl-O-toloxy) ethylaminoethyl ester hydrochloride; ethylamine dihydrogen citrate), prep- diethylaminocarbethoxy-bicyclohexyl arations meeting all the following con- hydrochloride) preparations meeting ditions: all the following conditions: (i) The phenyltoloxamine dihydrogen (i) The dicyclomine hydrochloride is citrate is prepared, with or without prepared with suitable antacid and other drugs, in tablet or other dosage other components, in tablet or other

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dosage form for oral use in self-medica- (iii) If the preparation is a new drug, tion, and containing no drug limited to an application pursuant to section prescription sale under the provisions 505(b) of the act is approved for it. of section 503(b)(1) of the act. (iv) The preparation contains not (ii) The dicyclomine hydrochloride more than 5 percent by weight of and all other components of the prepa- hexadenol. ration meet their professed standards (v) The preparation is labeled with of identity, strength, quality, and pu- adequate directions for use by external rity. application in the treatment of minor (iii) If the preparation is a new drug, burns and minor skin irritations. an application pursuant to section (vi) The labeling bears, in juxtaposi- 505(b) of the act is approved for it. tion with the directions for use, clear (iv) The preparation contains not warning statements against: more than 5 milligrams of dicyclomine (a) Use on serious burns or skin con- hydrochloride per dosage unit, or if it ditions or prolonged use, except as di- is in liquid form not more than 0.5 mil- rected by a physician. ligram of dicyclomine hydrochloride (b) Spraying the preparation in the per milliliter. vicinity of eyes, mouth, nose, or ears. (v) The preparation is labeled with (12) Sulfur dioxide preparations adequate directions for use only by meeting all the following conditions: 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. (ii) The sulfur dioxide and all other (vii) The labeling bears, in juxtaposi- components of the preparation meet tion with the dosage recommendations, their professed standards of identity, clear warning statements against: strength, quality, and purity. (a) Exceeding the recommended dos- (iii) If the preparation is a new drug, age. an application pursuant to section (b) Prolonged use, except as directed 505(b) of the act is approved for it. by a physician, since persistent or re- (iv) The preparation contains not curring symptoms may indicate a seri- more than 5 grams of sulfur dioxide per ous disease requiring medical atten- 100 milliliters of solution. tion. (v) The preparation is labeled with (c) Administration to children under adequate directions for use by external 12 years of age except as directed by a application to the smooth skin in the physician. prevention or treatment of minor con- (9)–(10) [Reserved] ditions in which it is indicated. (11) Hexadenol (a mixture of tetra- (vi) The directions for use rec- cosanes and their oxidation products) ommend or suggest not more than two preparations meeting all the following applications a day for not more than 1 conditions: week, except as directed by a physi- (i) The hexadenol is prepared and cian. packaged, with or without other drugs, (13)–(15) [Reserved] solvents, and propellants, in a form (16) Tuaminoheptane sulfate (2-ami- suitable for self-medication by external noheptane sulfate) preparations meet- application to the skin as a spray, and ing all the following conditions: containing no drug limited to prescrip- (i) The tuaminoheptane sulfate is tion sale under the provisions of sec- prepared, with or without other drugs, tion 503(b)(1) of the act. in an aqueous vehicle suitable for ad- (ii) The hexadenol and all other com- ministration in self-medication as nose ponents of the preparation meet their drops, and containing no drug limited professed standards of identity, to prescription sale under the provi- strength, quality, and purity. sions of section 503(b)(1) of the act.

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(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 per dose, and 5 doses in a 24-hour pe- (e) Puncturing the container or riod; for infants under 1 year of age, 2 throwing the container into fire. drops of a 1 percent solution per nostril (19) Pramoxine hydrochloride (4-N- per dose, and 5 doses in a 24-hour pe- butoxyphenyl g-morpholinopropyl riod. ether hydrochloride) preparations (viii) The labeling bears, in jux- meeting all the following conditions: taposition with the dosage rec- (i) The pramoxine hydrochloride is ommendations: prepared, with or without other drugs, (a) Clear warning statements against in a dosage form suitable for use in use of more than 5 doses daily, and self-medication by external application against use longer than 4 days unless to the skin, and containing no drug directed by a physician. limited to prescription sale under the (b) A clear warning statement to the provisions of section 503(b)(1) of the effect that frequent use may cause act. nervousness or sleeplessness, and that (ii) The pramoxine hydrochloride and individuals with high blood pressure, all other components of the prepara- heart disease, diabetes, or thyroid dis- tion meet their professed standards of ease should not use the preparation un- identity, strength, quality, and purity. less directed by a physician. (iii) If the preparation is a new drug, (17) [Reserved] an application pursuant to section (18) Vibesate (a mixture of copoly- 505(b) of the act is approved for it. mers of hydroxy-vinyl chlorideacetate, (iv) The preparation contains not sebacic acid, and modified maleic rosin more than 1.0 percent of pramoxine hy- ester) preparations meeting all the fol- drochloride. lowing conditions. (v) The preparation is labeled with (i) The vibesate is prepared and pack- adequate directions for use by external aged, with or without other drugs, sol- application to the skin for the tem- vents, and propellants, in a form suit- porary relief of pain or itching due to able for self-medication by external ap- minor burns and sunburn, nonpoi- plication to the skin as a spray, and sonous insect bites, and minor skin ir- containing no drug limited to prescrip- ritations. tion sale under the provisions of sec- (vi) The directions for use rection 503(b)(1) of the act. ommend or suggest not more than four

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applications of the preparation per day, children under 2 years of age, unless di- unless directed by a physician. rected by a physician. (vii) The labeling bears, in juxtaposi- (b) Clear warning statements against tion with the directions for use, clear use of the drug in the presence of high warning statements against: fever or if cough persists, since per- (a) Prolonged use. sistent cough as well as high fever may (b) Application to large areas of the indicate the presence of a serious con- body. dition. (c) Continued use if redness, irrita- (21) Pamabrom (2-amino-2-methyl- tion, swelling, or pain persists or in- propanol-1-8-bromotheophyllinate) creases, unless directed by a physician. preparations meeting all the following (d) Use in the eyes or nose. conditions: (20) Carbetapentane citrate (2-(2-di- (i) The pamabrom is prepared with ethylaminoethoxy)-ethyl-1-phenyl- appropriate amounts of a suitable an- cyclopentyl-1-carboxylate citrate) algesic and with or without other preparations meeting all the following drugs, in tablet or other dosage form conditions: (i) The carbetanentane citrate is pre- suitable for oral use in self-medication, pared, with or without other drugs, in and containing no drug limited to pre- tablet or other dosage form suitable for scription sale under the provisions of oral use in self-medication, and con- section 503(b)(1) of the act. taining no drug limited to prescription (ii) The pamabrom and all other com- sale under the provisions of section ponents of the preparation meet their 503(b)(1) of the act. professed standards of identity, (ii) The carbetapentane citrate and strength, quality, and purity. all other components of the prepara- (iii) If the preparation is a new drug, tion meet their professed standards of an application pursuant to section identity, strength, quality, and purity. 505(b) of the act is approved for it. (iii) If the preparation is a new drug, (iv) The preparation contains not and application pursuant to section more than 50 milligrams of pamabrom 505(b) of the act is approved for it. per dosage unit. (iv) The preparation contains not (v) The preparation is labeled with more than 25 milligrams of carbeta- adequate directions for use in the tem- pentane citrate per dosage unit; or if it porary relief of the minor pains and is in liquid form, not more than 1.5 mil- discomforts that may occur a few days ligrams of carbetapentane citrate per before and during the menstrual pe- milliliter. riod. (v) The preparation is labeled with (vi) The dosages recommended or adequate directions for use in the tem- suggested in the labeling do not exceed porary relief of cough due to minor 50 milligrams of pamabrom per dose or conditions in which it is indicated. 200 milligrams per 24-hour period. (vi) The dosages recommended or (22) Diphemanil methylsulfate (4-di- suggested in the labeling do not exceed: phenylmethylene-1,1-dimethyl-piper- For adults, 30 milligrams of carbeta- idinium methylsulfate) preparations pentane citrate per dose or 120 milligrams of carbetapentane citrate per 24- meeting all the following conditions: hour period; for children 4 to 12 years (i) The diphemanil methylsulfate is of age, 7.5 milligrams per dose or 30 prepared, with or without other drugs, milligrams per 24-hour period; for chil- in a dosage form suitable for use in dren 2 to 4 years of age, 4.0 milligrams self-medication by external application per dose or 16.0 milligrams per 24-hour to the skin, and containing no drug period. limited to prescription sale under the (vii) The label bears a conspicuous provisions of section 503(b)(1) of the warning to keep the drug out of the act. reach of children, and the labeling (ii) The diphemanil methylsulfate bears, in juxtaposition with the dosage and all other components of the prepa- recommendations: ration meet their professed standards (a) A clear warning statement of identity, strength, quality, and pu- against administration of the drug to rity.

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(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) 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 (b) Use in case of rectal bleeding, as adequate directions for use by external this may indicate serious disease. application to the skin for the relief of (c) Use in the eyes. symptoms of mild poison ivy, oak, and (d) Prolonged use. sumac and other minor irritations and (e) Application to large areas of the itching of the skin. body. (vi) The directions for use rec- (f) Use for deep or puncture wounds ommend or suggest not more than four or serious burns. applications of the preparation per day, (24) Chlorothen citrate (chlorometha- unless directed by a physician. pyrilene citrate; N,N-dimethyl-N′-(2- (vii) The labeling bears, in juxtaposi- pyridyl)-N′-(5-chloro-2-thenyl) ethyl- tion with the directions for use, a clear enediamine citrate) preparations meet- warning statement, such as: ‘‘Caution: ing all the following conditions: If redness, irritation, swelling, or pain (i) The chlorothen citrate is pre- persists or increases, discontinue use pared, with or without other drugs, in and consult physician.’’ tablet or other dosage form suitable for (23) Dyclonine hydrochloride (4-but- oral use in self-medication, and con- oxy-3-piperidinopropiophenone hydro- taining no drug limited to prescription chloride; 4-n-butoxy-b-piperidono- sale under the provisions of section propiophenone hydrochloride) prepara- 503(b)(1) of the act. tions meeting all the following condi- (ii) The chlorothen citrate and all tions: other components of the preparation (i) The dyclonine hydrochloride is meet their professed standards of iden- prepared, with or without other drugs, tity, strength, quality, and purity. in a dosage form suitable for use as a (iii) If the preparation is a new drug, cream or ointment in self-medication an application pursuant to section by external application to the skin, or 505(b) of the act is approved for it. rectally, and contains no drug limited (iv) The preparation contains not to prescription sale under the provi- more than 25 milligrams of chlorothen sions of section 503(b)(1) of the act. citrate per dosage unit. (v) The preparation is labeled with (ii) The dyclonine hydrochloride and adequate directions for use in the tem- all other components of the prepara- porary relief of the symptoms of hay tion meet their professed standards of fever and/or the symptoms of other identity, strength, quality, and purity. minor conditions in which it is indi- (iii) If the preparation is a new drug, cated. an application pursuant to section (vi) The dosages recommended or 505(b) of the act is approved for it. suggested in the labeling do not exceed: (iv) The preparation contains not For adults, 25 milligrams of chlorothen more than 1.0 percent of dyclonine hy- citrate per dose or 150 milligrams of drochloride. chlorothen citrate per 24-hour period; (v) The preparation is labeled with for children 6 to 12 years of age, one- adequate directions for use: half of the maximum adult dose or dos- (a) By external application to the age. skin for the temporary relief of pain (vii) The labeling bears, in juxtaposi- and itching in sunburn, nonpoisonous tion with the dosage recommendations: insect bites, minor burns, cuts, abra- (a) Clear warning statements against sions, and other minor skin irritations. administration of the drug to children (b) [Reserved] under 6 years of age or exceeding the (c) In the prevention or treatment of recommended dosage, unless directed other minor conditions in which it is by a physician, and against driving a indicated. car or operating machinery while using

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the drug, since it may cause drowsi- high blood pressure, heart disease, dia- ness. betes, or thyroid disease should not use (b) If the article is offered for the the preparation unless directed by a temporary relief of symptoms of colds, physician. a statement that continued adminis- (c) A clear warning statement tration for such use should not exceed against use of the drug in the presence 3 days, unless directed by a physician. of high fever or if cough persists, since (25) [Reserved] persistent cough as well as high fever (26) Methoxyphenamine hydro- may indicate the presence of a serious chloride (b-(o-methoxyphenyl)-iso- condition. propyl-methylamine hydrochloride; 1- (27) Biphenamine hydrochloride (b-di- (o-methoxyphenyl)- 2-methylamino- ethylaminoethyl-3-phenyl-2-hydroxy- propane hydrochloride) preparations benzoate hydrochloride) preparations meeting all the following conditions: meeting all the following conditions: (i) The methoxyphenamine hydro- (i) The biphenamine hydrochloride is chloride is prepared with appropriate prepared in a form suitable for use as a amounts of a suitable antitussive, with shampoo and contains no drug limited or without other drugs, in a dosage to prescription sale under the provi- form suitable for oral use in self-medi- sions of section 503(b)(1) of the act. cation, and containing no drug limited (ii) The biphenamine hydrochloride to prescription sale under the provi- meets its professed standards of iden- sions of section 503(b)(1) of the act. tity, strength, quality, and purity. (ii) The methoxyphenamine hydro- (iii) If the preparation is a new drug, chloride and all other components of an application pursuant to section the preparation meet their professed 505(b) of the act is approved for it. standards of identity, strength, qual- (iv) The preparation contains not ity, and purity. more than 1 percent of biphenamine (iii) If the preparation is a new drug, hydrochloride. an application pursuant to section (v) The preparation is labeled with 505(b) of the act is approved for it. adequate directions for use for the tem- (iv) The preparation contains not porary relief of itching and scaling due more than 3.5 milligrams of methoxy- to dandruff. phenamine hydrochloride per milli- (vi) The label bears a conspicuous liter. warning to keep the drug out of the (v) The preparation is labeled with reach of children. adequate directions for use in the tem- (28) Tyloxapol (an alkylarylpolyether porary relief of cough due to minor alcohol) and benzalkonium chloride conditions in which it is indicated. ophthalmic preparations meeting all (vi) The dosages recommended or the following conditions: suggested in the labeling do not exceed: (i) The tyloxapol and benzalkonium For adults, 35 milligrams of methoxy- chloride are prepared, with other ap- phenamine hydrochloride per dose or propriate ingredients which are not 140 milligrams of methoxyphenamine drugs limited to prescription sale hydrochloride per 24-hour period; for under the provisions of section 503(b)(1) children 6 to 12 years of age, one-half of of the act, as a sterile, isotonic aque- the maximum adult dose or dosage. ous solution suitable for use in self- (vii) The label bears a conspicuous medication on eye prostheses. warning to keep the drug out of the (ii) The preparation is so packaged as reach of children, and the labeling to volume and type of container as to 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

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meet their professed standards of iden- ability of the drugs for widespread clin- tity, strength, quality, and purity. ical use pending completion of such (iv) An application pursuant to sec- long-term studies. In such cases, the tion 505(b) of the act is approved for Food and Drug Administration may ap- the drug. prove the new drug application on con- (v) The preparation contains 0.25 per- dition that the necessary long-term cent of tyloxapol and 0.02 percent of studies will be conducted and the re- benzalkonium chloride. sults recorded and reported in an orga- (vi) The label bears a conspicuous nized fashion. The procedures required warning to keep the drug out of the by paragraph (b) of this section will be reach of children and the labeling followed in order to list such a drug in bears, in juxtaposition with the dosage § 310.304. recommendations, a clear warning that (b) A proposal to require additional if irritation occurs, persists, or in- or continued studies with a drug for creases, use of the drug should be dis- which a new drug application has been continued and a physician consulted. approved may be made by the Commis- The labeling includes a statement that sioner on his own initiative or on the the dropper or other dispensing tip petition of any interested person, pur- should not touch any surface, since suant to part 10 of this chapter. Prior this may contaminate the solution. to issuance of such a proposal, the ap- (29) [Reserved] plicant will be provided an opportunity (b) [Reserved] for a conference with representatives of the Food and Drug Administration. [39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 52 FR 15892, Apr. 30, When appropriate, investigators or 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, other individuals may be invited to Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR participate in the conference. All re- 49898, Sept. 23, 1993; 59 FR 4218, Jan. 28, 1994; quirements for special studies, records, 60 FR 52507, Oct. 6, 1995] and reports will be published in § 310.304. Subpart D—Records and Reports [39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 FR 15674, Mar. 22, § 310.303 Continuation of long-term 1977] studies, records, and reports on certain drugs for which new drug ap- § 310.305 Records and reports con- plications have been approved. cerning adverse drug experiences (a) A new drug may not be approved on marketed prescription drugs for for marketing unless it has been shown human use without approved new to be safe and effective for its intended drug applications. use(s). After approval, the applicant is (a) Scope. FDA is requiring manufac- required to establish and maintain turers, packers, and distributors of records and make reports related to marketed prescription drug products clinical experience or other data or in- that are not the subject of an approved formation necessary to make or facili- new drug or abbreviated new drug ap- tate a determination of whether there plication to establish and maintain are or may be grounds under section records and make reports to FDA of all 505(e) of the act for suspending or with- serious, unexpected adversedrug expe- drawing approval of the application. riences associated with the use of their Some drugs, because of the nature of drug products. Any person subject to 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

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drug related, including the following: greater severity) if the labeling only An adverse event occurring in the referred to elevated hepatic enzymes or course of the use of a drug product in hepatitis. Similarly, cerebral thrombo- professional practice; an adverse event embolism and cerebral vasculitis would occurring from drug overdose whether be unexpected (by virtue of greater accidental or intentional; an adverse specificity) if the labeling only listed event occurring from drug abuse; an cerebral vascular accidents. ‘‘Unex- adverse event occurring from drug pected,’’ as used in this definition, re- withdrawal; and any failure of expected fers to an adverse drug experience that pharmacological action. has not been previously observed (i.e., Disability. A substantial disruption of included in the labeling) rather than a person’s ability to conduct normal from the perspective of such experience life functions. not being anticipated from the pharma- Life-threatening adverse drug experi- cological properties of the pharma- ence. Any adverse drug experience that ceutical product. places the patient, in the view of the (c) Reporting requirements. Each per- initial reporter, at immediate risk of son identified in paragraph (c)(1)(i) of death from the adverse drug experience this section shall report to FDA ad- as it occurred, i.e., it does not include verse drug experience information as an adverse drug experience that, had it described in this section and shall sub- occurred in a more severe form, might mit one copy of each report to the Di- have caused death. vision of Pharmacovigilance and Epide- Serious adverse drug experience. Any miology (HFD–730), Center for Drug adverse drug experience occurring at Evaluation and Research, Food and any dose that results in any of the fol- Drug Administration, 5600 Fishers lowing outcomes: Death, a life-threat- Lane, Rockville, MD 20857. ening adverse drug experience, inpa- (1) Postmarketing 15-day ‘‘Alert re- tient hospitalization or prolongation of ports’’. (i) Any person whose name ap- existing hospitalization, a persistent or pears on the label of a marketed pre- significant disability/incapacity, or a scription drug product as its manufac- congenital anomaly/birth defect. Im- turer, packer, or distributor shall re- portant medical events that may not result in death, be life-threatening, or port to FDA each adverse drug experi- require hospitalization may be consid- ence received or otherwise obtained ered a serious adverse drug experience that is both serious and unexpected as when, based upon appropriate medical soon as possible, but in no case later judgment, they may jeopardize the pa- than 15 calendar days of initial receipt tient or subject and may require med- of the information by the person whose ical or surgical intervention to prevent name appears on the label. Each report one of the outcomes listed in this defi- shall be accompanied by a copy of the nition. Examples of such medical current labeling for the drug product. events include allergic bronchospasm (ii) A person identified in paragraph requiring intensive treatment in an (c)(1)(i) of this section is not required emergency room or at home, blood to submit a 15-day ‘‘Alert report’’ for dyscrasias or convulsions that do not an adverse drug experience obtained result in inpatient hospitalization, or from a postmarketing study (whether the development of drug dependency or or not conducted under an investiga- drug abuse. tional new drug application) unless the Unexpected adverse drug experience. applicant concludes that there is a rea- Any adverse drug experience that is sonable possibility that the drug not listed in the current labeling for caused the adverse experience. the drug product. This includes events (2) Postmarketing 15-day ‘‘Alert re- that may be symptomatically and ports’’—followup. Each person identified pathophysiologically related to an in paragraph (c)(1)(i) of this section event listed in the labeling, but differ shall promptly investigate all serious, from the event because of greater se- unexpected adverse drug experiences verity or specificity. For example, that are the subject of these post- under this definition, hepatic necrosis marketing 15-day Alert reports and would be unexpected (by virtue of shall submit followup reports within 15

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calendar days of receipt of new infor- 3500A or, if preferred, on a CIOMS I mation or as requested by FDA. If addi- form). tional information is not obtainable, (2) Each completed FDA Form 3500A records should be maintained of the un- should pertain only to an individual successful steps taken to seek addi- patient. tional information. Postmarketing 15- (3) Instead of using Form FDA Form day Alert reports and followups to 3500A, a manufacturer, packer, or dis- them shall be submitted under separate tributor may use a computer-generated cover. FDA Form 3500A or other alternative (3) Submission of reports. To avoid un- format (e.g., a computer-generated necessary duplication in the submis- tape or tabular listing) provided that: sion of, and followup to, reports re- (i) The content of the alternative for- quired in this section, a packer’s or dis- mat is equivalent in all elements of in- tributor’s obligations may be met by formation to those specified in FDA submission of all reports of serious ad- Form 3500A, and verse drug experiences to the manufac- (ii) The format is agreed to in ad- turer of the drug product. If a packer vance by MedWatch: The FDA Medical or distributor elects to submit these Products Reporting Program. adverse drug experience reports to the (4) Ten copies or fewer of FDA Form manufacturer rather than to FDA, it 3500A and/or a copy of the instructions shall submit each report to the manu- for completing the form may be ob- facturer within 5 calendar days of its tained from the Division of receipt by the packer or distributor, Pharmacovigilance and Epidemiology and the manufacturer shall then com- (HFD–730), Center for Drug Evaluation ply with the requirements of this sec- and Research, Food and Drug Adminis- tion even if its name does not appear tration, 5600 Fishers Lane, Rockville, on the label of the drug product. Under MD 20857. More than 10 copies of the this circumstance, the packer or dis- form may be obtained by writing to the tributor shall maintain a record of this Consolidated Forms and Publications action which shall include: Distribution Center, Washington Com- (i) A copy of each adverse drug expe- merce Center, 3222 Hubbard Rd., Land- rience report; over, MD 20785. (ii) The date the report was received (e) Patient privacy. Manufacturers, by the packer or distributor; packers, and distributors should not in- (iii) The date the report was sub- clude in reports under this section the mitted to the manufacturer; and names and addresses of individual pa- (iv) The name and address of the tients; instead, the manufacturer, manufacturer. packer, and distributor should assign a (4) Each report submitted to FDA unique code number to each report, under this section shall bear prominent preferably not more than eight char- identification as to its contents, i.e., acters in length. The manufacturer, ‘‘15-day Alert report,’’ or ‘‘15-day Alert packer, and distributor should include report-followup.’’ the name of the reporter from whom (5) A person identified in paragraph the information was received. Names of (c)(1)(i) of this section is not required patients, individual reporters, health to resubmit to FDA adverse drug expe- care professionals, hospitals, and geo- rience reports forwarded to that person graphical identifiers in adverse drug by FDA; however, the person must sub- experience reports are not releasable to mit all followup information on such the public under FDA’s public informa- reports to FDA. tion regulations in part 20 of this chap- (d) Reporting form. (1) Except as pro- ter. vided in paragraph (d)(3) of this sec- (f) Recordkeeping. (1) Each manufac- tion, each person identified in para- turer, packer, and distributor shall graph (c)(1)(i) of this section shall sub- maintain for a period of 10 years mit each report of a serious and unex- records of all adverse drug experiences pected adverse drug experience on an required under this section to be re- FDA Form 3500A (foreign events may ported, including raw data and any cor- be submitted either on an FDA Form respondence relating to the adverse

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drug experiences, and the records re- competent patient (or to the agent of quired to be maintained under para- either). The patient package insert is graph (c)(4) of this section. required to be placed in or accompany (2) Manufacturers and packers may each package dispensed to the patient. retain the records required in para- (b) Distribution requirements. (1) For graph (f)(1) of this section as part of its oral contraceptive drug products, the complaint files maintained under manufacturer and distributor shall pro- § 211.198 of this chapter. vide a patient package insert in or with (3) Manufacturers, packers, and dis- each package of the drug product that tributors shall permit any authorized the manufacturer or distributor in- FDA employee, at all reasonable times, tends to be dispensed to a patient. to have access to and copy and verify (2) Patient package inserts for oral the records established and maintained contraceptives dispensed in acute-care under this section. hospitals or long-term care facilities (g) Disclaimer. A report or informa- will be considered to have been pro- tion submitted by a manufacturer, vided in accordance with this section if packer, or distributor under this sec- provided to the patient before adminis- tion (and any release by FDA of that tration of the first oral contraceptive report or information) does not nec- and every 30 days thereafter, as long as essarily reflect a conclusion by the the therapy continues. manufacturer, packer, or distributor, (c) Contents of patient package insert. or by FDA, that the report or informa- A patient package insert for an oral tion constitutes an admission that the contraceptive drug product is required drug caused or contributed to an ad- to contain the following: verse effect. The manufacturer, packer, (1) The name of the drug. or distributor need not admit, and may (2) A summary including a statement deny, that the report or information concerning the effectiveness of oral submitted under this section con- contraceptives in preventing preg- stitutes an admission that the drug nancy, the contraindications to the caused or contributed to an adverse ef- drug’s use, and a statement of the risks fect. and benefits associated with the drug’s [51 FR 24479, July 3, 1986, as amended at 52 use. FR 37936, Oct. 13, 1987; 55 FR 11578, Mar. 29, (3) A statement comparing the effec- 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, tiveness of oral contraceptives to other June 25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR methods of contraception. 9585, Mar. 4, 2002] (4) A boxed warning concerning the increased risks associated with ciga- Subpart E—Requirements for rette smoking and oral contraceptive Specific New Drugs or Devices use. (5) A discussion of the contraindica- § 310.501 Patient package inserts for tions to use, including information oral contraceptives. that the patient should provide to the (a) Requirement for a patient package prescriber before taking the drug. insert. The safe and effective use of oral (6) A statement of medical conditions contraceptive drug products requires that are not contraindications to use that patients be fully informed of the but deserve special consideration in benefits and the risks involved in their connection with oral contraceptive use use. An oral contraceptive drug prod- and about which the patient should in- uct that does not comply with the re- form the prescriber. quirements of this section is mis- (7) A warning regarding the most se- branded under section 502 of the Fed- rious side effects of oral contracep- eral Food, Drug, and Cosmetic Act. tives. Each dispenser of an oral contraceptive (8) A statement of other serious ad- drug product shall provide a patient verse reactions and potential safety package insert to each patient (or to hazards that may result from the use an agent of the patient) to whom the of oral contraceptives. product is dispensed, except that the (9) A statement concerning common, dispenser may provide the insert to the but less serious side effects which may parent or legal guardian of a legally in- help the patient evaluate the benefits

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and risks from the use of oral contra- assistance in meeting the requirements ceptives. of this section. A request for a copy of (10) Information on precautions the the guidance texts should be directed patients should observe while taking to the Center for Drug Evaluation and oral contraceptives, including the fol- Research, Division of Metabolism and lowing: Endocrine Drug Products (HFD–510), (i) A statement of risks to the moth- Food and Drug Administration, 5600 er and unborn child from the use of Fishers Lane, Rockville, MD 20857. oral contraceptives before or during (f) Requirement to supplement approved early pregnancy; application. Holders of approved appli- (ii) A statement concerning excretion cations for oral contraceptive drug of the drug in human milk and associ- products that are subject to the re- ated risks to the nursing infant; quirements of this section are required (iii) A statement about laboratory to submit supplements under § 314.70(c) tests which may be affected by oral of this chapter to provide for the label- contraceptives; and ing required by this section. Such la- (iv) A statement that identifies ac- beling may be put into use without ad- tivities and drugs, foods, or other sub- vance approval by the Food and Drug stances the patient should avoid be- Administration. cause of their interactions with oral [54 FR 22587, May 25, 1989] contraceptives. (11) Information about how to take § 310.502 Certain drugs accorded new oral contraceptives properly, including drug status through rulemaking information about what to do if the pa- procedures. tient forgets to take the product, infor- (a) The drugs listed in this paragraph mation about becoming pregnant after have been determined by rulemaking discontinuing use of the drug, a state- procedures to be new drugs within the ment that the drug product has been meaning of section 201(p) of the act. An prescribed for the use of the patient approved new drug application under and should not be used for other condi- section 505 of the act and part 314 of tions or given to others, and a state- this chapter is required for marketing ment that the patient’s pharmacist or the following drugs: practitioner has a more technical leaf- (1) Aerosol drug products for human let about the drug product that the pa- use containing 1,1,1-trichloroethane. tient may ask to review. (2) Aerosol drug products containing (12) A statement of the possible bene- zirconium. fits associated with oral contraceptive (3) Amphetamines (amphetamine, use. dextroamphetamine, and their salts, (13) The following information about and levamfetamine and its salts) for the drug product and the patient pack- human use. age insert: (4) Camphorated oil drug products. (i) The name and place of business of (5) Certain halogenated salicyl- the manufacturer, packer, or dis- anilides (tribromsalan (TBS, 3,4′,5-tri- tributor, or the name and place of busi- bromosalicylanilide), dibromsalan ness of the dispenser of the product. (DBS, 4′, 5-dibromosalicylanilide), (ii) The date, identified as such, of metabromsalan (MBS, 3, 5-dibromo- the most recent revision of the patient salicylanilide), and 3,3′, 4,5′-tetra- package insert placed prominently im- chlorosalicylanilide (TC–SA)) as an in- mediately after the last section of the gredient in drug products. labeling. (6) Chloroform used as an ingredient (d) Other indications. The patient (active or inactive) in drug products. package insert may identify indica- (7) Cobalt preparations intended for tions in addition to contraception that use by man. are identified in the professional label- (8) Intrauterine devices for human ing for the drug product. use for the purpose of contraception (e) Labeling guidance texts. The Food that incorporate heavy metals, drugs, and Drug Administration issues infor- or other active substances. mal labeling guidance texts under (9) Oral prenatal drugs containing § 10.90(b)(9) of this chapter to provide fluorides intended for human use.

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(10) Parenteral drug products in plas- Isotope Chemical form Use tic containers. Do ...... do ...... Red blood cell label- (11) Sterilization of drugs by irradia- ing and survival tion. studies. (12) Sweet spirits of nitre drug prod- Do ...... Labeled human Gastrointestinal pro- ucts. serum albumin. tein loss studies. Do ...... do ...... Placenta localiza- (13) Thorium dioxide for drug use. tion. (14) Timed release dosage forms. Do ...... Labeled red blood Do. (15) Vinyl chloride as an ingredient, cells. Cobalt 58 or Labeled cyano- Intestinal absorption including propellant, in aerosol drug Cobalt 60. cobalamin. studies. products. Gold 198 ...... Colloidal ...... Liver scans. (b) [Reserved] Do ...... do ...... Intracavitary treatment of pleural ef- [62 FR 12084, Mar. 14, 1997, as amended at 64 fusions and/or as- FR 401, Jan. 5, 1999] cites. Do ...... do ...... Interstitial treatment § 310.503 Requirements regarding cer- of cancer. Iodine 131 ...... Iodide ...... Diagnosis of thyroid tain radioactive drugs. functions. (a) On January 8, 1963 (28 FR 183), the Do ...... do ...... Thyroid scans. Commissioner of Food and Drugs ex- Do ...... do ...... Treatment of hyper- thyroidism and/or empted investigational radioactive new cardiac dysfunc- drugs from part 312 of this chapter pro- tion. vided they were shipped in complete Do ...... do ...... Treatment of thyroid conformity with the regulations issued carcinoma. Do ...... Iodinated human Blood volume deter- by the Nuclear Regulatory Commis- serum albumin. minations. sion. This exemption also applied to in- Do ...... do ...... Cisternography. vestigational radioactive biologics. Do ...... do ...... Brain tumor localiza- (b) It is the opinion of the Nuclear tion. Regulatory Commission, and the Food Do ...... do ...... Placenta localization. and Drug Administration that this ex- Do ...... do ...... Cardiac scans for emption should not apply for certain determination of specific drugs and that these drugs pericardial effu- should be appropriately labeled for uses sions. Do ...... Rose Bengal ...... Liver function stud- for which safety and effectiveness can ies. be demonstrated by new drug applica- Do ...... do ...... Liver scans. tions or through licensing under the Do ...... Iodopyracet, sodium Kidney function Public Health Service Act (42 U.S.C. 262 iodohippurate, so- studies and kid- dium diatrizoate, ney scans. et seq.) in the case of biologics. Contin- diatrizoate methyl- ued distribution under the investiga- glucamine, so- tional exemption when the drugs are dium diprotrizoate, intended for established uses will not sodium acetrizoate, or so- be permitted. dium iothalamate. (c) Based on its experience in regu- Do ...... Labeled fats and/or Fat absorption stud- lating investigational radioactive fatty acids. ies. pharmaceuticals, the Nuclear Regu- Do ...... Cholografin ...... Cardiac scans for determination of latory Commission has compiled a list pericardial effu- of reactor-produced isotopes for which sions. it considers that applicants may rea- Do ...... Macroaggregated io- Lung scans. sonably be expected to submit ade- dinated human serum albumin. quate evidence of safety and effective- Do ...... Colloidal micro- Liver scans. ness for use as recommended in appro- aggregated priate labeling. Such use may include, human serum al- among others, the uses in this tabula- bumin. Iodine 125 ...... Iodide ...... Diagnosis of thyroid tion: function. Do ...... Iodinated human Blood volume deter- Isotope Chemical form Use serum albumin. minations. Do ...... Rose Bengal ...... Liver function stud- Chromium 51 ... Chromate ...... Spleen scans. ies. Do ...... do ...... Placenta localization.

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Isotope Chemical form Use any drug or biologic containing any of the isotopes listed in paragraph (c) of Do ...... Iodopyracet, sodium Kidney function iodohippurate, so- studies. this section, in the ‘‘chemical form’’ dium diatrizoate, and intended for the uses stated, is ter- diatrizoate methyl- minated on March 3, 1972, except as glucamine, so- provided in paragraph (d)(3) of this sec- dium diprotrizoate, sodium tion. acetrizoate, or so- (3) The exemption referred to in para- dium iothalamate. graph (a) of this section, as applied to Do ...... Labeled fats and/or Fat absorption stud- any drug or biologic containing any of fatty acids. ies. Iron 59 ...... Chloride, citrate Iron turnover stud- the isotopes listed in paragraph (c) of and/or sulfate. ies. this section, in the ‘‘chemical form’’ Krypton 85 ...... Gas ...... Diagnosis of cardiac and intended for the uses stated, for abnormalities. Mercury 197 .... Chlormerodrin ...... Kidney scans. which drug a new drug application or a Do ...... do ...... Brain scans. ‘‘Investigational New Drug Applica- Mercury 203 1 ...... do ...... Kidney scans. tion’’ was submitted prior to March 3, Do ...... do ...... Brain scans. 1972, or for which biologic an applica- Phosphorus 32 Soluble phosphate .. Treatment of poly- cythemia vera. tion for product license or ‘‘Investiga- Do ...... do ...... Treatment of leu- tional New Drug Application’’ was sub- kemia and bone mitted prior to March 3, 1972, is termi- metastasis. Do ...... Colloidal chromic Intracavitary treat- nated on August 20, 1976, unless an ap- phosphate. ment of pleural ef- provable notice was issued on or before fusions and/or as- August 20, 1976, in which case the ex- cites. emption is terminated either upon the Do ...... do ...... Interstitial treatment of cancer. subsequent issuance of a nonapprovable Potassium 42 .. Chloride ...... Potassium space notice for the new drug application or studies. on November 20, 1976, whichever occurs Selenium 75 .... Labeled methionine Pancreas scans. Strontium 85 .... Nitrate or chloride ... Bone scans on pa- first. tients with diag- (e) No exemption from section 505 of nosed cancer. the act or from part 312 of this chapter Technetium Pertechnetate ...... Brain scans. is in effect or has been in effect for ra- 99m. Do ...... do ...... Thyroid scans. dioactive drugs prepared from accel- Do ...... Sulfur colloid ...... Liver and spleen erator-produced radioisotopes, natu- scans. rally occurring isotopes, or nonradio- Do ...... Pertechnetate ...... Placenta localization. active substances used in conjunction Do ...... do ...... Blood pool scans. with isotopes. Do ...... do ...... Salivary gland (f)(1) Based on its experience in regu- scans. lating investigational radioactive Do ...... Diethylenetri-amine Kidney scans. pentaacetic acid pharmaceuticals, the Nuclear Regu- (DTPA). latory Commission has compiled a list Xenon 133 ...... Gas ...... Diagnosis of cardia of reactor-produced isotopes for which abnormalities. it considers that applicants may rea- Cerebral bloodflow studies. Pul- sonably be expected to submit ade- monary function quate evidence of safety and effective- studies. Muscle ness for use as recommended in appro- bloodflow studies. priate labeling; such use may include, 1 This item has been removed from the AEC list for kidney among others, the uses in this tabula- scans but is included as the requirements of this order are applicable.Starttime Tuesday, April 20, 1999 16:55:11 tion:

(d)(1) In view of the extent of experi- Isotope Chemical form Use ence with the isotopes listed in para- Fluorine 18 ...... Fluoride ...... Bone imaging. graph (c) of this section, the Nuclear Indium-113m ... Diethylenetriamine Brain imaging; kid- Regulatory Commission and the Food pentaacetic acid ney imaging. and Drug Administration conclude that (DTPA). such isotopes should not be distributed Do ...... Chloride ...... Placenta imaging; blood pool imag- under investigational-use labeling ing. when they are actually intended for Technetium Human serum albu- Lung imaging. use in medical practice. 99m. min microspheres. Do ...... Diethylenetriamine Kidney imaging; kid- (2) The exemption referred to in para- pentaacetic acid ney function stud- graph (a) of this section, as applied to (Sn). ies.

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Isotope Chemical form Use or ‘‘Investigational New Drug Applica- tion’’ was submitted to the Center for Do ...... do ...... Brain imaging. Do ...... Polyphosphates ...... Bone imaging. Drug Evaluation and Research on or Do ...... Technetated aggre- Lung imaging. before August 25, 1975 is terminated on gated albumin August 20, 1976, unless an approvable (human). Do ...... Disodium etidronate Bone imaging. notice was issued on or before August 20, 1976, in which case the exemption is (2) In view of the extent of experience terminated either upon the subsequent with the isotopes listed in paragraph issuance of a nonapprovable notice for (f)(1) of this section, the Nuclear Regu- the new drug application or on Novem- latory Commission and the Food and ber 20, 1976, whichever occurs first. Drug Administration conclude that (ii) The exemption referred to in they should not be distributed under paragraph (a) of this section, as applied investigational-use labeling when they to any biologic containing any of the are actually intended for use in med- isotopes listed in paragraph (f)(1) of ical practice. this section in the ‘‘chemical form’’ (3) Any manufacturer or distributor and intended for the uses stated, for interested in continuing to ship in which biologic an application for prod- interstate commerce drugs containing uct license or ‘‘Investigational New the isotopes listed in paragraph (f)(1) of Drug Application’’ was submitted to this section for any of the indications the Center for Biologics Evaluation listed, shall submit, on or before Au- and Research on or before August 25, gust 25, 1975 to the Center for Drug 1975 is terminated on October 20, 1976, Evaluation and Research, Food and unless an approvable notice was issued Drug Administration, 5600 Fishers on or before October 20, 1976, in which Lane, Rockville, MD 20857, a new drug case the exemption is terminated ei- application or a ‘‘Investigational New ther upon the subsequent issuance of a Drug Application’’ for each such drug nonapprovable notice for the new drug for which the manufacturer or dis- application or on January 20, 1977, tributor does not have an approved new whichever occurs first. drug application pursuant to section (g) The exemption referred to in 505(b) of the act. If the drug is a bio- paragraph (a) of this section, as applied logic, a ‘‘Investigational New Drug Ap- to any drug intended solely for inves- plication’’ or an application for a li- tigational use as part of a research cense under section 351 of the Public project, which use had been approved Health Service Act shall be submitted on or before July 25, 1975 in accordance to the Center for Biologics Evaluation with 10 CFR 35.11 (or equivalent regula- and Research, Food and Drug Adminis- tion of an Agreement State) is termi- tration, 8800 Rockville Pike, Bethesda, nated on February 20, 1976 if the manu- MD 20014, in lieu of any submission to facturer of such drug or the sponsor of the Center for Drug Evaluation and Re- the investigation of such drug submits search. on or before August 25, 1975 to the Food (4) The exemption referred to in para- and Drug Administration, Bureau of graph (a) of this section, as applied to Drugs, HFD–150, 5600 Fishers Lane, any drug or biologic containing any of Rockville, MD 20857, the following in- the isotopes listed in paragraph (f)(1) of formation: this section, in the ‘‘chemical form’’ (1) The research project title; and intended for the uses stated, is ter- (2) A brief description of the purpose minated on August 26, 1975 except as of the project; provided in paragraph (f)(5) of this sec- (3) The name of the investigator re- tion. sponsible; (5)(i) Except as provided in paragraph (4) The name and license number of (f)(5)(ii) of this section, the exemption the institution holding the specific li- referred to in paragraph (a) of this sec- cense under 10 CFR 35.11 (or equivalent tion, as applied to any drug containing regulation of an Agreement State); any of the isotopes listed in paragraph (5) The name and maximum amount (f)(1) of this section, in the ‘‘chemical per subject of the radionuclide used; form’’ and intended for the uses stated, (6) The number of subjects involved; for which drug a new drug application and

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(7) The date on which the administra- Public Health Service Act of July 1, tion of the radioactive drugs is ex- 1944 (42 U.S.C. 201). pected to be completed. [62 FR 12084, Mar. 14, 1997] (h) The exemption referred to in paragraph (a) of this section, as applied § 310.515 Patient package inserts for to any drug not referred to in para- estrogens. graphs (d), (f), and (g) of this section, is (a) Requirement for a patient package terminated on August 26, 1975. insert. FDA concludes that the safe and effective use of drug products con- [39 FR 11680, Mar. 29, 1974, as amended at 40 taining estrogens requires that pa- FR 31307, July 25, 1975; 40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, tients be fully informed of the benefits Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR and risks involved in the use of these 11578, Mar. 29, 1990; 64 FR 56449, Oct. 20, 1999] drugs. Accordingly, except as provided in paragraph (e) of this section, each § 310.509 Parenteral drug products in estrogen drug product restricted to plastic containers. prescription distribution, including products containing estrogens in fixed (a) Any parenteral drug product combinations with other drugs, shall packaged in a plastic immediate con- be dispensed to patients with a patient tainer is not generally recognized as package insert containing information safe and effective, is a new drug within concerning the drug’s benefits and the meaning of section 201(p) of the risks. An estrogen drug product that act, and requires an approved new drug does not comply with the requirements application as a condition for mar- of this section is misbranded under sec- keting. An ‘‘Investigational New Drug tion 502(a) of the Federal Food, Drug, Application’’ set forth in part 312 of and Cosmetic Act. this chapter is required for clinical in- (b) Distribution requirements. (1) For vestigations designed to obtain evi- estrogen drug products, the manufac- dence of safety and effectiveness. turer and distributor shall provide a (b) As used in this section, the term patient package insert in or with each ‘‘large volume parenteral drug prod- package of the drug product that the uct’’ means a terminally sterilized manufacturer or distributor intends to aqueous drug product packaged in a be dispensed to a patient. single-dose container with a capacity (2) In the case of estrogen drug prod- of 100 milliliters or more and intended ucts in bulk packages intended for to be administered or used intra- multiple dispensing, and in the case of venously in a human. injectables in multiple-dose vials, a (c) Until the results of compatibility sufficient number of patient labeling studies are evaluated, a large volume pieces shall be included in or with each parenteral drug product for intra- package to assure that one piece can be venous use in humans that is packaged included with each package or dose dis- in a plastic immediate container on or pensed or administered to every pa- after April 16, 1979, is misbranded un- tient. Each bulk package shall be la- less its labeling contains a warning beled with instructions to the that includes the following informa- dispensor to include one patient labeling piece with each package dispensed tion: or, in the case of injectables, with each (1) A statement that additives may dose administered to the patient. This be incompatible. section does not preclude the manufac- (2) A statement that, if additive turer or labeler from distributing addi- drugs are introduced into the paren- tional patient labeling pieces to the teral system, aseptic techniques should dispensor. be used and the solution should be (3) Patient package inserts for estro- thoroughly mixed. gens dispensed in acute-care hospitals (3) A statement that a solution con- or long-term care facilities will be containing an additive drug should not be sidered to have been provided in ac- stored. cordance with this section if provided (d) This section does not apply to a to the patient before administration of biological product licensed under the the first estrogen and every 30 days

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thereafter, as long as the therapy con- association between the administration tinues. of tolbutamide and increased cardio- (c) Patient package insert contents. A vascular mortality. The Food and Drug patient package insert for an estrogen Administration has concluded that this drug product is required to contain the reported association provides adequate following information: basis for a warning in the labeling. In (1) The name of the drug. view of the similarities in chemical (2) The name and place of business of structure and mode of action, the Food the manufacturer, packer, or dis- and Drug Administration also believes tributor. it is prudent from a safety standpoint (3) A statement regarding the bene- to consider that the possible increased fits and proper uses of estrogens. risk of cardiovascular mortality from (4) The contraindications to use, i.e., tolbutamide applies to all other sulfo- when estrogens should not be used. nylurea drugs as well. Therefore, the (5) A description of the most serious labeling for oral hypoglycemic drugs of risks associated with the use of estro- the sulfonylurea class shall include a gens. warning concerning the possible in- (6) A brief summary of other side ef- creased risk of cardiovascular mor- fects of estrogens. tality associated with such use, as set (7) Instructions on how a patient may forth in paragraph (b) of this section. reduce the risks of estrogen use. (b) Labeling for oral hypoglycemic (8) The date, identified as such, of the drugs of the sulfonylurea class shall in- most recent revision of the patient clude in boldface type at the beginning package insert. of the ‘‘Warnings’’ section of the label- (d) Guidance language. The Food and ing the following statement: Drug Administration issues informal labeling guidance texts under SPECIAL WARNING ON INCREASED RISK § 10.90(b)(9) of this chapter to provide OF CARDIOVASCULAR MORTALITY assistance in meeting the requirements of paragraph (c) of this section. Re- The administration of oral hypoglycemic quests for a copy of the guidance text drugs has been reported to be associated should be directed to the Center for with increased cardiovascular mortality as Drug Evaluation and Research, Divi- compared to treatment with diet alone or diet plus insulin. This warning is based on sion of Metabolism and Endocrine Drug the study conducted by the University Group Products (HFD–510), Food and Drug Ad- Diabetes Program (UGDP), a long-term pro- ministration, 5600 Fishers Lane, Rock- spective clinical trial designed to evaluate ville, MD 20857. the effectiveness of glucose-lowering drugs (e) Exemptions. This section does not in preventing or delaying vascular complica- apply to estrogen-progestogen oral con- tions in patients with non-insulin-dependent traceptives. Labeling requirements for diabetes. The study involved 823 patients these products are set forth in § 310.501. who were randomly assigned to one of four (f) Requirement to supplement approved treatment groups (Diabetes, 19 (supp. 2): 747– 830, 1970). application. Holders of approved appli- UGDP reported that patients treated for 5 cations for estrogen drug products that to 8 years with diet plus a fixed dose of tol- are subject to the requirements of this butamide (1.5 grams per day) had a rate of section must submit supplements cardiovascular mortality approximately 21⁄2 under § 314.70(c) of this chapter to pro- times that of patients treated with diet vide for the labeling required by para- alone. A significant increase in total mor- graph (a) of this section. Such labeling tality was not observed, but the use of tolbutamide was discontinued based on the in- may be put into use without advance crease in cardiovascular mortality, thus lim- approval by the Food and Drug Admin- iting the opportunity for the study to show istration. an increase in overall mortality. Despite [55 FR 18723, May 4, 1990] controversy regarding the interpretation of these results, the findings of the UGDP study § 310.517 Labeling for oral hypo- provide an adequate basis for this warning. glycemic drugs of the sulfonylurea The patient should be informed of the poten- class. tial risks and advantages of (name of drug) and of alternative modes of therapy. (a) The University Group Diabetes Although only one drug in the sulfonylurea Program clinical trial has reported an class (tolbutamide) was included in this

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study, it is prudent from a safety standpoint empt from the requirements of para- to consider that this warning may also apply graph (a) of this section. to other oral hypoglycemic drugs in this class, in view of their close similarities in [68 FR 59715, Oct. 17, 2003] mode of action and chemical structure. § 310.519 Drug products marketed as [49 FR 14331, Apr. 11, 1984] over-the-counter (OTC) daytime sedatives. § 310.518 Drug products containing iron or iron salts. (a) Antihistamines, bromides, and scopolamine compounds, either singly Drug products containing elemental or in combinations, have been mar- iron or iron salts as an active ingre- keted as ingredients in over-the- dient in solid oral dosage form, e.g., counter (OTC) drug products for use as tablets or capsules shall meet the fol- daytime sedatives. The following lowing requirements: claims have been made for daytime (a) Labeling. (1) The label of any drug sedative products: ‘‘occasional simple in solid oral dosage form (e.g., tablets nervous tension,’’ ‘‘nervous irrita- or capsules) that contains iron or iron bility,’’ ‘‘nervous tension headache,’’ salts for use as an iron source shall ‘‘simple nervousness due to common bear the following statement: every day overwork and fatigue,’’ ‘‘a WARNING: Accidental overdose or iron- relaxed feeling,’’ ‘‘calming down and containing products is a leading cause of relaxing,’’ ‘‘gently soothe away the fatal poisoning in children under 6. Keep this tension,’’ ‘‘calmative,’’ ‘‘resolving that product out of reach of children. In case of irritability that ruins your day,’’ accidental overdose, call a doctor or poison ‘‘helps you relax,’’ ‘‘restlessness,’’ control center immediately. ‘‘when you’re under occasional stress . (2)(i) The warning statement required . . helps you work relaxed.’’ Based on by paragraph (a)(1) of this section shall evidence presently available, there are appear prominently and conspicuously no ingredients that can be generally on the information panel of the imme- recognized as safe and effective for use diate container label. as OTC daytime sedatives. (ii) If a drug product is packaged in (b) Any OTC drug product that is labeled, represented, or promoted as an unit-dose packaging, and if the imme- OTC daytime sedative (or any similar diate container bears labeling but not a or related indication) is regarded as a label, the warning statement required new drug within the meaning of section by paragraph (a)(1) of this section shall 201(p) of the Federal Food, Drug, and appear prominently and conspicuously Cosmetic Act for which an approved on the immediate container labeling in new drug application under section 505 a way that maximizes the likelihood of the act and part 314 of this chapter that the warning is intact until all of is required for marketing. the dosage units to which it applies are (c) Clinical investigations designed used. to obtain evidence that any drug prod- (3) Where the immediate container is uct labeled, represented, or promoted not the retail package, the warning as an OTC daytime sedative (or any statement required by paragraph (a)(1) similar or related indication) is safe of this section shall also appear promi- and effective for the purpose intended nently and conspicuously on the infor- must comply with the requirements mation panel of the retail package and procedures governing the use of in- label. vestigational new drugs set forth in (4) The warning statement shall ap- part 312 of this chapter. pear on any labeling that contains (d) Any OTC daytime sedative drug warnings. product introduced into interstate (5) The warning statement required commerce after December 24, 1979, that by paragraph (a)(1) of this section shall is not in compliance with this section be set off in a box by use of hairlines. is subject to regulatory action. (b) The iron-containing inert tablets [44 FR 36380, June 22, 1979; 45 FR 47422, July supplied in monthly packages of oral 15, 1980, as amended at 55 FR 11579, Mar. 29, contraceptives are categorically ex- 1990]

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§ 310.527 Drug products containing ac- or initially delivered for introduction tive ingredients offered over-the- into interstate commerce that is not in counter (OTC) for external use as compliance with this section is subject hair growers or for hair loss pre- to regulatory action. vention. [54 FR 28777, July 7, 1989] (a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, biotin and § 310.528 Drug products containing ac- all other B-vitamins, dexpanthenol, es- tive ingredients offered over-the- tradiol and other topical hormones, counter (OTC) for use as an aphro- jojoba oil, lanolin, nucleic acids, poly- disiac. sorbate 20, polysorbate 60, sulfa- (a) Any product that bears labeling nilamide, sulfur 1 percent on carbon in claims that it will arouse or increase a fraction of paraffinic hydrocarbons, sexual desire, or that it will improve tetracaine hydrochloride, urea, and sexual performance, is an aphrodisiac wheat germ oil have been marketed as drug product. Anise, cantharides, don ingredients in OTC drug products for qual, estrogens, fennel, ginseng, golden external use as hair growers or for hair seal, gotu kola, Korean ginseng, lico- loss prevention. There is a lack of ade- rice, mandrake, methyltestosterone, quate data to establish general rec- minerals, nux vomica, Pega Palo, sar- ognition of the safety and effectiveness saparilla, strychnine, testosterone, vi- of these or any other ingredients in- tamins, yohimbine, yohimbine hydro- tended for OTC external use as a hair chloride, and yohimbinum have been grower or for hair loss prevention. present as ingredients in such drug Based on evidence currently available, products. Androgens (e.g., testosterone all labeling claims for OTC hair grower and methyltestosterone) and estrogens and hair loss prevention drug products are powerful hormones when adminis- for external use are either false, mis- tered internally and are not safe for leading, or unsupported by scientific use except under the supervision of a data. Therefore, any OTC drug product physician. There is a lack of adequate for external use containing an ingre- data to establish general recognition of dient offered for use as a hair grower or the safety and effectiveness of any of for hair loss prevention cannot be con- these ingredients, or any other ingre- sidered generally recognized as safe dient, for OTC use as an aphrodisiac. and effective for its intended use. Labeling claims for aphrodisiacs for (b) Any OTC drug product that is la- OTC use are either false, misleading, or beled, represented, or promoted for ex- unsupported by scientific data. The fol- ternal use as a hair grower or for hair lowing claims are examples of some loss prevention is regarded as a new that have been made for aphrodisiac drug within the meaning of section drug products for OTC use: ‘‘acts as an 201(p) of the Federal Food, Drug, and aphrodisiac;’’ ‘‘arouses or increases Cosmetic Act (the act), for which an sexual desire and improves sexual per- approved new drug application under formance;’’ ‘‘helps restore sexual vigor, section 505 of the act and part 314 of potency, and performance;’’ ‘‘improves this chapter is required for marketing. performance, staying power, and sexual In the absence of an approved new drug potency;’’ and ‘‘builds virility and sex- application, such product is also mis- ual potency.’’ Based on evidence cur- branded under section 502 of the act. rently available, any OTC drug product (c) Clinical investigations designed containing ingredients for use as an to obtain evidence that any drug prod- aphrodisiac cannot be generally recog- uct labeled, represented, or promoted nized as safe and effective. for OTC external use as a hair grower (b) Any OTC drug product that is la- or for hair loss prevention is safe and beled, represented, or prompted for use effective for the purpose intended must as an aphrodisiac is regarded as a new 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.

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In the absence of an approved new drug application, such product is also mis- application, such product is also misbranded under section 502 of the act. branded under section 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 labeled, represented, or promoted OTC for oral use as an insect repellent for OTC use as an aphrodisiac is safe is safe and effective for the purpose in- and effective for the purpose intended tended must comply with the require- must comply with the requirements ments and procedures governing the and procedures governing the use of in- use of investigational new drugs set vestigational new drugs set forth in forth in part 312 of this chapter. part 312 of this chapter. (d) Any such drug product in inter- (d) After January 8, 1990, any such state commerce after December 17, OTC drug product initially introduced 1985, that is not in compliance with or initially delivered for introduction this section is subject to regulatory ac- into interstate commerce that is not in tion. compliance with this section is subject [40 FR 25171, June 17, 1985, as amended at 55 to regulatory action. FR 11579, Mar. 29, 1990] [54 FR 28786, July 7, 1989] § 310.530 Topically applied hormone- § 310.529 Drug products containing ac- containing drug products for over- tive ingredients offered over-the- the-counter (OTC) human use. counter (OTC) for oral use as insect (a) The term ‘‘hormone’’ is used repellents. broadly to describe a chemical sub- (a) Thiamine hydrochloride (vitamin stance formed in some organ of the B–1) has been marketed as an ingre- body, such as the adrenal glands or the dient in over-the-counter (OTC) drug pituitary, and carried to another organ products for oral use as an insect repel- or tissue, where it has a specific effect. lent (an orally administered drug prod- Hormones include, for example, estro- uct intended to keep insects away). gens, progestins, androgens, anabolic There is a lack of adequate data to es- steroids, and adrenal corticosteroids, tablish the effectiveness of this, or any and synthetic analogs. Estrogens, pro- other ingredient for OTC oral use as an gesterone, pregnenolone, and pregneno- insect repellent. Labeling claims for lone acetate have been present as in- OTC orally administered insect repel- gredients in OTC drug products mar- lent drug products are either false, keted for topical use as hormone misleading, or unsupported by sci- creams. However, there is a lack of entific data. The following claims are adequate data to establish effective- examples of some that have been made ness for any OTC drug use of these infor orally administered OTC insect re- gredients. Therefore, with the excep- pellent drug products: ‘‘Oral mosquito tion of those hormones identified in repellent,’’ ‘‘mosquitos avoid you,’’ paragraph (e) of this section, any OTC ‘‘bugs stay away,’’ ‘‘keep mosquitos drug product containing an ingredient away for 12 to 24 hours,’’ and ‘‘the new- offered for use as a topically applied est way to fight mosquitos.’’ Therefore, hormone cannot be considered gen- any drug product containing ingredi- erally recognized as safe and effective ents offered for oral use as an insect re- for its intended use. The intended use pellent cannot be generally recognized of the product may be inferred from as safe and effective. the product’s labeling, promotional (b) Any OTC drug product that is la- material, advertising, and any other beled, represented, or promoted for oral relevant factor. The use of the word use as an insect repellent is regarded as ‘‘hormone’’ in the text of the labeling 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

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the labeling indicating that ‘‘hor- methyl salicylate, oxyguinoline sul- mones’’ are present in the product, or fate, petrolatum, phenol, pine tar, any statement that features or empha- rosin, rosin cerate, sassafras oil, sulfur, sizes the presence of a hormone ingre- thymol, triclosan, and zinc oxide have dient in the product, will be considered been present in OTC boil treatment to be a therapeutic claim for the prod- drug products. There is a lack of ade- uct, or a claim that the product will af- quate data to establish general rec- fect the structure or function of the ognition of the safety and effectiveness body, and will consequently cause the of these or any other ingredient for product to be a drug. OTC use for the treatment of boils. (b) Any OTC drug product that is la- Treatment is defined as reducing the beled, represented, or promoted as a size of a boil or reducing an infection topically applied hormone-containing related to a boil. Treatment has in- product for drug use, with the excep- volved the use of ‘‘drawing salves’’ for tion of those hormones identified in these purposes. These ‘‘drawing salves’’ paragraph (e) of this section, is re- contained various ingredients. Based garded as a new drug within the mean- on evidence currently available, any ing of section 201(p) of the act, for OTC drug product offered for the treat- which an approved application or ab- ment of boils cannot be considered gen- breviated application under section 505 erally recognized as safe and effective. of the act and part 314 of this chapter (b) Any OTC drug product that is la- is required for marketing. In the ab- beled, represented, or promoted for the sence of an approved new drug applica- treatment of boils is regarded as a new tion or abbreviated new drug applica- drug within the meaning of section tion, such product is also misbranded 201(p) of the Federal Food, Drug, and under section 502 of the act. Cosmetic Act (the act), for which an (c) Clinical investigations designed approved application or abbreviated to obtain evidence that any drug prod- application under section 505 of the act uct labeled, represented, or promoted and part 314 of this chapter is required for OTC use as a topically applied hor- for marketing. In the absence of an ap- mone-containing drug product is safe proved new drug application or abbre- and effective for the purpose intended viated new drug application, such prod- must comply with the requirements uct is also misbranded under section and procedures governing the use of in- 502 of the act. vestigational new drugs set forth in (c) Clinical investigations designed part 312 of this chapter. to obtain evidence that any OTC boil (d) After March 9, 1994, any such OTC treatment drug product is safe and ef- drug product initially introduced or fective for the purpose intended must initially delivered for introduction into comply with the requirements and pro- interstate commerce that is not in cedures governing the use of investiga- compliance with this section is subject tional new drugs set forth in part 312 of to regulatory action. this chapter. (e) This section does not apply to hy- (d) After May 7, 1991, any such OTC drocortisone and hydrocortisone ace- drug product that contains aminacrine tate labeled, represented, or promoted hydrochloride, bismuth subnitrate, cal- for OTC topical use in accordance with omel, camphor, cholesterol, ergot fluid part 348 of this chapter. extract, hexachlorophene, isobu- [58 FR 47610, Sept. 9, 1993] tamben, juniper tar (oil of cade), lanolin, magnesium sulfate, menthol, § 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,

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ichthammol, sulfur, or triclosan ini- misbranded under section 502 of the tially introduced or initially delivered act. for introduction into interstate com- (c) Clinical investigations designed merce that is not in compliance with to obtain evidence that any drug prod- this section is subject to regulatory ac- uct labeled, represented, or promoted tion. for OTC use to relieve the symptoms of (f) This section does not apply to benign prostatic hypertrophy is safe drug products that contain benzocaine and effective for the purpose intended labeled, represented, or promoted for must comply with the requirements OTC topical use in accordance with and procedures governing the use of in- part 348 of this chapter. vestigational new drugs set forth in part 312 of this chapter. [58 FR 60336, Nov. 15, 1993] (d) After August 27, 1990, any such § 310.532 Drug products containing ac- OTC drug product initially introduced tive ingredients offered over-the- or initially delivered for introduction counter (OTC) to relieve the symp- into interstate commerce that is not in toms of benign prostatic hyper- compliance with this section is subject trophy. to regulatory action. (a) The amino acids glycine, alanine, [55 FR 6930, Feb. 27, 1990] and glutamic acid (alone or in combination) and the ingredient sabal have § 310.533 Drug products containing ac- been present in over-the-counter (OTC) tive ingredients offered over-the- drug products to relieve the symptoms counter (OTC) for human use as an of benign prostatic hypertrophy, e.g., anticholinergic in cough-cold drug urinary urgency and frequency, exces- products. sive urinating at night, and delayed (a) Atropine sulfate, belladonna alka- urination. There is a lack of adequate loids, and belladonna alkaloids as con- data to establish general recognition of tained in Atropa belladonna and Datu- the safety and effectiveness of these or ra stramonium have been present as in- any other ingredients for OTC use in gredients in cough-cold drug products relieving the symptoms of benign pros- for use as an anticholinergic. Anticho- tatic hypertrophy. In addition, there is linergic drugs have been marketed OTC no definitive evidence that any drug in cough-cold drug products to relieve product offered for the relief of the excessive secretions of the nose and symptoms of benign prostatic hyper- eyes, symptoms that are commonly as- trophy would alter the obstructive or sociated with hay fever, allergy, rhi- inflammatory signs and symptoms of nitis, and the common cold. Atropine this condition. Therefore, self-medica- sulfate for oral use as an anticho- tion with OTC drug products might un- linergic is probably safe at dosages necessarily delay diagnosis and treat- that have been used in marketed ment of progressive obstruction and cough-cold products (0.2 to 0.3 milli- secondary infections. Based on evi- gram); however, there are inadequate dence currently available, any OTC data to establish general recognition of drug product containing ingredients of- the effectiveness of this ingredient. fered for use in relieving the symptoms The belladonna alkaloids, which con- of benign prostatic hypertrophy cannot tain atropine (d, dl hyoscyamine) and be generally recognized as safe and ef- scopolamine (l- hyoscine), are probably fective. safe for oral use at dosages that have (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

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to establish general recognition of the to establish general recognition of the safety and/or effectiveness or any of effectiveness of these ingredients as these ingredients, or any other ingre- oral wound healing agents. dient, for OTC use as an anticho- (b) Any OTC drug product that is la- linergic in cough-cold drug products. beled, represented, or promoted for use (b) Any OTC cough-cold drug product as an oral wound healing agent is re- that is labeled, represented, or pro- garded as a new drug within the mean- moted for use as an anticholinergic is ing of section 201(p) of the Federal regarded as a new drug within the Food, Drug, and Cosmetic Act, for meaning of section 201(p) of the Fed- which an approved new drug applica- eral Food, Drug, and Cosmetic Act, for tion under section 505 of the act and which an approved new drug applica- part 314 of this chapter is required for tion under section 505 of the act and marketing. In the absence of an ap- part 314 of this chapter is required for proved new drug application, such marketing. In the absence of an ap- product is also misbranded under sec- proved new drug application, such tion 502 of the act. product is also misbranded under sec- (c) Clinical investigations designed tion 502 of the act. to obtain evidence that any drug prod- (c) Clinical investigations designed uct labeled, represented, or promoted to obtain evidence that any cough-cold for OTC use as an oral wound healing drug product labeled, represented, or agent is safe and effective for the pur- promoted for OTC use as an anticho- pose intended must comply with the re- linergic is safe and effective for the quirements and procedures governing purpose intended must comply with the the use of investigational new drugs requirements and procedures governing set forth in part 312 of this chapter. the use of investigational new drugs (d) After the effective date of the set forth in part 312 of this chapter. final regulation, any OTC drug product (d) After the effective date of the that is labeled, represented, or pro- final regulation, any such OTC cough- moted for use as an oral wound healing cold drug product that is labeled, rep- agent may not be initially introduced resented, or promoted for use as an or initially delivered for introduction anticholinergic may not be initially in- into interstate commerce unless it is troduced or initially delivered for in- the subject of an approved new drug ap- troduction into interstate commerce plication. unless it is the subject of an approved [51 FR 26114, July 18, 1986, as amended at 55 new drug application. FR 11579, Mar. 29, 1990] [50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990] § 310.536 Drug products containing active ingredients offered over-the- § 310.534 Drug products containing ac- counter (OTC) for use as a nail- tive ingredients offered over-the- biting or thumbsucking deterrent. counter (OTC) for human use as (a) Denatonium benzoate and sucrose oral wound healing agents. octaacetate have been present in OTC (a) Allantoin, carbamide peroxide in nailbiting and thumbsucking deterrent anhydrous glycerin, water soluble drug products. There is a lack of ade- chlorophyllins, and hydrogen peroxide quate data to establish general rec- in aqueous solution have been present ognition of the safety and effectiveness in oral mucosal injury drug products of these and any other ingredients 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

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is regarded as a new drug within the section 201(p) of the Federal Food, meaning of section 201(p) of the Fed- Drug, and Cosmetic Act (the act), for eral Food, Drug, and Cosmetic Act (the which an approved application under act) for which an approved application section 505 of the act and part 314 of or abbreviated application under sec- this chapter is required for marketing. tion 505 of the act and part 314 of this In the absence of an approved applica- chapter is required for marketing. In tion, such product is also misbranded the absence of an approved new drug under section 502 of the act. application or abbreviated new drug (c) Clinical investigations designed application, such product is also mis- to obtain evidence that any drug prod- branded under section 502 of the act. uct for oral administration labeled, (c) Clinical investigations designed represented, or promoted for OTC use to obtain evidence that any drug prod- to treat or relieve the symptoms or dis- uct labeled, represented, or promoted comfort of fever blisters and cold sores for OTC use as a nailbiting or thumb- is safe and effective for the purpose in- sucking deterrent is safe and effective tended must comply with the require- for the purpose intended must comply ments and procedures governing the with the requirements and procedures use of investigational new drugs set governing the use of investigational forth in part 312 of this chapter. new drugs set forth in part 312 of this (d) After December 30, 1992, any such chapter. OTC drug product initially introduced (d) After March 2, 1994, any such OTC or initially delivered for introduction drug product initially introduced or into interstate commerce that is not in initially delivered for introduction into compliance with this section is subject interstate commerce that is not in to regulatory action. compliance with this section is subject [57 FR 29173, June 30, 1992] to regulatory action. [58 FR 46754, Sept. 2, 1993] § 310.538 Drug products containing active ingredients offered over-the- § 310.537 Drug products containing ac- counter (OTC) for use for ingrown tive ingredients offered over-the- toenail relief. counter (OTC) for oral administra- (a) Any product that bears labeling tion for the treatment of fever blis- claims such as for ‘‘temporary relief of ters and cold sores. discomfort from ingrown toenails,’’ or (a) L-lysine (lysine, lysine hydro- ‘‘ingrown toenail relief product,’’ or chloride), Lactobacillus acidophilus, and ‘‘ingrown toenail reliever,’’ or similar Lactobacillus bulgaricus have been claims is considered an ingrown toenail present in orally administered OTC relief drug product. Benzocaine, chloro- drug products to treat fever blisters butanol, chloroxylenol, dibucaine, tan- and cold sores. There is a lack of ade- nic acid, and urea have been present as quate data to establish general rec- ingredients in such products. There is ognition of the safety and effectiveness lack of adequate data to establish gen- of these or any other orally adminis- eral recognition of the safety and effec- tered ingredients for OTC use to treat tiveness of these or any other ingredi- or relieve the symptoms or discomfort ents for OTC use for ingrown toenail of fever blisters and cold sores. Based relief. Based on evidence currently on evidence currently available, any available, any OTC drug product con- 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

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for marketing. In the absence of an ap- tion, such product is also misbranded proved new drug application or abbre- under section 502 of the act. viated new drug application, such prod- (c) Clinical investigations designed uct is also misbranded under section to obtain evidence that any drug prod- 502 of the act. uct labeled, represented, or promoted (c) Clinical investigations designed as a stomach acidifier for OTC use is to obtain evidence that any drug prod- safe and effective for the purpose in- uct labeled, represented, or promoted tended must comply with the require- for OTC use for ingrown toenail relief ments and procedures governing the is safe and effective for the purpose in- use of investigational new drugs set tended must comply with the require- forth in part 312 of this chapter. ments and procedures governing the (d) After the effective date of the use of investigational new drugs set final regulation, any such OTC drug forth in part 312 of this chapter. product initially introduced or ini- (d) After March 9, 1994, any such OTC tially delivered for introduction into drug product initially introduced or interstate commerce that is not in initially delivered for introduction into compliance with this section is subject interstate commerce that is not in to regulatory action. compliance with this section is subject [53 FR 31271, Aug. 17, 1988] to regulatory action. (e) This section does not apply to so- § 310.541 Over-the-counter (OTC) drug dium sulfide labeled, represented, or products containing active ingredi- promoted for OTC topical use for in- ents offered for use in the treat- grown toenail relief in accordance with ment of hypophosphatemia. part 358, subpart D of this chapter, (a) Hypophosphatemia is a condition after June 6, 2003. in which an abnormally low plasma [58 FR 47605, Sept. 9, 1993, as amended at 68 level of phosphate occurs in the blood. FR 24348, May 7, 2003] This condition is not amenable to self- diagnosis or self-treatment. Treatment § 310.540 Drug products containing ac- of this condition should be restricted tive ingredients offered over-the- to the supervision of a physician. For counter (OTC) for use as stomach this reason, any drug product con- acidifiers. taining ingredients offered for OTC use (a) Betaine hydrochloride, glutamic in the treatment of hypophosphatemia acid hydrochloride, diluted hydro- cannot be considered generally recog- chloric acid, and pepsin have been nized as safe and effective. present as ingredients in over-the- (b) Any drug product that is labeled, counter (OTC) drug products for use as represented, or promoted for OTC use stomach acidifiers. Because of the lack in the treatment of hypophosphatemia of adequate data to establish the effec- is regarded as a new drug within the tiveness of these or any other ingredi- meaning of section 201(p) of the Fed- ents for use in treating achlorhydria eral Food, Drug, and Cosmetic Act (the and hypochlorhydria, and because such act), for which an approved application conditions are asymptomatic, any OTC under section 505 of the act and part 314 drug product containing ingredients of- of this chapter is required for mar- fered for use as a stomach acidifier keting. In the absence of an approved 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.

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(d) After November 12, 1990, any such gredients in exocrine pancreatic insuf- OTC drug product initially introduced ficiency drug products. Pancreatin and or initially delivered for introduction pancrelipase are composed of enzymes: into interstate commerce that is not in amylase, trypsin (protease), and lipase. compliance with this section is subject Significant differences have been to regulatory action. shown in the bioavailability of mar- [55 FR 19858, May 11, 1990] keted exocrine pancreatic insufficiency drug products produced by different § 310.542 Over-the-counter (OTC) drug manufacturers. These differences raise products containing active ingredi- a potential for serious risk to patients ents offered for use in the treatment of hyperphosphatemia. using these drug products. The bioavailability of pancreatic enzymes is (a) Hyperphosphatemia is a condition dependent on the process used to man- in which an abnormally high plasma ufacture the drug products. Informa- level of phosphate occurs in the blood. This condition in not amenable to self- tion on this process is not included in diagnosis or self-treatment. Treatment an OTC drug monograph. Therefore, of this condition should be restricted the safe and effective use of these en- to the supervision of a physician. For zymes for treating exocrine pancreatic this reason, any drug product con- insufficiency cannot be regulated ade- taining ingredients offered for OTC use quately by an OTC drug monograph. in the treatment of hyperphosphatemia Information on the product’s formula- cannot be considered generally recog- tion, manufacture, quality control pro- nized as safe and effective. cedures, and final formulation effec- (b) Any drug product that is labeled, tiveness testing are necessary in an ap- represented, or promoted for OTC use proved application to ensure that a in the treatment of hyperphosphatemia company has the ability to manufac- is regarded as a new drug within the ture a proper bioactive formulation. In meaning of section 201(p) of the Fed- addition, continuous physician moni- eral Food, Drug, and Cosmetic Act (the toring of patients who take these drug act), for which an approved application products is a collateral measure nec- under section 505 of the act and part 314 essary to the safe and effective use of of this chapter is required for mar- these enzymes, causing such products keting. In the absence of an approved to be available by prescription only. application, such product is also misbranded under section 502 of the act. (b) Any drug product that is labeled, (c) Clinical investigations designed represented, or promoted for OTC use to obtain evidence that any drug prod- in the treatment of exocrine pancreatic uct labeled, represented, or promoted insufficiency is regarded as a new drug for use in the treatment of hyper- within the meaning of section 201(p) of phosphatemia is safe and effective for the Federal Food, Drug, and Cosmetic the purpose intended must comply with Act (the act), for which an approved the requirements and procedures gov- application under section 505 of the act erning use of investigational new drugs and part 314 of this chapter is required set forth in part 312 of this chapter. for marketing. In the absence of an ap- (d) After November 12, 1990, any such proved application, such product is also OTC drug product initially introduced misbranded under section 502 of the or initially delivered for introduction act. into interstate commerce that is not in (c) Clinical investigations designed compliance with this section is subject to obtain evidence that any drug prod- to regulatory action. uct labeled, represented, or promoted [55 FR 19858, May 11, 1990] for OTC use in the treatment of exocrine pancreatic insufficiency is safe § 310.543 Drug products containing ac- and effective for the purpose intended tive ingredients offered over-the- must comply with the requirements counter (OTC) for human use in exocrine pancreatic insufficiency. and procedures governing the use of investigational new drugs set forth in (a) Hemicellulase, pancreatin, and part 312 of this chapter. pancrelipase have been present as in-

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(d) After May 7, 1991, any such OTC (c) Clinical investigations designed drug product that contains hemi- to obtain evidence that any drug prod- cellulase initially introduced or ini- uct labeled, represented, or promoted tially delivered for introduction into for OTC use as a smoking deterrent is interstate commerce that is not in safe and effective for the purpose in- compliance with this section is subject tended must comply with the require- to regulatory action. ments and procedures governing the (e) After October 24, 1995, any such use of investigational new drugs set OTC drug product that contains pan- forth in part 312 of this chapter. creatin or pancrelipase initially intro- (d) After May 7, 1991, any such OTC duced or initially delivered for intro- drug product containing cloves, cori- duction into interstate commerce that ander, eucalyptus oil, ginger (Ja- is not in compliance with this section maica), lemon oil (terpeneless), licorice is subject to regulatory action. root extract, menthol, methyl salicy- [60 FR 20165, Apr. 24, 1995] late, quinine ascorbate, silver nitrate, and/or thymol initially introduced or § 310.544 Drug products containing ac- initially delivered for introduction into tive ingredients offered over-the- interstate commerce that is not in counter (OTC) for use as a smoking compliance with this section is subject deterrent. to regulatory action. After December 1, (a) Any product that bears labeling 1993, any such OTC drug product con- claims that it ‘‘helps stop or reduce the taining lobeline (in the form of lobeline cigarette urge,’’ ‘‘helps break the ciga- sulfate or natural lobelia alkaloids or rette habit,’’ ‘‘helps stop or reduce Lobelia inflata herb), povidone-silver ni- smoking,’’ or similar claims is a smok- trate, silver acetate, or any other in- ing deterrent drug product. Cloves, co- gredients initially introduced or ini- riander, eucalyptus oil, ginger (Ja- tially delivered for introduction into maica), lemon oil (terpeneless), licorice interstate commerce that is not in root extract, lobeline (in the form of compliance with this section is subject lobeline sulfate or natural lobelia alka- to regulatory action. loids or Lobelia inflata herb), menthol, [58 FR 31241, June 1, 1993] methyl salicylate, povidone-silver nitrate, quinine ascorbate, silver acetate, § 310.545 Drug products containing silver nitrate, and thymol have been certain active ingredients offered present as ingredients in such drug over-the-counter (OTC) for certain products. There is a lack of adequate uses. data to establish general recognition of (a) A number of active ingredients the safety and effectiveness of these or have been present in OTC drug prod- any other ingredients for OTC use as a ucts for various uses, as described smoking deterrent. Based on evidence below. However, based on evidence cur- currently available, any OTC drug rently available, there are inadequate product containing ingredients offered data to establish general recognition of for use as a smoking deterrent cannot the safety and effectiveness of these in- be generally recognized as safe and ef- gredients for the specified uses: fective. (1) Topical acne drug products. (b) Any OTC drug product that is labeled, represented, or promoted as a Alcloxa Alkyl isoquinolinium bromide smoking deterrent is regarded as a new Aluminum chlorohydrex drug within the meaning of section Aluminum hydroxide 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 and part 314 of this chapter is required Calcium thiosulfate for marketing. In the absence of an ap- Camphor 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

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Magnesium aluminum silicate Aluminum sulfate Magnesium sulfate Aluminum sulfate, buffered (aerosol only) Phenol Sodium aluminum chlorohydroxy lactate Phenolate sodium Phenyl salicylate (5) [Reserved] Povidone-iodine (6) Cold, cough, allergy, bronchodilator, Pyrilamine maleate and antiasthmatic drug products—(i) Resorcinol (as single ingredient) Antihistamine drug products—(A) Ingre- Resorcinol monoacetate (as single ingredients. dient) Salicylic acid (over 2 up to 5 percent) Methapyrilene hydrochloride Sodium borate Methapyrilene fumarate Sodium thiosulfate Thenyldiamine hydrochloride Tetracaine hydrochloride Thymol (B) Ingredients. Vitamin E Phenyltoloxamine dihydrogen citrate Zinc oxide Methapyrilene hydrochloride Zinc stearate Methapyrilene fumarate Zinc sulfide Thenyldiamine hydrochloride (2) Anticaries drug products—(i) Ap- (ii) Nasal decongestant drug products— proved as of May 7, 1991. (A) Approved as of May 7, 1991. Hydrogen fluoride Allyl isothiocyanate Sodium carbonate Camphor (lozenge) Sodium monofluorophosphate (6 percent Creosote, beechwood (oral) rinse) Eucalyptol (lozenge) Sodium phosphate Eucalyptol (mouthwash) (ii) Approved as of October 7, 1996. Eucalyptus oil (lozenge) Eucalyptus oil (mouthwash) Calcium sucrose phosphate Menthol (mouthwash) Dicalcium phosphate dihydrate Peppermint oil (mouthwash) Disodium hydrogen phosphate 1 Thenyldiamine hydrochloride Phosphoric acid1 Thymol Sodium dihydrogen phosphate Thymol (lozenge) Sodium dihydrogen phosphate monohydrate Thymol (mouthwash) Sodium phosphate, dibasic anhydrous rea- Turpentine oil gent1 (B) Approved as of August 23, 1995. (3) Antidiarrheal drug products. Bornyl acetate (topical) Aluminum hydroxide Cedar leaf oil (topical) Atropine sulfate Creosote, beechwood (topical) Calcium carbonate Ephedrine (oral) Carboxymethylcellulose sodium Ephedrine hydrochloride (oral) Glycine Ephedrine sulfate (oral) Homatropine methylbromide Racephedrine hydrochloride (oral/topical) Hyoscyamine sulfate Lactobacillus acidophilus (iii) Expectorant drug products. Lactobacillus bulgaricus Opium, powdered Ammonium chloride Opium tincture Antimony potassium tartrate Paregoric Beechwood creosote Phenyl salicylate Benzoin preparations (compound tincture of Scopolamine hydrobromide benzoin, tincture of benzoin) Zinc phenolsulfonate Camphor Chloroform (4) Antiperspirant drug products. Eucalyptol/eucalyptus oil Horehound Alum, potassium Iodides (calcium iodide anyhydrous, hydroid- Aluminum bromohydrate ic acid syrup, iodized lime, potassium io- Aluminum chloride (alcoholic solutions) dide) Aluminum chloride (aqueous solution) (aer- Ipecac osol only) Ipecac fluidextract Ipecac syrup 1 These ingredients are nonmonograph ex- Menthol/peppermint oil cept when used to prepare acidulated phos- Pine tar preparations (extract white pine phate fluoride treatment rinses identified in compound, pine tar, syrup of pine tar, com- § 355.10(a)(3) of this chapter. pound white pine syrup, white pine)

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Potassium guaiacolsulfonate Resorcinol Sodium citrate Sodium borate Squill preparations (squill, squill extract) Sodium salicylate Terpin hydrate preparations (terpin hydrate, Thymol terpin hydrate elixir) Undecylenic acid Tolu preparations (tolu, tolu balsam, tolu balsam tincture) (8) Digestive aid drug products—(i) Ap- Turpentine oil (spirits of turpentine) proved as of May 7, 1991. (iv) Bronchodilator drug products—(A) Bismuth sodium tartrate Approved as of October 2, 1987. Calcium carbonate Cellulase Aminophylline Dehydrocholic acid Belladonna alkaloids Dihydroxyaluminum sodium carbonate Euphorbia pilulifera Duodenal substance Metaproterenol sulfate Garlic, dehydrated Methoxyphenamine hydrochloride Glutamic acid hydrochloride Pseudoephedrine hydrochloride Hemicellulase Pseudoephedrine sulfate Homatropine methylbromide Theophylline, anhydrous Magnesium hydroxide Theophylline calcium salicylate Magnesium trisilicate Theophylline sodium glycinate Ox bile extract Pancreatin (B) Approved as of January 29, 1996. Pancrelipase Any combination drug product con- Papain taining theophylline (e.g., theophylline Peppermint oil and ephedrine, or theophylline and Pepsin ephedrine and phenobarbital). Sodium bicarbonate (C) Approved as of June 19, 1996. Any Sodium citrate ingredient(s) in a pressurized metered- Sorbitol dose inhaler container. (ii) Approved as of November 10, 1993. (D) Approved as of October 29, 2001. Any oral bronchodilator active ingre- Alcohol dient (e.g., ephedrine, ephedrine hydro- Aluminum hydroxide Amylase chloride, ephedrine sulfate, Anise seed racephedrine hydrochloride, or any Aromatic powder other ephedrine salt) in combination Asafetida with any analgesic(s) oranalgesic-anti- Aspergillus oryza enzymes (except lactase pyretic(s), anticholinergic, antihis- enzyme derived from Aspergillus oryzae) tamine, oralantitussive, or stimulant Bacillus acidophilus active ingredient. Bean (7) Dandruff/seborrheic dermatitis/psori- Belladonna alkaloids Belladonna leaves, powdered extract asis drug products. Betaine hydrochloride Alkyl isoquinolinium bromide Bismuth subcarbonate Allantoin Bismuth subgallate Benzalkonium chloride Black radish powder Benzethonium chloride Blessed thistle (cnicus benedictus) Boric acid Buckthorn Calcium undecylenate Calcium gluconate Captan Capsicum Chloroxylenol Capsicum, fluid extract of Colloidal oatmeal Carbon Cresol, saponated Cascara sagrada extract Ethohexadiol Catechu, tincture Eucalyptol Catnip Juniper tar Chamomile flowers Lauryl isoquinolinium bromide Charcoal, wood Menthol Chloroform Mercury oleate Cinnamon oil Methylbenzethonium chloride Cinnamon tincture Methyl salicylate Citrus pectin Phenol Diastase Phenolate sodium Diastase malt Pine tar Dog grass Povidone-iodine Elecampane

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Ether Chloral hydrate Fennel acid Eucalyptus oil Galega Ginger (iii) Male genital desensitizer drug Glycine products. Hydrastis canadensis (golden seal) Benzyl alcohol Hectorite Camphorated metacresol Horsetail Ephedrine hydrochloride Huckleberry Hydrastis fluid extract (iv) Diaper rash drug products. Hydrochloric acid Any ingredient(s) labeled with claims Iodine or directions for use in the treatment Iron ox bile and/or prevention of diaper rash. Johnswort (v) Fever blister and cold sore treatment Juniper drug products. Kaolin, colloidal Knotgrass Allyl isothiocyanate Lactic acid Aspirin Lactose Bismuth sodium tartrate Lavender compound, tincture of Camphor (exceeding 3 percent) Linden Capsaicin Lipase Capsicum Lysine hydrochloride Capsicum oleoresin Mannitol Chloral hydrate Mycozyme Chlorobutanol Myrrh, fluid extract of Cyclomethycaine sulfate 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 (vi) Insect bite and sting drug products. Strychnine Tannic acid Alcohol Trillium Alcohol, ethoxylated alkyl Woodruff Benzalkonium chloride Calamine (iii) Charcoal, activated Ergot fluidextract (9) [Reserved] Ferric chloride (10) External analgesic drug products— Panthenol (i) Analgesic and anesthetic drug prod- Peppermint oil ucts. Pyrilamine maleate Sodium borate Aspirin Trolamine salicylate Chloral hydrate Turpentine oil Chlorobutanol Zinc oxide Cyclomethycaine sulfate Zirconium oxide Eugenol Hexylresorcinol (vii) Poison ivy, poison oak, and poison Methapyrilene hydrochloride sumac drug products. Salicylamide Thymol Alcohol Aspirin (ii) Counterirritant drug products. Benzethonium chloride

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Benzocaine (0.5 to 1.25 percent) Gamboge Bithionol Ipomea Calamine Jalap Cetalkonium chloride Ox bile Chloral hydrate Podophyllum resin Chlorobutanol Prune concentrate dehydrate Chlorpheniramine maleate Prune powder Creosote, beechwood Rhubarb, Chinese Cyclomethycaine sulfate Sodium Oleate Dexpanthenol (iv)(B) Stimulant laxatives—Approved Diperodon hydrochloride as of January 29, 1999. Eucalyptus oil Eugenol Danthron Glycerin Phenolphthalein Glycol salicylate Hectorite (C) Stimulant laxatives—Approved as of Hexylresorcinol November 5, 2002. Hydrogen peroxide Aloe ingredients (aloe, aloe extract, aloe Impatiens biflora tincture flower extract) Iron oxide Cascara sagrada ingredients (casanthranol, Isopropyl alcohol cascara fluidextract aromatic, cascara Lanolin sagrada bark, cascara sagrada extract, cas- Lead acetate cara sagrada fluidextract). Merbromin Mercuric chloride (13) [Reserved] Methapyrilene hydrochloride (14) Oral health care drug products Panthenol (nonantimicrobial). Parethoxycaine hydrochloride Phenyltoloxamine dihydrogen citrate Antipyrine Povidone-vinylacetate copolymers Camphor Pyrilamine maleate Cresol Salicylamide Dibucaine Salicylic acid Dibucaine hydrochloride Simethicone Eucalyptol Sulfur Lidocaine Tannic acid Lidocaine hydrochloride Thymol Methly salicylate Trolamine salicylate Myrrh tincture Pyrilamine maleate Turpentine oil Sorbitol Zirconium oxide Sugars Zyloxin Tetracaine (11) [Reserved] Tetracaine hydrochloride (12) Laxative drug products—(i) Bulk Thymol laxatives. (15) Topical otic drug products—(i) For Agar the prevention of swimmer’s ear and for Carrageenan (degraded) the drying of water-clogged ears, ap- Carrageenan (native) proved as of May 7, 1991. Guar gun Acetic acid (ii) Saline laxative. (ii) For the prevention of swimmer’s Tartaric acid ear, approved as of August 15, 1995. (iii) Stool softener. Glycerin and anhydrous glycerin Isopropyl alcohol Poloxamer 188 (16) Poison treatment drug products. (iv)(A) Stimulant laxatives—Approved as of May 7, 1991. Ipecac fluidextract Ipecac tincture Aloin Zinc sulfate Bile salts/acids Calcium pantothenate (17) Skin bleaching drug products. Calomel Mercury, ammoniated Colocynth Elaterin resin (18) Skin protectant drug products. (i) Frangula Ingredients.

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Allantoin (wound healing claims only) Pyridoxine hydrochloride Sulfur Sulfur Tannic acid Tannic acid Zinc acetate (wound healing claims only) Topical starch Trolamine (ii) Astringent drug products. Zinc sulfate Acetone (v) Insect bite and sting drug products. Alcohol Alum, ammonium Alcohol Alum, potassium Alcohol, ethoxylated alkyl Aluminum chlorhydroxy complex Ammonia solution, strong Aromatics Ammonium hydroxide Benzalkonium chloride Benzalkonium chloride Benzethonium chloride Camphor Benzocaine Ergot fluidextract Benzoic acid Ferric chloride Boric acid Menthol Calcium acetate Peppermint oil Camphor gum Phenol Clove oil Pyrilamine maleate Colloidal oatmeal Sodium borate Cresol Trolamine Cupric sulfate Turpentine oil Eucalyptus oil Zirconium oxide Eugenol Ferric subsulfate (Monsel’s Solution) (vi) Poison ivy, poison oak, and poison Honey sumac drug products. Isopropyl alcohol Alcohol Menthol Anion and cation exchange resins buffered Methyl salicylate Benzethonium chloride Oxyquinoline sulfate Benzocaine P-t-butyl-m-cresol Benzyl alcohol Peppermint oil Bismuth subnitrate Phenol Bithionol Polyoxeythylene laurate Boric acid Potassium ferrocyanide Camphor Sage oil Silver nitrate Cetalkonium chloride Sodium borate Chloral hydrate Sodium diacetate Chlorpheniramine maleate Talc Creosote Tannic acid glycerite Diperodon hydrochloride Thymol Diphenhydramine hydrochloride Topical starch Eucalyptus oil Zinc chloride Ferric chloride Zinc oxide Glycerin Zinc phenolsulfonate Hectorite Zinc stearate Hydrogen peroxide Zinc sulfate Impatiens biflora tincture Iron oxide (iii) Diaper rash drug products. Isopropyl alcohol Lanolin Aluminum hydroxide Lead acetate Cocoa butter Lidocaine Cysteine hydrochloride Menthol Glycerin Merbromin Protein hydrolysate Mercuric chloride Racemethionine Panthenol Sulfur Parethoxycaine hydrochloride Tannic acid Phenol Zinc acetate Phenyltoloxamine dihydrogen citrate Zinc carbonate Povidone-vinylacetate copolymers (iv) Fever blister and cold sore treat- Salicylic acid ment drug products. Simethicone Tannic acid Bismuth subnitrate Topical starch Boric acid Trolamine

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Turpentine oil Magnesium oxide Zirconium oxide Malt Zyloxin Maltodextrin Manganese citrate (19) [Reserved] Mannitol (20) Weight control drug products. Methionine Methylcellulose Alcohol Mono- and di-glycerides Alfalfa Niacinamide Alginic acid Organic vegetables Anise oil Pancreatin Arginine Pantothenic acid Ascorbic acid Papain Bearberry Papaya enzymes Biotin Pepsin Bone marrow, red Phenacetin Buchu Phenylalanine Buchu, potassium extract Phosphorus Caffeine Phytolacca Caffeine citrate Pineapple enzymes Calcium Plantago seed Calcium carbonate Potassium citrate Calcium caseinate Pyridoxine hydrochloride (vitamin B6) Calcium lactate Riboflavin Calcium pantothenate Rice polishings Carboxymethylcellulose sodium Saccharin Carrageenan Sea minerals Cholecalcierol Sesame seed Choline Sodium Chondrus Sodium bicarbonate Citric acid Sodium caseinate Cnicus benedictus Sodium chloride (salt) Copper Soybean protein Copper gluconate Soy meal Corn oil Sucrose Corn syrup Thiamine hydrochloride (vitamin B1) Corn silk, potassium extract Thiamine mononitrate (vitamin B1 mono- Cupric sulfate nitrate) Threonine Cyanocobalamin (vitamin B12) Cystine Tricalcium phosphate Dextrose Tryptophan Docusate sodium Tyrosine Ergocalciferol Uva ursi, potassium extract Ferric ammonium citrate Valine Ferric pyrophosphate Vegetable Vitamin A Ferrous fumarate Vitamin A acetate Ferrous gluconate Vitamin A palmitate Ferrous sulfate (iron) Vitamin E Flax seed Wheat germ Folic acid Xanthan gum Fructose Yeast Guar gum Histidine (21) Ophthalmic drug products. Hydrastis canadensis (i) Ophthalmic anesthetic drug prod- Inositol ucts. Iodine Isoleucine Antipyrine Juniper, potassium extract Piperocaine hydrochloride Karaya gum Kelp (ii) Ophthalmic anti-infective drug Lactose products. Lecithin Boric acid Leucine Mild silver protein Liver concentrate Yellow mercuric oxide Lysine Lysine hydrochloride (iii) Ophthalmic astringent drug prod- Magnesium ucts.

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Infusion of rose petals Antipyrine Aspirin, aluminum (iv) Ophthalmic demulcent drug prod- Calcium salicylate ucts. Codeine Polyethylene glycol 6000 Codeine phosphate Codeine sulfate (v) Ophthalmic vasoconstrictor drug Iodoantipyrine products. Lysine aspirin Methapyrilene fumarate Phenylephrine hydrochloride (less than 0.08 Phenacetin percent) Pheniramine maleate (22) Topical antifungal drug products. Pyrilamine maleate (i) Diaper rash drug products. Any in- Quinine Salsalate gredient(s) labeled with claims or di- Sodium aminobenzoate rections for use in the treatment and/ or prevention of diaper rash. (ii) Approved as of February 22, 1999. (ii) Ingredients. Any atropine ingredient Alcloxa Any ephedrine ingredient Alum, potassium (24) Orally administered menstrual drug Aluminum sulfate products. (i) Approved as of November 10, Amyltricresols, secondary Basic fuchsin 1993. Benzethonium chloride Alcohol Benzoic acid Alfalfa leaves Benzoxiquine Aloes Boric acid Asclepias tuberosa Camphor Asparagus Candicidin Barosma Chlorothymol Bearberry (extract of uva ursi) Coal tar Bearberry fluidextract (extract of bearberry) Dichlorophen Blessed thistle (cnicus benedictus) Menthol Buchu powdered extract (extract of buchu) Methylparaben Calcium lactate Oxyquinoline Calcium pantothenate Oxyquinoline sulfate Capsicum oleoresin Phenol Cascara fluidextract, aromatic (extract of Phenolate sodium cascara) Phenyl salicylate Chlorprophenpyridamine maleate Propionic acid Cimicifuga racemosa Propylparaben Codeine Resorcinol Collinsonia (extract stone root) Salicylic acid Sodium borate Corn silk Sodium caprylate Couch grass Sodium propionate Dog grass extract Sulfur Ethyl nitrite Tannic acid Ferric chloride Thymol Ferrous sulfate Tolindate Gentiana lutea (gentian) Triacetin Glycyrrhiza (licorice) Zinc caprylate Homatropine methylbromide Zinc propionate Hydrangea, powdered extract (extract of hydrangea) (iii) Any ingredient(s) labeled with Hydrastis canadensis (golden seal) claims or directions for use on the Hyoscyamine sulfate scalp or on the nails. Juniper oil (oil of juniper) (iv) Ingredients. Magnesium sulfate Methapyrilene hydrochloride Camphorated metacresol Methenamine Chloroxylenol Methylene blue m-cresol Natural estrogenic hormone Nystatin Niacinamide (23) Internal analgesic drug products. Nutmeg oil (oil of nutmeg) (i) Approved as of November 10, 1993. Oil of erigeron Parsley Aminobenzoic acid Peppermint spirit

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Pepsin, essence (iv) Counterirritant drug products. Phenacetin Phenindamine tartrate Camphor (greater than 3 to 11 percent) Phenyl salicylate Hydrastis Piscidia erythrina Menthol (1.25 to 16 percent) Pipsissewa Turpentine oil (rectified) (6 to 50 percent) Potassium acetate (v) Keratolytic drug products. Potassium nitrate Riboflavin Precipitated sulfur Saw palmetto Sublimed sulfur Senecio aureus Sodium benzoate (vi) Local anesthetic drug products. Sodium nitrate Diperodon Sucrose Phenacaine hydrochloride Sulferated oils of turpentine Taraxacum officinale (vii) Other druq products. 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 druq products. Any atropine ingredient Bismuth oxide Any ephedrine ingredient Bismuth subcarbonate (25) Pediculicide drug products—(i) Ap- Bismuth subgallate proved as of November 10, 1993. Bismuth subnitrate Lanolin alcohols Benzocaine Benzyl alcohol (ix) Vasoconstrictor druq products. Benzyl benzoate Epinephrine undecylenate Chlorophenothane (dichlorodiphenyl trichloroethane) (x) Wound healinq druq products. Coconut oil soap, aqueous Cholecalciferol Copper oleate Cod liver oil Docusate sodium Live yeast cell derivative Formic acid Peruvian balsam Isobornyl thiocyanoacetate Shark liver oil Picrotoxin Vitamin A Propylene glycol Sabadilla alkaloids (xi) Combination drug products. Any Sulfur, sublimed combination drug product containing Thiocyanoacetate hydrocortisone and pramoxine hydro- (ii) Approved as of June 14, 1994. The chloride. combination of pyrethrum extract (for- (27) Topical antimicrobial drug prod- merly named pyrethrins) and piperonyl ucts—(i) First aid antiseptic drug prod- butoxide in an aerosol dosage formula- ucts. tion. Ammoniated mercury (26) Anorectal druq products—(i) Anti- Calomel (mercurous chloride) cholinergic drug products. Merbromin (mercurochrome) Mercufenol chloride (ortho- Atropine chloromercuriphenol, ortho- Belladonna extract hydroxyphenylmercuric chloride) (ii) Antiseptic drug products. Mercuric chloride (bichloride of mercury, mercury chloride) Boric acid Mercuric oxide, yellow Boroglycerin Mercuric salicylate Hydrastis Mercuric sulfide, red Phenol Mercury Resorcinol Mercury oleate Sodium salicylic acid phenolate Mercury sulfide (iii) Astringent drug products. Nitromersol Para-chloromercuriphenol Tannic acid Phenylmercuric nitrate

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Thimerosal (1) May 7, 1991, for products subject Vitromersol to paragraphs (a)(1) through (a)(2)(i), Zyloxin (a)(3) through (a)(4), (a)(6)(i)(A), (ii) Diaper rash drug products. (a)(6)(ii)(A), (a)(7) (except as covered by paragraph (d)(3) of this section), Para-chloromercuriphenol Any other ingredient containing mercury (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), (a)(14) (28) Vaginal contraceptive drug prod- through (a)(15)(i), and (a)(16) through ucts—(i) Approved as of October 22, 1998. (a)(18) of this section. Dodecaethylene glycol monolaurate (poly- (2) February 10, 1992, for products ethylene glycol 600 monolaurate) subject to paragraph (a)(20) of this sec- Laureth 10S tion. Methoxypolyoxyethyleneglycol 550 laurate (3) December 4, 1992, for products sub- Phenylmercuric acetate ject to paragraph (a)(7) of this section Phenylmercuric nitrate Any other ingredient containing mercury that contain menthol as an antipruritic in combination with the anti- (ii) Approved as of November 5, 2002. dandruff ingredient coal tar identified Octoxynol 9 in § 358.710(a)(1) of this chapter. (29) Sunscreen drug products. (4) February 28, 1990, for products subject to paragraph (a)(6)(iii) of this Diethanolamine methoxycinnamate section, except those that contain ipe- Digalloyl trioleate Ethyl 4-[bis(hydroxypropyl)] aminobenzoate cac. Glyceryl aminobenzoate (5) September 14, 1993, for products Lawsone with dihydroxyacetone subject to paragraph (a)(6)(iii) of this Red petrolatum section that contain ipecac. (30) [Reserved] (6) December 9, 1993, for products sub- (b) Any OTC drug product that is la- ject to paragraph (a)(6)(i)(B) of this beled, represented, or promoted for the section. uses specified and containing any ac- (7) March 6, 1989, for products subject tive ingredient(s) as specified in para- to paragraph (a)(21) of this section, ex- graph (a) of this section is regarded as cept those that contain ophthalmic a new drug within the meaning of sec- anti–infective ingredients listed in tion 210(p) of the Federal Food, Drug, paragraph (a)(21)(ii). and Cosmetic Act (the Act), for which (8) June 18, 1993, for products subject an approved new drug application to paragraph (a)(21) of this section that under section 505 of the Act and part contain ophthalmic anti–infective in- 314 of this chapter is required for mar- gredients. keting. In the absence of an approved (9) June 18, 1993, for products subject new drug application, such product is to paragraph (a)(10)(iv) of this section. also misbranded under section 502 of (10) June 18, 1993, for products subject the Act. to paragraph (a)(22)(i) of this section. (c) Clinical investigations designed (11) November 10, 1993, for products to obtain evidence that any drug prod- subject to paragraphs (a)(8)(ii), uct labeled, represented, or promoted (a)(10)(v) through (a)(10)(vii), (a)(18)(ii) for the OTC uses and containing any (except products that contain ferric active ingredient(s) as specified in subsulfate) through (a)(18)(vi), paragraph (a) of this section is safe and (a)(22)(ii), (a)(23)(i), (a)(24)(i), and (a)(25) effective for the purpose intended must of this section. comply with the requirements and pro- (12) March 2, 1994, for products sub- cedures governing the use of investiga- ject to paragraph (a)(22)(iii) of this sec- tional new drugs set forth in part 312 of tion. this chapter. (13) August 5, 1991, for products sub- (d) Any OTC drug product that is not ject to paragraph (a)(26) of this section, in compliance with this section is sub- except for those that contain live yeast ject to regulatory action if initially in- cell derivative and a combination of troduced or initially delivered for in- hydrocortisone and pramoxine hydro- troduction into interstate commerce chloride. after the dates specified in paragraphs (14) September 2, 1994, for products (d)(1) through (d)(37) of this section. subject to paragraph (a)(26)(vii) and

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(a)(26)(x) of this section that contain (37) September 25, 2003, for products live yeast cell derivative. subject to paragraph (a)(26)(xi) of this (15) September 23, 1994, for products section. subject to paragraph (a)(22)(iv) of this [55 FR 46919, Nov. 7, 1990] section. (16) June 14, 1994, for products subject EDITORIAL NOTE: For FEDERAL REGISTER ci- to paragraph (a)(25)(ii) of this section. tations affecting § 310.545, see the List of CFR Sections Affected, which appears in the (17) [Reserved] Finding Aids section of the printed volume (18) August 15, 1995, for products sub- and on GPO Access. ject to paragraph (a)(15)(ii) of this sec- EFFECTIVE DATE NOTE 1: At 61 FR 9571, tion. Mar. 8, 1996, in § 310.545 in paragraph (19) October 2, 1987, for products sub- (a)(6)(ii)(B), the entry for ‘‘l-desoxyephedrine ject to paragraph (a)(6)(iv)(A) of this (topical)’’ was stayed until further notice. section. EFFECTIVE DATE NOTE 2: At 68 FR 18881, (20) January 29, 1996, for products April 17, 2003, § 310.545 was amended by add- subject to paragraph (a)(6)(iv)(B) of ing paragraph (a)(3)(i) heading, paragraphs this section. (a)(3)(ii) and (d)(17), and by revising para- (21) April 21, 1994, for products sub- graph (d)(1), effective April 19, 2004. For the ject to paragraph (a)(8)(iii) of this sec- convenience of the user, the added and re- tion. vised parts are set forth below. (22) April 21, 1993, for products sub- § 310.545 Drug products containing certain ject to paragraph (a)(18)(ii) of this sec- active ingredients offered over-the- tion that contain ferric subsulfate. counter (OTC) for certain uses. (23) August 23, 1995, for products sub- (a) * * * ject to paragraph (a)(6)(ii)(B) of this (3) Antidiarrheal drug products—(i) Approved section. as of May 7, 1991. (24) October 7, 1996, for products subject to paragraph (a)(2)(ii) of this sec- * * * * * tion. (ii) Approved as of April 19, 2004; April 18, (25) June 19, 1996, for products subject 2005, for products with annual sales less than to paragraph (a)(6)(iv)(C) of this sec- $25,000. tion. Attapulgite, activated (26) February 22, 1999, for products Bismuth subnitrate subject to paragraphs (a)(23)(ii) and Calcium hydroxide (a)(24)(ii) of this section. Calcium polycarbophil (27) [Reserved] (28) October 22, 1998, for products sub- Charcoal (activated) ject to paragraphs (a)(27) and (a)(28)(i) Pectin of this section. Polycarbophil (29) January 29, 1999, for products Potassium carbonate subject to paragraph (a)(12)(iv)(B) of Rhubarb fluidextract this section. (30) November 5, 2002, for products * * * * * subject to paragraph (a)(12)(iv)(C) of this section. (d) * * * (31) December 31, 2002, for products (1) May 7, 1991, for products subject to paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), subject to paragraph (a)(29) of this sec- (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except tion. as covered by paragraph (d)(3) of this sec- (32) [Reserved] tion), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), (33) October 29, 2001, for products sub- (a)(12)(i) through (a)(12)(iv)(A), (a)(14) ject to paragraph (a)(6)(iv)(D) of this through (a)(15)(i), and (a)(16) through section. (a)(18)(i)(A) of this section. (34)–(35)[Reserved] (36) November 5, 2002, for products * * * * * subject to paragraph (a)(28)(ii) of this (17) April 19, 2004, for products subject to section. paragraph (a)(3)(ii) of this section. April 18,

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2005, for products with annual sales less than Pyrilamine maleate $25,000. Sodium borate Trolamine * * * * * Turpentine oil Zirconium oxide EFFECTIVE DATE NOTE 3: At 68 FR 37963, (B) Ingredients—Approved as of June 4, 2004; June 26, 2003, the amendment to § 310.545 that June 6, 2005, for products with annual sales less published on Apr. 17, 2003 at 68 FR 18881 was than $25,000. corrected in paragraph (d)(1), line 8, by correcting ‘‘(a)(18)(i)(A) of this section’’ to read Beeswax ‘‘(a)(18) of this section (except as covered by Bismuth subnitrate paragraph (d)(22) of this section).’’, effective Boric acid Apr. 19, 2004. Cetyl alcohol EFFECTIVE DATE NOTE 4: At 68 FR 33376, Glyceryl stearate June 4, 2003, § 310.545 was amended by revis- Isopropyl palmitate ing paragraphs (a)(18)(i), (a)(18)(v), (a)(18)(vi), and (d)(1), and by adding paragraph (d)(32), Live yeast cell derivative effective June 4, 2004. For the convenience of Shark liver oil the user, the revised text is set forth as fol- Stearyl alcohol lows: (vi) Poison ivy, poison oak, and poison sumac drug products. § 310.545 Drug products containing certain (A) Ingredients—Approved as of May 7, 1991. active ingredients offered over-the- counter (OTC) for certain uses. Alcohol (a) * * * Anion and cation exchange resins buffered (18) * * * Benzethonium chloride (i)(A) Ingredients—Approved as of May 7, Benzocaine 1991. Benzyl alcohol Allantoin (wound healing claims only) Bismuth subnitrate Sulfur Bithionol Tannic acid Boric acid Zinc acetate (wound healing claims only) (B) Ingredients—Approved as of June 4, 2004; Camphor June 6, 2005, for products with annual sales less Cetalkonium chloride than $25,000. Chloral hydrate Beeswax Chlorpheniramine maleate Bismuth subnitrate Creosote Boric acid Diperodon hydrochloride Cetyl alcohol Diphenhydramine hydrochloride Glyceryl stearate Eucalyptus oil Isopropyl palmitate Ferric chloride Live yeast cell derivative Glycerin Shark liver oil Hectorite Stearyl alcohol Hydrogen peroxide Impatiens biflora tincture * * * * * Iron oxide (v) Insect bite and sting drug products. Isopropyl alcohol (A) Ingredients—Approved as of May 7, 1991. Lanolin Alcohol Lead acetate Alcohol, ethoxylated alkyl Lidocaine Ammonia solution, strong Menthol Ammonium hydroxide Merbromin Benzalkonium chloride Mercuric chloride Camphor Panthenol Ergot fluid extract Parethoxycaine hydrochloride Ferric chloride Phenol Menthol Phenyltoloxamine dihydrogen citrate Peppermint oil Povidone-vinylacetate copolymers Phenol Salicylic acid

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Simethicone Aluminum sulfate buffered with sodium alu- Tannic acid minum lactate Topical starch * * * * * Trolamine Turpentine oil (d) * * * (1) May 7, 1991, for products subject to Zirconium oxide paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), Zyloxin (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (ex- (B) Ingredients—Approved as of June 4, 2004; cept as covered by paragraph (d)(3) of this June 6, 2005, for products with annual sales less section), (a)(8)(i), (a)(10)(i) through than $25,000. (a)(10)(iii), (a)(12)(i) through (a)(12)(iv)(A), Beeswax (a)(14) through (a)(15)(i), (a)(16) through (a)(18)(i)(A), (a)(18)(ii) (except as covered by Bismuth subnitrate paragraph (d)(22) of this section), (a)(18)(iii), Boric acid (a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of Cetyl alcohol this section. Glyceryl stearate Isopropyl palmitate * * * * * Live yeast cell derivative (34) December 9, 2004, for products subject to paragraph (a)(4)(ii) of this section. June 9, Shark liver oil 2005, for products with annual sales less than Stearyl alcohol $25,000.

* * * * * * * * * * (d) * * * (1) May 7, 1991, for products subject to § 310.546 Drug products containing ac- paragraphs (a)(1) through (a)(2)(i), (a)(3)(i), tive ingredients offered over-the- (a)(4), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) (except counter (OTC) for the treatment as covered by paragraph (d)(3) of this sec- and/or prevention of nocturnal leg tion), (a)(8)(i), (a)(10)(i) through (a)(10)(iii), muscle cramps. (a)(12)(i) through (a)(12)(iv)(A), (a)(14) (a) Quinine sulfate alone or in com- through (a)(15)(i), (a)(16) through bination with vitamin E has been (a)(18)(i)(A), (a)(18)(ii) (except as covered by present in over-the-counter (OTC) drug paragraph (d)(22) of this section), (a)(18)(iii), products for the treatment and/or pre- (a)(18)(iv), (a)(18)(v)(A), and (a)(18)(vi)(A) of vention of nocturnal leg muscle this section. cramps, i.e., a condition of localized pain in the lower extremities usually * * * * * occurring in middle life and beyond (32) June 4, 2004, for products subject to with no regular pattern concerning paragraphs (a)(18)(i)(B), (a)(18)(v)(B), and time or severity. There is a lack of ade- (a)(18)(vi)(B) of this section. June 6, 2005, for quate data to establish general rec- products with annual sales less than $25,000. ognition of the safety and effectiveness EFFECTIVE DATE NOTE 5: At 68 FR 34291, of quinine sulfate, vitamin E, or any June 9, 2003, § 310.545 was amended by redesig- other ingredients for OTC use in the nating the text of paragraph (a)(4) as para- treatment and/or prevention of noc- graph (a)(4)(i), by adding new paragraph turnal leg muscle cramps. In the doses (a)(4)(i) heading and paragraphs (a)(4)(ii) and used to treat or prevent this condition, (d)(34), and by revising paragraph (d)(1), ef- quinine sulfate has caused adverse fective Dec. 9, 2004. For the convenience of the user, the added and revised text is set events such as transient visual and au- forth as follows: ditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. Qui- § 310.545 Drug products containing certain nine sulfate may cause unpredictable active ingredients offered over-the- serious and life-threatening hyper- counter (OTC) for certain uses. sensitivity reactions requiring medical (a) * * * intervention and hospitalization; fa- (4) * * * (i) Ingredients—Approved as of May 7, 1991. talities have been reported. The risk *** associated with use of quinine sulfate, (ii) Approved as of December 9, 2004; June 9, in the absence of evidence of its effec- 2005, for products with annual sales less than tiveness, outweighs any potential ben- $25,000. efit in treating and/or preventing this

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

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strong silver protein, silver, silver ion, 312.23 IND content and format. silver chloride, silver cyanide, silver 312.30 Protocol amendments. iodide, silver oxide, and silver phos- 312.31 Information amendments. phate. 312.32 IND safety reports. 312.33 Annual reports. (b) Any OTC drug product containing 312.34 Treatment use of an investigational colloidal silver ingredients or silver new drug. salts that is labeled, represented, or 312.35 Submissions for treatment use. promoted for the treatment and/or pre- 312.36 Emergency use of an investigational vention of any disease is regarded as a new drug. new drug within the meaning of section 312.38 Withdrawal of an IND. 201(p) of the Federal Food, Drug, and Cosmetic Act (the act) for which an ap- Subpart C—Administrative Actions proved application or abbreviated ap- 312.40 General requirements for use of an in- plication under section 505 of the act vestigational new drug in a clinical in- and part 314 of this chapter is required vestigation. for marketing. In the absence of an ap- 312.41 Comment and advice on an IND. proved new drug application or abbre- 312.42 Clinical holds and requests for modification. viated new drug application, such prod- 312.44 Termination. uct is also misbranded under section 312.45 Inactive status. 502 of the act. 312.47 Meetings. (c) Clinical investigations designed 312.48 Dispute resolution. to obtain evidence that any drug product containing colloidal silver or silver Subpart D—Responsibilities of Sponsors salts labeled, represented, or promoted and Investigators for any OTC drug use is safe and effec- 312.50 General responsibilities of sponsors. tive for the purpose intended must 312.52 Transfer of obligations to a contract comply with the requirements and pro- research organization. cedures governing the use of investiga- 312.53 Selecting investigators and monitors. tional new drugs as set forth in part 312 312.54 Emergency research under § 50.24 of of this chapter. this chapter. (d) After September 16, 1999, any such 312.55 Informing investigators. OTC drug product containing colloidal 312.56 Review of ongoing investigations. 312.57 Recordkeeping and record retention. silver or silver salts initially intro- 312.58 Inspection of sponsor’s records and duced or initially delivered for intro- reports. duction into interstate commerce that 312.59 Disposition of unused supply of inves- is not in compliance with this section tigational drug. is subject to regulatory action. 312.60 General responsibilities of investigators. [64 FR 44658, Aug. 17, 1999] 312.61 Control of the investigational drug. 312.62 Investigator recordkeeping and PART 312—INVESTIGATIONAL NEW record retention. DRUG APPLICATION 312.64 Investigator reports. 312.66 Assurance of IRB review. 312.68 Inspection of investigator’s records Subpart A—General Provisions and reports. Sec. 312.69 Handling of controlled substances. 312.1 Scope. 312.70 Disqualification of a clinical investi- 312.2 Applicability. gator. 312.3 Definitions and interpretations. 312.6 Labeling of an investigational new Subpart E—Drugs Intended to Treat Life- drug. threatening and Severely-debilitating 312.7 Promotion and charging for investiga- Illnesses tional drugs. 312.10 Waivers. 312.80 Purpose. 312.81 Scope. Subpart B—Investigational New Drug 312.82 Early consultation. Application (IND) 312.83 Treatment protocols. 312.84 Risk-benefit analysis in review of 312.20 Requirement for an IND. marketing applications for drugs to treat 312.21 Phases of an investigation. life-threatening and severely-debilitating 312.22 General principles of the IND submis- illnesses. sion. 312.85 Phase 4 studies.

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312.86 Focused FDA regulatory research. Health Service Act (58 Stat. 632, as 312.87 Active monitoring of conduct and amended (42 U.S.C. 201 et seq.)). evaluation of clinical trials. (b) Exemptions. (1) The clinical inves- 312.88 Safeguards for patient safety. tigation of a drug product that is lawfully marketed in the United States is Subpart F—Miscellaneous exempt from the requirements of this 312.110 Import and export requirements. part if all the following apply: 312.120 Foreign clinical studies not con- (i) The investigation is not intended ducted under an IND. to be reported to FDA as a well-con- 312.130 Availability for public disclosure of trolled study in support of a new indi- data and information in an IND. cation for use nor intended to be used 312.140 Address for correspondence. to support any other significant change 312.145 Guidance documents. in the labeling for the drug; Subpart G—Drugs for Investigational Use in (ii) If the drug that is undergoing in- Laboratory Research Animals or in vestigation is lawfully marketed as a Vitro Tests prescription drug product, the investigation is not intended to support a 312.160 Drugs for investigational use in lab- significant change in the advertising oratory research animals or in vitro for the product; tests. (iii) The investigation does not in- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, volve a route of administration or dos- 355, 371; 42 U.S.C. 262. age level or use in a patient population SOURCE: 52 FR 8831, Mar. 19, 1987, unless or other factor that significantly in- otherwise noted. creases the risks (or decreases the ac- ceptability of the risks) associated EDITORIAL NOTE: Nomenclature changes to with the use of the drug product; part 312 can be found at 69 FR 13717, Mar. 24, 2004. (iv) The investigation is conducted in compliance with the requirements for institutional review set forth in part 56 Subpart A—General Provisions and with the requirements for informed consent set forth in part 50; and § 312.1 Scope. (v) The investigation is conducted in (a) This part contains procedures and compliance with the requirements of requirements governing the use of in- § 312.7. vestigational new drugs, including pro- (2)(i) A clinical investigation involv- cedures and requirements for the sub- ing an in vitro diagnostic biological mission to, and review by, the Food product listed in paragraph (b)(2)(ii) of and Drug Administration of investiga- this section is exempt from the re- tional new drug applications (IND’s). quirements of this part if (a) it is in- An investigational new drug for which tended to be used in a diagnostic proce- an IND is in effect in accordance with dure that confirms the diagnosis made this part is exempt from the premar- by another, medically established, di- keting approval requirements that are agnostic product or procedure and (b) it otherwise applicable and may be is shipped in compliance with § 312.160. shipped lawfully for the purpose of con- (ii) In accordance with paragraph ducting clinical investigations of that (b)(2)(i) of this section, the following drug. products are exempt from the require- (b) References in this part to regula- ments of this part: (a) blood grouping tions in the Code of Federal Regula- serum; (b) reagent red blood cells; and tions are to chapter I of title 21, unless (c) anti-human globulin. otherwise noted. (3) A drug intended solely for tests in vitro or in laboratory research animals § 312.2 Applicability. is exempt from the requirements of (a) Applicability. Except as provided this part if shipped in accordance with in this section, this part applies to all § 312.160. clinical investigations of products that (4) FDA will not accept an applica- are subject to section 505 of the Federal tion for an investigation that is ex- Food, Drug, and Cosmetic Act or to the empt under the provisions of paragraph licensing provisions of the Public (b)(1) of this section.

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(5) A clinical investigation involving FDA means the Food and Drug Ad- use of a placebo is exempt from the re- ministration. quirements of this part if the inves- IND means an investigational new tigation does not otherwise require drug application. For purposes of this submission of an IND. part, ‘‘IND’’ is synonymous with ‘‘No- (6) A clinical investigation involving tice of Claimed Investigational Exemp- an exception from informed consent tion for a New Drug.’’ under § 50.24 of this chapter is not ex- Investigational new drug means a new empt from the requirements of this drug or biological drug that is used in part. a clinical investigation. The term also (c) Bioavailability studies. The applica- includes a biological product that is bility of this part to in vivo bio- used in vitro for diagnostic purposes. availability studies in humans is sub- The terms ‘‘investigational drug’’ and ject to the provisions of § 320.31. ‘‘investigational new drug’’ are deemed (d) Unlabeled indication. This part to be synonymous for purposes of this does not apply to the use in the prac- part. tice of medicine for an unlabeled indi- Investigator means an individual who cation of a new drug product approved actually conducts a clinical investiga- under part 314 or of a licensed biologi- tion (i.e., under whose immediate di- cal product. rection the drug is administered or dis- (e) Guidance. FDA may, on its own pensed to a subject). In the event an in- initiative, issue guidance on the appli- vestigation is conducted by a team of cability of this part to particular in- individuals, the investigator is the re- vestigational uses of drugs. On request, sponsible leader of the team. ‘‘Sub- FDA will advise on the applicability of investigator’’ includes any other indi- this part to a planned clinical inves- vidual member of that team. tigation. Marketing application means an appli- [52 FR 8831, Mar. 19, 1987, as amended at 61 cation for a new drug submitted under FR 51529, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999] section 505(b) of the act or a biologics license application for a biological § 312.3 Definitions and interpretations. product submitted under the Public (a) The definitions and interpreta- Health Service Act. tions of terms contained in section 201 Sponsor means a person who takes re- of the Act apply to those terms when sponsibility for and initiates a clinical used in this part: investigation. The sponsor may be an (b) The following definitions of terms individual or pharmaceutical company, also apply to this part: governmental agency, academic insti- Act means the Federal Food, Drug, tution, private organization, or other and Cosmetic Act (secs. 201–902, 52 organization. The sponsor does not ac- Stat. 1040 et seq., as amended (21 U.S.C. tually conduct the investigation unless 301–392)). the sponsor is a sponsor-investigator. A Clinical investigation means any ex- person other than an individual that periment in which a drug is adminis- uses one or more of its own employees tered or dispensed to, or used involv- to conduct an investigation that it has ing, one or more human subjects. For initiated is a sponsor, not a sponsor-in- the purposes of this part, an experi- vestigator, and the employees are in- ment is any use of a drug except for the vestigators. use of a marketed drug in the course of Sponsor-Investigator means an indi- medical practice. vidual who both initiates and conducts Contract research organization means a an investigation, and under whose im- person that assumes, as an independent mediate direction the investigational contractor with the sponsor, one or drug is administered or dispensed. The more of the obligations of a sponsor, term does not include any person other e.g., design of a protocol, selection or than an individual. The requirements monitoring of investigations, evalua- applicable to a sponsor-investigator tion of reports, and preparation of ma- under this part include both those ap- terials to be submitted to the Food and plicable to an investigator and a spon- Drug Administration. sor.

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Subject means a human who partici- (d) Charging for and commercialization pates in an investigation, either as a of investigational drugs—(1) Clinical recipient of the investigational new trials under an IND. Charging for an in- drug or as a control. A subject may be vestigational drug in a clinical trial a healthy human or a patient with a under an IND is not permitted without disease. the prior written approval of FDA. In requesting such approval, the sponsor [52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999] shall provide a full written explanation of why charging is necessary in order § 312.6 Labeling of an investigational for the sponsor to undertake or con- new drug. tinue the clinical trial, e.g., why distribution of the drug to test subjects (a) The immediate package of an in- should not be considered part of the vestigational new drug intended for normal cost of doing business. human use shall bear a label with the statement ‘‘Caution: New Drug—Lim- (2) Treatment protocol or treatment ited by Federal (or United States) law IND. A sponsor or investigator may to investigational use.’’ charge for an investigational drug for a treatment use under a treatment pro- (b) The label or labeling of an inves- tocol or treatment IND provided: (i) tigational new drug shall not bear any There is adequate enrollment in the statement that is false or misleading in ongoing clinical investigations under any particular and shall not represent the authorized IND; (ii) charging does that the investigational new drug is not constitute commercial marketing safe or effective for the purposes for of a new drug for which a marketing which it is being investigated. application has not been approved; (iii) § 312.7 Promotion and charging for in- the drug is not being commercially vestigational drugs. promoted or advertised; and (iv) the sponsor of the drug is actively pursuing (a) Promotion of an investigational new marketing approval with due diligence. drug. A sponsor or investigator, or any FDA must be notified in writing in ad- person acting on behalf of a sponsor or vance of commencing any such investigator, shall not represent in a charges, in an information amendment promotional context that an investiga- submitted under § 312.31. Authorization tional new drug is safe or effective for for charging goes into effect automati- the purposes for which it is under in- cally 30 days after receipt by FDA of vestigation or otherwise promote the the information amendment, unless the drug. This provision is not intended to sponsor is notified to the contrary. restrict the full exchange of scientific (3) Noncommercialization of investiga- information concerning the drug, in- tional drug. Under this section, the cluding dissemination of scientific sponsor may not commercialize an in- findings in scientific or lay media. vestigational drug by charging a price Rather, its intent is to restrict pro- larger than that necessary to recover motional claims of safety or effective- costs of manufacture, research, devel- ness of the drug for a use for which it opment, and handling of the investiga- is under investigation and to preclude tional drug. commercialization of the drug before it is approved for commercial distribu- (4) Withdrawal of authorization. Au- tion. thorization to charge for an investigational drug under this section may be (b) Commercial distribution of an inves- withdrawn by FDA if the agency finds tigational new drug. A sponsor or inves- that the conditions underlying the au- tigator shall not commercially dis- thorization are no longer satisfied. tribute or test market an investigational new drug. [52 FR 8831, Mar. 19, 1987, as amended at 52 (c) Prolonging an investigation. A FR 19476, May 22, 1987; 67 FR 9585, Mar. 4, sponsor shall not unduly prolong an in- 2002] vestigation after finding that the results of the investigation appear to es- § 312.10 Waivers. tablish sufficient data to support a (a) A sponsor may request FDA to marketing application. waive applicable requirement under

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

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

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proposed changes in the research activ- (iii) If the drug has been withdrawn ity in accordance with the require- from investigation or marketing in any ments of part 56. country for any reason related to safe- (v) A commitment to conduct the in- ty or effectiveness, identification of vestigation in accordance with all the country(ies) where the drug was other applicable regulatory require- withdrawn and the reasons for the ments. withdrawal. (vi) The name and title of the person (iv) A brief description of the overall responsible for monitoring the conduct plan for investigating the drug product and progress of the clinical investiga- for the following year. The plan should tions. include the following: (a) The rationale (vii) The name(s) and title(s) of the for the drug or the research study; (b) person(s) responsible under § 312.32 for the indication(s) to be studied; (c) the review and evaluation of information general approach to be followed in relevant to the safety of the drug. evaluating the drug; (d) the kinds of clinical trials to be conducted in the (viii) If a sponsor has transferred any first year following the submission (if obligations for the conduct of any clin- plans are not developed for the entire ical study to a contract research orga- year, the sponsor should so indicate); nization, a statement containing the (e) the estimated number of patients to name and address of the contract re- be given the drug in those studies; and search organization, identification of (f) any risks of particular severity or the clinical study, and a listing of the seriousness anticipated on the basis of obligations transferred. If all obliga- the toxicological data in animals or tions governing the conduct of the prior studies in humans with the drug study have been transferred, a general or related drugs. statement of this transfer—in lieu of a (4) [Reserved] listing of the specific obligations trans- (5) Investigator’s brochure. If required ferred—may be submitted. under § 312.55, a copy of the investiga- (ix) The signature of the sponsor or tor’s brochure, containing the fol- the sponsor’s authorized representa- lowing information: tive. If the person signing the applica- (i) A brief description of the drug tion does not reside or have a place of substance and the formulation, includ- business within the United States, the ing the structural formula, if known. IND is required to contain the name (ii) A summary of the pharma- and address of, and be countersigned cological and toxicological effects of by, an attorney, agent, or other au- the drug in animals and, to the extent thorized official who resides or main- known, in humans. tains a place of business within the (iii) A summary of the pharmaco- United States. kinetics and biological disposition of (2) A table of contents. the drug in animals and, if known, in (3) Introductory statement and general humans. investigational plan. (i) A brief introduc- (iv) A summary of information relat- tory statement giving the name of the ing to safety and effectiveness in hu- drug and all active ingredients, the mans obtained from prior clinical stud- drug’s pharmacological class, the ies. (Reprints of published articles on structural formula of the drug (if such studies may be appended when known), the formulation of the dosage useful.) form(s) to be used, the route of admin- (v) A description of possible risks and istration, and the broad objectives and side effects to be anticipated on the planned duration of the proposed clin- basis of prior experience with the drug ical investigation(s). under investigation or with related (ii) A brief summary of previous drugs, and of precautions or special human experience with the drug, with monitoring to be done as part of the in- reference to other IND’s if pertinent, vestigational use of the drug. and to investigational or marketing ex- (6) Protocols. (i) A protocol for each perience in other countries that may planned study. (Protocols for studies be relevant to the safety of the pro- not submitted initially in the IND posed clinical investigation(s). should be submitted in accordance with

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

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

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

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

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(c) New investigator. A sponsor shall before its implementation. Protocol submit a protocol amendment when a amendments to add a new investigator new investigator is added to carry out or to provide additional information a previously submitted protocol, except about investigators may be grouped that a protocol amendment is not re- and submitted at 30-day intervals. quired when a licensed practitioner is When several submissions of new proto- added in the case of a treatment pro- cols or protocol changes are antici- tocol under § 312.34. Once the investi- pated during a short period, the spon- gator is added to the study, the inves- sor is encouraged, to the extent fea- tigational drug may be shipped to the sible, to include these all in a single investigator and the investigator may submission. begin participating in the study. The [52 FR 8831, Mar. 19, 1987, as amended at 52 sponsor shall notify FDA of the new in- FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, vestigator within 30 days of the inves- 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. tigator being added. 4, 2002] (d) Content and format. A protocol amendment is required to be promi- § 312.31 Information amendments. nently identified as such (i.e., ‘‘Pro- (a) Requirement for information amend- tocol Amendment: New Protocol’’, ment. A sponsor shall report in an in- ‘‘Protocol Amendment: Change in Pro- formation amendment essential infor- tocol’’, or ‘‘Protocol Amendment: New mation on the IND that is not within Investigator’’), and to contain the fol- the scope of a protocol amendment, lowing: IND safety reports, or annual report. (1)(i) In the case of a new protocol, a Examples of information requiring an copy of the new protocol and a brief de- information amendment include: scription of the most clinically signifi- (1) New toxicology, chemistry, or cant differences between it and pre- other technical information; or vious protocols. (2) A report regarding the discontinu- (ii) In the case of a change in pro- ance of a clinical investigation. tocol, a brief description of the change (b) Content and format of an informa- and reference (date and number) to the tion amendment. An information amend- submission that contained the pro- ment is required to bear prominent tocol. identification of its contents (e.g., ‘‘In- (iii) In the case of a new investigator, formation Amendment: Chemistry, the investigator’s name, the qualifica- Manufacturing, and Control’’, ‘‘Infor- tions to conduct the investigation, ref- mation Amendment: Pharmacology- erence to the previously submitted pro- Toxicology’’, ‘‘Information Amend- tocol, and all additional information ment: Clinical’’), and to contain the about the investigator’s study as is re- following: quired under § 312.23(a)(6)(iii)(b). (1) A statement of the nature and (2) Reference, if necessary, to specific purpose of the amendment. technical information in the IND or in (2) An organized submission of the a concurrently submitted information data in a format appropriate for sci- amendment to the IND that the spon- entific review. sor relies on to support any clinically (3) If the sponsor desires FDA to com- significant change in the new or ment on an information amendment, a amended protocol. If the reference is request for such comment. made to supporting information already in the IND, the sponsor shall (c) When submitted. Information identify by name, reference number, amendments to the IND should be sub- volume, and page number the location mitted as necessary but, to the extent of the information. feasible, not more than every 30 days. (3) If the sponsor desires FDA to com- [52 FR 8831, Mar. 19, 1987, as amended at 52 ment on the submission, a request for FR 23031, June 17, 1987; 53 FR 1918, Jan. 25, such comment and the specific ques- 1988; 67 FR 9585, Mar. 4, 2002] tions FDA’s response should address. (e) When submitted. A sponsor shall § 312.32 IND safety reports. submit a protocol amendment for a (a) Definitions. The following defini- new protocol or a change in protocol tions of terms apply to this section:–

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Associated with the use of the drug. virtue of greater specificity) if the in- There is a reasonable possibility that vestigator brochure only listed cere- the experience may have been caused bral vascular accidents. ‘‘Unexpected,’’ by the drug. as used in this definition, refers to an Disability. A substantial disruption of adverse drug experience that has not a person’s ability to conduct normal been previously observed (e.g., included life functions. in the investigator brochure) rather Life-threatening adverse drug experi- than from the perspective of such expe- ence. Any adverse drug experience that rience not being anticipated from the places the patient or subject, in the pharmacological properties of the view of the investigator, at immediate pharmaceutical product. risk of death from the reaction as it oc- (b) Review of safety information. The curred, i.e., it does not include a reac- sponsor shall promptly review all infor- tion that, had it occurred in a more se- mation relevant to the safety of the vere form, might have caused death. drug obtained or otherwise received by Serious adverse drug experience: Any the sponsor from any source, foreign or adverse drug experience occurring at domestic, including information de- any dose that results in any of the fol- rived from any clinical or epidemiolog- lowing outcomes: Death, a life-threat- ical investigations, animal investiga- ening adverse drug experience, inpa- tions, commercial marketing experi- tient hospitalization or prolongation of ence, reports in the scientific lit- existing hospitalization, a persistent or erature, and unpublished scientific pa- significant disability/incapacity, or a pers, as well as reports from foreign congenital anomaly/birth defect. Im- regulatory authorities that have not portant medical events that may not already been previously reported to the result in death, be life-threatening, or agency by the sponsor. require hospitalization may be consid- (c) IND safety reports. (1) Written re- ered a serious adverse drug experience ports—(i) The sponsor shall notify FDA when, based upon appropriate medical and all participating investigators in a judgment, they may jeopardize the pa- written IND safety report of: tient or subject and may require medical or surgical intervention to prevent (A) Any adverse experience associ- one of the outcomes listed in this defi- ated with the use of the drug that is nition. Examples of such medical both serious and unexpected; or events include allergic bronchospasm (B) Any finding from tests in labora- requiring intensive treatment in an tory animals that suggests a signifi- emergency room or at home, blood cant risk for human subjects including dyscrasias or convulsions that do not reports of mutagenicity, result in inpatient hospitalization, or teratogenicity, or carcinogenicity. the development of drug dependency or Each notification shall be made as soon drug abuse. as possible and in no event later than Unexpected adverse drug experience: 15 calendar days after the sponsor’s ini- Any adverse drug experience, the speci- tial receipt of the information. Each ficity or severity of which is not con- written notification may be submitted sistent with the current investigator on FDA Form 3500A or in a narrative brochure; or, if an investigator bro- format (foreign events may be sub- chure is not required or available, the mitted either on an FDA Form 3500A specificity or severity of which is not or, if preferred, on a CIOMS I form; re- consistent with the risk information ports from animal or epidemiological described in the general investiga- studies shall be submitted in a nar- tional plan or elsewhere in the current rative format) and shall bear promi- application, as amended. For example, nent identification of its contents, i.e., under this definition, hepatic necrosis ‘‘IND Safety Report.’’ Each written no- would be unexpected (by virtue of tification to FDA shall be transmitted greater severity) if the investigator to the FDA new drug review division in brochure only referred to elevated he- the Center for Drug Evaluation and Re- patic enzymes or hepatitis. Similarly, search or the product review division cerebral thromboembolism and cere- in the Center for Biologics Evaluation bral vasculitis would be unexpected (by and Research that has responsibility

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for review of the IND. If FDA deter- section is so reportable, the sponsor mines that additional data are needed, shall report such experience in a writ- the agency may require further data to ten safety report as soon as possible, be submitted. but in no event later than 15 calendar (ii) In each written IND safety re- days after the determination is made. port, the sponsor shall identify all safe- (4) Results of a sponsor’s investiga- ty reports previously filed with the tion of other safety information shall IND concerning a similar adverse expe- be submitted, as appropriate, in an in- rience, and shall analyze the signifi- formation amendment or annual re- cance of the adverse experience in light port. of the previouos, similar reports. (e) Disclaimer. A safety report or (2) Telephone and facsimile trans- other information submitted by a spon- mission safety reports. The sponsor shall sor under this part (and any release by also notify FDA by telephone or by fac- FDA of that report or information) simile transmission of any unexpected does not necessarily reflect a conclu- fatal or life-threatening experience as- sion by the sponsor or FDA that the re- sociated with the use of the drug as port or information constitutes an ad- soon as possible but in no event later mission that the drug caused or con- than 7 calendar days after the spon- tributed to an adverse experience. A sor’s initial receipt of the information. sponsor need not admit, and may deny, Each telephone call or facsimile trans- that the report or information submission to FDA shall be transmitted to mitted by the sponsor constitutes an the FDA new drug review division in admission that the drug caused or con- the Center for Drug Evaluation and Re- tributed to an adverse experience. search or the product review division in the Center for Biologics Evaluation [52 FR 8831, Mar. 19, 1987, as amended at 52 and Research that has responsibility FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, 1990; 62 FR 52250, Oct. 7, 1997; 67 FR 9585, Mar. for review of the IND. 4, 2002] (3) Reporting format or frequency. FDA may request a sponsor to submit IND § 312.33 Annual reports. safety reports in a format or at a frequency different than that required A sponsor shall within 60 days of the under this paragraph. The sponsor may anniversary date that the IND went also propose and adopt a different re- into effect, submit a brief report of the porting format or frequency if the progress of the investigation that in- change is agreed to in advance by the cludes: director of the new drug review divi- (a) Individual study information. A sion in the Center for Drug Evaluation brief summary of the status of each and Research or the director of the study in progress and each study com- products review division in the Center pleted during the previous year. The for Biologics Evaluation and Research summary is required to include the fol- which is responsible for review of the lowing information for each study: IND. (1) The title of the study (with any (4) A sponsor of a clinical study of a appropriate study identifiers such as marketed drug is not required to make protocol number), its purpose, a brief a safety report for any adverse experi- statement identifying the patient pop- ence associated with use of the drug ulation, and a statement as to whether that is not from the clinical study the study is completed. itself. (2) The total number of subjects ini- (d) Followup. (1) The sponsor shall tially planned for inclusion in the promptly investigate all safety infor- study; the number entered into the mation received by it. study to date, tabulated by age group, (2) Followup information to a safety gender, and race; the number whose report shall be submitted as soon as participation in the study was com- the relevant information is available. pleted as planned; and the number who (3) If the results of a sponsor’s inves- dropped out of the study for any rea- tigation show that an adverse drug ex- son. perience not initially determined to be (3) If the study has been completed, reportable under paragraph (c) of this or if interim results are known, a brief

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description of any available study requests or expects a reply, comment, or sults. meeting. (b) Summary information. Information [52 FR 8831, Mar. 19, 1987, as amended at 52 obtained during the previous year’s FR 23031, June 17, 1987; 63 FR 6862, Feb. 11, clinical and nonclinical investigations, 1998; 67 FR 9585, Mar. 4, 2002] including: (1) A narrative or tabular summary § 312.34 Treatment use of an investiga- showing the most frequent and most tional new drug. serious adverse experiences by body (a) General. A drug that is not ap- system. proved for marketing may be under (2) A summary of all IND safety re- clinical investigation for a serious or ports submitted during the past year. immediately life-threatening disease (3) A list of subjects who died during condition in patients for whom no com- participation in the investigation, with parable or satisfactory alternative the cause of death for each subject. drug or other therapy is available. Dur- (4) A list of subjects who dropped out ing the clinical investigation of the during the course of the investigation drug, it may be appropriate to use the in association with any adverse experi- drug in the treatment of patients not ence, whether or not thought to be in the clinical trials, in accordance drug related. with a treatment protocol or treat- (5) A brief description of what, if any- ment IND. The purpose of this section thing, was obtained that is pertinent to is to facilitate the availability of an understanding of the drug’s actions, promising new drugs to desperately ill including, for example, information patients as early in the drug develop- about dose response, information from ment process as possible, before gen- controlled trails, and information eral marketing begins, and to obtain about bioavailability. additional data on the drug’s safety (6) A list of the preclinical studies and effectiveness. In the case of a seri- (including animal studies) completed ous disease, a drug ordinarily may be or in progress during the past year and made available for treatment use under a summary of the major preclinical this section during Phase 3 investiga- findings. tions or after all clinical trials have (7) A summary of any significant been completed; however, in appro- manufacturing or microbiological priate circumstances, a drug may be changes made during the past year. made available for treatment use dur- (c) A description of the general inves- ing Phase 2. In the case of an imme- tigational plan for the coming year to diately life-threatening disease, a drug replace that submitted 1 year earlier. may be made available for treatment The general investigational plan shall use under this section earlier than contain the information required under Phase 3, but ordinarily not earlier than § 312.23(a)(3)(iv). Phase 2. For purposes of this section, (d) If the investigator brochure has the ‘‘treatment use’’ of a drug includes been revised, a description of the revi- the use of a drug for diagnostic pur- sion and a copy of the new brochure. poses. If a protocol for an investiga- (e) A description of any significant tional drug meets the criteria of this Phase 1 protocol modifications made section, the protocol is to be submitted during the previous year and not pre- as a treatment protocol under the pro- viously reported to the IND in a provisions of this section. tocol amendment. (b) Criteria. (1) FDA shall permit an (f) A brief summary of significant investigational drug to be used for a foreign marketing developments with treatment use under a treatment pro- the drug during the past year, such as tocol or treatment IND if: approval of marketing in any country (i) The drug is intended to treat a se- or withdrawal or suspension from mar- rious or immediately life-threatening keting in any country. disease; (g) If desired by the sponsor, a log of (ii) There is no comparable or satis- any outstanding business with respect factory alternative drug or other ther- to the IND for which the sponsor re- apy available to treat that stage of the

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disease in the intended patient popu- treatment protocol or treatment IND lation; in accordance with § 312.42. (iii) The drug is under investigation [52 FR 19476, May 22, 1987, as amended at 57 in a controlled clinical trial under an FR 13248, Apr. 15, 1992] IND in effect for the trial, or all clinical trials have been completed; and § 312.35 Submissions for treatment (iv) The sponsor of the controlled use. clinical trial is actively pursuing mar- (a) Treatment protocol submitted by keting approval of the investigational IND sponsor. Any sponsor of a clinical drug with due diligence. investigation of a drug who intends to (2) Serious disease. For a drug in- sponsor a treatment use for the drug tended to treat a serious disease, the shall submit to FDA a treatment pro- Commissioner may deny a request for tocol under § 312.34 if the sponsor believes the criteria of § 312.34 are satis- treatment use under a treatment pro- fied. If a protocol is not submitted tocol or treatment IND if there is in- under § 312.34, but FDA believes that sufficient evidence of safety and effec- the protocol should have been sub- tiveness to support such use. mitted under this section, FDA may (3) Immediately life-threatening disease. deem the protocol to be submitted (i) For a drug intended to treat an im- under § 312.34. A treatment use under a mediately life-threatening disease, the treatment protocol may begin 30 days Commissioner may deny a request for after FDA receives the protocol or on treatment use of an investigational earlier notification by FDA that the drug under a treatment protocol or treatment use described in the protocol treatment IND if the available sci- may begin. entific evidence, taken as a whole, fails (1) A treatment protocol is required to provide a reasonable basis for con- to contain the following: cluding that the drug: (i) The intended use of the drug. (A) May be effective for its intended (ii) An explanation of the rationale use in its intended patient population; for use of the drug, including, as appro- or priate, either a list of what available (B) Would not expose the patients to regimens ordinarily should be tried before using the investigational drug or whom the drug is to be administered to an explanation of why the use of the an unreasonable and significant addi- investigational drug is preferable to tional risk of illness or injury. the use of available marketed treat- (ii) For the purpose of this section, ments. an ‘‘immediately life-threatening’’ dis- (iii) A brief description of the criteria ease means a stage of a disease in for patient selection. which there is a reasonable likelihood (iv) The method of administration of that death will occur within a matter the drug and the dosages. of months or in which premature death (v) A description of clinical proce- is likely without early treatment. dures, laboratory tests, or other meas- (c) Safeguards. Treatment use of an ures to monitor the effects of the drug investigational drug is conditioned on and to minimize risk. the sponsor and investigators com- (2) A treatment protocol is to be sup- plying with the safeguards of the IND ported by the following: process, including the regulations gov- (i) Informational brochure for sup- erning informed consent (21 CFR part plying to each treating physician. 50) and institutional review boards (21 (ii) The technical information that is relevant to safety and effectiveness of CFR part 56) and the applicable provi- the drug for the intended treatment sions of part 312, including distribution purpose. Information contained in the of the drug through qualified experts, sponsor’s IND may be incorporated by maintenance of adequate manufac- reference. turing facilities, and submission of IND (iii) A commitment by the sponsor to safety reports. assure compliance of all participating (d) Clinical hold. FDA may place on investigators with the informed con- clinical hold a proposed or ongoing sent requirements of 21 CFR part 50.

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(3) A licensed practioner who receives (vi) The practitioner’s statement of an investigational drug for treatment familiarity with information on the use under a treatment protocol is an drug’s safety and effectiveness derived ‘‘investigator’’ under the protocol and from previous clinical and nonclinical is responsible for meeting all applica- experience with the drug. ble investigator responsibilities under (vii) Agreement to report to FDA this part and 21 CFR parts 50 and 56. safety information in accordance with (b) Treatment IND submitted by li- § 312.32. censed practitioner. (1) If a licensed med- (2) A licensed practitioner who sub- ical practitioner wants to obtain an in- mits a treatment IND under this sec- vestigational drug subject to a con- tion is the sponsor-investigator for trolled clinical trial for a treatment such IND and is responsible for meet- use, the practitioner should first ating all applicable sponsor and investi- tempt to obtain the drug from the gator responsibilities under this part sponsor of the controlled trial under a and 21 CFR parts 50 and 56. treatment protocol. If the sponsor of the controlled clinical investigation of [52 FR 19477, May 22, 1987, as amended at 57 the drug will not establish a treatment FR 13249, Apr. 15, 1992; 67 FR 9585, Mar. 4, protocol for the drug under paragraph 2002] (a) of this section, the licensed medical practitioner may seek to obtain the § 312.36 Emergency use of an inves- drug from the sponsor and submit a tigational new drug. treatment IND to FDA requesting au- Need for an investigational drug may thorization to use the investigational arise in an emergency situation that drug for treatment use. A treatment does not allow time for submission of use under a treatment IND may begin an IND in accordance with § 312.23 or 30 days after FDA receives the IND or § 312.34. In such a case, FDA may au- on earlier notification by FDA that the thorize shipment of the drug for a spec- treatment use under the IND may ified use in advance of submission of an begin. A treatment IND is required to IND. A request for such authorization contain the following: may be transmitted to FDA by tele- (i) A cover sheet (Form FDA 1571) phone or other rapid communication meeting § 312.23(g)(1). means. For investigational biological (ii) Information (when not provided drugs, the request should be directed to by the sponsor) on the drug’s chem- the Division of Biological Investiga- istry, manufacturing, and controls, and tional New Drugs (HFB–230), Center for prior clinical and nonclinical experi- Biologics Evaluation and Research, ence with the drug submitted in ac- 8800 Rockville Pike, Bethesda, MD cordance with § 312.23. A sponsor of a 20892, 301–443–4864. For all other inves- clinical investigation subject to an IND tigational drugs, the request for au- who supplies an investigational drug to thorization should be directed to the a licensed medical practitioner for pur- Document Management and Reporting poses of a separate treatment clinical Branch (HFD–53), Center for Drug Eval- investigation shall be deemed to au- uation and Research, 5600 Fishers Lane, thorize the incorporation-by-reference Rockville, MD 20857, 301–443–4320. After of the technical information contained normal working hours, eastern stand- in the sponsor’s IND into the medical ard time, the request should be di- practitioner’s treatment IND. rected to the FDA Division of Emer- (iii) A statement of the steps taken by the practitioner to obtain the drug gency and Epidemiological Operations, under a treatment protocol from the 202–857–8400. Except in extraordinary drug sponsor. circumstances, such authorization will (iv) A treatment protocol containing be conditioned on the sponsor making the same information listed in para- an appropriate IND submission as soon graph (a)(1) of this section. as practicable after receiving the au- (v) A statement of the practitioner’s thorization. qualifications to use the investiga- [52 FR 8831, Mar. 19, 1987, as amended at 52 tional drug for the intended treatment FR 23031, June 17, 1987; 55 FR 11579, Mar. 29, use. 1990; 67 FR 9585, Mar. 4, 2002]

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§ 312.38 Withdrawal of an IND. (2) On earlier FDA authorization to ship the drug. (a) At any time a sponsor may withdraw 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 IND. turned to the sponsor or otherwise disposed 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 relating to an IND. Examples of such [52 FR 8831, Mar. 19, 1987, as amended at 52 advice may include advice on the ade- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, 2002] quacy of technical data to support an investigational plan, on the design of a clinical trial, and on whether proposed Subpart C—Administrative Actions 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] (2) Each participating investigator conducts his or her investigation in § 312.42 Clinical holds and requests for compliance with the requirements of modification. this part and parts 50 and 56. (a) General. A clinical hold is an order (b) An IND goes into effect: issued by FDA to the sponsor to delay (1) Thirty days after FDA receives a proposed clinical investigation or to the IND, unless FDA notifies the spon- suspend an ongoing investigation. The sor that the investigations described in clinical hold order may apply to one or the IND are subject to a clinical hold more of the investigations covered by under § 312.42; or an IND. When a proposed study is (2) On earlier notification by FDA placed on clinical hold, subjects may that the clinical investigations in the not be given the investigational drug. IND may begin. FDA will notify the When an ongoing study is placed on sponsor in writing of the date it re- clinical hold, no new subjects may be ceives the IND. recruited to the study and placed on (c) A sponsor may ship an investiga- the investigational drug; patients al- tional new drug to investigators named ready in the study should be taken off in the IND: therapy involving the investigational (1) Thirty days after FDA receives drug unless specifically permitted by the IND; or FDA in the interest of patient safety.

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(b) Grounds for imposition of clinical (2) Clinical hold of a Phase 2 or 3 study hold—(1) Clinical hold of a Phase 1 study under an IND. FDA may place a pro- under an IND. FDA may place a proposed or ongoing Phase 2 or 3 inves- posed or ongoing Phase 1 investigation tigation on clinical hold if it finds on clinical hold if it finds that: that: (i) Human subjects are or would be (i) Any of the conditions in para- exposed to an unreasonable and signifi- graphs (b)(1)(i) through (b)(1)(v) of this cant risk of illness or injury; section apply; or (ii) The clinical investigators named (ii) The plan or protocol for the in- in the IND are not qualified by reason vestigation is clearly deficient in de- of their scientific training and experi- sign to meet its stated objectives. ence to conduct the investigation de- (3) Clinical hold of a treatment IND scribed in the IND; or treatment protocol. (iii) The investigator brochure is (i) Proposed use. FDA may place a misleading, erroneous, or materially proposed treatment IND or treatment incomplete; or protocol on clinical hold if it is determined that: (iv) The IND does not contain suffi- (A) The pertinent criteria in cient information required under § 312.34(b) for permitting the treatment § 312.23 to assess the risks to subjects of use to begin are not satisfied; or the proposed studies. (B) The treatment protocol or treat- (v) The IND is for the study of an in- ment IND does not contain the infor- vestigational drug intended to treat a mation required under § 312.35 (a) or (b) life-threatening disease or condition to make the specified determination that affects both genders, and men or under § 312.34(b). women with reproductive potential (ii) Ongoing use. FDA may place an who have the disease or condition ongoing treatment protocol or treat- being studied are excluded from eligi- ment IND on clinical hold if it is deter- bility because of a risk or potential mined that: risk from use of the investigational (A) There becomes available a com- drug of reproductive toxicity (i.e., af- parable or satisfactory alternative fecting reproductive organs) or devel- drug or other therapy to treat that opmental toxicity (i.e., affecting poten- stage of the disease in the intended pa- tial offspring). The phrase ‘‘women tient population for which the inves- with reproductive potential’’ does not tigational drug is being used; include pregnant women. For purposes (B) The investigational drug is not of this paragraph, ‘‘life-threatening ill- under investigation in a controlled nesses or diseases’’ are defined as ‘‘dis- clinical trial under an IND in effect for eases or conditions where the likeli- the trial and not all controlled clinical hood of death is high unless the course trials necessary to support a mar- of the disease is interrupted.’’ The clin- keting application have been com- ical hold would not apply under this pleted, or a clinical study under the paragraph to clinical studies con- IND has been placed on clinical hold: ducted: (C) The sponsor of the controlled (A) Under special circumstances, clinical trial is not pursuing marketing such as studies pertinent only to one approval with due diligence; gender (e.g., studies evaluating the ex- (D) If the treatment IND or treat- cretion of a drug in semen or the ef- ment protocol is intended for a serious fects on menstrual function); disease, there is insufficient evidence (B) Only in men or women, as long as of safety and effectiveness to support a study that does not exclude members such use; or of the other gender with reproductive (E) If the treatment protocol or potential is being conducted concur- treatment IND was based on an imme- rently, has been conducted, or will diately life-threatening disease, the take place within a reasonable time available scientific evidence, taken as agreed upon by the agency; or a whole, fails to provide a reasonable (C) Only in subjects who do not suffer basis for concluding that the drug: from the disease or condition for which (1) May be effective for its intended the drug is being studied. use in its intended population; or

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(2) Would not expose the patients to section would only apply to additional whom the drug is to be administered to enrollment in nonconcurrently con- an unreasonable and significant addi- trolled trials rather than eliminating tional risk of illness or injury. continued access to individuals already (iii) FDA may place a proposed or on- receiving the investigational drug. going treatment IND or treatment pro- (5) Clinical hold of any investigation in- tocol on clinical hold if it finds that volving an exception from informed con- any of the conditions in paragraph sent under § 50.24 of this chapter. FDA (b)(4)(i) through (b)(4)(viii) of this sec- may place a proposed or ongoing inves- tion apply. tigation involving an exception from (4) Clinical hold of any study that is informed consent under § 50.24 of this not designed to be adequate and well-con- chapter on clinical hold if it is deter- trolled. FDA may place a proposed or mined that: ongoing investigation that is not de- (i) Any of the conditions in para- signed to be adequate and well-con- graphs (b)(1) or (b)(2) of this section trolled on clinical hold if it finds that: apply; or (i) Any of the conditions in para- (ii) The pertinent criteria in § 50.24 of graph (b)(1) or (b)(2) of this section this chapter for such an investigation apply; or to begin or continue are not submitted (ii) There is reasonable evidence the or not satisfied. investigation that is not designed to be (6) Clinical hold of any investigation adequate and well-controlled is imped- involving an exception from informed ing enrollment in, or otherwise inter- fering with the conduct or completion consent under § 50.23(d) of this chapter. of, a study that is designed to be an FDA may place a proposed or ongoing adequate and well-controlled investiga- investigation involving an exception tion of the same or another investiga- from informed consent under § 50.23(d) tional drug; or of this chapter on clinical hold if it is (iii) Insufficient quantities of the in- determined that: vestigational drug exist to adequately (i) Any of the conditions in para- conduct both the investigation that is graphs (b)(1) or (b)(2) of this section not designed to be adequate and well- apply; or controlled and the investigations that (ii) A determination by the President are designed to be adequate and well- to waive the prior consent requirement controlled; or for the administration of an investiga- (iv) The drug has been studied in one tional new drug has not been made. or more adequate and well-controlled (c) Discussion of deficiency. Whenever investigations that strongly suggest FDA concludes that a deficiency exists lack of effectiveness; or in a clinical investigation that may be (v) Another drug under investigation grounds for the imposition of clinical or approved for the same indication hold FDA will, unless patients are ex- and available to the same patient popu- posed to immediate and serious risk, lation has demonstrated a better po- attempt to discuss and satisfactorily tential benefit/risk balance; or resolve the matter with the sponsor be- (vi) The drug has received marketing fore issuing the clinical hold order. approval for the same indication in the (d) Imposition of clinical hold. The same patient population; or clinical hold order may be made by (vii) The sponsor of the study that is telephone or other means of rapid com- designed to be an adequate and well- munication or in writing. The clinical controlled investigation is not actively hold order will identify the studies pursuing marketing approval of the in- under the IND to which the hold ap- vestigational drug with due diligence; plies, and will briefly explain the basis or for the action. The clinical hold order (viii) The Commissioner determines will be made by or on behalf of the Di- that it would not be in the public inter- vision Director with responsibility for est for the study to be conducted or review of the IND. As soon as possible, continued. FDA ordinarily intends that and no more than 30 days after imposi- clinical holds under paragraphs tion of the clinical hold, the Division (b)(4)(ii), (b)(4)(iii) and (b)(4)(v) of this Director will provide the sponsor a

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written explanation of the basis for the the disposition of all unused supplies of hold. the drug. A termination action may be (e) Resumption of clinical investiga- based on deficiencies in the IND or in tions. An investigation may only re- the conduct of an investigation under sume after FDA (usually the Division an IND. Except as provided in para- Director, or the Director’s designee, graph (d) of this section, a termination with responsibility for review of the shall be preceded by a proposal to ter- IND) has notified the sponsor that the minate by FDA and an opportunity for investigation may proceed. Resump- the sponsor to respond. FDA will, in tion of the affected investigation(s) general, only initiate an action under will be authorized when the sponsor this section after first attempting to corrects the deficiency(ies) previously resolve differences informally or, when cited or otherwise satisfies the agency appropriate, through the clinical hold that the investigation(s) can proceed. procedures described in § 312.42. 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] 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.

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(xi) The sponsor fails to delay a pro- dividuals, the agency shall imme- posed investigation under the IND or diately, by written notice to the spon- to suspend an ongoing investigation sor from the Director of the Center for that has been placed on clinical hold Drug Evaluation and Research or the under § 312.42(b)(4). Director of the Center for Biologics (2) Phase 2 or 3. FDA may propose to Evaluation and Research, terminate terminate an IND during Phase 2 or the IND. An IND so terminated is sub- Phase 3 if FDA finds that: ject to reinstatement by the Director (i) Any of the conditions in para- on the basis of additional submissions graphs (b)(1)(i) through (b)(1)(xi) of this that eliminate such danger. If an IND section apply; or is terminated under this paragraph, the (ii) The investigational plan or pro- agency will afford the sponsor an op- tocol(s) is not reasonable as a bona fide portunity for a regulatory hearing scientific plan to determine whether or 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 (c) Opportunity for sponsor response. may be placed by FDA on inactive sta- (1) If FDA proposes to terminate an tus. This action may be taken by FDA IND, FDA will notify the sponsor in either on request of the sponsor or on writing, and invite correction or explanation within a period of 30 days. FDA’s own initiative. If FDA seeks to (2) On such notification, the sponsor act on its own initiative under this sec- may provide a written explanation or tion, it shall first notify the sponsor in correction or may request a conference writing of the proposed inactive status. with FDA to provide the requested ex- Upon receipt of such notification, the planation or correction. If the sponsor sponsor shall have 30 days to respond does not respond to the notification as to why the IND should continue to within the allocated time, the IND remain active. shall be terminated. (b) If an IND is placed on inactive (3) If the sponsor responds but FDA status, all investigators shall be so no- does not accept the explanation or cor- tified and all stocks of the drug shall rection submitted, FDA shall inform be returned or otherwise disposed of in the sponsor in writing of the reason for accordance with § 312.59. the nonacceptance and provide the (c) A sponsor is not required to sub- sponsor with an opportunity for a regu- mit annual reports to an IND on inac- latory hearing before FDA under part tive status. An inactive IND is, how- 16 on the question of whether the IND ever, still in effect for purposes of the should be terminated. The sponsor’s re- public disclosure of data and informa- quest for a regulatory hearing must be tion under § 312.130. made within 10 days of the sponsor’s receipt of FDA’s notification of non- (d) A sponsor who intends to resume acceptance. clinical investigation under an IND (d) Immediate termination of IND. Not- placed on inactive status shall submit withstanding paragraphs (a) through a protocol amendment under § 312.30 (c) of this section, if at any time FDA containing the proposed general inves- concludes that continuation of the in- tigational plan for the coming year and vestigation presents an immediate and appropriate protocols. If the protocol substantial danger to the health of in-

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amendment relies on information pre- (‘‘pre-NDA’’ meetings) are helpful in viously submitted, the plan shall ref- developing methods of presentation erence such information. Additional in- and submission of data in the mar- formation supporting the proposed in- keting application that facilitate re- vestigation, if any, shall be submitted view and allow timely FDA response. in an information amendment. Not- (1) End-of-Phase 2 meetings—(i) Pur- withstanding the provisions of § 312.30, pose. The purpose of an end-of-phase 2 clinical investigations under an IND on meeting is to determine the safety of inactive status may only resume (1) 30 proceeding to Phase 3, to evaluate the days after FDA receives the protocol Phase 3 plan and protocols and the ade- amendment, unless FDA notifies the quacy of current studies and plans to sponsor that the investigations de- assess pediatric safety and effective- scribed in the amendment are subject ness, and to identify any additional in- to a clinical hold under § 312.42, or (2) formation necessary to support a mar- on earlier notification by FDA that the keting application for the uses under clinical investigations described in the investigation. protocol amendment may begin. (ii) Eligibility for meeting. While the (e) An IND that remains on inactive end-of-Phase 2 meeting is designed pri- status for 5 years or more may be ter- marily for IND’s involving new molec- minated under § 312.44. ular 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, request and obtain an end-of-Phase 2 2002] meeting. (iii) Timing. To be most useful to the § 312.47 Meetings. 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

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review of the IND. The meeting will be mit FDA to provide the sponsor with scheduled by FDA at a time convenient the most useful advice on preparing a to both FDA and the sponsor. Both the marketing application, the sponsor sponsor and FDA may bring consult- should submit to FDA’s reviewing divi- ants to the meeting. The meeting sion at least 1 month in advance of the should be directed primarily at estab- meeting the following information: lishing agreement between FDA and (i) A brief summary of the clinical the sponsor of the overall plan for studies to be submitted in the applica- Phase 3 and the objectives and design tion. of particular studies. The adequacy of (ii) A proposed format for organizing the technical information to support the submission, including methods for Phase 3 studies and/or a marketing ap- presenting the data. plication may also be discussed. FDA (iii) Information on the status of will also provide its best judgment, at needed or ongoing pediatric studies. that time, of the pediatric studies that (iv) Any other information for discus- will be required for the drug product sion at the meeting. and whether their submission will be [52 FR 8831, Mar. 19, 1987, as amended at 52 deferred until after approval. Agree- FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, ments reached at the meeting on these 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. matters will be recorded in minutes of 4, 2002] the conference that will be taken by FDA in accordance with § 10.65 and pro- § 312.48 Dispute resolution. vided to the sponsor. The minutes (a) General. The Food and Drug Ad- along with any other written material ministration is committed to resolving provided to the sponsor will serve as a differences between sponsors and FDA permanent record of any agreements reviewing divisions with respect to re- reached. Barring a significant sci- quirements for IND’s as quickly and entific development that requires oth- amicably as possible through the coop- erwise, studies conducted in accord- erative exchange of information and ance with the agreement shall be pre- views. sumed to be sufficient in objective and (b) Administrative and procedural design for the purpose of obtaining issues. When administrative or proce- marketing approval for the drug. dural disputes arise, the sponsor should (2) ‘‘Pre-NDA’’ and ‘‘pre-BLA’’ meet- first attempt to resolve the matter ings. FDA has found that delays associ- with the division in FDA’s Center for ated with the initial review of a mar- Drug Evaluation and Research or Cen- keting application may be reduced by ter for Biologics Evaluation and Re- exchanges of information about a pro- search which is responsible for review posed marketing application. The pri- of the IND, beginning with the con- mary purpose of this kind of exchange sumer safety officer assigned to the ap- is to uncover any major unresolved plication. If the dispute is not resolved, problems, to identify those studies that the sponsor may raise the matter with the sponsor is relying on as adequate the person designated as ombudsman, and well-controlled to establish the whose function shall be to investigate drug’s effectiveness, to identify the what has happened and to facilitate a status of ongoing or needed studies timely and equitable resolution. Appro- adequate to assess pediatric safety and priate issues to raise with the ombuds- effectiveness, to acquaint FDA review- man include resolving difficulties in ers with the general information to be scheduling meetings and obtaining submitted in the marketing applica- timely replies to inquiries. Further de- tion (including technical information), tails on this procedure are contained in to discuss appropriate methods for sta- FDA Staff Manual Guide 4820.7 that is tistical analysis of the data, and to dis- publicly available under FDA’s public cuss the best approach to the presen- information regulations in part 20. tation and formatting of data in the (c) Scientific and medical disputes. (1) marketing application. Arrangements When scientific or medical disputes for such a meeting are to be initiated arise during the drug investigation by the sponsor with the division re- process, sponsors should discuss the sponsible for review of the IND. To per- matter directly with the responsible

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reviewing officials. If necessary, spon- with respect to the drug. Additional sors may request a meeting with the specific responsibilities of sponsors are appropriate reviewing officials and described elsewhere in this part. management representatives in order to seek a resolution. Requests for such § 312.52 Transfer of obligations to a meetings shall be directed to the direc- contract research organization. tor of the division in FDA’s Center for (a) A sponsor may transfer responsi- Drug Evaluation and Research or Cen- bility for any or all of the obligations ter for Biologics Evaluation and Re- set forth in this part to a contract research which is responsible for review search organization. Any such transfer of the IND. FDA will make every at- shall be described in writing. If not all tempt to grant requests for meetings obligations are transferred, the writing that involve important issues and that is required to describe each of the obli- 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 to resolve a scientific or medical dis- (b) A contract research organization pute, applicants may suggest that FDA that assumes any obligation of a spon- seek the advice of outside experts, in sor shall comply with the specific regu- which case FDA may, in its discretion, lations in this chapter applicable to invite to the meeting one or more of its this obligation and shall be subject to advisory committee members or other the same regulatory action as a spon- consultants, as designated by the agen- sor for failure to comply with any obli- cy. Applicants may rely on, and may gation assumed under these regula- bring to any meeting, their own con- tions. Thus, all references to ‘‘sponsor’’ sultants. For major scientific and med- in this part apply to a contract re- ical policy issues not resolved by infor- search organization to the extent that mal meetings, FDA may refer the mat- it assumes one or more obligations of ter to one of its standing advisory com- the sponsor. mittees for its consideration and recommendations. § 312.53 Selecting investigators and monitors. [52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990] (a) Selecting investigators. A sponsor 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 § 312.50 General responsibilities of ship investigational new drugs only to sponsors. investigators participating in the investigation. Sponsors are responsibile for selecting qualified investigators, providing (c) Obtaining information from the in- them with the information they need vestigator. Before permitting an investi- to conduct an investigation properly, gator to begin participation in an in- ensuring proper monitoring of the investigation, the sponsor shall obtain vestigation(s), ensuring that the inves- the following: tigation(s) is conducted in accordance (1) A signed investigator statement with the general investigational plan (Form FDA–1572) containing: and protocols contained in the IND, (i) The name and address of the in- maintaining an effective IND with re- vestigator; spect to the investigations, and ensur- (ii) The name and code number, if ing that FDA and all participating in- any, of the protocol(s) in the IND iden- vestigators are promptly informed of tifying the study(ies) to be conducted significant new adverse effects or risks by the investigator;

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(iii) The name and address of any search without IRB approval, except medical school, hospital, or other re- where necessary to eliminate apparent search facility where the clinical inves- immediate hazards to the human sub- tigation(s) will be conducted; jects. (iv) The name and address of any (viii) A list of the names of the sub- clinical laboratory facilities to be used investigators (e.g., research fellows, in the study; residents) who will be assisting the in- (v) The name and address of the IRB vestigator in the conduct of the inves- that is responsible for review and ap- tigation(s). proval of the study(ies); (2) Curriculum vitae. A curriculum (vi) A commitment by the investi- vitae or other statement of qualifica- gator that he or she: (a) Will conduct the study(ies) in actions of the investigator showing the cordance with the relevant, current education, training, and experience protocol(s) and will only make changes that qualifies the investigator as an ex- in a protocol after notifying the spon- pert in the clinical investigation of the sor, except when necessary to protect drug for the use under investigation. the safety, the rights, or welfare of (3) Clinical protocol. (i) For Phase 1 in- subjects; vestigations, a general outline of the (b) Will comply with all requirements planned investigation including the es- regarding the obligations of clinical in- timated duration of the study and the vestigators and all other pertinent re- maximum number of subjects that will quirements in this part; be involved. (c) Will personally conduct or super- (ii) For Phase 2 or 3 investigations, vise the described investigation(s); an outline of the study protocol includ- (d) Will inform any potential subjects ing an approximation of the number of that the drugs are being used for inves- subjects to be treated with the drug tigational purposes and will ensure and the number to be employed as con- that the requirements relating to ob- trols, if any; the clinical uses to be in- taining informed consent (21 CFR part vestigated; characteristics of subjects 50) and institutional review board re- by age, sex, and condition; the kind of view and approval (21 CFR part 56) are clinical observations and laboratory met; tests to be conducted; the estimated (e) Will report to the sponsor adverse experiences that occur in the course of duration of the study; and copies or a the investigation(s) in accordance with description of case report forms to be § 312.64; used. (f) Has read and understands the in- (4) Financial disclosure information. formation in the investigator’s bro- Sufficient accurate financial informa- chure, including the potential risks tion to allow the sponsor to submit and side effects of the drug; and complete and accurate certification or (g) Will ensure that all associates, disclosure statements required under colleagues, and employees assisting in part 54 of this chapter. The sponsor the conduct of the study(ies) are in- shall obtain a commitment from the formed about their obligations in clinical investigator to promptly up- meeting the above commitments. date this information if any relevant (vii) A commitment by the investi- changes occur during the course of the gator that, for an investigation subject investigation and for 1 year following to an institutional review requirement the completion of the study. under part 56, an IRB that complies (d) Selecting monitors. A sponsor shall with the requirements of that part will select a monitor qualified by training be responsible for the initial and con- and experience to monitor the progress tinuing review and approval of the clin- of the investigation. ical investigation and that the investigator will promptly report to the IRB [52 FR 8831, Mar. 19, 1987, as amended at 52 all changes in the research activity and FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, all unanticipated problems involving 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. risks to human subjects or others, and 4, 2002] will not make any changes in the re-

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§ 312.54 Emergency research under quired to be relayed to investigators in § 50.24 of this chapter. accordance with § 312.32. (a) The sponsor shall monitor the [52 FR 8831, Mar. 19, 1987, as amended at 52 progress of all investigations involving FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, an exception from informed consent 2002] under § 50.24 of this chapter. When the sponsor receives from the IRB informa- § 312.56 Review of ongoing investigation concerning the public disclosures tions. required by § 50.24(a)(7)(ii) and (a)(7)(iii) (a) The sponsor shall monitor the of this chapter, the sponsor promptly progress of all clinical investigations shall submit to the IND file and to being conducted under its IND. Docket Number 95S–0158 in the Divi- (b) A sponsor who discovers that an sion of Dockets Management (HFA– investigator is not complying with the 305), Food and Drug Administration, signed agreement (Form FDA–1572), the 5630 Fishers Lane, rm. 1061, Rockville, general investigational plan, or the re- MD 20852, copies of the information quirements of this part or other appli- that was disclosed, identified by the cable parts shall promptly either se- IND number. cure compliance or discontinue ship- (b) The sponsor also shall monitor ments of the investigational new drug such investigations to identify when an to the investigator and end the inves- IRB determines that it cannot approve tigator’s participation in the investiga- the research because it does not meet tion. If the investigator’s participation the criteria in the exception in in the investigation is ended, the spon- § 50.24(a) of this chapter or because of sor shall require that the investigator other relevant ethical concerns. The dispose of or return the investigational sponsor promptly shall provide this in- drug in accordance with the require- formation in writing to FDA, inves- ments of § 312.59 and shall notify FDA. tigators who are asked to participate (c) The sponsor shall review and in this or a substantially equivalent evaluate the evidence relating to the clinical investigation, and other IRB’s safety and effectiveness of the drug as that are asked to review this or a sub- it is obtained from the investigator. stantially equivalent investigation. The sponsors shall make such reports to FDA regarding information relevant [61 FR 51530, Oct. 2, 1996, as amended at 68 FR 24879, May 9, 2003] to the safety of the drug as are required under § 312.32. The sponsor shall § 312.55 Informing investigators. make annual reports on the progress of the investigation in accordance with (a) Before the investigation begins, a § 312.33. sponsor (other than a sponsor-investi- (d) A sponsor who determines that its gator) shall give each participating investigational drug presents an unrea- clinical investigator an investigator sonable and significant risk to subjects brochure containing the information shall discontinue those investigations described in § 312.23(a)(5). that present the risk, notify FDA, all (b) The sponsor shall, as the overall institutional review boards, and all in- investigation proceeds, keep each par- vestigators who have at any time participating investigator informed of new ticipated in the investigation of the observations discovered by or reported discontinuance, assure the disposition to the sponsor on the drug, particu- of all stocks of the drug outstanding as larly with respect to adverse effects required by § 312.59, and furnish FDA and safe use. Such information may be with a full report of the sponsor’s ac- distributed to investigators by means tions. The sponsor shall discontinue of periodically revised investigator the investigation as soon as possible, brochures, reprints or published stud- and in no event later than 5 working ies, reports or letters to clinical inves- days after making the determination tigators, or other appropriate means. Important safety information is re-

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that the investigation should be dis- employee to have access to and copy continued. Upon request, FDA will con- and verify any records and reports refer with a sponsor on the need to dis- lating to a clinical investigation con- continue an investigation. ducted under this part. Upon written [52 FR 8831, Mar. 19, 1987, as amended at 52 request by FDA, the sponsor shall sub- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, mit the records or reports (or copies of 2002] them) to FDA. The sponsor shall discontinue shipments of the drug to any § 312.57 Recordkeeping and record re- investigator who has failed to maintain tention. or make available records or reports of (a) A sponsor shall maintain ade- the investigation as required by this quate records showing the receipt, part. shipment, or other disposition of the (b) Controlled substances. If an inves- investigational drug. These records are required to include, as appropriate, the tigational new drug is a substance list- name of the investigator to whom the ed in any schedule of the Controlled drug is shipped, and the date, quantity, Substances Act (21 U.S.C. 801; 21 CFR and batch or code mark of each such part 1308), records concerning ship- shipment. ment, delivery, receipt, and disposition (b) A sponsor shall maintain com- of the drug, which are required to be plete and accurate records showing any kept under this part or other applica- financial interest in § 54.4(a)(3)(i), ble parts of this chapter shall, upon the (a)(3)(ii), (a)(3)(iii), and (a)(3)(iv) of this request of a properly authorized em- chapter paid to clinical investigators ployee of the Drug Enforcement Ad- by the sponsor of the covered study. A ministration of the U.S. Department of sponsor shall also maintain complete Justice, be made available by the in- and accurate records concerning all vestigator or sponsor to whom the re- other financial interests of investiga- quest is made, for inspection and copy- tors subject to part 54 of this chapter. ing. In addition, the sponsor shall as- (c) A sponsor shall retain the records sure that adequate precautions are and reports required by this part for 2 taken, including storage of the inves- years after a marketing application is tigational drug in a securely locked, approved for the drug; or, if an applica- substantially constructed cabinet, or tion is not approved for the drug, until other securely locked, substantially 2 years after shipment and delivery of constructed enclosure, access to which the drug for investigational use is discontinued and FDA has been so noti- is limited, to prevent theft or diversion fied. of the substance into illegal channels (d) A sponsor shall retain reserve of distribution. samples of any test article and reference standard identified in, and used § 312.59 Disposition of unused supply of investigational drug. in any of the bioequivalence or bioavailability studies described in, The sponsor shall assure the return § 320.38 or § 320.63 of this chapter, and of all unused supplies of the investiga- release the reserve samples to FDA tional drug from each individual inves- upon request, in accordance with, and tigator whose participation in the infor the period specified in § 320.38. vestigation is discontinued or termi- [52 FR 8831, Mar. 19, 1987, as amended at 52 nated. The sponsor may authorize al- FR 23031, June 17, 1987; 58 FR 25926, Apr. 28, ternative disposition of unused supplies 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. of the investigational drug provided 4, 2002] this alternative disposition does not expose humans to risks from the drug. § 312.58 Inspection of sponsor’s records and reports. The sponsor shall maintain written records of any disposition of the drug (a) FDA inspection. A sponsor shall in accordance with § 312.57. upon request from any properly authorized officer or employee of the [52 FR 8831, Mar. 19, 1987, as amended at 52 Food and Drug Administration, at rea- FR 23031, June 17, 1987; 67 FR 9586, Mar. 4, sonable times, permit such officer or 2002]

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§ 312.60 General responsibilities of in- progress notes of the physician, the investigators. dividual’s hospital chart(s), and the An investigator is responsible for en- nurses’ notes. The case history for each suring that an investigation is con- individual shall document that in- ducted according to the signed investi- formed consent was obtained prior to gator statement, the investigational participation in the study. plan, and applicable regulations; for (c) Record retention. An investigator protecting the rights, safety, and wel- shall retain records required to be fare of subjects under the investiga- maintained under this part for a period tor’s care; and for the control of drugs of 2 years following the date a mar- under investigation. An investigator keting application is approved for the shall, in accordance with the provi- drug for the indication for which it is sions of part 50 of this chapter, obtain being investigated; or, if no application the informed consent of each human is to be filed or if the application is not subject to whom the drug is adminis- approved for such indication, until 2 tered, except as provided in §§ 50.23 or years after the investigation is discon- 50.24 of this chapter. Additional spe- tinued and FDA is notified. cific responsibilities of clinical investigators are set forth in this part and [52 FR 8831, Mar. 19, 1987, as amended at 52 in parts 50 and 56 of this chapter. FR 23031, June 17, 1987; 61 FR 57280, Nov. 5, 1996; 67 FR 9586, Mar. 4, 2002] [52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51530, Oct. 2, 1996] § 312.64 Investigator reports. § 312.61 Control of the investigational (a) Progress reports. The investigator drug. shall furnish all reports to the sponsor An investigator shall administer the of the drug who is responsible for col- drug only to subjects under the inves- lecting and evaluating the results ob- tigator’s personal supervision or under tained. The sponsor is required under the supervision of a subinvestigator re- § 312.33 to submit annual reports to sponsible to the investigator. The in- FDA on the progress of the clinical investigator shall not supply the inves- vestigations. tigational drug to any person not au- (b) Safety reports. An investigator thorized under this part to receive it. shall promptly report to the sponsor any adverse effect that may reasonably § 312.62 Investigator recordkeeping be regarded as caused by, or probably and record retention. caused by, the drug. If the adverse ef- (a) Disposition of drug. An investi- fect is alarming, the investigator shall gator is required to maintain adequate report the adverse effect immediately. records of the disposition of the drug, (c) Final report. An investigator shall including dates, quantity, and use by provide the sponsor with an adequate subjects. If the investigation is termi- report shortly after completion of the nated, suspended, discontinued, or investigator’s participation in the in- completed, the investigator shall re- vestigation. turn the unused supplies of the drug to (d) Financial disclosure reports. The the sponsor, or otherwise provide for clinical investigator shall provide the disposition of the unused supplies of sponsor with sufficient accurate finan- the drug under § 312.59. cial information to allow an applicant (b) Case histories. An investigator is to submit complete and accurate cer- required to prepare and maintain ade- tification or disclosure statements as quate and accurate case histories that record all observations and other data required under part 54 of this chapter. pertinent to the investigation on each The clinical investigator shall prompt- individual administered the investiga- ly update this information if any rel- tional drug or employed as a control in evant changes occur during the course the investigation. Case histories in- of the investigation and for 1 year fol- clude the case report forms and sup- lowing the completion of the study. porting data including, for example, [52 FR 8831, Mar. 19, 1987, as amended at 52 signed and dated consent forms and FR 23031, June 17, 1987; 63 FR 5252, Feb. 2, medical records including, for example, 1998; 67 FR 9586, Mar. 4, 2002]

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§ 312.66 Assurance of IRB review. FDA or to the sponsor false informa- An investigator shall assure that an tion in any required report, the Center IRB that complies with the require- for Drug Evaluation and Research or ments set forth in part 56 will be re- the Center for Biologics Evaluation sponsible for the initial and continuing and Research will furnish the investi- review and approval of the proposed gator written notice of the matter 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 application submitted under part 314 con- If the investigational drug is subject taining data reported by an investi- to the Controlled Substances Act, the 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

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public health exists, however, the Com- Drug Administration (FDA) has deter- missioner shall terminate the IND im- mined that it is appropriate to exercise mediately and notify the sponsor of the the broadest flexibility in applying the determination. In such case, the spon- statutory standards, while preserving sor shall have an opportunity for a reg- appropriate guarantees for safety and ulatory hearing before FDA under part effectiveness. These procedures reflect 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 to withdraw approval of the drug prod- benefits of the drug need to be evalu- uct in accordance with the applicable ated in light of the severity of the dis- provisions of the act. ease being treated. The procedure out- (f) An investigator who has been de- lined in this section should be inter- termined to be ineligible to receive in- preted consistent with that purpose. vestigational drugs may be reinstated as eligible when the Commissioner de- § 312.81 Scope. termines that the investigator has pre- This section applies to new drug and sented adequate assurances that the in- biological products that are being stud- vestigator will employ investigatioal ied for their safety and effectiveness in drugs solely in compliance with the treating life-threatening or severely- provisions of this part and of parts 50 debilitating diseases. and 56. (a) For purposes of this section, the [52 FR 8831, Mar. 19, 1987, as amended at 52 term ‘‘life-threatening’’ means: FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, (1) Diseases or conditions where the 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586, likelihood of death is high unless the Mar. 4, 2002] course of the disease is interrupted; and Subpart E—Drugs Intended to (2) Diseases or conditions with poten- Treat Life-threatening and Se- tially fatal outcomes, where the end verely-debilitating Illnesses point of clinical trial analysis is survival. AUTHORITY: 21 U.S.C. 351, 352, 353, 355, 371; (b) For purposes of this section, the 42 U.S.C. 262. term ‘‘severely debilitating’’ means SOURCE: 53 FR 41523, Oct. 21, 1988, unless diseases or conditions that cause major otherwise noted. irreversible morbidity. (c) Sponsors are encouraged to con- § 312.80 Purpose. sult with FDA on the applicability of The purpose of this section is to es- these procedures to specific products. tablish procedures designed to expedite the development, evaluation, and mar- [53 FR 41523, Oct. 21, 1988, as amended at 64 FR 401, Jan. 5, 1999] keting of new therapies intended to treat persons with life-threatening and § 312.82 Early consultation. severely-debilitating illnesses, especially where no satisfactory alter- For products intended to treat life- native therapy exists. As stated threatening or severely-debilitating ill- § 314.105(c) of this chapter, while the nesses, sponsors may request to meet statutory standards of safety and effec- with FDA-reviewing officials early in tiveness apply to all drugs, the many the drug development process to review kinds of drugs that are subject to and reach agreement on the design of them, and the wide range of uses for necessary preclinical and clinical stud- those drugs, demand flexibility in ap- ies. Where appropriate, FDA will invite plying the standards. The Food and to such meetings one or more outside

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expert scientific consultants or advi- (unless grounds exist for clinical hold sory committee members. To the ex- of ongoing protocols, as provided in tent FDA resources permit, agency re- § 312.42(b)(3)(ii)). viewing officials will honor requests for such meetings § 312.84 Risk-benefit analysis in review (a) Pre-investigational new drug (IND) of marketing applications for drugs meetings. Prior to the submission of the to treat life-threatening and se- initial IND, the sponsor may request a verely-debilitating illnesses. meeting with FDA-reviewing officials. (a) FDA’s application of the statu- The primary purpose of this meeting is tory standards for marketing approval to review and reach agreement on the shall recognize the need for a medical design of animal studies needed to ini- risk-benefit judgment in making the tiate human testing. The meeting may final decision on approvability. As part also provide an opportunity for dis- of this evaluation, consistent with the cussing the scope and design of phase 1 statement of purpose in § 312.80, FDA testing, plans for studying the drug will consider whether the benefits of product in pediatric populations, and the drug outweigh the known and po- the best approach for presentation and tential risks of the drug and the need formatting of data in the IND. to answer remaining questions about (b) End-of-phase 1 meetings. When data risks and benefits of the drug, taking from phase 1 clinical testing are avail- into consideration the severity of the able, the sponsor may again request a disease and the absence of satisfactory meeting with FDA-reviewing officials. alternative therapy. The primary purpose of this meeting is (b) In making decisions on whether to review and reach agreement on the to grant marketing approval for prod- design of phase 2 controlled clinical ucts that have been the subject of an trials, with the goal that such testing end-of-phase 1 meeting under § 312.82, will be adequate to provide sufficient FDA will usually seek the advice of data on the drug’s safety and effective- outside expert scientific consultants or ness to support a decision on its ap- advisory committees. Upon the filing provability for marketing, and to dis- of such a marketing application under cuss the need for, as well as the design § 314.101 or part 601 of this chapter, FDA and timing of, studies of the drug in pe- will notify the members of the relevant diatric patients. For drugs for life- standing advisory committee of the ap- threatening diseases, FDA will provide plication’s filing and its availability its best judgment, at that time, wheth- for review. er pediatric studies will be required (c) If FDA concludes that the data and whether their submission will be presented are not sufficient for mar- deferred until after approval. The pro- keting approval, FDA will issue (for a cedures outlined in § 312.47(b)(1) with drug) a not approvable letter pursuant respect to end-of-phase 2 conferences, to § 314.120 of this chapter, or (for a bio- including documentation of agree- logic) a deficiencies letter consistent ments reached, would also be used for with the biological product licensing end-of-phase 1 meetings. procedures. Such letter, in describing [53 FR 41523, Oct. 21, 1988, as amended at 63 the deficiencies in the application, will FR 66669, Dec. 2, 1998] address why the results of the research design agreed to under § 312.82, or in § 312.83 Treatment protocols. subsequent meetings, have not pro- If the preliminary analysis of phase 2 vided sufficient evidence for marketing test results appears promising, FDA approval. Such letter will also describe may ask the sponsor to submit a treat- any recommendations made by the ad- ment protocol to be reviewed under the visory committee regarding the appli- procedures and criteria listed in cation. §§ 312.34 and 312.35. 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.

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§ 312.85 Phase 4 studies. ter), and postmarketing adverse reac- Concurrent with marketing approval, tion reporting (§ 314.80 of this chapter). FDA may seek agreement from the 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 research. is the domestic agent of a foreign sponsor, 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 initiated, FDA will undertake such re- (b) Exports. An investigational new search efforts as a means for meeting a drug intended for export from the public health need in facilitating the United States complies with the re- development of therapies to treat life- quirements of this part as follows: threatening or severely debilitating ill- (1) If an IND is in effect for the drug nesses. under § 312.40 and each person who receives the drug is an investigator § 312.87 Active monitoring of conduct named in the application; or and evaluation of clinical trials. (2) If FDA authorizes shipment of the For drugs covered under this section, drug for use in a clinical investigation. the Commissioner and other agency of- Authorization may be obtained as fol- ficials will monitor the progress of the lows: conduct and evaluation of clinical (i) Through submission to the Inter- trials and be involved in facilitating national Affairs Staff (HFY–50), Asso- their appropriate progress. ciate Commissioner for Health Affairs, Food and Drug Administration, 5600 § 312.88 Safeguards for patient safety. Fishers Lane, Rockville, MD 20857, of a All of the safeguards incorporated written request from the person that within parts 50, 56, 312, 314, and 600 of seeks to export the drug. A request this chapter designed to ensure the must provide adequate information safety of clinical testing and the safety about the drug to satisfy FDA that the of products following marketing ap- drug is appropriate for the proposed in- proval apply to drugs covered by this vestigational use in humans, that the section. This includes the requirements drug will be used for investigational for informed consent (part 50 of this purposes only, and that the drug may chapter) and institutional review be legally used by that consignee in the boards (part 56 of this chapter). These importing country for the proposed in- safeguards further include the review vestigational use. The request shall of animal studies prior to initial specify the quantity of the drug to be human testing (§ 312.23), and the moni- shipped per shipment and the fre- toring of adverse drug experiences quency of expected shipments. If FDA through the requirements of IND safe- authorizes exportation under this para- ty reports (§ 312.32), safety update re- graph, the agency shall concurrently ports during agency review of a mar- notify the government of the importing keting application (§ 314.50 of this chap- country of such authorization.

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(ii) Through submission to the Inter- (b) Data submissions. A sponsor who national Affairs Staff (HFY–50), Asso- wishes to rely on a foreign clinical ciate Commissioner for Health Affairs, study to support an IND or to support Food and Drug Administration, 5600 an application for marketing approval Fishers Lane, Rockville, MD 20857, of a shall submit to FDA the following informal request from an authorized offi- formation: cial of the government of the country (1) A description of the investigator’s to which the drug is proposed to be qualifications; shipped. A request must specify that (2) A description of the research fa- the foreign government has adequate cilities; information about the drug and the proposed investigational use, that the (3) A detailed summary of the pro- drug will be used for investigational tocol and results of the study, and, purposes only, and that the foreign should FDA request, case records main- government is satisfied that the drug tained by the investigator or addi- may legally be used by the intended tional background data such as hos- consignee in that country. Such a re- pital or other institutional records; quest shall specify the quantity of drug (4) A description of the drug sub- to be shipped per shipment and the fre- stance and drug product used in the quency of expected shipments. study, including a description of com- (iii) Authorization to export an in- ponents, formulation, specifications, vestigational drug under paragraph and bioavailability of the specific drug (b)(2)(i) or (ii) of this section may be product used in the clinical study, if revoked by FDA if the agency finds available; and that the conditions underlying its au- (5) If the study is intended to support thorization are not longer met. the effectiveness of a drug product, in- (3) This paragraph applies only where formation showing that the study is the drug is to be used for the purpose of adequate and well controlled under clinical investigation. § 314.126. (4) This paragraph does not apply to (c) Conformance with ethical principles. the export of new drugs (including bio- (1) Foreign clinical research is required logical products, antibiotic drugs, and to have been conducted in accordance insulin) approved or authorized for ex- with the ethical principles stated in port under section 802 of the act (21 the ‘‘Declaration of Helsinki’’ (see U.S.C. 382) or section 351(h)(1)(A) of the paragraph (c)(4) of this section) or the Public Health Service Act (42 U.S.C. laws and regulations of the country in 262(h)(1)(A)). which the research was conducted, [52 FR 8831, Mar. 19, 1987, as amended at 52 whichever represents the greater pro- FR 23031, June 17, 1987; 64 FR 401, Jan. 5, 1999; tection of the individual. 67 FR 9586, Mar. 4, 2002] (2) For each foreign clinical study § 312.120 Foreign clinical studies not submitted under this section, the spon- conducted under an IND. sor shall explain how the research con- (a) Introduction. This section de- formed to the ethical principles con- scribes the criteria for acceptance by tained in the ‘‘Declaration of Helsinki’’ FDA of foreign clinical studies not con- or the foreign country’s standards, ducted under an IND. In general, FDA whichever were used. If the foreign accepts such studies provided they are country’s standards were used, the well designed, well conducted, per- sponsor shall explain in detail how formed by qualified investigators, and those standards differ from the ‘‘Dec- conducted in accordance with ethical laration of Helsinki’’ and how they principles acceptable to the world com- offer greater protection. munity. Studies meeting these criteria (3) When the research has been ap- may be utilized to support clinical in- proved by an independent review com- vestigations in the United States and/ mittee, the sponsor shall submit to or marketing approval. Marketing ap- FDA documentation of such review and proval of a new drug based solely on approval, including the names and foreign clinical data is governed by qualifications of the members of the § 314.106. committee. In this regard, a ‘‘review

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committee’’ means a committee com- relieved from criminal, civil and ethical re- posed of scientists and, where prac- sponsibilities under the laws of their own ticable, individuals who are otherwise countries. qualified (e.g., other health profes- I. Basic Principles sionals or laymen). The investigator may not vote on any aspect of the re- 1. Biomedical research involving human subjects must conform to generally accepted view of his or her protocol by a review scientific principles and should be based on committee. adequately performed laboratory and animal (4) The ‘‘Declaration of Helsinki’’ experimentation and on a thorough knowl- states as follows: edge of the scientific literature. 2. The design and performance of each ex- RECOMMENDATIONS GUIDING PHYSICIANS IN perimental procedure involving human sub- BIOMEDICAL RESEARCH INVOLVING HUMAN jects should be clearly formulated in an ex- SUBJECTS perimental protocol which should be transmitted for consideration, comment and guid- Introduction ance to a specially appointed committee It is the mission of the physician to safe- independent of the investigator and the guard the health of the people. His or her sponsor provided that this independent com- knowledge and conscience are dedicated to mittee is in conformity with the laws and the fulfillment of this mission. regulations of the country in which the re- The Declaration of Geneva of the World search experiment is performed. Medical Association binds the physician with 3. Biomedical research involving human the words, ‘‘The health of my patient will be subjects should be conducted only by sci- my first consideration,’’ and the Inter- entifically qualified persons and under the national Code of Medical Ethics declares supervision of a clinically competent med- that, ‘‘A physician shall act only in the pa- ical person. The responsibility for the human tient’s interest when providing medical care subject must always rest with a medically which might have the effect of weakening qualified person and never rest on the sub- the physical and mental condition of the pa- ject of the research, even though the subject tient.’’ has given his or her consent. The purpose of biomedical research involv- 4. Biomedical research involving human ing human subjects must be to improve diag- subjects cannot legitimately be carried out nostic, therapeutic and prophylactic proce- unless the importance of the objective is in dures and the understanding of the aetiology proportion to the inherent risk to the sub- and pathogenesis of disease. ject. In current medical practice most diag- 5. Every biomedical research project in- nostic, therapeutic or prophylactic proce- volving human subjects should be preceded dures involve hazards. This applies espe- by careful assessment of predictable risks in cially to biomedical research. comparison with foreseeable benefits to the Medical progress is based on research subject or to others. Concern for the inter- which ultimately must rest in part on ex- ests of the subject must always prevail over perimentation involving human subjects. the interests of science and society. In the field of biomedical research a funda- 6. The right of the research subject to safe- mental distinction must be recognized be- guard his or her integrity must always be re- tween medical research in which the aim is spected. Every precaution should be taken to essentially diagnostic or therapeutic for a respect the privacy of the subject and to patient, and medical research, the essential minimize the impact of the study on the sub- object of which is purely scientific and with- ject’s physical and mental integrity and on out implying direct diagnostic or thera- the personality of the subject. peutic value to the person subjected to the 7. Physicians should abstain from engaging research. in research projects involving human sub- Special caution must be exercised in the jects unless they are satisfied that the haz- conduct of research which may affect the en- ards involved are believed to be predictable. vironment, and the welfare of animals used Physicians should cease any investigation if for research must be respected. the hazards are found to outweigh the poten- Because it is essential that the results of tial benefits. laboratory experiments be applied to human 8. In publication of the results of his or her beings to further scientific knowledge and to research, the physician is obliged to preserve help suffering humanity, the World Medical the accuracy of the results. Reports of ex- Association has prepared the following rec- perimentation not in accordance with the ommendations as a guide to every physician principles laid down in this Declaration in biomedical research involving human sub- should not be accepted for publication. jects. They should be kept under review in 9. In any research on human beings, each the future. It must be stressed that the potential subject must be adequately in- standards as drafted are only a guide to phy- formed of the aims, methods, anticipated sicians all over the world. Physicians are not benefits and potential hazards of the study

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and the discomfort it may entail. He or she III. Non-Therapeutic Biomedical Research In- should be informed that he or she is at lib- volving Human Subjects (Non-Clinical Bio- erty to abstain from participation in the medical Research) study and that he or she is free to withdraw 1. In the purely scientific application of his or her consent to participation at any medical research carried out on a human time. The physician should then obtain the being, it is the duty of the physician to re- subject’s freely-given informed consent, pref- main the protector of the life and health of erably in writing. that person on whom biomedical research is 10. When obtaining informed consent for being carried out. the research project the physician should be 2. The subjects should be volunteers—ei- particularly cautious if the subject is in a ther healthy persons or patients for whom dependent relationship to him or her or may the experimental design is not related to the consent under duress. In that case the inpatient’s illness. formed consent should be obtained by a phy- 3. The investigator or the investigating sician who is not engaged in the investiga- team should discontinue the research if in tion and who is completely independent of his/her or their judgment it may, if contin- this official relationship. ued, be harmful to the individual. 11. In case of legal incompetence, informed 4. In research on man, the interest of consent should be obtained from the legal science and society should never take prece- guardian in accordance with national legis- dence over considerations related to the lation. Where physical or mental incapacity well-being of the subject. makes it impossible to obtain informed consent, or when the subject is a minor, permis- [52 FR 8831, Mar. 19, 1987, as amended at 52 sion from the responsible relative replaces FR 23031, June 17, 1987; 56 FR 22113, May 14, that of the subject in accordance with na- 1991; 64 FR 401, Jan. 5, 1999; 67 FR 9586, Mar. tional legislation. 4, 2002] Whenever the minor child is in fact able to give a consent, the minor’s consent must be § 312.130 Availability for public disclo- obtained in addition to the consent of the sure of data and information in an minor’s legal guardian. IND. 12. The research protocol should always (a) The existence of an investiga- contain a statement of the ethical consider- tional new drug application will not be ations involved and should indicate that the disclosed by FDA unless it has pre- principles enunciated in the present Declara- viously been publicly disclosed or action are complied with. knowledged. II. Medical Research Combined with (b) The availability for public disclo- Professional Care (Clinical Research) sure of all data and information in an investigational new drug application 1. In the treatment of the sick person, the physician must be free to use a new diag- for a new drug will be handled in ac- nostic and therapeutic measure, if in his or cordance with the provisions estab- her judgment it offers hope of saving life, re- lished in § 314.430 for the confidentiality establishing health or alleviating suffering. of data and information in applications 2. The potential benefits, hazards and dis- submitted in part 314. The availability comfort of a new method should be weighed for public disclosure of all data and in- against the advantages of the best current formation in an investigational new diagnostic and therapeutic methods. drug application for a biological prod- 3. In any medical study, every patient—in- uct will be governed by the provisions cluding those of a control group, if any— should be assured of the best proven diag- of §§ 601.50 and 601.51. nostic and therapeutic method. (c) Notwithstanding the provisions of 4. The refusal of the patient to participate § 314.430, FDA shall disclose upon rein a study must never interfere with the phy- quest to an individual to whom an in- sician-patient relationship. vestigational new drug has been given 5. If the physician considers it essential a copy of any IND safety report relat- not to obtain informed consent, the specific ing to the use in the individual. reasons for this proposal should be stated in (d) The availability of information the experimental protocol for transmission required to be publicly disclosed for in- to the independent committee (I, 2). vestigations involving an exception 6. The physician can combine medical re- from informed consent under § 50.24 of search with professional care, the objective being the acquisition of new medical knowl- this chapter will be handled as follows: edge, only to the extent that medical re- Persons wishing to request the publicly search is justified by its potential diagnostic disclosable information in the IND that or therapeutic value for the patient. was required to be filed in Docket

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Number 95S–0158 in the Division of (c) All correspondence relating to bi- Dockets Management (HFA–305), Food ological products for human use which and Drug Administration, 5630 Fishers are also radioactive drugs shall be sub- Lane, rm. 1061, Rockville, MD 20852, mitted to the Division of Oncology and shall submit a request under the Free- Radiopharmaceutical Drug Products dom of Information Act. (HFD–150), Center for Drug Evaluation and Research, Food and Drug Adminis- [52 FR 8831, Mar. 19, 1987. Redesignated at 53 tration, 5600 Fishers Lane, Rockville, FR 41523, Oct. 21, 1988, as amended at 61 FR MD 20857, except that applications for 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 FR 24879, May 9, 2003] coupled antibodies shall be submitted in accordance with paragraph (b) of § 312.140 Address for correspondence. this section. (d) All correspondence relating to ex- (a) Except as provided in paragraph port of an investigational drug under (b) of this section, a sponsor shall send § 312.110(b)(2) shall be submitted to the an initial IND submission to the Cen- International Affairs Staff (HFY–50), tral Document Room, Center for Drug Office of Health Affairs, Food and Drug Evaluation and Research, Food and Administration, 5600 Fishers Lane, Drug Administration, 5901–B Rockville, MD 20857. Ammendale Rd., Beltsville, MD 20705– 1266. On receiving the IND, FDA will inform the sponsor which one of the di- [52 FR 8831, Mar. 19, 1987, as amended at 52 visions in the Center for Drug Evalua- FR 23031, June 17, 1987; 55 FR 11580, Mar. 29, tion and Research or the Center for 1990; 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004] Biologics Evaluation and Research is responsible for the IND. Amendments, § 312.145 Guidance documents. reports, and other correspondence relating to matters covered by the IND should be directed to the appropriate (a) FDA has made available guidance division. The outside wrapper of each documents under § 10.115 of this chapter submission shall state what is con- to help you to comply with certain retained in the submission, for example, quirements of this part. ‘‘IND Application’’, ‘‘Protocol Amend- ment’’, etc. (b) The Center for Drug Evaluation (b) Applications for the products list- and Research (CDER) and the Center ed below should be submitted to the Di- for Biologics Evaluation and Research vision of Biological Investigational (CBER) maintain lists of guidance doc- New Drugs (HFB-230), Center for Bio- uments that apply to the centers’ regu- logics Evaluation and Research, Food lations. The lists are maintained on and Drug Administration, 8800 Rock- the Internet and are published annu- ville Pike, Bethesda, MD 20892. (1) ally in the FEDERAL REGISTER. A re- Products subject to the licensing provi- quest for a copy of the CDER list sions of the Public Health Service Act should be directed to the Office of of July 1, 1944 (58 Stat. 682, as amended Training and Communications, Divi- (42 U.S.C. 201 et seq.)) or subject to part sion of Communications Management, 600; (2) ingredients packaged together Drug Information Branch (HFD–210), with containers intended for the collec- Center for Drug Evaluation and Re- tion, processing, or storage of blood or search, Food and Drug Administration, blood components; (3) urokinase prod- 5600 Fishers Lane, Rockville, MD 20857. ucts; (4) plasma volume expanders and A request for a copy of the CBER list hydroxyethyl starch for leukapheresis; should be directed to the Office of Com- and (5) coupled antibodies, i.e., prod- munication, Training, and Manufactur- ucts that consist of an antibody com- ers Assistance (HFM–40), Center for ponent coupled with a drug or radio- Biologics Evaluation and Research, Food and Drug Administration, 1401 nuclide component in which both com- Rockville Pike, Rockville, MD 20852– ponents provide a pharmacological ef- 1448. fect but the biological component determines the site of action. [65 FR 56479, Sept. 19, 2000]

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Subpart G—Drugs for Investiga- (1) The sponsor of the investigation tional Use in Laboratory Re- has failed to comply with any of the search Animals or In Vitro conditions for shipment established under this section; or Tests (2) The continuance of the investiga- § 312.160 Drugs for investigational use tion is unsafe or otherwise contrary to in laboratory research animals or the public interest or the drug is used in vitro tests. for purposes other than bona fide scientific investigation. FDA will notify (a) Authorization to ship. (1)(i) A per- the person shipping the drug of its find- son may ship a drug intended solely for ing and invite immediate correction. If tests in vitro or in animals used only correction is not immediately made, for laboratory research purposes if it is the person shall have an opportunity labeled as follows: for a regulatory hearing before FDA CAUTION: Contains a new drug for inves- pursuant to part 16. tigational use only in laboratory research (c) Disposition of unused drug. The animals, or for tests in vitro. Not for use in person who ships the drug under para- humans. graph (a) of this section shall assure (ii) A person may ship a biological the return of all unused supplies of the product for investigational in vitro di- drug from individual investigators agnostic use that is listed in whenever the investigation discon- § 312.2(b)(2)(ii) if it is labeled as follows: tinues or the investigation is terminated. The person who ships the drug CAUTION: Contains a biological product for investigational in vitro diagnostic tests may authorize in writing alternative only. disposition of unused supplies of the drug provided this alternative disposi- (2) A person shipping a drug under tion does not expose humans to risks paragraph (a) of this section shall use from the drug, either directly or indi- due diligence to assure that the con- rectly (e.g., through food-producing signee is regularly engaged in con- animals). The shipper shall maintain ducting such tests and that the ship- records of any alternative disposition. ment of the new drug will actually be used for tests in vitro or in animals [52 FR 8831, Mar. 19, 1987, as amended at 52 used only for laboratory research. FR 23031, June 17, 1987. Redesignated at 53 (3) A person who ships a drug under FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, 2002] paragraph (a) of this section shall maintain adequate records showing the name and post office address of the ex- PART 314—APPLICATIONS FOR FDA pert to whom the drug is shipped and APPROVAL TO MARKET A NEW the date, quantity, and batch or code DRUG mark of each shipment and delivery. Records of shipments under paragraph Subpart A—General Provisions (a)(1)(i) of this section are to be main- Sec. tained for a period of 2 years after the 314.1 Scope of this part. shipment. Records and reports of data 314.2 Purpose. and shipments under paragraph 314.3 Definitions. (a)(1)(ii) of this section are to be maintained in accordance with § 312.57(b). Subpart B—Applications The person who ships the drug shall 314.50 Content and format of an application. upon request from any properly au- 314.52 Notice of certification of invalidity thorized officer or employee of the or noninfringement of a patent. Food and Drug Administration, at rea- 314.53 Submission of patent information. sonable times, permit such officer or 314.54 Procedure for submission of an appli- employee to have access to and copy cation requiring investigations for ap- and verify records required to be main- proval of a new indication for, or other tained under this section. change from, a listed drug. 314.55 Pediatric use information. (b) Termination of authorization to 314.60 Amendments to an unapproved appli- ship. FDA may terminate authoriza- cation. tion to ship a drug under this section if 314.65 Withdrawal by the applicant of an unit finds that: approved application.

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314.70 Supplements and other changes to an 314.152 Notice of withdrawal of approval of approved application. an application or abbreviated application 314.71 Procedures for submission of a sup- for a new drug. plement to an approved application. 314.153 Suspension of approval of an abbre- 314.72 Change in ownership of an applica- viated new drug application. tion. 314.160 Approval of an application or abbre- 314.80 Postmarketing reporting of adverse viated application for which approval drug experiences. was previously refused, suspended, or 314.81 Other postmarketing reports. withdrawn. 314.90 Waivers. 314.161 Determination of reasons for voluntary withdrawal of a listed drug. Subpart C—Abbreviated Applications 314.162 Removal of a drug product from the list. 314.92 Drug products for which abbreviated 314.170 Adulteration and misbranding of an applications may be submitted. approved drug. 314.93 Petition to request a change from a listed drug. Subpart E—Hearing Procedures for New 314.94 Content and format of an abbreviated Drugs application. 314.200 Notice of opportunity for hearing; 314.95 Notice of certification of invalidity notice of participation and request for or noninfringement of a patent. hearing; grant or denial of hearing. 314.96 Amendments to an unapproved abbre- 314.201 Procedure for hearings. viated application. 314.235 Judicial review. 314.97 Supplements and other changes to an approved abbreviated application. Subpart F [Reserved] 314.98 Postmarketing reports. 314.99 Other responsibilities of an applicant Subpart G—Miscellaneous Provisions of an abbreviated application. 314.410 Imports and exports of new drugs. Subpart D—FDA Action on Applications 314.420 Drug master files. and Abbreviated Applications 314.430 Availability for public disclosure of data and information in an application 314.100 Timeframes for reviewing applica- or abbreviated application. tions and abbreviated applications. 314.440 Addresses for applications and ab- 314.101 Filing an application and receiving breviated applications. an abbreviated new drug application. 314.445 Guidance documents. 314.102 Communications between FDA and applicants. Subpart H—Accelerated Approval of New 314.103 Dispute resolution. Drugs for Serious or Life-Threatening Ill- 314.104 Drugs with potential for abuse. nesses 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 Approvable letter to the applicant. 314.540 Postmarketing safety reporting. 314.120 Not approvable letter to the appli- 314.550 Promotional materials. cant. 314.560 Termination of requirements. 314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) petition that re- Subpart I—Approval of New Drugs When lies on, a listed drug that is no longer Human Efficacy Studies Are Not Ethical marketed. or Feasible 314.125 Refusal to approve an application. 314.126 Adequate and well-controlled stud- 314.600 Scope. ies. 314.610 Approval based on evidence of effec- 314.127 Refusal to approve an abbreviated tiveness from studies in animals. new drug application. 314.620 Withdrawal procedures. 314.150 Withdrawal of approval of an appli- 314.630 Postmarketing safety reporting. cation or abbreviated application. 314.640 Promotional materials. 314.650 Termination of requirements. 314.151 Withdrawal of approval of an abbreviated new drug application under sec- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, tion 505(j)(5) of the act. 355, 355a, 356, 356a, 356b, 356c, 371, 374, 379e.

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SOURCE: 50 FR 7493, Feb. 22, 1985, unless viated new drug application and an ab- otherwise noted. breviated antibiotic application. EDITORIAL NOTE: Nomenclature changes to Act means the Federal Food, Drug, part 314 can be found at 69 FR 13717, Mar. 24, and Cosmetic Act (sections 201–901 (21 2004. U.S.C. 301–392)). Applicant means any person who sub- Subpart A—General Provisions mits an application or abbreviated application or an amendment or supple- § 314.1 Scope of this part. ment to them under this part to obtain (a) This part sets forth procedures FDA approval of a new drug or an anti- and requirements for the submission biotic drug and any person who owns to, and the review by, the Food and an approved application or abbreviated Drug Administration of applications application. and abbreviated applications to market Application means the application de- a new drug under section 505 of the scribed under § 314.50, including all Federal Food, Drug, and Cosmetic Act, amendements and supplements to the as well as amendments, supplements, application. and postmarketing reports to them. 505(b)(2) Application means an appli- (b) This part does not apply to drug cation submitted under section products subject to licensing by FDA 505(b)(1) of the act for a drug for which under the Public Health Service Act (58 the investigations described in section Stat. 632 as amended (42 U.S.C. 201 et 505(b)(1)(A) of the act and relied upon seq.)) and subchapter F of chapter I of by the applicant for approval of the ap- title 21 of the Code of Federal Regula- plication were not conducted by or for tions. the applicant and for which the appli- (c) References in this part to regula- cant has not obtained a right of ref- tions in the Code of Federal Regula- erence or use from the person by or for tions are to chapter I of title 21, unless whom the investigations were con- otherwise noted. ducted. Approvable letter means a written [50 FR 7493, Feb. 22, 1985, as amended at 57 communication to an applicant from FR 17981, Apr. 28, 1992; 64 FR 401, Jan. 5, 1999] FDA stating that the agency will ap- § 314.2 Purpose. prove the application or abbreviated application if specific additional infor- The purpose of this part is to estab- mation or material is submitted or spe- lish an efficient and thorough drug re- cific conditions are met. An approvable view process in order to: (a) Facilitate letter does not constitute approval of the approval of drugs shown to be safe any part of an application or abbre- and effective; and (b) ensure the dis- viated application and does not permit approval of drugs not shown to be safe marketing of the drug that is the sub- and effective. These regulations are ject of the application or abbreviated also intended to establish an effective application. system for FDA’s surveillance of mar- Approval letter means a written com- keted drugs. These regulations shall be munication to an applicant from FDA construed in light of these objectives. approving an application or an abbreviated application. § 314.3 Definitions. Drug product means a finished dosage (a) The definitions and interpreta- form, for example, tablet, capsule, or tions contained in section 201 of the act solution, that contains a drug sub- apply to those terms when used in this stance, generally, but not necessarily, part. in association with one or more other (b) The following definitions of terms ingredients. apply to this part: Drug substance means an active ingre- Abbreviated application means the ap- dient that is intended to furnish phar- plication described under § 314.94, in- macological activity or other direct ef- cluding all amendments and supple- fect in the diagnosis, cure, mitigation, ments to the application. ‘‘Abbreviated treatment, or prevention of disease or application’’ applies to both an abbre- to affect the structure or any function

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of the human body, but does not in- Subpart B—Applications clude intermediates use in the synthesis of such ingredient. § 314.50 Content and format of an ap- FDA means the Food and Drug Ad- plication. ministration. Applications and supplements to ap- Listed drug means a new drug product proved applications are required to be that has an effective approval under submitted in the form and contain the section 505(c) of the act for safety and information, as appropriate for the par- effectiveness or under section 505(j) of ticular submission, required under this the act, which has not been withdrawn section. Three copies of the application or suspended under section 505(e)(1) are required: An archival copy, a re- through (e)(5) or (j)(5) of the act, and view copy, and a field copy. An applica- which has not been withdrawn from tion for a new chemical entity will gen- sale for what FDA has determined are erally contain an application form, an reasons of safety or effectiveness. List- index, a summary, five or six technical ed drug status is evidenced by the drug sections, case report tabulations of pa- product’s identification as a drug with tient data, case report forms, drug an effective approval in the current samples, and labeling, including, if ap- edition of FDA’s ‘‘Approved Drug Prod- plicable, any Medication Guide re- ucts with Therapeutic Equivalence quired under part 208 of this chapter. Evaluations’’ (the list) or any current Other applications will generally con- supplement thereto, as a drug with an tain only some of those items, and information will be limited to that need- effective approval. A drug product is ed to support the particular submis- deemed to be a listed drug on the date sion. These include an application of of effective approval of the application the type described in section 505(b)(2) or abbreviated application for that of the act, an amendment, and a sup- drug product. plement. The application is required to Not approvable letter means a written contain reports of all investigations of communication to an applicant from the drug product sponsored by the ap- FDA stating that the agency does not plicant, and all other information consider the application or abbreviated about the drug pertinent to an evalua- application approvable because one or tion of the application that is received more deficiencies in the application or or otherwise obtained by the applicant abbreviated application preclude the from any source. FDA will maintain agency from approving it. guidance documents on the format and Reference listed drug means the listed content of applications to assist appli- drug identified by FDA as the drug cants in their preparation. product upon which an applicant relies (a) Application form. The applicant in seeking approval of its abbreviated shall submit a completed and signed application. application form that contains the fol- Right of reference or use means the au- lowing: thority to rely upon, and otherwise (1) The name and address of the ap- use, an investigation for the purpose of plicant; the date of the application; the obtaining approval of an application, application number if previously issued including the ability to make available (for example, if the application is a re- the underlying raw data from the in- submission, an amendment, or a sup- vestigation for FDA audit, if necessary. plement); the name of the drug prod- The list means the list of drug product, including its established, propri- ucts with effective approvals published etary, code, and chemical names; the in the current edition of FDA’s publi- dosage form and strength; the route of cation ‘‘Approved Drug Products with administration; the identification numbers of all investigational new Therapeutic Equivalence Evaluations’’ drug applications that are referenced and any current supplement to the in the application; the identification publication. numbers of all drug master files and [50 FR 7493, Feb. 22, 1985, as amended at 57 other applications under this part that FR 17981, Apr. 28, 1992] are referenced in the application; and

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the drug product’s proposed indications officials whose duties require an under- for use. standing of the application. To the ex- (2) A statement whether the submis- tent possible, data in the summary sion is an original submission, a should be presented in tabular and 505(b)(2) application, a resubmission, or graphic forms. FDA has prepared a a supplement to an application under guideline under § 10.90(b) that provides § 314.70. information about how to prepare a (3) A statement whether the appli- summary. The summary required cant proposes to market the drug prod- under this paragraph may be used by uct as a prescription or an over-the- FDA or the applicant to prepare the counter product. Summary Basis of Approval document (4) A check-list identifying what en- for public disclosure (under closures required under this section the § 314.430(e)(2)(ii)) when the application applicant is submitting. is approved. (5) The applicant, or the applicant’s (2) The summary is required to con- attorney, agent, or other authorized official shall sign the application. If the tain the following information: person signing the application does not (i) The proposed text of the labeling, reside or have a place of business with- including, if applicable, any Medica- in the United States, the application is tion Guide required under part 208 of required to contain the name and ad- this chapter, for the drug, with annota- dress of, and be countersigned by, an tions to the information in the sum- attorney, agent, or other authorized of- mary and technical sections of the ap- ficial who resides or maintains a place plication that support the inclusion of of business within the United States. each statement in the labeling, and, if (b) Index. The archival copy of the the application is for a prescription application is required to contain a drug, statements describing the rea- comprehensive index by volume num- sons for omitting a section or sub- ber and page number to the summary section of the labeling format in § 201.57 under paragraph (c) of this section, the of this chapter. technical sections under paragraph (d) (ii) A statement identifying the phar- of this section, and the supporting in- macologic class of the drug and a dis- formation under paragraph (f) of this cussion of the scientific rationale for section. the drug, its intended use, and the po- (c) Summary. (1) An application is re- tential clinical benefits of the drug quired to contain a summary of the ap- product. plication in enough detail that the (iii) A brief description of the mar- reader may gain a good general under- keting history, if any, of the drug outstanding of the data and information in side the United States, including a list the application, including an under- of the countries in which the drug has standing of the quantitative aspects of been marketed, a list of any countries the data. The summary is not required in which the drug has been withdrawn for supplements under § 314.70. Re- from marketing for any reason related submissions of an application should to safety or effectiveness, and a list of contain an updated summary, as appro- countries in which applications for priate. The summary should discuss all marketing are pending. The descrip- aspects of the application, and syn- thesize the information into a well- tion is required to describe both mar- structured and unified document. The keting by the applicant and, if known, summary should be written at approxi- the marketing history of other persons. mately the level of detail required for (iv) A summary of the chemistry, publication in, and meet the editorial manufacturing, and controls section of standards generally applied by, ref- the application. ereed scientific and medical journals. (v) A summary of the nonclinical In addition to the agency personnel re- pharmacology and toxicology section viewing the summary in the context of of the application. their review of the application, FDA (vi) A summary of the human phar- may furnish the summary to FDA advi- macokinetics and bioavailability sec- sory committee members and agency tion of the application.

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(vii) A summary of the microbiology they appear in the drug product); and a section of the application (for anti-in- statement of the composition of the fective drugs only). drug product; a statement of the speci- (viii) A summary of the clinical data fications and analytical methods for section of the application, including each component; the name and address the results of statistical analyses of of each manufacturer the drug product; the clinical trials. a description of the manufacturing and (ix) A concluding discussion that pre- packaging procedures and in-process sents the benefit and risk consider- controls for the drug product; such ations related to the drug, including a specifications and analytical methods discussion of any proposed additional as are necessary to assure the identity, studies or surveillance the applicant strength, quality, purity, and bio- intends to conduct postmarketing. availability of the drug product, in- (d) Technical sections. The application cluding, for example, specifications re- is required to contain the technical lating to sterility, dissolution rate, sections described below. Each tech- containers and closure systems; and nical section is required to contain stability data with proposed expiration data and information in sufficient de- dating. The application may provide tail to permit the agency to make a additionally for the use of alternatives knowledgeable judgment about wheth- to meet any of these requirements, in- er to approve the application or wheth- cluding alternative components, manu- er grounds exist under section 505(d) of facturing and packaging procedures, the act to refuse to approve the appli- in-process controls, methods, and spec- cation. The required technical sections ifications. Reference to the current are as follows: edition of the U.S. Pharmacopeia and (1) Chemistry, manufacturing, and con- the National Formulary may satisfy trols section. A section describing the relevant requirements in this para- composition, manufacture, and speci- graph. fication of the drug substance and the (b) Unless provided by paragraph drug product, including the following: (d)(1)(ii)(a) of this section, for each (i) Drug substance. A full description batch of the drug product used to con- of the drug substance including its duct a bioavailability or bioequiva- physical and chemical characteristics lence study described in § 320.38 or and stability; the name and address of § 320.63 of this chapter or used to con- its manufacturer; the method of syn- duct a primary stability study: The thesis (or isolation) and purification of batch production record; the specifica- the drug substance; the process con- tions and test procedures for each com- trols used during manufacture and ponent and for the drug product; the packaging; and such specifications and names and addresses of the sources of analytical methods as are necessary to the active and noncompendial inactive assure the identity, strength, quality, components and of the container and and purity of the drug substance and closure system for the drug product; the bioavailability of the drug products the name and address of each contract made from the substance, including, facility involved in the manufacture, for example, specifications relating to processing, packaging, or testing of the stability, sterility, particle size, and drug product and identification of the crystalline form. The application may operation performed by each contract provide additionally for the use of al- facility; and the results of any test per- ternatives to meet any of these re- formed on the components used in the quirements, including alternative manufacture of the drug product as resources, process controls, methods, and quired by § 211.84(d) of this chapter and specifications. Reference to the current on the drug product as required by edition of the U.S. Pharmacopeia and § 211.165 of this chapter. the National Formulary may satisfy (c) The proposed or actual master relevant requirements in this para- production record, including a descrip- graph. tion of the equipment, to be used for (ii)(a) Drug product. A list of all com- the manufacture of a commercial lot of ponents used in the manufacture of the the drug product or a comparably de- drug product (regardless of whether tailed description of the production

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process for a representative batch of human bioavailability data, or infor- the drug product. mation supporting a waiver of the sub- (iii) Environmental impact. The appli- mission of in vivo bioavailability data cation is required to contain either a under subpart B of part 320, including claim for categorical exclusion under the following: § 25.30 or 25.31 of this chapter or an en- (i) A description of each of the bio- vironmental assessment under § 25.40 of availability and pharmacokinetic stud- this chapter. ies of the drug in humans performed by (iv) The applicant may, at its option, or on behalf of the applicant that in- submit a complete chemistry, manu- cludes a description of the analytical facturing, and controls section 90 to 120 and statistical methods used in each days before the anticipated submission study and a statement with respect to of the remainder of the application. each study that it either was con- FDA will review such early submis- ducted in compliance with the institu- sions as resources permit. tional review board regulations in part (v) Except for a foreign applicant, the 56, or was not subject to the regula- applicant shall include a statement tions under § 56.104 or § 56.105, and that certifying that the field copy of the ap- it was conducted in compliance with plication has been provided to the ap- the informed consent regulations in plicant’s home FDA district office. part 50. (2) Nonclinical pharmacology and toxi- (ii) If the application describes in the cology section. A section describing, chemistry, manufacturing, and con- with the aid of graphs and tables, ani- trols section specifications or analyt- mal and in vitro studies with drug, in- ical methods needed to assure the bio- cluding the following: availability of the drug product or drug (i) Studies of the pharmacological ac- substance, or both, a statement in this tions of the drug in relation to its pro- section of the rationale for establishing posed therapeutic indication and stud- the specification or analytical meth- ies that otherwise define the pharma- ods, including data and information cologic properties of the drug or are supporting the rationale. pertinent to possible adverse effects. (iii) A summarizing discussion and (ii) Studies of the toxicological ef- analysis of the pharmacokinetics and fects of the drug as they relate to the metabolism of the active ingredients drug’s intended clinical uses, includ- and the bioavailability or bioequiva- ing, as appropriate, studies assessing lence, or both, of the drug product. the drug’s acute, subacute, and chronic (4) Microbiology section. If the drug is toxicity; carcinogenicity; and studies an anti-infective drug, a section de- of toxicities related to the drug’s par- scribing the microbiology data, includ- ticular mode of administration or con- ing the following: ditions of use. (i) A description of the biochemical (iii) Studies, as appropriate, of the ef- basis of the drug’s action on microbial fects of the drug on reproduction and physiology. on the developing fetus. (ii) A description of the anti- (iv) Any studies of the absorption, microbial spectra of the drug, includ- distribution, metabolism, and excre- ing results of in vitro preclinical stud- tion of the drug in animals. ies to demonstrate concentrations of (v) For each nonclinical laboratory the drug required for effective use. study subject to the good laboratory (iii) A description of any known practice regulations under part 58 a mechanisms of resistance to the drug, statement that it was conducted in including results of any known epi- compliance with the good laboratory demiologic studies to demonstrate practice regulations in part 58, or, if prevalence of resistance factors. the study was not conducted in compli- (iv) A description of clinical microbi- ance with those regulations, a brief ology laboratory methods (for example, statement of the reason for the non- in vitro sensitivity discs) needed for ef- compliance. fective use of the drug. (3) Human pharmacokinetics and bio- (5) Clinical data section. A section de- availability section. A section describing scribing the clinical investigations of the human pharmacokinetic data and the drug, including the following:

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(i) A description and analysis of each (vi) A summary and updates of safety clinical pharmacology study of the information, as follows: drug, including a brief comparison of (a) The applicant shall submit an in- the results of the human studies with tegrated summary of all available in- the animal pharmacology and toxi- formation about the safety of the drug cology data. product, including pertinent animal (ii) A description and analysis of each data, demonstrated or potential ad- controlled clinical study pertinent to a verse effects of the drug, clinically sig- proposed use of the drug, including the nificant drug/drug interactions, and protocol and a description of the statis- other safety considerations, such as tical analyses used to evaluate the data from epidemiological studies of study. If the study report is an interim related drugs. The safety data shall be analysis, this is to be noted and a pro- presented by gender, age, and racial jected completion date provided. Con- subgroups. When appropriate, safety trolled clinical studies that have not data from other subgroups of the popu- been analyzed in detail for any reason lation of patients treated also shall be (e.g., because they have been discon- presented, such as for patients with tinued or are incomplete) are to be in- renal failure or patients with different cluded in this section, including a copy levels of severity of the disease. A de- of the protocol and a brief description scription of any statistical analyses of the results and status of the study. performed in analyzing safety data (iii) A description of each uncon- should also be included, unless already included under paragraph (d)(5)(ii) of trolled clinical study, a summary of this section. the results, and a brief statement ex- (b) The applicant shall, under section plaining why the study is classified as 505(i) of the act, update periodically its uncontrolled. pending application with new safety in- (iv) A description and analysis of any formation learned about the drug that other data or information relevant to may reasonably affect the statement of an evaluation of the safety and effec- contraindications, warnings, pre- tiveness of the drug product obtained cautions, and adverse reactions in the or otherwise received by the applicant draft labeling and, if applicable, any from any source, foreign or domestic, Medication Guide required under part including information derived from 208 of this chapter. These ‘‘safety up- clinical investigations, including con- date reports’’ are required to include trolled and uncontrolled studies of uses the same kinds of information (from of the drug other than those proposed clinical studies, animal studies, and in the application, commercial mar- other sources) and are required to be keting experience, reports in the sci- submitted in the same format as the entific literature, and unpublished sci- integrated summary in paragraph entific papers. (d)(5)(vi)(a) of this section. In addition, (v) An integrated summary of the the reports are required to include the data demonstrating substantial evi- case report forms for each patient who dence of effectiveness for the claimed died during a clinical study or who did indications. Evidence is also required not complete the study because of an to support the dosage and administra- adverse event (unless this requirement tion section of the labeling, including is waived). The applicant shall submit support for the dosage and dose inter- these reports (1) 4 months after the ini- val recommended. The effectiveness tial submission; (2) following receipt of data shall be presented by gender, age, an approvable letter; and (3) at other and racial subgroups and shall identify times as requested by FDA. Prior to any modifications of dose or dose inter- the submission of the first such report, val needed for specific subgroups. Ef- applicants are encouraged to consult fectiveness data from other subgroups with FDA regarding further details on of the population of patients treated, its form and content. when appropriate, such as patients (vii) If the drug has a potential for with renal failure or patients with dif- abuse, a description and analysis of ferent levels of severity of the disease, studies or information related to abuse also shall be presented. of the drug, including a proposal for

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scheduling under the Controlled Sub- (7) Pediatric use section. A section de- stances Act. A description of any stud- scribing the investigation of the drug ies related to overdosage is also re- for use in pediatric populations, includ- quired, including information on dialy- ing an integrated summary of the in- sis, antidotes, or other treatments, if formation (the clinical pharmacology known. studies, controlled clinical studies, or (viii) An integrated summary of the uncontrolled clinical studies, or other benefits and risks of the drug, includ- data or information) that is relevant to ing a discussion of why the benefits ex- the safety and effectiveness and bene- ceed the risks under the conditions fits and risks of the drug in pediatric stated in the labeling. populations for the claimed indica- (ix) A statement with respect to each tions, a reference to the full descrip- clinical study involving human sub- tions of such studies provided under jects that it either was conducted in paragraphs (d)(3) and (d)(5) of this sec- compliance with the institutional re- tion, and information required to be view board regulations in part 56, or submitted under § 314.55. was not subject to the regulations (e) Samples and labeling. (1) Upon re- under § 56.104 or § 56.105, and that it was quest from FDA, the applicant shall conducted in compliance with the in- submit the samples described below to formed consent regulations in part 50. the places identified in the agency’s re- (x) If a sponsor has transferred any quest. FDA will generally ask appli- obligations for the conduct of any clin- cants to submit samples directly to ical study to a contract research orga- two or more agency laboratories that nization, a statement containing the will perform all necessary tests on the name and address of the contract re- samples and validate the applicant’s search organization, identification of analytical methods. the clinical study, and a listing of the (i) Four representative samples of the obligations transferred. If all obliga- following, each sample in sufficient tions governing the conduct of the quantity to permit FDA to perform study have been transferred, a general three times each test described in the statement of this transfer—in lieu of a application to determine whether the listing of the specific obligations trans- drug substance and the drug product ferred—may be submitted. meet the specifications given in the ap- (xi) If original subject records were plication: audited or reviewed by the sponsor in the course of monitoring any clinical (a) The drug product proposed for study to verify the accuracy of the case marketing; reports submitted to the sponsor, a list (b) The drug substance used in the identifying each clinical study so au- drug product from which the samples dited or reviewed. of the drug product were taken; and (6) Statistical section. A section de- (c) Reference standards and blanks scribing the statistical evaluation of (except that reference standards recog- clinical data, including the following: nized in an official compendium need (i) A copy of the information sub- not be submitted). mitted under paragraph (d)(5)(ii) of this (ii) Samples of the finished market section concerning the description and package, if requested by FDA. analysis of each controlled clinical (2) The applicant shall submit the study, and the documentation and sup- following in the archival copy of the porting statistical analyses used in application: evaluating the controlled clinical stud- (i) Three copies of the analytical ies. methods 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 methods.

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The related descriptive information in- or who did not complete the study be- cludes a description of each sample; cause of an adverse event, whether be- the proposed regulatory specifications lieved to be drug related or not, includ- for the drug; a detailed description of ing patients receiving reference drugs the methods of analysis; supporting or placebo. This requirement may be data for accuracy, specificity, precision waived by FDA for specific studies if and ruggedness; and complete results the case report forms are unnecessary of the applicant’s tests on each sample. for a proper review of the study. (ii) Copies of the label and all label- (3) Additional data. The applicant ing for the drug product (including, if shall submit to FDA additional case re- applicable, any Medication Guide report forms and tabulations needed to quired under part 208 of this chapter) conduct a proper review of the applica- for the drug product (4 copies of draft tion, as requested by the director of labeling or 12 copies of final printed la- the FDA division responsible for re- beling). viewing the application. The appli- (f) Case report forms and tabulations. cant’s failure to submit information re- The archival copy of the application is quested by FDA within 30 days after re- required to contain the following case ceipt of the request may result in the report tabulations and case report agency viewing any eventual submis- forms: sion as a major amendment under (1) Case report tabulations. The appli- § 314.60 and extending the review period cation is required to contain tabula- as necessary. If desired by the appli- tions of the data from each adequate cant, the FDA division director will and well-controlled study under verify in writing any request for addi- § 314.126 (Phase 2 and Phase 3 studies as tional data that was made orally. described in §§ 312.21 (b) and (c) of this (4) Applicants are invited to meet chapter), tabulations of the data from with FDA before submitting an appli- the earliest clinical pharmacology cation to discuss the presentation and studies (Phase 1 studies as described in format of supporting information. If § 312.21(a) of this chapter), and tabula- the applicant and FDA agree, the appli- tions of the safety data from other cant may submit tabulations of patient clinical studies. Routine submission of data and case report forms in a form other patient data from uncontrolled other than hard copy, for example, on studies is not required. The tabulations microfiche or computer tapes. are required to include the data on (g) Other. The following general re- each patient in each study, except that quirements apply to the submission of the applicant may delete those tabula- information within the summary under tions which the agency agrees, in ad- paragraph (c) of this section and within vance, are not pertinent to a review of the technical sections under paragraph the drug’s safety or effectiveness. Upon (d) of this section. request, FDA will discuss with the ap- (1) The applicant ordinarily is not re- plicant in a ‘‘pre-NDA’’ conference quired to resubmit information pre- those tabulations that may be appro- viously submitted, but may incor- priate for such deletion. Barring un- porate the information by reference. A foreseen circumstances, tabulations reference to information submitted agreed to be deleted at such a con- previously is required to identify the ference will not be requested during file by name, reference number, vol- 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

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that is not in English. The applicant the manufacture, use, or sale of the shall submit a copy of each original lit- drug product for which the application erature publication for which an is submitted. The applicant shall enti- English translation is submitted. tle such a certification ‘‘Paragraph IV (3) If an applicant who submits a new Certification’’. This certification shall drug application under section 505(b) of be submitted in the following form: the act obtains a ‘‘right of reference or use,’’ as defined under § 314.3(b), to an I, (name of applicant), certify that Patent No. investigation described in clause (A) of llllll (is invalid, unenforceable, or will section 505(b)(1) of the act, the appli- not be infringed by the manufacture, use, or sale of) (name of proposed drug product) for cant shall include in its application a which this application is submitted. written statement signed by the owner of the data from each such investiga- The certification shall be accompanied tion that the applicant may rely on in by a statement that the applicant will support of the approval of its applica- comply with the requirements under tion, and provide FDA access to, the § 314.52(a) with respect to providing a underlying raw data that provide the notice to each owner of the patent or basis for the report of the investigation their representatives and to the holder submitted in its application. of the approved application for the (h) Patent information. The applica- drug product which is claimed by the tion is required to contain the patent patent or a use of which is claimed by information described under § 314.53. the patent and with the requirements (i) Patent certification—(1) Contents. A under § 314.52(c) with respect to the 505(b)(2) application is required to con- content of the notice. tain the following: (i) Patents claiming drug, drug product, (B) If the drug on which investiga- or method of use. (A) Except as provided tions that are relied upon by the appli- in paragraph (i)(2) of this section, a cant were conducted is itself a licensed certification with respect to each pat- generic drug of a patented drug first ent issued by the United States Patent approved under section 505(b) of the and Trademark Office that, in the opin- act, the appropriate patent certifi- ion of the applicant and to the best of cation under this section with respect its knowledge, claims a drug (the drug to each patent that claims the first-ap- product or drug substance that is a proved patented drug or that claims an component of the drug product) on approved use for such a drug. which investigations that are relied (ii) No relevant patents. If, in the opin- upon by the applicant for approval of ion of the applicant and to the best of its application were conducted or that its knowledge, there are no patents de- claims an approved use for such drug scribed in paragraph (i)(1)(i) of this sec- and for which information is required tion, a certification in the following to be filed under section 505(b) and (c) form: of the act and § 314.53. For each such patent, the applicant shall provide the In the opinion and to the best knowledge of patent number and certify, in its opin- (name of applicant), there are no patents that claim the drug or drugs on which investiga- ion and to the best of its knowledge, tions that are relied upon in this application one of the following circumstances: were conducted or that claim a use of such (1) That the patent information has drug or drugs. not been submitted to FDA. The applicant shall entitle such a certification (iii) Method of use patent. (A) If infor- ‘‘Paragraph I Certification’’; mation that is submitted under section (2) That the patent has expired. The 505(b) or (c) of the act and § 314.53 is for applicant shall entitle such a certifi- a method of use patent, and the label- cation ‘‘Paragraph II Certification’’; ing for the drug product for which the (3) The date on which the patent will applicant is seeking approval does not expire. The applicant shall entitle such include any indications that are cov- a certification ‘‘Paragraph III Certifi- ered by the use patent, a statement ex- cation’’; or plaining that the method of use patent (4) That the patent is invalid, unen- does not claim any of the proposed in- forceable, or will not be infringed by dications.

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(B) If the labeling of the drug product evance of patent information sub- for which the applicant is seeking ap- mitted to FDA, the applicant may seek proval includes an indication that, ac- a confirmation of the correctness of cording to the patent information sub- the patent information in accordance mitted under section 505(b) or (c) of the with the procedures under § 314.53(f). act and § 314.53 or in the opinion of the Unless the patent information is with- applicant, is claimed by a use patent, drawn or changed, the applicant must the applicant shall submit an applica- submit an appropriate certification for ble certification under paragraph each relevant patent. (i)(1)(i) of this section. (6) Amended certifications. A certifi- (2) Method of manufacturing patent. cation submitted under paragraphs An applicant is not required to make a (i)(1)(i) through (i)(1)(iii) of this section certification with respect to any pat- may be amended at any time before the ent that claims only a method of man- effective date of the approval of the ap- ufacturing the drug product for which plication. An applicant shall submit an the applicant is seeking approval. amended certification as an amend- (3) Licensing agreements. If a 505(b)(2) application is for a drug or method of ment to a pending application or by using a drug claimed by a patent and letter to an approved application. If an the applicant has a licensing agree- applicant with a pending application ment with the patent owner, the appli- voluntarily makes a patent certifi- cant shall submit a certification under cation for an untimely filed patent, the paragraph (i)(1)(i)(A)(4) of this section applicant may withdraw the patent (‘‘Paragraph IV Certification’’) as to certification for the untimely filed pat- that patent and a statement that it has ent. Once an amendment or letter for been granted a patent license. If the the change in certification has been patent owner consents to an immediate submitted, the application will no effective date upon approval of the longer be considered to be one con- 505(b)(2) application, the application taining the prior certification. shall contain a written statement from (i) After finding of infringement. An ap- the patent owner that it has a licens- plicant who has submitted a certifi- ing agreement with the applicant and cation under paragraph (i)(1)(i)(A)(4) of that it consents to an immediate effec- this section and is sued for patent in- tive date. fringement within 45 days of the re- (4) Late submission of patent informa- ceipt of notice sent under § 314.52 shall tion. If a patent described in paragraph amend the certification if a final judg- (i)(1)(i)(A) of this section is issued and ment in the action is entered finding the holder of the approved application the patent to be infringed unless the for the patented drug does not submit final judgment also finds the patent to the required information on the patent be invalid. In the amended certifi- within 30 days of issuance of the pat- cation, the applicant shall certify ent, an applicant who submitted a under paragraph (i)(1)(i)(A)(3) of this 505(b)(2) application that, before the section that the patent will expire on a submission of the patent information, specific date. contained an appropriate patent certification is not required to submit an (ii) After removal of a patent from the amended certification. An applicant list. If a patent is removed from the whose 505(b)(2) application is filed after list, any applicant with a pending ap- a late submission of patent informa- plication (including a tentatively ap- tion or whose 505(b)(2) application was proved application with a delayed ef- previously filed but did not contain an fective date) who has made a certifi- appropriate patent certification at the cation with respect to such patent time of the patent submission shall shall amend its certification. The ap- submit a certification under paragraph plicant shall certify under paragraph (i)(1)(i) or (i)(1)(ii) of this section or a (i)(1)(ii) of this section that no patents statement under paragraph (i)(1)(iii) of described in paragraph (i)(1)(i) of this this section as to that patent. section claim the drug or, if other rel- (5) Disputed patent information. If an evant patents claim the drug, shall applicant disputes the accuracy or rel- amend the certification to refer only to

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those relevant patents. In the amend- (4) If the applicant claims exclusivity ment, the applicant shall state the rea- under § 314.108(b)(4) or (b)(5), the fol- son for the change in certification lowing information to show that the (that the patent is or has been removed application contains ‘‘new clinical in- from the list). A patent that is the sub- vestigations’’ that are ‘‘essential to ap- ject of a lawsuit under § 314.107(c) shall proval of the application or supple- not be removed from the list until FDA ment’’ and were ‘‘conducted or spon- determines either that no delay in ef- sored by the applicant:’’ fective dates of approval is required (i) ‘‘New clinical investigations.’’ A cer- under that section as a result of the tification that to the best of the appli- lawsuit, that the patent has expired, or cant’s knowledge each of the clinical that any such period of delay in effec- investigations included in the applica- tive dates of approval is ended. An ap- tion meets the definition of ‘‘new clin- plicant shall submit an amended cer- ical investigation’’ set forth in tification as an amendment to a pend- § 314.108(a). ing application. Once an amendment (ii) ‘‘Essential to approval.’’ A list of for the change has been submitted, the all published studies or publicly avail- application will no longer be consid- able reports of clinical investigations ered to be one containing a certifi- known to the applicant through a lit- cation under paragraph (i)(1)(i)(A)(4) of erature search that are relevant to the this section. conditions for which the applicant is (iii) Other amendments. (A) Except as seeking approval, a certification that provided in paragraphs (i)(4) and the applicant has thoroughly searched (i)(6)(iii)(B) of this section, an appli- the scientific literature and, to the cant shall amend a submitted certifi- best of the applicant’s knowledge, the cation if, at any time before the effec- list is complete and accurate and, in tive date of the approval of the applica- the applicant’s opinion, such published tion, the applicant learns that the sub- studies or publicly available reports do mitted certification is no longer accu- not provide a sufficient basis for the rate. approval of the conditions for which the applicant is seeking approval with- (B) An applicant is not required to out reference to the new clinical inves- amend a submitted certification when tigation(s) in the application, and an information on an otherwise applicable explanation as to why the studies or patent is submitted after the effective reports are insufficient. date of approval for the 505(b)(2) appli- (iii) ‘‘Conducted or sponsored by.’’ If cation. the applicant was the sponsor named in (j) Claimed exclusivity. A new drug the Form FDA–1571 for an investiga- product, upon approval, may be enti- tional new drug application (IND) tled to a period of marketing exclu- under which the new clinical investiga- sivity under the provisions of § 314.108. tion(s) that is essential to the approval If an applicant believes its drug prod- of its application was conducted, iden- uct is entitled to a period of exclu- tification of the IND by number. If the sivity, it shall submit with the new applicant was not the sponsor of the drug application prior to approval the IND under which the clinical investiga- following information: tion(s) was conducted, a certification (1) A statement that the applicant is that the applicant or its predecessor in claiming exclusivity. interest provided substantial support (2) A reference to the appropriate for the clinical investigation(s) that is paragraph under § 314.108 that supports essential to the approval of its applica- its claim. tion, and information supporting the (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

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have conducted or sponsored the study (3) The applicant shall submit a field if the applicant’s financial contribu- copy of the application that contains tion to the study is less than 50 percent the technical section described in para- or the applicant did not sponsor the in- graph (d)(1) of this section, a copy of vestigational new drug. A predecessor the application form required under in interest is an entity, e.g., a corpora- paragraph (a) of this section, a copy of tion, that the applicant has taken over, the summary required under paragraph merged with, or purchased, or from (c) of this section, and a certification which the applicant has purchased all that the field copy is a true copy of the rights to the drug. Purchase of non- technical section described in para- exclusive rights to a clinical investiga- graph (d)(1) of this section contained in tion after it is completed is not suffi- the archival and review copies of the cient to satisfy this definition. application. (k) Financial certification or disclosure (4) The applicant may obtain from statement. The application shall contain FDA sufficient folders to bind the ar- a financial certification or disclosure chival, the review, and the field copies statement or both as required by part of the application. 54 of this chapter. [50 FR 7493, Feb. 22, 1985] (l) Format of an original application. (1) The applicant shall submit a com- EDITORIAL NOTE: For FEDERAL REGISTER ci- plete archival copy of the application tations affecting § 314.50, see the List of CFR that contains the information required Sections Affected, which appears in the Finding Aids section of the printed volume under paragraphs (a) through (f) of this and on GPO Access. section. FDA will maintain the archival copy during the review of the appli- EFFECTIVE DATE NOTE: At 68 FR 69019, Dec. cation to permit individual reviewers 11, 2003, § 314.50 was amended by revising paragraph (l)(1); by adding headings for para- to refer to information that is not con- graphs (l)(2), (l)(3), and (l)(4); by removing tained in their particular technical from paragraphs (l)(2) and (l)(3) the word sections of the application, to give ‘‘shall’’ and adding in its place the word other agency personnel access to the ‘‘must’’; and by adding paragraph (l)(5), ef- application for official business, and to fective June 8, 2004. For the convenience of maintain in one place a complete copy the user, the revised text is set forth as fol- of the application. An applicant may lows: submit on microfiche the portions of § 314.50 Content and format of an applica- the archival copy of the application de- tion. scribed in paragraphs (b) through (d) of this section. Information relating to * * * * * samples and labeling (including, if applicable, any Medication Guide re- (l) Format of an original application. (1) Ar- chival copy. The applicant must submit a quired under part 208 of this chapter), complete archival copy of the application described in paragraph (e) of this sec- that contains the information required under tion, is required to be submitted in paragraphs (a) through (f) of this section. hard copy. Tabulations of patient data FDA will maintain the archival copy during and case report forms, described in the review of the application to permit indi- paragraph (f) of this section, may be vidual reviewers to refer to information that submitted on microfiche only if the ap- is not contained in their particular technical plicant and FDA agree. If FDA agrees, sections of the application, to give other agency personnel access to the application the applicant may use another suitable for official business, and to maintain in one microform system. place a complete copy of the application. Ex- (2) The applicant shall submit a re- cept as required by paragraph (l)(1)(i) of this view copy of the application. Each of section, applicants may submit the archival the technical sections, described in copy on paper or in electronic format pro- paragraphs (d)(1) through (d)(6) of this vided that electronic submissions are made section, in the review copy is required in accordance with part 11 of this chapter. to be separately bound with a copy of (i) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter the application form required under (commonly referred to as the package insert paragraph (a) of this section and a copy or professional labeling), including all text, of the summary required under para- tables, and figures, must be submitted to the graph (c) of this section. agency in electronic format as described in

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paragraph (l)(5) of this section. This require- ter for Drug Evaluation and Research, ment is in addition to the requirements of Food and Drug Administration, 5600 paragraph (e)(2)(ii) of this section that copies Fishers Lane, Rockville, MD 20857. of the formatted label and all labeling be submitted. Submissions under this para- (3) This paragraph does not apply to graph must be made in accordance with part a use patent that claims no uses for 11 of this chapter, except for the require- which the applicant is seeking ap- ments of § 11.10(a), (c) through (h), and (k), proval. and the corresponding requirements of (b) Sending the notice. The applicant § 11.30. shall send the notice required by para- (ii) [Reserved] (2) Review copy. *** graph (a) of this section when it re- (3) Field copy. *** ceives from FDA an acknowledgment (4) Binding folders. *** letter stating that its application has (5) Electronic format submissions. Electronic been filed. At the same time, the appli- format submissions must be in a form that cant shall amend its application to in- FDA can process, review, and archive. FDA clude a statement certifying that the will periodically issue guidance on how to notice has been provided to each person provide the electronic submission (e.g., method of transmission, media, file formats, identified under paragraph (a) of this preparation and organization of files). section and that the notice met the content requirement under paragraph § 314.52 Notice of certification of inva- (c) of this section. lidity or noninfringement of a pat- (c) Content of a notice. In the notice, ent. the applicant shall cite section (a) Notice of certification. For each 505(b)(3)(B) of the act and shall include, patent which claims the drug or drugs but not be limited to, the following in- on which investigations that are relied formation: upon by the applicant for approval of (1) A statement that a 505(b)(2) appli- its application were conducted or cation submitted by the applicant has which claims a use for such drug or been filed by FDA. drugs and which the applicant certifies (2) The application number. under § 314.50(i)(1)(i)(A)(4) that a patent (3) The established name, if any, as is invalid, unenforceable, or will not be defined in section 502(e)(3) of the act, of infringed, the applicant shall send no- the proposed drug product. tice of such certification by registered (4) The active ingredient, strength, or certified mail, return receipt re- and dosage form of the proposed drug quested to each of the following per- product. sons: (1) Each owner of the patent that is (5) The patent number and expiration the subject of the certification or the date, as submitted to the agency or as representative designated by the owner known to the applicant, of each patent to receive the notice. The name and ad- alleged to be invalid, unenforceable, or dress of the patent owner or its rep- not infringed. resentative may be obtained from the (6) A detailed statement of the fac- United States Patent and Trademark tual and legal basis of the applicant’s Office; and opinion that the patent is not valid, (2) The holder of the approved appli- unenforceable, or will not be infringed. cation under section 505(b) of the act The applicant shall include in the de- for each drug product which is claimed tailed statement: by the patent or a use of which is (i) For each claim of a patent alleged claimed by the patent and for which not to be infringed, a full and detailed the applicant is seeking approval, or, if explanation of why the claim is not in- the application holder does not reside fringed. or maintain a place of business within (ii) For each claim of a patent al- the United States, the application leged to be invalid or unenforceable, a holder’s attorney, agent, or other au- full and detailed explanation of the thorized official. The name and address grounds supporting the allegation. of the application holder or its attor- (7) If the applicant does not reside or ney, agent, or authorized official may have a place of business in the United be obtained from the Division of Drug States, the name and address of an Information Resources (HFD–80), Cen- agent in the United States authorized

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to accept service of process for the ap- mit the required information on the plicant. declaration form set forth in paragraph (d) Amendment to an application. If an (c) of this section for each patent that application is amended to include the claims the drug or a method of using certification described in § 314.50(i), the the drug that is the subject of the new applicant shall send the notice required drug application or amendment or sup- by paragraph (a) of this section at the plement to it and with respect to which same time that the amendment to the a claim of patent infringement could application is submitted to FDA. reasonably be asserted if a person not (e) Documentation of receipt of notice. licensed by the owner of the patent en- The applicant shall amend its applica- gaged in the manufacture, use, or sale tion to document receipt of the notice of the drug product. For purposes of required under paragraph (a) of this this part, such patents consist of drug section by each person provided the no- substance (active ingredient) patents, tice. The applicant shall include a copy drug product (formulation and com- of the return receipt or other similar position) patents, and method-of-use evidence of the date the notification patents. For patents that claim the was received. FDA will accept as ade- drug substance, the applicant shall quate documentation of the date of resubmit information only on those pat- ceipt a return receipt or a letter ac- ents that claim the drug substance knowledging receipt by the person pro- that is the subject of the pending or ap- vided the notice. An applicant may proved application or that claim a drug rely on another form of documentation substance that is the same as the ac- only if FDA has agreed to such docu- tive ingredient that is the subject of mentation in advance. A copy of the the approved or pending application. notice itself need not be submitted to For patents that claim a polymorph the agency. that is the same as the active ingre- (f) Approval. If the requirements of dient described in the approved or this section are met, the agency will pending application, the applicant presume the notice to be complete and shall certify in the declaration forms sufficient, and it will count the day fol- that the applicant has test data, as set lowing the date of receipt of the notice forth in paragraph (b)(2) of this section, by the patent owner or its representa- demonstrating that a drug product tive and by the approved application containing the polymorph will perform holder as the first day of the 45-day pe- the same as the drug product described riod provided for in section 505(c)(3)(C) in the new drug application. For pat- of the act. FDA may, if the applicant ents that claim a drug product, the ap- amends its application with a written plicant shall submit information only statement that a later date should be on those patents that claim a drug used, count from such later date. product, as is defined in § 314.3, that is [59 FR 50362, Oct. 3, 1994, as amended at 68 FR described in the pending or approved 36703, June 18, 2003; 69 FR 11310, Mar. 10, 2004] application. For patents that claim a method of use, the applicant shall sub- § 314.53 Submission of patent informa- mit information only on those patents tion. that claim indications or other condi- (a) Who must submit patent informa- tions of use that are described in the tion. This section applies to any appli- pending or approved application. The cant who submits to FDA a new drug applicant shall separately identify application or an amendment to it each pending or approved method of under section 505(b) of the act and use and related patent claim. For ap- § 314.50 or a supplement to an approved proved applications, the applicant sub- application under § 314.70, except as mitting the method-of-use patent shall provided in paragraph (d)(2) of this sec- identify with specificity the section of tion. the approved labeling that corresponds (b) Patents for which information must to the method of use claimed by the be submitted and patents for which infor- patent submitted. Process patents, pat- mation must not be submitted—(1) General ents claiming packaging, patents requirements. An applicant described in claiming metabolites, and patents paragraph (a) of this section shall sub- claiming intermediates are not covered

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by this section, and information on requirements described in paragraph these patents must not be submitted to (b) of this section. We will not accept FDA. the patent information unless it is (2) Test Data for Submission of Patent complete and submitted on the appro- Information for Patents That Claim a priate forms, FDA Forms 3542 or 3542a. Polymorph. The test data, referenced in These forms may be obtained on the paragraph (b)(1) of this section, must Internet at http://www.fda.gov by include the following: searching for ‘‘forms’’. (i) A full description of the poly- (2) Drug substance (active ingredient), morphic form of the drug substance, in- drug product (formulation or composi- cluding its physical and chemical char- tion), and method-of-use patents—(i) acteristics and stability; the method of Original Declaration. For each patent synthesis (or isolation) and purifi- that claims a drug substance (active cation of the drug substance; the proc- ingredient), drug product (formulation ess controls used during manufacture and composition), or method of use, the and packaging; and such specifications applicant shall submit FDA Form and analytical methods as are nec- 3542a. The following information and essary to assure the identity, strength, verification is required: quality, and purity of the polymorphic (A) New drug application number; form of the drug substance; (ii) The executed batch record for a (B) Name of new drug application drug product containing the poly- sponsor; morphic form of the drug substance (C) Trade name (or proposed trade and documentation that the batch was name) of new drug; manufactured under current good man- (D) Active ingredient(s) of new drug; ufacturing practice requirements; (E) Strength(s) of new drug; (iii) Demonstration of bioequivalence (F) Dosage form of new drug; between the executed batch of the drug (G) United States patent number, product that contains the polymorphic issue date, and expiration date of pat- form of the drug substance and the ent submitted; drug product as described in the NDA; (H) The patent owner’s name, full ad- (iv) A list of all components used in dress, phone number and, if available, the manufacture of the drug product fax number and e-mail address; containing the polymorphic form and a (I) The name, full address, phone statement of the composition of the number and, if available, fax number drug product; a statement of the speci- and e-mail address of an agent or rep- fications and analytical methods for resentative who resides or maintains a each component; a description of the place of business within the United manufacturing and packaging proce- States authorized to receive notice of dures and in-process controls for the patent certification under sections drug product; such specifications and 505(b)(3) and 505(j)(2)(B) of the act and analytical methods as are necessary to §§ 314.52 and 314.95 (if patent owner or assure the identity, strength, quality, new drug application applicant or hold- purity, and bioavailability of the drug er does not reside or have a place of product, including release and stability business within the United States); data complying with the approved product specifications to demonstrate (J) Information on whether the pat- pharmaceutical equivalence and com- ent has been submitted previously for parable product stability; and the new drug application; (v) Comparative in vitro dissolution (K) Information on whether the expi- testing on 12 dosage units each of the ration date is a new expiration date if executed test batch and the new drug the patent had been submitted pre- application product. viously for listing; (c) Reporting requirements—(1) General (L) Information on whether the pat- requirements. An applicant described in ent is a product-by-process patent in paragraph (a) of this section shall sub- which the product claimed is novel; mit the required patent information (M) Information on the drug sub- described in paragraph (c)(2) of this stance (active ingredient) patent in- section for each patent that meets the cluding the following:

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(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 sup- the new drug application or supple- plement pending under section 505 of the 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 require- application or supplement; ments of the regulation. I verify under pen- (3) Whether the applicant has test alty of perjury that the foregoing is true and data, described in paragraph (b)(2) of correct.’’; and this section, demonstrating that a drug (R) Information on whether the ap- product containing the polymorph will plicant, patent owner or attorney, perform the same as the drug product agent, representative or other author- described in the new drug application ized official signed the form; the name or supplement, and a description of the of the person; and the full address, polymorphic form(s) claimed by the phone number and, if available, the fax patent for which such test data exist; number and e-mail address. (4) Whether the patent claims only a (ii) Submission of patent information metabolite of the active ingredient; upon and after approval. Within 30 days and after the date of approval of its appli- (5) Whether the patent claims only cation or supplement, the applicant an intermediate; shall submit FDA Form 3542 for each (N) Information on the drug product patent that claims the drug substance (composition/formulation) patent in- (active ingredient), drug product (for- cluding the following: mulation and composition), or ap- (1) Whether the patent claims the proved method of use. FDA will rely drug product for which approval is only on the information submitted on being sought, as defined in § 314.3; and this form and will not list or publish (2) Whether the patent claims only patent information if the patent dec- an intermediate; laration is incomplete or indicates the (O) Information on each method-of- patent is not eligible for listing. Patent use patent including the following: information must also be submitted for (1) Whether the patent claims one or patents issued after the date of ap- more methods of using the drug prod- proval of the new drug application as uct for which use approval is being required in paragraph (c)(2)(ii) of this sought and a description of each pend- section. As described in paragraph ing method of use or related indication (d)(4) of this section, patent informa- and related patent claim of the patent tion must be submitted to FDA within being submitted; and 30 days of the date of issuance of the (2) Identification of the specific sec- patent. If the applicant submits the re- tion of the proposed labeling for the quired patent information within the drug product that corresponds to the 30 days, but we notify an applicant that method of use claimed by the patent a declaration form is incomplete or submitted; shows that the patent is not eligible for listing, the applicant must submit (P) Whether there are no relevant an acceptable declaration form within patents that claim the drug substance 15 days of FDA notification to be con- (active ingredient), drug product (for- sidered timely filed. The following in- mulation or composition) or method(s) formation and verification statement of use, for which the applicant is seek- is required: ing approval and with respect to which a claim of patent infringement could (A) New drug application number; reasonably be asserted if a person not (B) Name of new drug application licensed by the owner of the patent en- sponsor; gaged in the manufacture, use, or sale (C) Trade name of new drug; of the drug product; (D) Active ingredient(s) of new drug; (Q) A signed verification which (E) Strength(s) of new drug; states: (F) Dosage form of new drug;

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(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 holder does not reside or have a place of submitted; and business within the United States); (3) The description of the patented (K) Information on whether the pat- method of use as required for publica- ent has been submitted previously for tion; the new drug application; (Q) Whether there are no relevant (L) Information on whether the expi- patents that claim the approved drug ration date is a new expiration date if substance (active ingredient), the ap- the patent had been submitted pre- proved drug product (formulation or viously for listing; composition) or approved method(s) of (M) Information on whether the pat- use and with respect to which a claim ent is a product-by-process patent in of patent infringement could reason- which the product claimed is novel; ably be asserted if a person not li- (N) Information on the drug sub- censed by the owner of the patent en- stance (active ingredient) patent in- gaged in the manufacture, use, or sale cluding the following: of the drug product; (1) Whether the patent claims the (R) A signed verification which drug substance that is the active ingre- states: ‘‘The undersigned declares that dient in the drug product described in this is an accurate and complete sub- the approved application; mission of patent information for the (2) Whether the patent claims a poly- NDA, amendment or supplement ap- morph that is the same as the active proved under section 505 of the Federal ingredient that is described in the ap- Food, Drug, and Cosmetic Act. This proved application; time-sensitive patent information is (3) Whether the applicant has test submitted pursuant to 21 CFR 314.53. I data, described at paragraph (b)(2) of attest that I am familiar with 21 CFR this section, demonstrating that a drug 314.53 and this submission complies product containing the polymorph will with the requirements of the regula- perform the same as the drug product tion. I verify under penalty of perjury described in the approved application that the foregoing is true and cor- and a description of the polymorphic rect.’’; and form(s) claimed by the patent for (S) Information on whether the appli- which such test data exist; cant, patent owner or attorney, agent, (4) Whether the patent claims only a representative or other authorized offi- metabolite of the active ingredient; cial signed the form; the name of the and person; and the full address, phone (5) Whether the patent claims only number and, if available, the fax num- an intermediate; ber and e-mail address. (O) Information on the drug product (3) No relevant patents. If the appli- (composition/formulation) patent in- cant believes that there are no relevant cluding the following: patents that claim the drug substance

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(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 with FDA and for which patent infor- copy, to the Central Document Room, mation is required to be submitted Center for Drug Evaluation and Re- under this section. If a patent is issued search, Food and Drug Administration, after the application is filed with FDA 5901–B Ammendale Rd., Beltsville, MD but before the application is approved, 20705–1266. The applicant shall submit the applicant shall, within 30 days of the patent information by letter sepa- the date of issuance of the patent, sub- rate from, but at the same time as, mit the required patent information in submission of the supplement. an amendment to the application under (5) Submission date. Patent informa- § 314.60. tion shall be considered to be sub- (2) Supplements. (i) An applicant shall mitted to FDA as of the date the infor- submit patent information required mation is received by the Central Doc- under paragraph (c) of this section for ument Room. a patent that claims the drug, drug (6) Identification. Each submission of product, or method of use for which ap- patent information, except information proval is sought in any of the following submitted with an original application, supplements: and its mailing cover shall bear promi- (A) To change the formulation; nent identification as to its contents, (B) To add a new indication or other i.e., ‘‘Patent Information,’’ or, if sub- condition of use, including a change in mitted after approval of an applica- route of administration; tion, ‘‘Time Sensitive Patent Informa- (C) To change the strength; tion.’’ (D) To make any other patented (e) Public disclosure of patent informa- change regarding the drug, drug prod- tion. FDA will publish in the list the uct, or any method of use. patent number and expiration date of (ii) If the applicant submits a supple- each patent that is required to be, and ment for one of the changes listed is, submitted to FDA by an applicant, under paragraph (d)(2)(i) of this section and for each use patent, the approved and existing patents for which informa- indications or other conditions of use tion has already been submitted to covered by a patent. FDA will publish

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such patent information upon approval § 314.54 Procedure for submission of of the application, or, if the patent in- an application requiring investiga- formation is submitted by the appli- tions for approval of a new indica- cant after approval of an application as tion for, or other change from, a provided under paragraph (d)(2) of this listed drug. section, as soon as possible after the (a) The act does not permit approval submission to the agency of the patent of an abbreviated new drug application information. Patent information sub- for a new indication, nor does it permit mitted by the last working day of a approval of other changes in a listed month will be published in that drug if investigations, other than bio- month’s supplement to the list. Patent availability or bioequivalence studies, information received by the agency be- are essential to the approval of the tween monthly publication of supple- change. Any person seeking approval of ments to the list will be placed on pub- a drug product that represents a modi- lic display in FDA’s Freedom of Infor- fication of a listed drug (e.g., a new in- mation Staff. A request for copies of dication or new dosage form) and for the file shall be sent in writing to the which investigations, other than bio- Freedom of Information Staff (HFI–35), availability or bioequivalence studies, Food and Drug Administration, rm. are essential to the approval of the 12A–16, 5600 Fishers Lane, Rockville, changes may, except as provided in MD 20857. paragraph (b) of this section, submit a (f) Correction of patent information er- 505(b)(2) application. This application rors. If any person disputes the accu- need contain only that information racy or relevance of patent information needed to support the modification(s) submitted to the agency under this sec- of the listed drug. tion and published by FDA in the list, (1) The applicant shall submit a com- or believes that an applicant has failed plete archival copy of the application to submit required patent information, that contains the following: that person must first notify the agen- (i) The information required under cy in writing stating the grounds for § 314.50(a), (b), (c), (d)(1), (d)(3), (e), and disagreement. Such notification should (g), except that § 314.50(d)(1)(ii)(c) shall be directed to the Drug Information contain the proposed or actual master Services Branch (HFD–84), Center for production record, including a description of the equipment, to be used for Drug Evaluation and Research, Food the manufacture of a commercial lot of and Drug Administration, 5600 Fishers the drug product. Lane, Rockville, MD 20857. The agency (ii) The information required under will then request of the applicable new § 314.50 (d)(2), (d)(4) (if an anti-infective drug application holder that the cor- drug), (d)(5), (d)(6), and (f) as needed to rectness of the patent information or support the safety and effectiveness of omission of patent information be con- the drug product. firmed. Unless the application holder (iii) Identification of the listed drug withdraws or amends its patent infor- for which FDA has made a finding of mation in response to FDA’s request, safety and effectiveness and on which the agency will not change the patent finding the applicant relies in seeking information in the list. If the new drug approval of its proposed drug product application holder does not change the by established name, if any, propri- patent information submitted to FDA, etary name, dosage form, strength, a 505(b)(2) application or an abbre- route of administration, name of listed viated new drug application under sec- drug’s application holder, and listed tion 505(j) of the act submitted for a drug’s approved application number. drug that is claimed by a patent for (iv) If the applicant is seeking ap- which information has been submitted proval only for a new indication and must, despite any disagreement as to not for the indications approved for the the correctness of the patent informa- listed drug on which the applicant re- tion, contain an appropriate certifi- lies, a certification so stating. cation for each listed patent. (v) Any patent information required [59 FR 50363, Oct. 3, 1994, as amended at 68 FR under section 505(b)(1) of the act with 36703, June 18, 2003; 69 FR 13473, Mar. 23, 2004] respect to any patent which claims the

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drug for which approval is sought or a product whose only difference from the method of using such drug and to reference listed drug is that: which a claim of patent infringement (1) The extent to which its active in- could reasonably be asserted if a person gredient(s) is absorbed or otherwise not licensed by the owner of the patent made available to the site of action is engaged in the manufacture, use, or less than that of the reference listed sale of the drug product. drug; or (vi) Any patent certification or state- (2) The rate at which its active ingre- ment required under section 505(b)(2) of dient(s) is absorbed or otherwise made the act with respect to any relevant available to the site of action is unin- patents that claim the listed drug or tentionally less than that of the ref- that claim any other drugs on which erence listed drug. investigations relied on by the appli- [57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. cant for approval of the application 28, 1992, as amended at 58 FR 47351, Sept. 8, were conducted, or that claim a use for 1993; 59 FR 50364, Oct. 3, 1994] the listed or other drug. § 314.55 Pediatric use information. (vii) If the applicant believes the change for which it is seeking approval (a) Required assessment. Except as pro- is entitled to a period of exclusivity, vided in paragraphs (b), (c), and (d) of the information required under this section, each application for a new § 314.50(j). active ingredient, new indication, new (2) The applicant shall submit a re- dosage form, new dosing regimen, or view copy that contains the technical new route of administration shall contain 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 manufacture of a commercial lot of the for which the drug is safe and effective. drug product, and paragraph (d)(3), and Where the course of the disease and the the technical sections described in effects of the drug are sufficiently paragraphs (d)(2), (d)(4), (d)(5), (d)(6), similar in adults and pediatric pa- and (f) when needed to support the tients, FDA may conclude that pedi- modification. Each of the technical atric effectiveness can be extrapolated sections in the review copy is required from adequate and well-controlled to be separately bound with a copy of studies in adults usually supplemented the information required under § 314.50 with other information obtained in pe- (a), (b), and (c) and a copy of the pro- diatric patients, such as pharmaco- posed labeling. kinetic studies. Studies may not be (3) The information required by needed in each pediatric age group, if § 314.50 (d)(2), (d)(4) (if an anti-infective data from one age group can be extrap- drug), (d)(5), (d)(6), and (f) for the listed olated to another. Assessments of safe- drug on which the applicant relies shall ty and effectiveness required under this be satisfied by reference to the listed section for a drug product that rep- drug under paragraph (a)(1)(iii) of this resents a meaningful therapeutic ben- section. efit over existing treatments for pedi- (4) The applicant shall submit a field atric patients must be carried out copy of the application that contains using appropriate formulations for the technical section described in each age group(s) for which the assess- § 314.50(d)(1), a copy of the information ment is required. required under § 314.50(a) and (c), and (b) Deferred submission. (1) FDA may, certification that the field copy is a on its own initiative or at the request true copy of the technical section de- of an applicant, defer submission of scribed in § 314.50(d)(1) contained in the some or all assessments of safety and archival and review copies of the appli- effectiveness described in paragraph (a) cation. of this section until after approval of (b) An application may not be sub- the drug product for use in adults. De- mitted under this section for a drug ferral may be granted if, among other

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reasons, the drug is ready for approval (ii) Necessary studies are impossible in adults before studies in pediatric pa- or highly impractical because, e.g., the tients are complete, or pediatric stud- number of patients in that age group is ies should be delayed until additional so small or geographically dispersed; safety or effectiveness data have been (iii) There is evidence strongly sug- collected. If an applicant requests de- gesting that the drug product would be ferred submission, the request must ineffective or unsafe in that age group; provide a certification from the appli- or cant of the grounds for delaying pedi- (iv) The applicant can demonstrate atric studies, a description of the that reasonable attempts to produce a planned or ongoing studies, and evi- pediatric formulation necessary for dence that the studies are being or will that age group have failed. be conducted with due diligence and at (4) FDA action on waiver. FDA shall the earliest possible time. grant a full or partial waiver, as appro- (2) If FDA determines that there is priate, if the agency finds that there is an adequate justification for tempo- a reasonable basis on which to con- rarily delaying the submission of as- clude that one or more of the grounds sessments of pediatric safety and effec- for waiver specified in paragraphs (c)(2) tiveness, the drug product may be ap- or (c)(3) of this section have been met. proved for use in adults subject to the If a waiver is granted on the ground requirement that the applicant submit that it is not possible to develop a pedi- the required assessments within a spec- atric formulation, the waiver will ified time. cover only those pediatric age groups (c) Waivers—(1) General. FDA may requiring that formulation. If a waiver grant a full or partial waiver of the re- is granted because there is evidence quirements of paragraph (a) of this sec- that the product would be ineffective tion on its own initiative or at the re- or unsafe in pediatric populations, this quest of an applicant. A request for a information will be included in the waiver must provide an adequate jus- product’s labeling. tification. (5) Definition of ‘‘meaningful thera- (2) Full waiver. An applicant may re- peutic benefit’’. For purposes of this sec- quest a waiver of the requirements of tion and § 201.23 of this chapter, a drug paragraph (a) of this section if the ap- will be considered to offer a meaningful plicant certifies that: therapeutic benefit over existing thera- (i) The drug product does not rep- pies if FDA estimates that: resent a meaningful therapeutic ben- (i) If approved, the drug would rep- efit over existing treatments for pedi- resent a significant improvement in atric patients and is not likely to be the treatment, diagnosis, or prevention used in a substantial number of pedi- of a disease, compared to marketed atric patients; products adequately labeled for that (ii) Necessary studies are impossible use in the relevant pediatric popu- or highly impractical because, e.g., the lation. Examples of how improvement number of such patients is so small or might be demonstrated include, for ex- geographically dispersed; or ample, evidence of increased effective- (iii) There is evidence strongly sug- ness in treatment, prevention, or diag- gesting that the drug product would be nosis of disease, elimination or sub- ineffective or unsafe in all pediatric stantial reduction of a treatment-lim- age groups. iting drug reaction, documented en- (3) Partial waiver. An applicant may hancement of compliance, or evidence request a waiver of the requirements of of safety and effectiveness in a new paragraph (a) of this section with re- subpopulation; or spect to a specified pediatric age group, (ii) The drug is in a class of drugs or if the applicant certifies that: for an indication for which there is a (i) The drug product does not rep- need for additional therapeutic op- resent a meaningful therapeutic ben- tions. efit over existing treatments for pedi- (d) Exemption for orphan drugs. This atric patients in that age group, and is section does not apply to any drug for not likely to be used in a substantial an indication or indications for which number of patients in that age group; orphan designation has been granted

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under part 316, subpart C, of this chap- described in paragraph (b)(1)(ii) of this ter. section; and [63 FR 66670, Dec. 2, 1998] (iv) The report of the investigation described in paragraph (b)(1)(ii) of this § 314.60 Amendments to an unap- section would be essential to the approved application. proval of the unapproved application. (a) Except as provided in paragraph (2) The submission of an amendment (b) of this section, the applicant may described in paragraph (b)(1) of this submit an amendment to an applica- section will cause the unapproved ap- tion that is filed under § 314.100, but not plication to be deemed to be withdrawn yet approved. The submission of a by the applicant under § 314.65 on the major amendment (for example, an date of receipt by FDA of the amend- amendment that contains significant ment. The amendment will be consid- new data from a previously unreported ered a resubmission of the application, study or detailed newnalyses of pre- which may not be accepted except as viously submitted data), whether on provided in accordance with section the applicant’s own initiative or at the 505(c)(3)(D)(ii) of the act. invitation of the agency, constitutes (c) The applicant shall submit a field an agreement by the applicant under copy of each amendment to section 505(c) of the act to extend the § 314.50(d)(1). The applicant, other than date by which the agency is required to a foreign applicant, shall include in its reach a decision on the application. Or- submission of each such amendment to dinarily, the agency will extend the re- FDA a statement certifying that a field view period for a major amendment but copy of the amendment has been sent only for the time necessary to review to the applicant’s home FDA district the new information. However, the office. agency may not extend the review period more than 180 days. If the agency [50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, extends the review period for the appli- 1993; 63 FR 5252, Feb. 2, 1998] cation, the director of the division responsible for reviewing the application § 314.65 Withdrawal by the applicant will notify the applicant of the length of an unapproved application. of the extension. The submission of an An applicant may at any time with- amendment that is not a major amend- draw an application that is not yet ap- ment will not extend the review period. proved by notifying the Food and Drug An amendment that contains new clin- Administration in writing. The agency ical data from a previously unreported will consider an applicant’s failure to study shall contain a financial certifi- respond within 10 days to an approv- cation or disclosure statement or both able letter under § 314.110 or a not ap- as required by part 54 of this chapter, provable letter under § 314.120 to be a or FDA may refuse to accept any such request by the applicant to withdraw amendment. the application. A decision to withdraw (b)(1) An unapproved application may the application is without prejudice to not be amended if all of the following refiling. The agency will retain the ap- conditions apply: plication and will provide a copy to the (i) The unapproved application is for applicant on request under the fee a drug for which a previous application schedule in § 20.45 of FDA’s public in- has been approved and granted a period formation regulations. of exclusivity in accordance with section 505(c)(3)(D)(ii) of the act that has [50 FR 7493, Feb. 22, 1985, as amended at 68 not expired; FR 25287, May 12, 2003] (ii) The applicant seeks to amend the unapproved application to include a § 314.70 Supplements and other published report of an investigation changes to an approved application. that was conducted or sponsored by the (a) Changes to an approved application. applicant entitled to exclusivity for The applicant shall notify FDA about the drug; each change in each condition estab- (iii) The applicant has not obtained a lished in an approved application be- right of reference to the investigation yond the variations already provided

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for in the application. The notice is re- solvents and a change in the route of quired to describe the change fully. De- synthesis. pending on the type of change, the ap- (v) To use a different facility or es- plicant shall notify FDA about it in a tablishment to manufacture the drug supplemental application under para- substance, where: (a) the manufac- graph (b) or (c) of this section or by in- turing process in the new facility or es- clusion of the information in the an- tablishment differs materially from nual report to the application under that in the former facility or establish- paragraph (d) of this section. Notwith- ment, or (b) the new facility or estab- standing the requirements of para- lishment has not received a satisfac- graphs (b) and (c) of this section, an ap- tory current good manufacturing prac- plicant shall make a change provided tice (CGMP) inspection within the pre- for in those paragraphs (for example, vious 2 years covering that manufac- the deletion of an ingredient common turing process. to many drug products) in accordance (2) Drug product. A change affecting with a notice, or regulation published the drug product to accomplish any of in the FEDERAL REGISTER that provides the following: for a less burdensome notification of (i) To add or delete an ingredient, or the change (for example, by notifica- otherwise to change the composition of tion at the time a supplement is sub- the drug product, other than deletion mitted or in the next annual report). of an ingredient intended only to affect Except for a supplemental application the color of the drug product; providing for a change in the labeling, (ii) To relax the limits for a speci- the applicant, other than a foreign ap- fication; plicant, shall include in each supple- (iii) To establish a new regulatory mental application providing for a analytical method; change under paragraph (b) or (c) of (iv) To delete a specification or regu- this section a statement certifying latory analytical method; that a field copy of the supplement has (v) To change the method of manu- been provided to the applicant’s home facture of the drug product, including FDA district office. changing or relaxing an in-process con- (b) Supplements requiring FDA ap- trol; proval before the change is made. An ap- (vi) To use a different facility or es- plicant shall submit a supplement, and tablishment, including a different contract laboratory or labeler, to manu- obtain FDA approval of it, before mak- facture, process, or pack the drug prod- ing the changes listed below in the con- uct; ditions in an approved application, un- (vii) To change the container and clo- less the change is made to comply with sure system for the drug product (for an official compendium. An applicant example, glass to high density poly- may ask FDA to expedite its review of ethylene (HDPE), or HDPE to poly- a supplement if a delay in making the vinyl chloride) or change a specifica- change described in it would impose an tion or regulatory analytical method extraordinary hardship on the appli- for the container and closure system; cant. Such a supplement and its mail- (viii) To change the size of the con- ing cover should be plainly marked: tainer, except for solid dosage forms, ‘‘Supplement—Expedited Review Re- without a change in the container and quested.’’ closure system. (1) Drug substance. A change affecting (ix) To extend the expiration date of the drug substance to accomplish any the drug product based on data ob- of the following: tained under a new or revised stability (i) To relax the limits for a specifica- testing protocol that has not been ap- tion; proved in the application. (ii) To establish a new regulatory an- (x) To establish a new procedure for alytical method; reprocessing a batch of the drug prod- (iii) To delete a specification or regu- uct that fails to meet specifications. latory analytical method; (xi) To add a code imprint by print- (iv) To change the synthesis of the ing with ink on a solid oral dosage drug substance, including a change in form drug product.

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(xii) To add a code imprint by em- turing process in the new facility or es- bossing, debossing, or engraving on a tablishment does not differ materially modified release solid oral dosage form from that in the former facility or es- drug product. tablishment, and (ii) the new facility (3) Labeling. (i) Any change in label- or establishment has received a satis- ing, except one described in paragraphs factory current good manufacturing (c)(2) or (d) of this section. practice (CGMP) inspection within the (ii) If applicable, any change to a previous 2 years covering that manu- Medication Guide required under part facturing process. 208 of this chapter, except for changes (d) Changes described in the annual rein the information specified in port. An applicant shall not submit a § 208.20(b)(8)(iii) and (b)(8)(iv). supplement to make any change in the (c) Supplements for changes that may conditions in an approved application, be made before FDA approval. An appli- unless otherwise required under para- cant shall submit a supplement at the graph (b) or (c) of this section, but time the applicant makes any kind of shall describe the change in the next change listed below in the conditions annual report required under § 314.81. in an approved application, unless the Some examples of changes that can be change is made to comply with an offi- described in the annual report are the cial compendium. A supplement under following: this paragraph is required to give a full (1) Any change made to comply with explanation of the basis for the change, an official compendium. identify the date on which the change (2) A change in the labeling con- is made, and, if the change concerns la- cerning the description of the drug beling, include 12 copies of final print- product or in the information about ed labeling. The applicant shall how the drug product is supplied, that promptly revise all promotional label- does not involve a change in the dosage ing and drug advertising to make it strength or dosage form. consistent with any change in the la- (3) An editorial or similar minor beling. The supplement and its mailing change in labeling. cover should be plainly marked: ‘‘Spe- (4) The deletion of an ingredient in- cial Supplement—Changes Being Ef- tended only to affect the color of the fected.’’ drug product. (1) Adds a new specification or test (5) An extension of the expiration method or changes in the methods, fa- date based upon full shelf-life data ob- cilities (except a change to a new facil- tained from a protocol approved in the ity), or controls to provide increased application. assurance that the drug will have the (6) A change within the container and characteristics of identity, strength, closure system for the drug product quality, and purity which it purports (for example, a change from one high or is represented to possess; density polyethylene (HDPE) to an- (2) Changes labeling to accomplish other HDPE), except a change in con- any of the following: tainer size for nonsolid dosage forms, (i) To add or strengthen a contra- based upon a showing of equivalency to indication, warning, precaution, or ad- the approved system under a protocol verse reaction; approved in the application or pub- (ii) To add or strengthen a statement lished in an official compendium. about drug abuse, dependence, or over- (7) The addition or deletion of an al- dosage; or ternate analytical method. (iii) To add or strengthen an instruc- (8) A change in the size of a container tion about dosage and administration for a solid dosage form, without a that is intended to increase the safe change from one container and closure use of the product. system to another. (iv) To delete false, misleading, or (9) The addition by embossing, de- unsupported indications for use or bossing, or engraving of a code imprint claims for effectiveness. to a solid oral dosage form drug prod- (3) To use a different facility or es- uct other than a modified release dos- tablishment to manufacture the drug age form, or a minor change in an ex- substance, where: (i) The manufac- isting code imprint.

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(e) Patent information. The applicant tion, or substitution of steps in an shall comply with the patent informa- aseptic processing operation. tion requirements under section (iii) The applicant must obtain ap- 505(c)(2) of the act. proval of the supplement from FDA (f) Claimed exclusivity. If an applicant prior to distribution of the product claims exclusivity under § 314.108 upon made using the change. Except for sub- approval of a supplemental application missions under paragraph (g)(4) of this for a change to its previously approved section, the following shall be con- drug product, the applicant shall in- tained in the supplement: clude with its supplemental applica- (A) A detailed description of the pro- tion the information required under posed change; § 314.50(j). (B) The product(s) involved; (g) Exception. An applicant proposing (C) The manufacturing site(s) or to make a change of a type described in area(s) affected; paragraphs (a), (b)(1), (b)(2), (c)(1), (D) A description of the methods used (c)(3), (d)(1), and (d)(4) through (d)(9) of and studies performed to evaluate the this section affecting a recombinant effect of the change on the identity, DNA-derived protein/polypeptide prod- strength, quality, purity, or potency of uct or a complex or conjugate of a drug the product as they may relate to the with a monoclonal antibody regulated safety or effectiveness of the product; under the Federal Food, Drug, and Cos- (E) The data derived from such stud- metic Act shall comply with the fol- ies; lowing: (F) Relevant validation protocols and (1) Changes requiring supplement sub- data; and mission and approval prior to distribution (G) A reference list of relevant stand- of the product made using the change ard operating procedures (SOP’s). (major changes). (i) A supplement shall (2) Changes requiring supplement sub- be submitted for any change in the mission at least 30 days prior to distribu- product, production process, quality tion of the product made using the controls, equipment, or facilities that change. (i) A supplement shall be sub- has a substantial potential to have an mitted for any change in the product, adverse effect on the identity, production process, quality controls, strength, quality, purity, or potency of equipment, or facilities that has a the product as they may relate to the moderate potential to have an adverse safety or effectiveness of the product. effect on the identity, strength, qual- (ii) These changes include, but are ity, purity, or potency of the product not limited to: as they may relate to the safety or ef- (A) Changes in the qualitative or fectiveness of the product. The supple- quantitative formulation or other spec- ment shall be labeled ‘‘Supplement— ifications as provided in the approved Changes Being Effected in 30 Days’’ or, application or in the regulations; if applicable under paragraph (g)(2)(v) (B) Changes requiring completion of of this section, ‘‘Supplement—Changes an appropriate human study to dem- Being Effected.’’ onstrate the equivalence of the iden- (ii) These changes include, but are tity, strength, quality, purity, or po- not limited to: tency of the product as they may re- (A) Change in the site of testing from late to the safety or effectiveness of one facility to another; the product; (B) An increase or decrease in pro- (C) Changes in the virus or adven- duction scale during finishing steps titious agent removal or inactivation that involves new or different equip- method(s); ment; and (D) Changes in the source material or (C) Replacement of equipment with cell line; that of similar, but not identical, de- (E) Establishment of a new master sign and operating principle that does cell bank or seed; and not affect the process methodology or (F) Changes which may affect prod- process operating parameters. uct sterility assurance, such as (iii) Pending approval of the supple- changes in product or component steri- ment by FDA, and except as provided lization method(s) or an addition, dele- in paragraph (g)(2)(v) of this section,

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distribution of the product made using (B) The deletion of an ingredient in- the change may begin not less than 30 tended only to affect the color of the days after receipt of the supplement by product; FDA. The information listed in para- (C) An extension of an expiration graph (g)(1)(iii)(A) through (g)(1)(iii)(G) date based upon full shelf life data ob- of this section shall be contained in the tained from a protocol approved in the supplement. application; (iv) If within 30 days following FDA’s (D) A change within the container receipt of the supplement, FDA in- and closure system for solid dosage forms the applicant that either: forms, based upon a showing of equiva- (A) The change requires approval lency to the approved system under a prior to distribution of the product in protocol approved in the application or accordance with paragraph (g)(1) of published in an official compendium; this section; or (E) A change in the size of a con- (B) Any of the information required tainer for a solid dosage form, without under paragraph (g)(2)(iii) of this sec- a change from one container and clo- tion is missing; the applicant shall not sure system to another; distribute the product made using the (F) The addition by embossing, de- change until FDA determines that bossing, or engraving of a code imprint compliance with this section is to a solid dosage form drug product achieved. other than a modified release dosage (v) In certain circumstances, FDA form, or a minor change in an existing may determine that, based on experi- code imprint; and ence with a particular type of change, (G) The addition or deletion of an al- the supplement for such change is usu- ternate analytical method. ally complete and provides the proper (4) An applicant may submit one or information, and on particular assur- more protocols describing the specific ances that the proposed change has tests and validation studies and accept- been appropriately submitted, the able limits to be achieved to dem- product made using the change may be onstrate the lack of adverse effect for distributed immediately upon receipt specified types of manufacturing of the supplement by FDA. These cir- changes on the identity, strength, cumstances may include substantial quality, purity, or potency of the prod- similarity with a type of change regu- uct as they may relate to the safety or effectiveness of the product. Any such larly involving a ‘‘Supplement— protocols, or change to a protocol, Changes Being Effected’’ supplement, shall be submitted as a supplement re- or a situation in which the applicant quiring approval from FDA prior to presents evidence that the proposed distribution of the product which, if change has been validated in accord- approved, may justify a reduced report- ance with an approved protocol for ing category for the particular change such change under paragraph (g)(4) of because the use of the protocol for that this section. type of change reduces the potential (3) Changes to be described in an an- risk of an adverse effect. nual report (minor changes). (i) Changes in the product, production process, [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, quality controls, equipment, or facili- 1985, as amended at 50 FR 21238, May 23, 1985; ties that have a minimal potential to 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 8, 1993; 58 FR 47959, Sept. 13, 1993; 59 FR 50364, have an adverse effect on the identity, Oct. 3, 1994; 62 FR 39900, July 24, 1997; 63 FR strength, quality, purity, or potency of 66399, Dec. 1, 1998; 65 FR 56479, Sept. 19, 2000; the product as they may relate to the 67 FR 9586, Mar. 4, 2002] safety or effectiveness of the product shall be documented by the applicant § 314.71 Procedures for submission of in the next annual report in accordance a supplement to an approved appli- with § 314.81(b)(2)(iv). cation. (ii) These changes include, but are (a) Only the applicant may submit a not limited to: supplement to an application. (A) Any change made to comply with (b) All procedures and actions that an official compendium that is con- apply to an application under § 314.50 sistent with FDA requirements; also apply to supplements, except that

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the information required in the supple- or the name of its manufacturer, pack- ment is limited to that needed to super, or distributor. port the change. A supplement is re- [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, quired to contain an archival copy and 1985, as amended at 50 FR 21238, May 23, 1985; a review copy that include an applica- 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, tion form and appropriate technical 2003] sections, samples, and labeling; except that a supplement for a change other § 314.80 Postmarketing reporting of than a change in labeling is required adverse drug experiences. also to contain a field copy. (a) Definitions. The following defini- (c) All procedures and actions that tions of terms apply to this section:– apply to applications under this part, Adverse drug experience. Any adverse including actions by applicants and the event associated with the use of a drug Food and Drug Administration, also in humans, whether or not considered apply to supplements. drug related, including the following: An adverse event occurring in the [50 FR 7493, Feb. 22, 1985, as amended at 50 course of the use of a drug product in FR 21238, May 23, 1985; 58 FR 47352, Sept. 8, 1993; 67 FR 9586, Mar. 4, 2002] professional practice; an adverse event occurring from drug overdose whether § 314.72 Change in ownership of an ap- accidental or intentional; an adverse plication. event occurring from drug abuse; an adverse event occurring from drug (a) An applicant may transfer owner- withdrawal; and any failure of expected ship of its application. At the time of pharmacological action. transfer the new and former owners are Disability. A substantial disruption of required to submit information to the a person’s ability to conduct normal Food and Drug Administration as fol- life functions. lows: Life-threatening adverse drug experi- (1) The former owner shall submit a ence. Any adverse drug experience that letter or other document that states places the patient, in the view of the that all rights to the application have initial reporter, at immediate risk of been transferred to the new owner. death from the adverse drug experience (2) The new owner shall submit an as it occurred, i.e., it does not include application form signed by the new an adverse drug experience that, had it owner and a letter or other document occurred in a more severe form, might containing the following: 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 except the new owner may advise FDA events include allergic bronchospasm in the next annual report about a requiring intensive treatment in an change in the drug product’s label or emergency room or at home, blood labeling to change the product’s brand dyscrasias or convulsions that do not

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result in inpatient hospitalization, or this section. The applicant shall sub- the development of drug dependency or mit two copies of each report described drug abuse. in this section to the Central Docu- Unexpected adverse drug experience. ment Room, 5901–B Ammendale Rd., Any adverse drug experience that is Beltsville, MD 20705–1266. FDA may not listed in the current labeling for waive the requirement for the second the drug product. This includes events copy in appropriate instances. 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- nonapplicant may be met by submis- cants are not required to resubmit to sion of all reports of serious adverse FDA adverse drug experience reports drug experiences to the applicant. If a forwarded to the applicant by FDA; nonapplicant elects to submit adverse however, applicants must submit all drug experience reports to the appli- followup information on such reports cant rather than to FDA, the non- to FDA. Any person subject to the re- applicant shall submit each report to porting requirements under paragraph the applicant within 5 calendar days of (c) of this section shall also develop receipt of the report by the non- written procedures for the surveillance, applicant, and the applicant shall then receipt, evaluation, and reporting of comply with the requirements of this postmarketing adverse drug experi- section. Under this circumstance, the ences to FDA. nonapplicant shall maintain a record of (c) Reporting requirements. The appli- this action which shall include: cant shall report to FDA adverse drug (A) A copy of each adverse drug expe- experience information, as described in rience report;

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(B) The date the report was received (iii) Periodic reporting, except for in- by the nonapplicant; formation regarding 15-day Alert re- (C) The date the report was sub- ports, does not apply to adverse drug mitted to the applicant; and experience information obtained from (D) The name and address of the ap- postmarketing studies (whether or not plicant. conducted under an investigational (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 years from the date of approval of the section (i.e., serious, unexpected ad- application, and then at annual inter- verse drug experiences) apply only to vals. The applicant shall submit each reports found in scientific and medical 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 Di- agency may reestablish a quarterly revision of Pharmacovigilance and Epide- porting requirement following the ap- miology for an acceptable alternative proval of a major supplement. Fol- reporting 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 vestigational new drug application) un- report and an analysis of the 15-day less the applicant concludes that there Alert reports submitted during the re- is a reasonable possibility that the porting interval (all 15-day Alert reports 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).

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(2) Each completed FDA Form 3500A (i) Recordkeeping. The applicant shall should refer only to an individual pa- maintain for a period of 10 years tient or a single attached publication. records of all adverse drug experiences (3) Instead of using FDA Form 3500A, known to the applicant, including raw an applicant may use a computer-gen- data and any correspondence relating erated FDA Form 3500A or other alter- to adverse drug experiences. native format (e.g., a computer-gen- (j) Withdrawal of approval. If an appli- erated tape or tabular listing) provided cant fails to establish and maintain that: (i) The content of the alternative records and make reports required format is equivalent in all elements of under this section, FDA may withdraw information to those specified in FDA approval of the application and, thus, Form 3500A; and (ii) The format is prohibit continued marketing of the agreed to in advance by MedWatch: drug product that is the subject of the The FDA Medical Products Reporting application. Program. (k) Disclaimer. A report or informa- (4) Ten copies or fewer of FDA Form tion submitted by an applicant under 3500A and/or a copy of the instructions this section (and any release by FDA of for completing the form may be ob- that report or information) does not tained from the Division of necessarily reflect a conclusion by the Pharmacovigilance and Epidemiology applicant or FDA that the report or in- (HFD–730), Center for Drug Evaluation formation constitutes an admission and Research, Food and Drug Adminis- that the drug caused or contributed to tration, 5600 Fishers Lane, Rockville, an adverse effect. An applicant need MD 20857. More than 10 copies of the not admit, and may deny, that the re- form may be obtained by writing to the port or information submitted under Consolidated Forms and Publications this section constitutes an admission Distribution Center, Washington Com- that the drug caused or contributed to merce Center, 3222 Hubbard Rd., Land- an adverse effect. For purposes of this over, MD 20785. 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, 1985, as amended at 50 FR 21238, May 23, 1985; they were previously submitted as part 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, of the approved application. If a report 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] 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 num- Administration at the specified times ber to each report, preferably not more two copies of the following reports: than eight characters in length. The (1) NDA—Field alert report. The appli- applicant should include the name of cant shall submit information of the the reporter from whom the informa- following kinds about distributed drug tion was received. Names of patients, products and articles to the FDA dis- health care professionals, hospitals, trict office that is responsible for the and geographical identifiers in adverse facility involved within 3 working days drug experience reports are not releas- of receipt by the applicant. The infor- able to the public under FDA’s public mation may be provided by telephone information regulations in part 20. or other rapid communication means,

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with prompt written followup. The re- tion, including that distributed to dis- port and its mailing cover should be tributors. The information is required plainly marked: ‘‘NDA—Field Alert Re- to include the National Drug Code port.’’ (NDC) number, the total number of (i) Information concerning any inci- dosage units of each strength or po- dent that causes the drug product or tency distributed (e.g., 100,000/5 milli- its labeling to be mistaken for, or ap- gram tablets, 50,000/10 milliliter vials), plied to, another article. and the quantities distributed for do- (ii) Information concerning any bac- mestic use and the quantities distrib- teriological contamination, or any sig- uted for foreign use. Disclosure of fi- nificant chemical, physical, or other nancial or pricing data is not required. change or deterioration in the distrib- (iii) Labeling. Currently used profes- uted drug product, or any failure of one sional labeling, patient brochures or or more distributed batches of the drug package inserts (if any), a representa- product to meet the specifications es- tive sample of the package labels, and tablished for it in the application. a summary of any changes in labeling (2) Annual report. The applicant shall submit each year within 60 days of the that have been made since the last re- anniversary date of U.S. approval of port listed by date in the order in the application, two copies of the re- which they were implemented, or if no port to the FDA division responsible changes, a statement of that fact. for reviewing the application. Each an- (iv) Chemistry, manufacturing, and nual report is required to be accom- controls changes. (a) Reports of experi- panied by a completed transmittal ences, investigations, studies, or tests Form FDA 2252 (Transmittal of Peri- involving chemical or physical prop- odic Reports for Drugs for Human Use), erties, or any other properties of the and must include all the information drug (such as the drug’s behavior or required under this section that the ap- properties in relation to microorga- plicant received or otherwise obtained nisms, including both the effects of the during the annual reporting interval drug on microorganisms and the effects that ends on the U.S. anniversary date. of microorganisms on the drug). These The report is required to contain in the reports are only required for new infor- order listed: mation that may affect FDA’s previous (i) Summary. A brief summary of sig- conclusions about the safety or effec- nificant new information from the pre- tiveness of the drug product. vious year that might affect the safety, (b) A full description of the manufac- effectiveness, or labeling of the drug turing and controls changes not requir- product. The report is also required to ing a supplemental application under contain a brief description of actions § 314.70 (b) and (c), listed by date in the the applicant has taken or intends to order in which they were implemented. take as a result of this new informa- (v) Nonclinical laboratory studies. Cop- tion, for example, submit a labeling supplement, add a warning to the label- ies of unpublished reports and sum- ing, or initiate a new study. The summaries of published reports of new toxi- mary shall briefly state whether label- cological findings in animal studies ing supplements for pediatric use have and in vitro studies (e.g., mutage- been submitted and whether new stud- nicity) conducted by, or otherwise ob- ies in the pediatric population to sup- tained by, the applicant concerning the port appropriate labeling for the pedi- ingredients in the drug product. The atric population have been initiated. applicant shall submit a copy of a pub- Where possible, an estimate of patient lished report if requested by FDA. exposure to the drug product, with spe- (vi) Clinical data. (a) Published clin- cial reference to the pediatric popu- ical trials of the drug (or abstracts of lation (neonates, infants, children, and them), including clinical trials on safe- adolescents) shall be provided, includ- ty and effectiveness; clinical trials on ing dosage form. new uses; biopharmaceutic, pharmaco- (ii) Distribution data. Information kinetic, and clinical pharmacology about the quantity of the drug product studies; and reports of clinical experi- distributed under the approved applica- ence pertinent to safety (for example,

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epidemiologic studies or analyses of ex- (2) Product name. Include the ap- perience in a monitored series of pa- proved drug product’s established name tients) conducted by or otherwise ob- and proprietary name, if any. tained by the applicant. Review arti- (3) NDA, ANDA, and supplement num- cles, papers describing the use of the ber. drug product in medical practice, pa- (4) Date of U.S. approval of NDA or pers and abstracts in which the drug is ANDA. used as a research tool, promotional (5) Date of postmarketing study commit- articles, press clippings, and papers ment. that do not contain tabulations or (6) Description of postmarketing study summaries of original data should not commitment. The description must in- be reported. clude sufficient information to unique- (b) Summaries of completed unpub- ly describe the study. This information lished clinical trials, or prepublication may include the purpose of the study, manuscripts if available, conducted by, the type of study, the patient popu- or otherwise obtained by, the appli- lation addressed by the study and the cant. Supporting information should indication(s) and dosage(s) that are to not be reported. (A study is considered be studied. completed 1 year after it is concluded.) (7) Schedule for completion and report- (c) Analysis of available safety and ing of the postmarketing study commit- efficacy data in the pediatric popu- ment. The schedule should include the lation and changes proposed in the la- actual or projected dates for submis- beling based on this information. An sion of the study protocol to FDA, assessment of data needed to ensure completion of patient accrual or initi- appropriate labeling for the pediatric ation of an animal study, completion of population shall be included. the study, submission of the final (vii) Status reports of postmarketing study report to FDA, and any addi- study commitments. A status report of tional milestones or submissions for each postmarketing study of the drug which projected dates were specified as product concerning clinical safety, part of the commitment. In addition, it clinical efficacy, clinical pharma- should include a revised schedule, as cology, and nonclinical toxicology that appropriate. If the schedule has been is required by FDA (e.g., accelerated previously revised, provide both the approval clinical benefit studies, pedi- original schedule and the most recent, atric studies) or that the applicant has previously submitted revision. committed, in writing, to conduct either at the time of approval of an ap- (8) Current status of the postmarketing plication for the drug product or a sup- study commitment. The status of each plement to an application, or after ap- postmarketing study should be cat- proval of the application or a supple- egorized using one of the following ment. For pediatric studies, the status terms that describes the study’s status report shall include a statement indi- on the anniversary date of U.S. ap- cating whether postmarketing clinical proval of the application or other studies in pediatric populations were agreed upon date: required by FDA under § 201.23 of this (i) Pending. The study has not been chapter. The status of these post- initiated, but does not meet the cri- marketing studies shall be reported an- terion for delayed. nually until FDA notifies the appli- (ii) Ongoing. The study is proceeding cant, in writing, that the agency con- according to or ahead of the original curs with the applicant’s determina- schedule described under paragraph tion that the study commitment has (b)(2)(vii)(a)(7) of this section. been fulfilled or that the study is ei- (iii) Delayed. The study is behind the ther no longer feasible or would no original schedule described under para- longer provide useful information. graph (b)(2)(vii)(a)(7) of this section. (a) Content of status report. The fol- (iv) Terminated. The study was ended lowing information must be provided before completion but a final study re- for each postmarketing study reported port has not been submitted to FDA. under this paragraph: (v) Submitted. The study has been (1) Applicant’s name. completed or terminated and a final

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study report has been submitted to swered correspondence with the appli- FDA. cant). (9) Explanation of the study’s status. (3) Other reporting—(i) Advertisements Provide a brief description of the sta- and promotional labeling. The applicant tus of the study, including the patient shall submit specimens of mailing accrual rate (expressed by providing pieces and any other labeling or adver- the number of patients or subjects en- tising devised for promotion of the rolled to date, and the total planned drug product at the time of initial dis- enrollment), and an explanation of the semination of the labeling and at the study’s status identified under para- time of initial publication of the adver- graph (b)(2)(vii)(a)(8) of this section. If tisement for a prescription drug prod- the study has been completed, include uct. Mailing pieces and labeling that the date the study was completed and are designed to contain samples of a the date the final study report was sub- drug product are required to be committed to FDA, as applicable. Provide a plete, except the sample of the drug revised schedule, as well as the rea- product may be omitted. Each submis- son(s) for the revision, if the schedule sion is required to be accompanied by a under paragraph (b)(2)(vii)(a)(7) of this completed transmittal Form FDA–2253 section has changed since the last re- (Transmittal of Advertisements and port. Promotional Labeling for Drugs for (b) Public disclosure of information. Ex- Human Use) and is required to include cept for the information described in a copy of the product’s current profes- this paragraph, FDA may publicly dis- sional labeling. Form FDA–2253 may be close any information described in obtained from the PHS Forms and Pub- paragraph (b)(2)(vii) of this section, lications Distribution Center, 12100 concerning a postmarketing study, if Parklawn Dr., Rockville, MD 20857. the agency determines that the infor- (ii) Special reports. Upon written re- mation is necessary to identify the ap- quest the agency may require that the plicant or to establish the status of the applicant submit the reports under this study, including the reasons, if any, for section at different times than those failure to conduct, complete, and re- stated. port the study. Under this section, (iii) Withdrawal of approved drug prod- FDA will not publicly disclose trade se- uct from sale. (a) The applicant shall crets, as defined in § 20.61 of this chap- submit on Form FDA 2657 (Drug Prod- ter, or information, described in § 20.63 uct Listing), within 15 working days of of this chapter, the disclosure of which the withdrawal from sale of a drug would constitute an unwarranted inva- product, the following information: sion of personal privacy. (1) The National Drug Code (NDC) (viii) Status of other postmarketing number. studies. A status report of any post- (2) The identity of the drug product marketing study not included under by established name and by proprietary paragraph (b)(2)(vii) of this section name. that is being performed by, or on behalf (3) The new drug application or ab- of, the applicant. A status report is to breviated application number. be included for any chemistry, manu- (4) The date of withdrawal from sale. facturing, and controls studies that the It is requested but not required that applicant has agreed to perform and for the reason for withdrawal of the drug all product stability studies. product from sale be included with the (ix) Log of outstanding regulatory busi- information. ness. To facilitate communications be- (b) The applicant shall submit each tween FDA and the applicant, the re- Form FDA–2657 to the Drug Listing port may, at the applicant’s discretion, Branch (HFD–334), Center for Drug also contain a list of any open regu- Evaluation and Research, Food and latory business with FDA concerning Drug Administration, 5600 Fishers the drug product subject to the appli- Lane, Rockville, MD 20857. cation (e.g., a list of the applicant’s un- (c) Reporting under paragraph answered correspondence with the (b)(3)(iii) of this section constitutes agency, a list of the agency’s unan- compliance with the requirements

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under § 207.30(a) of this chapter to re- inserts (if any), and a representative sample port ‘‘at the discretion of the reg- of the package labels. istrant when the change occurs.’’ (b) The content of labeling required under (c) General requirements—(1) Multiple § 201.100(d)(3) of this chapter (i.e., the pack- applications. For all reports required by age insert or professional labeling), includ- this section, the applicant shall submit ing all text, tables, and figures, must be sub- the information common to more than mitted in electronic format. Electronic format submissions must be in a form that FDA one application only to the application can process, review, and archive. FDA will first approved, and shall not report sep- periodically issue guidance on how to pro- arately on each application. The sub- vide the electronic submission (e.g., method mission is required to identify all the of transmission, media, file formats, prepa- applications to which the report ap- ration and organization of files). Submis- plies. sions under this paragraph must be made in (2) Patient identification. Applicants accordance with part 11 of this chapter, ex- should not include in reports under cept for the requirements of § 11.10(a), (c) this section the names and addresses of through (h), and (k), and the corresponding individual patients; instead, the appli- requirements of § 11.30. cant should code the patient names (c) A summary of any changes in labeling whenever possible and retain the code that have been made since the last report in the applicant’s files. The applicant listed by date in the order in which they shall maintain sufficient patient iden- were implemented, or if no changes, a state- tification information to permit FDA, ment of that fact. by using that information alone or along with records maintained by the * * * * * investigator of a study, to identify the name and address of individual pa- § 314.90 Waivers. tients; this will ordinarily occur only (a) An applicant may ask the Food when the agency needs to investigate and Drug Administration to waive the reports further or when there is under this section any requirement reason to believe that the reports do that applies to the applicant under not represent actual results obtained. §§ 314.50 through 314.81. An applicant (d) Withdrawal of approval. If an ap- may ask FDA to waive under plicant fails to make reports required § 314.126(c) any criteria of an adequate under this section, FDA may withdraw and well-controlled study described in approval of the application and, thus, § 314.126(b). A waiver request under this prohibit continued marketing of the section is required to be submitted drug product that is the subject of the application. with supporting documentation in an application, or in an amendment or (Collection of information requirements ap- supplement to an application. The proved by the Office of Management and waiver request is required to contain Budget under control number 0910–0001) one of the following: [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, (1) An explanation why the appli- 1985, as amended at 50 FR 21238, May 23, 1985; cant’s compliance with the require- 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. ment is unnecessary or cannot be 5, 1999; 65 FR 64617, Oct. 30, 2000; 66 FR 10815, achieved; Feb. 20, 2001] (2) A description of an alternative EFFECTIVE DATE NOTE: At 68 FR 69019, Dec. submission that satisfies the purpose of 11, 2003, § 314.81 was amended by revising the requirement; or paragraph (b)(2)(iii), effective June 8, 2004. (3) Other information justifying a For the convenience of the user, the revised waiver. text is set forth as follows: (b) FDA may grant a waiver if it § 314.81 Other postmarketing reports. finds one of the following: (1) The applicant’s compliance with * * * * * the requirement is unnecessary for the agency to evaluate the application or (b) * * * (2) * * * compliance cannot be achieved; (iii) Labeling. (a) Currently used profes- (2) The applicant’s alternative sub- sional labeling, patient brochures or package mission satisfies the requirement; or

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(3) The applicant’s submission other- changes described in paragraph (b) of wise justifies a waiver. this section. Petitions to submit abbreviated new drug applications for other [50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, changes from a listed drug will not be 2002] approved. (b) A person who wants to submit an Subpart C—Abbreviated abbreviated new drug application for a Applications drug product which is not identical to a listed drug in route of administration, dosage form, and strength, or in SOURCE: 57 FR 17983, Apr. 28, 1992, unless which one active ingredient is sub- otherwise noted. stituted for one of the active ingredi- § 314.92 Drug products for which ab- ents in a listed combination drug, must breviated applications may be sub- first obtain permission from FDA to mitted. submit such an abbreviated applica- (a) Abbreviated applications are suit- tion. able for the following drug products (c) To obtain permission to submit an within the limits set forth under abbreviated new drug application for a § 314.93: change described in paragraph (b) of (1) Drug products that are the same this section, a person must submit and as a listed drug. A ‘‘listed drug’’ is de- obtain approval of a petition request- fined in § 314.3. For determining the ing the change. A person seeking per- suitability of an abbreviated new drug mission to request such a change from application, the term ‘‘same as’’ means a reference listed drug shall submit a identical in active ingredient(s), dosage petition in accordance with §10.20 of form, strength, route of administra- this chapter and in the format specified tion, and conditions of use, except that in § 10.30 of this chapter. The petition conditions of use for which approval shall contain the information specified cannot be granted because of exclu- in § 10.30 of this chapter and any addi- sivity or an existing patent may be tional information required by this sec- omitted. If a listed drug has been vol- tion. If any provision of § 10.20 or § 10.30 untarily withdrawn from or not offered of this chapter is inconsistent with any for sale by its manufacturer, a person provision of this section, the provisions who wishes to submit an abbreviated of this section apply. new drug application for the drug shall (d) The petitioner shall identify a comply with § 314.122. listed drug and include a copy of the (2) [Reserved] proposed labeling for the drug product (3) Drug products that have been de- that is the subject of the petition and clared suitable for an abbreviated new a copy of the approved labeling for the drug application submission by FDA listed drug. The petitioner may, under through the petition procedures set limited circumstances, identify more forth under § 10.30 of this chapter and than one listed drug, for example, when § 314.93. the proposed drug product is a com- (b) FDA will publish in the list listed bination product that differs from the drugs for which abbreviated applica- combination reference listed drug with tions may be submitted. The list is regard to an active ingredient, and the available from the Superintendent of different active ingredient is an active Documents, U.S. Government Printing ingredient of a listed drug. The peti- Office, Washington, DC 20402, 202–783– tioner shall also include information to 3238. show that: [57 FR 17983, Apr. 28, 1992, as amended at 64 (1) The active ingredients of the pro- FR 401, Jan. 5, 1999] posed drug product are of the same pharmacological or therapeutic class § 314.93 Petition to request a change as those of the reference listed drug. from a listed drug. (2) The drug product can be expected (a) The only changes from a listed to have the same therapeutic effect as drug for which the agency will accept a the reference listed drug when adminis- petition under this section are those tered to patients for each condition of

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use in the reference listed drug’s label- (D) The remaining active ingredients ing for which the applicant seeks ap- are not identical to those of the listed proval. combination drug; or (3) If the proposed drug product is a (iv) Any of the proposed changes combination product with one different from the listed drug would jeopardize active ingredient, including a different the safe or effective use of the product ester or salt, from the reference listed so as to necessitate significant labeling drug, that the different active ingre- changes to address the newly intro- dient has previously been approved in a duced safety or effectiveness problem; listed drug or is a drug that does not or meet the definition of ‘‘new drug’’ in (v) FDA has determined that the ref- section 201(b) of the act. erence listed drug has been withdrawn (e) No later than 90 days after the from sale for safety or effectiveness date a petition that is permitted under reasons under § 314.161, or the reference paragraph (a) of this section is sub- listed drug has been voluntarily with- mitted, FDA will approve or disapprove drawn from sale and the agency has the petition. not determined whether the with- (1) FDA will approve a petition prop- drawal is for safety or effectiveness erly submited under this section unless reasons. it finds that: (2) For purposes of this paragraph, (i) Investigations must be conducted ‘‘investigations must be conducted’’ to show the safety and effectiveness of means that information derived from the drug product or of any of its active animal or clinical studies is necessary ingredients, its route of administra- to show that the drug product is safe or effective. Such information may be tion, dosage form, or strength which contained in published or unpublished differs from the reference listed drug; reports. or (3) If FDA approves a petition sub- (ii) For a petition that seeks to mitted under this section, the agency’s change an active ingredient, the drug response may describe what additional product that is the subject of the peti- information, if any, will be required to tion is not a combination drug; or support an abbreviated new drug appli- (iii) For a combination drug product cation for the drug product. FDA may, that is the subject of the petition and at any time during the course of its re- has an active ingredient different from view of an abbreviated new drug appli- the reference listed drug: cation, request additional information (A) The drug product may not be ade- required to evaluate the change ap- quately evaluated for approval as safe proved under the petition. and effective on the basis of the infor- (f) FDA may withdraw approval of a mation required to be submitted under petition if the agency receives any in- § 314.94; or formation demonstrating that the peti- (B) The petition does not contain in- tion no longer satisfies the conditions formation to show that the different under paragraph (e) of this section. active ingredient of the drug product is of the same pharmacological or thera- § 314.94 Content and format of an ab- peutic class as the ingredient of the breviated application. reference listed drug that is to be Abbreviated applications are re- changed and that the drug product can quired to be submitted in the form and be expected to have the same thera- contain the information required under peutic effect as the reference listed this section. Three copies of the appli- drug when administered to patients for cation are required, an archival copy, a each condition of use in the listed review copy, and a field copy. FDA will drug’s labeling for which the applicant maintain guidance documents on the seeks approval; or format and content of applications to (C) The different active ingredient is assist applicants in their preparation. not an active ingredient in a listed (a) Abbreviated new drug applications. drug or a drug that meets the require- Except as provided in paragraph (b) of ments of section 201(p) of the act; or this section, the applicant shall submit

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a complete archival copy of the abbre- (5) Active ingredients. (i) For a single- viated new drug application that inactive-ingredient drug product, infor- cludes the following: mation to show that the active ingre- (1) Application form. The applicant dient is the same as that of the ref- shall submit a completed and signed erence single-active-ingredient listed application form that contains the in- drug, as follows: formation described under § 314.50(a)(1), (A) A statement that the active in- (a)(3), (a)(4), and (a)(5). The applicant gredient of the proposed drug product shall state whether the submission is is the same as that of the reference an abbreviated application under this listed drug. section or a supplement to an abbre- (B) A reference to the applicant’s an- viated application under § 314.97. notated proposed labeling and to the (2) Table of contents. the archival copy currently approved labeling for the ref- of the abbreviated new drug applica- erence listed drug provided under para- tion is required to contain a table of graph (a)(8) of this section. contents that shows the volume num- (ii) For a combination drug product, ber and page number of the contents of information to show that the active in- the submission. gredients are the same as those of the (3) Basis for abbreviated new drug ap- reference listed drug except for any different active ingredient that has been plication submission. An abbreviated the subject of an approved petition, as new drug application must refer to a follows: listed drug. Ordinarily, that listed drug (A) A statement that the active in- will be the drug product selected by the gredients of the proposed drug product agency as the reference standard for are the same as those of the reference conducting bioequivalence testing. The listed drug, or if one of the active in- application shall contain: gredients differs from one of the active (i) The name of the reference listed ingredients of the reference listed drug drug, including its dosage form and and the abbreviated application is sub- strength. For an abbreviated new drug mitted under the approval of a petition application based on an approverd peti- under § 314.93 to vary such active ingre- tion under §10.30 of this chapter or dient, information to show that the §314.93, the reference listed drug must other active ingredients of the drug be the same as the listed drug approved product are the same as the other ac- in the petition. tive ingredients of the reference listed (ii) A statement as to whether, ac- drug, information to show that the dif- cording to the information published in ferent active ingredient is an active in- the list, the reference listed drug is en- gredient of another listed drug or of a titled to a period of marketing exclu- drug that does not meet the definition sivity under section 505(j)(4)(D) of the of ‘‘new drug’’ in section 201(p) of the act. act, and such other information about (iii) For an abbreviated new drug ap- the different active ingredient that plication based on an approved petition FDA may require. under § 10.30 of this chapter or § 314.93, a (B) A reference to the applicant’s an- reference to FDA-assigned docket num- notated proposed labeling and to the ber for the petition and a copy of currently approved labeling for the ref- 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

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are the same as those of the reference taining that ingredient and approved listed drug. for the same indication as the proposed (B) A reference to the applicant’s an- drug product or is bioequivalent to a notated proposed labeling and to the drug product offered for that indication currently approved labeling for the ref- which does not meet the definition of erence listed drug provided under para- ‘‘new drug’’ under section 201(p) of the graph (a)(8) of this section. act. (ii) If the route of administration, (iii) For each in vivo bioequivalence dosage form, or strength of the drug study contained in the abbreviated new product differs from the reference list- drug application, a description of the ed drug and the abbreviated applica- analytical and statistical methods used tion is submitted under an approved in each study and a statement with re- petition under § 314.93, such informa- spect to each study that it either was tion about the different route of ad- conducted in compliance with the in- ministration, dosage form, or strength stitutional review board regulations in that FDA may require. part 56 of this chapter, or was not sub- (7) Bioequivalence. (i) Information ject to the regulations under § 56.104 or that shows that the drug product is § 56.105 of this chapter and that each bioequivalent to the reference listed study was conducted in compliance drug upon which the applicant relies; with the informed consent regulations or in part 50 of this chapter. (ii) If the abbreviated new drug appli- (8) Labeling—(i) Listed drug labeling. A cation is submitted under a petition copy of the currently approved labeling approved under § 314.93, the results of (including, if applicable, any Medica- any bioavailability of bioequivalence tion Guide required under part 208 of testing required by the agency, or any this chapter) for the listed drug re- other information required by the ferred to in the abbreviated new drug agency to show that the active ingredi- application, if the abbreviated new ents of the proposed drug product are drug application relies on a reference of the same pharmacological or thera- listed drug. peutic class as those in the reference listed drug and that the proposed drug (ii) Copies of proposed labeling. Copies product can be expected to have the of the label and all labeling for the same therapeutic effect as the ref- drug product including, if applicable, erence listed drug. If the proposed drug any Medication Guide required under product contains a different active in- part 208 of this chapter (4 copies of gredient than the reference listed drug, draft labeling or 12 copies of final FDA will consider the proposed drug printed labeling). product to have the same therapeutic (iii) Statement on proposed labeling. A effect as the reference listed drug if the statement that the applicant’s pro- applicant provides information dem- posed labeling including, if applicable, onstrating that: any Medication Guide required under (A) There is an adequate scientific part 208 of this chapter is the same as basis for determining that substitution the labeling of the reference listed drug of the specific proposed dose of the dif- except for differences annotated and ferent active ingredient for the dose of explained under paragraph (a)(8)(iv) of the member of the same pharma- this section. cological or therapeutic class in the (iv) Comparison of approved and pro- reference listed drug will yield a re- posed labeling. A side-by-side compari- sulting drug product whose safety and son of the applicant’s proposed labeling effectiveness have not been adversely including, if applicable, any Medica- affected. tion Guide required under part 208 of (B) The unchanged active ingredients this chapter with the approved labeling in the proposed drug product are bio- for the reference listed drug with all equivalent to those in the reference differences annotated and explained. listed drug. Labeling (including the container (C) The different active ingredient in label, package insert, and, if applica- the proposed drug product is bioequiva- ble, Medication Guide) proposed for the lent to an approved dosage form con- drug product must be the same as the

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labeling approved for the reference list- product intended for ophthalmic or ed drug, except for changes required be- otic use shall contain the same inac- cause of differences approved under a tive ingredients and in the same con- petition filed under § 314.93 or because centration as the reference listed drug the drug product and the reference list- identified by the applicant under para- ed drug are produced or distributed by graph (a)(3) of this section. However, different manufacturers. Such dif- an applicant may seek approval of a ferences between the applicant’s pro- drug product that differs from the ref- posed labeling and labeling approved erence listed drug in preservative, buff- for the reference listed drug may in- er, substance to adjust tonicity, or clude differences in expiration date, thickening agent provided that the ap- formulation, bioavailability, or phar- plicant identifies and characterizes the macokinetics, labeling revisions made differences and provides information to comply with current FDA labeling demonstrating that the differences do guidelines or other guidance, or omis- not affect the safety or efficacy of the sion of an indication or other aspect of proposed drug product, except that, in labeling protected by patent or ac- a product intended for ophthalmic use, corded exclusivity under section an applicant may not change a buffer 505(j)(4)(D) of the act. or substance to adjust tonicity for the (9) Chemistry, manufacturing, and con- purpose of claiming a therapeutic ad- trols. (i) The information required vantage over or difference from the under § 314.50(d)(1), except that listed drug, e.g., by using a balanced § 314.50(d)(1)(ii)(c) shall contain the pro- salt solution as a diluent as opposed to posed or actual master production an isotonic saline solution, or by mak- record, including a description of the ing a significant change in the pH or equipment, to be used for the manufac- other change that may raise questions ture of a commercial lot of the drug of irritability. product. (v) Inactive ingredient changes per- (ii) Inactive ingredients. Unless other- mitted in drug products intended for top- wise stated in paragraphs (a)(9)(iii) ical use. Generally, a drug product in- through (a)(9)(v) of this section, an ap- tended for topical use, solutions for plicant shall identify and characterize aerosolization or nebulization, and the inactive ingredients in the pro- nasal solutions shall contain the same posed drug product and provide infor- inactive ingredients as the reference mation demonstrating that such inac- listed drug identified by the applicant tive ingredients do not affect the safe- under paragraph (a)(3) of this section. ty or efficacy of the proposed drug However, an 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

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drug or that claims a use of such listed section, a certification in the following drug for which the applicant is seeking form: approval under section 505(j) of the act and for which information is required In the opinion and to the best knowledge of to be filed under section 505(b) and (c) (name of applicant), there are no patents that claim the listed drug referred to in this ap- of the act and § 314.53. For each such plication or that claim a use of the listed patent, the applicant shall provide the drug. patent number and certify, in its opinion and to the best of its knowledge, (iii) Method of use patent. (A) If pat- one of the following circumstances: ent information is submitted under (1) That the patent information has section 505(b) or (c) of the act and not been submitted to FDA. The appli- § 314.53 for a patent claiming a method cant shall entitle such a certification of using the listed drug, and the label- ‘‘Paragraph I Certification’’; ing for the drug product for which the (2) That the patent has expired. The applicant is seeking approval does not applicant shall entitle such a certifi- include any indications that are cov- cation ‘‘Paragraph II Certification’’; ered by the use patent, a statement ex- (3) The date on which the patent will plaining that the method of use patent expire. The applicant shall entitle such does not claim any of the proposed in- a certification ‘‘Paragraph III Certifi- 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 abbreviated cording to the patent information sub- application is submitted. The applicant mitted under section 505(b) or (c) of the shall entitle such a certification act and § 314.53 or in the opinion of the ‘‘Paragraph IV Certification’’. This cer- applicant, is claimed by a use patent, tification shall be submitted in the fol- an applicable certification under para- lowing form: graph (a)(12)(i) of this section. I, (name of applicant), certify that Patent (iv) Method of manufacturing patent. No. llllll (is invalid, unenforceable, or An applicant is not required to make a will not be infringed by the manufacture, use, or certification with respect to any pat- sale of) (name of proposed drug product) for ent that claims only a method of man- which this application is submitted. ufacturing the listed drug. The certification shall be accompanied (v) Licensing agreements. If the abbre- by a statement that the applicant will viated new drug application is for a comply with the requirements under drug or method of using a drug claimed § 314.95(a) with respect to providing a by a patent and the applicant has a li- notice to each owner of the patent or censing agreement with the patent their representatives and to the holder owner, a certification under paragraph of the approved application for the list- (a)(12)(i)(A)(4) of this section (‘‘Para- ed drug, and with the requirements graph IV Certification’’) as to that pat- under § 314.95(c) with respect to the ent and a statement that it has been content of the notice. granted a patent license. (B) If the abbreviated new drug appli- (vi) Late submission of patent informa- cation refers to a listed drug that is itself a licensed generic product of a tion. If a patent on the listed drug is patented drug first approved under sec- issued and the holder of the approved tion 505(b) of the act, the appropriate application for the listed drug does not patent certification under paragraph submit the required information on the (a)(12)(i) of this section with respect to patent within 30 days of issuance of the each patent that claims the first-ap- patent, an applicant who submitted an proved patented drug or that claims a abbreviated new drug application for use for such drug. that drug that contained an appro- (ii) No relevant patents. If, in the opin- priate patent certification before the ion of the applicant and to the best of submission of the patent information is its knowledge, there are no patents described in paragraph (a)(12)(i) of this

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not required to submit an amended cer- ceipt of notice sent under § 314.95 shall tification. An applicant whose abbre- amend the certification if a final judg- viated new drug application is sub- ment in the action against the appli- mitted after a late submission of pat- cant is entered finding the patent to be ent information, or whose pending ab- infringed. In the amended certification, breviated application was previously the applicant shall certify under para- submitted but did not contain an ap- graph (a)(12)(i)(A)(3) of this section propriate patent certification at the that the patent will expire on a specific time of the patent submission, shall date. Once an amendment or letter for submit a certification under paragraph the change has been submitted, the ap- (a)(12)(i) of this section or a statement plication will no longer be considered under paragraph (a)(12)(iii) of this sec- to be one containing a certification tion as to that patent. under paragraph (a)(12)(i)(A)(4) of this (vii) Disputed patent information. If an section. If a final judgment finds the applicant disputes the accuracy or rel- patent to be invalid and infringed, an evance of patent information sub- amended certification is not required. mitted to FDA, the applicant may seek (B) After removal of a patent from the a confirmation of the correctness of list. If a patent is removed from the the patent information in accordance list, any applicant with a pending ap- with the procedures under § 314.53(f). plication (including a tentatively ap- Unless the patent information is with- proved application with a delayed ef- drawn or changed, the applicant shall fective date) who has made a certifi- submit an appropriate certification for cation with respect to such patent each relevant patent. shall amend its certification. The ap- (viii) Amended certifications. A certifi- plicant shall certify under paragraph cation submitted under paragraphs (a)(12)(ii) of this section that no pat- (a)(12)(i) through (a)(12)(iii) of this sec- ents described in paragraph (a)(12)(i) of tion may be amended at any time be- this section claim the drug or, if other fore the effective date of the approval relevant patents claim the drug, shall of the application. However, an appli- amend the certification to refer only to cant who has submitted a paragraph IV those relevant patents. In the amend- patent certification may not change it ment, the applicant shall state the rea- to a paragraph III certification if a pat- son for the change in certification ent infringement suit has been filed (that the patent is or has been removed against another paragraph IV applicant from the list). A patent that is the sub- unless the agency has determined that ject of a lawsuit under § 314.107(c) shall 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.

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(2) An applicant is not required to under paragraphs (a)(3), (a)(7), and amend a submitted certification when (a)(8) of this section. Each of the sec- information on a patent on the listed tions in the review copy is required to drug is submitted after the effective contain a copy of the application form date of approval of the abbreviated ap- described under § 314.50(a). plication. (3) [Reserved] (13) Financial certification or disclosure (4) The applicant may obtain from statement. An abbreviated application FDA sufficient folders to bind the ar- shall contain a financial certification chival, the review, and the field copies or disclosure statement as required by of the abbreviated application. part 54 of this chapter. (5) The applicant shall submit a field (b) Drug products subject to the Drug copy of the abbreviated application Efficacy Study Implementation (DESI) re- that contains the technical section de- view. If the abbreviated new drug appli- scribed in paragraph (a)(9) of this sec- cation is for a duplicate of a drug prod- tion, a copy of the application form re- uct that is subject to FDA’s DESI required under paragraph (a)(1) of this view (a review of drug products ap- section, and a certification that the proved as safe between 1938 and 1962) or field copy is a true copy of the tech- other DESI-like review and the drug nical section described in paragraph product evaluated in the review is a (a)(9) of this section contained in the listed drug, the applicant shall comply archival and review copies of the ab- with the provisions of paragraph (a) of breviated application. this section. [57 FR 17983, Apr. 28, 1992; 57 FR 29353, July (c) [Reserved] 1, 1992, as amended at 58 FR 47352, Sept. 8, (d) Format of an abbreviated applica- 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. tion. (1) The applicant shall submit a 2, 1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, complete archival copy of the abbre- Jan. 5, 1999; 65 FR 56479, Sept. 19, 2000; 67 FR viated application as required under 77672, Dec. 19, 2002] paragraphs (a) and (c) of this section. EFFECTIVE DATE NOTE: At 68 FR 69019, Dec. FDA will maintain the archival copy 11, 2003, § 314.94 was amended by revising during the review of the application to paragraph (d)(1), effective June 8, 2004. For permit individual reviewers to refer to the convenience of the user, the revised text information that is not contained in is set forth as follows: their particular technical sections of § 314.94 Content and format of an abbre- the application, to give other agency viated application. personnel access to the application for official business, and to maintain in * * * * * one place a complete copy of the application. An applicant may submit all or (d) * * * (1) The applicant must submit a complete archival copy of the abbreviated portions of the archival copy of the ab- application as required under paragraphs (a) breviated application in any form (e.g., and (c) of this section. FDA will maintain microfiche, optical disc, and magnetic the archival copy during the review of the tape) that the applicant and FDA agree application to permit individual reviewers to is acceptable. refer to information that is not contained in (2) For abbreviated new drug applica- their particular technical sections of the ap- tions, the applicant shall submit a re- plication, to give other agency personnel ac- view copy of the abbreviated applica- cess to the application for official business, and to maintain in one place a complete tion that contains two separate sec- copy of the application. tions. One section shall contain the in- (i) Format of submission. An applicant may formation described under paragraphs submit portions of the archival copy of the (a)(2) through (a)(6), (a)(8), and (a)(9) of abbreviated application in any form that the this section 505(j)(2)(A)(vii) of the act applicant and FDA agree is acceptable, ex- and one copy of the analytical methods cept as provided in paragraph (d)(1)(ii) of this and descriptive information needed by section. FDA’s laboratories to perform tests on (ii) Labeling. The content of labeling required under § 201.100(d)(3) of this chapter samples of the proposed drug product (commonly referred to as the package insert and to validate the applicant’s analyt- or professional labeling), including all text, ical methods. The other section shall tables, and figures, must be submitted to the contain the information described agency in electronic format as described in

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paragraph (d)(1)(iii) of this section. This re- (3) This paragraph does not apply to quirement applies to the content of labeling a use patent that claims no uses for for the proposed drug product only and is in which the applicant is seeking ap- addition to the requirements of paragraph proval. (a)(8)(ii) of this section that copies of the formatted label and all proposed labeling be (b) Sending the notice. The applicant submitted. Submissions under this para- shall send the notice required by paragraph must be made in accordance with part graph (a) of this section when it re- 11 of this chapter, except for the require- ceives from FDA an acknowledgment ments of § 11.10(a), (c) through (h), and (k), letter stating that its abbreviated new and the corresponding requirements of drug application is sufficiently com- § 11.30. plete to permit a substantive review. (iii) Electronic format submissions. Elec- At the same time, the applicant shall tronic format submissions must be in a form that FDA can process, review, and archive. amend its abbreviated new drug appli- FDA will periodically issue guidance on how cation to include a statement certi- to provide the electronic submission (e.g., fying that the notice has been provided method of transmission, media, file formats, to each person identified under para- preparation and organization of files). graph (a) of this section and that the notice met the content requirements * * * * * under paragraph (c) of this section. (c) Contents of a notice. In the notice, § 314.95 Notice of certification of inva- the applicant shall cite section lidity or noninfringement of a pat- 505(j)(2)(B)(ii) of the act and shall in- ent. clude, but not be limited to, the fol- (a) Notice of certification. For each lowing information: patent that claims the listed drug or (1) A statement that FDA has re- that claims a use for such listed drug ceived an abbreviated new drug appli- for which the applicant is seeking ap- cation submitted by the applicant con- proval and that the applicant certifies taining any required bioavailability or under § 314.94(a)(12) is invalid, unen- bioequivalence data or information. forceable, or will not be infringed, the (2) The abbreviated application num- applicant shall send notice of such cer- ber. tification by registered or certified (3) The established name, if any, as mail, return receipt requested to each defined in section 502(e)(3) of the act, of of the following persons: the proposed drug product. (1) Each owner of the patent which is (4) The active ingredient, strength, the subject of the certification or the and dosage form of the proposed drug representative designated by the owner product. to receive the notice. The name and ad- (5) The patent number and expiration dress of the patent owner or its rep- date, as submitted to the agency or as resentative may be obtained from the known to the applicant, of each patent United States Patent and Trademark alleged to be invalid, unenforceable, or Office; and not infringed. (2) The holder of the approved appli- (6) A detailed statement of the fac- cation under section 505(b) of the act tual and legal basis of the applicant’s for the listed drug that is claimed by opinion that the patent is not valid, the patent and for which the applicant unenforceable, or will not be infringed. is seeking approval, or, if the applica- The applicant shall include in the de- tion holder does not reside or maintain tailed statement: a place of business within the United (i) For each claim of a patent alleged States, the application holder’s attor- not to be infringed, a full and detailed ney, agent, or other authorized official. explanation of why the claim is not in- The name and address of the applica- fringed. tion holder or its attorney, agent, or (ii) For each claim of a patent al- authorized official may be obtained leged to be invalid or unenforceable, a from the Division of Drug Information full and detailed explanation of the Resources (HFD–80), Center for Drug grounds supporting the allegation. Evaluation and Research, Food and (7) If the applicant does not reside or Drug Administration, 5600 Fishers have a place of business in the United Lane, Rockville, MD 20857. States, the name and address of an

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agent in the United States authorized review the significant data or informa- to accept service of process for the ap- tion and for no more than 180 days. plicant. (3) Submission of an amendment con- (d) Amendment to an abbreviated appli- taining significant data or information cation. If an abbreviated application is to resolve deficiencies in the applica- amended to include the certification tion as set forth in a not approvable described in § 314.94(a)(12)(i)(A)(4), the letter issued under § 314.120 constitutes applicant shall send the notice required an agreement between FDA and the ap- by paragraph (a) of this section at the plicant under section 505(j)(4)(A) of the same time that the amendment to the act to extend the date by which the abbreviated application is submitted to agency is required to reach a decision FDA. on the abbreviated new drug applica- (e) Documentation of receipt of notice. tion only for the time necessary to re- The applicant shall amend its abbre- view the significant data or informa- viated application to document receipt tion and for no more than 180 days. of the notice required under paragraph (b) The applicant shall submit a field (a) of this section by each person pro- copy of each amendment to vided the notice. The applicant shall § 314.94(a)(9). The applicant, other than include a copy of the return receipt or a foreign applicant, shall include in its other similar evidence of the date the submission of each such amendment to notification was received. FDA will ac- FDA a statement certifying that a field cept as adequate documentation of the copy of the amendment has been sent date of receipt a return receipt or a let- to the applicant’s home FDA district ter acknowledging receipt by the per- office. son provided the notice. An applicant [57 FR 17983, Apr. 28, 1992, as amended at 58 may rely on another form of docu- FR 47352, Sept. 8, 1993; 64 FR 401, Jan. 5, 1999] mentation only if FDA has agreed to such documentation in advance. A copy § 314.97 Supplements and other of the notice itself need not be sub- changes to an approved abbre- mitted to the agency. viated application. (f) Approval. If the requirements of The applicant shall comply with the this section are met, FDA will presume requirements of §§ 314.70 and 314.71 re- the notice to be complete and suffi- garding the submission of supple- cient, and it will count the day fol- mental applications and other changes lowing the date of receipt of the notice to an approved abbreviated applica- by the patent owner or its representation. tive and by the approved application holder as the first day of the 45-day pe- § 314.98 Postmarketing reports. riod provided for in section (a) Except as provided in paragraph 505(j)(4)(B)(iii) of the act. FDA may, if (b) of this section, each applicant hav- the applicant provides a written state- ing an approved abbreviated new drug ment to FDA that a later date should application under § 314.94 that is effec- be used, count from such later date. tive shall comply with the require- [59 FR 50366, Oct. 3, 1994, as amended at 68 FR ments of § 314.80 regarding the report- 36705, June 18, 2003; 69 FR 11310, Mar. 10, 2004] ing and recordkeeping of adverse drug experiences. § 314.96 Amendments to an unap- (b) Each applicant shall submit one proved abbreviated application. copy of each report required under (a) Abbreviated new drug application. § 314.80 to the Division of Epidemiology (1) An applicant may amend an abbre- and Surveillance (HFD–730), Center for viated new drug application that is Drug Evaluation and Research, Food submitted under § 314.94, but not yet and Drug Administration, 5600 Fishers approved, to revise existing informa- Lane, Rockville, MD 20857. tion or provide additional information. (c) Each applicant shall make the re- (2) Submission of an amendment con- ports required under § 314.81 and section taining significant data or information 505(k) of the act for each of its ap- constitutes an agreement between FDA proved abbreviated applications. and the applicant to extend the review [57 FR 17983, Apr. 28, 1992, as amended at 64 period only for the time necessary to FR 401, Jan. 5, 1999]

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§ 314.99 Other responsibilities of an determine whether the application may applicant of an abbreviated applica- be filed. The filing of an application tion. means that FDA has made a threshold (a) An applicant shall comply with determination that the application is the requirements of § 314.65 regarding sufficiently complete to permit a sub- withdrawal by the applicant of an un- stantive review. approved abbreviated application and (2) If FDA finds that none of the rea- § 314.72 regarding a change in ownership sons in paragraphs (d) and (e) of this of an abbreviated application. section for refusing to file the applica- (b) An applicant may ask FDA to tion apply, the agency will file the ap- waive under this section any require- plication and notify the applicant in ment that applies to the applicant writing. The date of filing will be the under §§ 314.92 through 314.99. The appli- date 60 days after the date FDA re- cant shall comply with the require- ceived the application. The date of fil- ments for a waiver under § 314.90. ing begins the 180-day period described in section 505(c) of the act. This 180-day period is called the ‘‘filing clock.’’ Subpart D—FDA Action on Appli- (3) If FDA refuses to file the applica- cations and Abbreviated Ap- tion, the agency will notify the appli- plications cant in writing and state the reason under paragraph (d) or (e) of this sec- SOURCE: 50 FR 7493, Feb. 22, 1985, unless tion for the refusal. If FDA refuses to otherwise noted. Redesignated at 57 FR 17983, file the application under paragraph (d) Apr. 28, 1992. of this section, the applicant may request in writing within 30 days of the § 314.100 Timeframes for reviewing ap- date of the agency’s notification an in- plications and abbreviated applications. formal conference with the agency about whether the agency should file (a) Within 180 days of receipt of an the application. If, following the infor- application for a new drug under sec- mal conference, the applicant requests tion 505(b) of the act, or of an abbre- that FDA file the application (with or viated application for a new drug under without amendments to correct the de- section 505(j) of the act, FDA will re- ficiencies), the agency will file the ap- view it and send the applicant either plication over protest under paragraph an approval letter under § 314.105, or an (a)(2) of this section, notify the appli- approvable letter under § 314.110, or a cant in writing, and review it as filed. not approvable letter under § 314.120. If the application is filed over protest, This 180-day period is called the ‘‘re- the date of filing will be the date 60 view clock.’’ days after the date the applicant re- (b) During the review period, an ap- quested the informal conference. The plicant may withdraw an application applicant need not resubmit a copy of under § 314.65 or an abbreviated applica- an application that is filed over pro- tion under § 314.99 and later resubmit test. If FDA refuses to file the applica- it. FDA will treat the resubmission as tion under paragraph (e) of this sec- a new application or abbreviated appli- tion, the applicant may amend the ap- cation. plication and resubmit it, and the (c) The review clock may be extended agency will make a determination by mutual agreement between FDA under this section whether it may be and an applicant or as provided in filed. §§ 314.60 and 314.96, as the result of a (b)(1) An abbreviated new drug appli- major amendment. cation will be reviewed after it is sub- [57 FR 17987, Apr. 28, 1992, as amended at 64 mitted to determine whether the ab- FR 402, Jan. 5, 1999] 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.

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(2) If FDA finds that none of the rea- brief statement of the reason for the sons in paragraphs (d) and (e) of this noncompliance. section for considering the abbreviated (7) The application does not contain a new drug application not to have been statement for each clinical study that received applies, the agency will re- it was conducted in compliance with ceive the abbreviated new drug applica- the institutional review board regulation and notify the applicant in writ- tions in part 56 of this chapter, or was ing. not subject to those regulations, and (3) If FDA considers the abbreviated that it was conducted in compliance new drug application not to have been with the informed consent regulations received under paragraph (d) or (e) of in part 50 of this chapter, or, if the this section, FDA will notify the appli- study was subject to but was not con- cant, ordinarily by telephone. The ap- ducted in compliance with those regu- plicant may then: lations, the application does not con- (i) Withdraw the abbreviated new tain a brief statement of the reason for drug application under § 314.99; or the noncompliance. (ii) Amend the abbreviated new drug (8) The drug product that is the sub- application to correct the deficiencies; ject of the submission is already cov- or ered by an approved application or ab- (iii) Take no action, in which case breviated application and the applicant FDA will refuse to receive the abbre- of the submission: viated new drug application. (i) Has an approved application or ab- (c) [Reserved] breviated application for the same drug (d) FDA may refuse to file an applica- product; or tion or may not consider an abbre- (ii) Is merely a distributor and/or re- viated new drug application to be re- packager of the already approved drug ceived if any of the following applies: product. (1) The application does not contain a completed application form. (9) The application is submitted as a (2) The application is not submitted 505(b)(2) application for a drug that is a in the form required under § 314.50 or duplicate of a listed drug and is eligible § 314.94. for approval under section 505(j) of the (3) The application or abbreviated ap- act. plication is incomplete because it does (e) The agency will refuse to file an not on its face contain information re- application or will consider an abbre- quired under section 505(b), section viated new drug application not to 505(j), or section 507 of the act and have been received if any of the fol- § 314.50 or § 314.94. lowing applies: (4) The applicant fails to submit a (1) The drug product is subject to li- complete environmental assessment, censing by FDA under the Public which addresses each of the items spec- Health Service Act (42 U.S.C. 201 et ified in the applicable format under seq.) and subchapter F of this chapter. § 25.40 of this chapter or fails to provide (2) In the case of a 505(b)(2) applica- sufficient information to establish that tion or an abbreviated new drug appli- 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

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§ 314.50(i)(1)(i)(A)(4) or plication or an abbreviated application § 314.94(a)(12)(i)(A)(4). when those deficiencies are discovered, (f)(1) Within 180 days after the date of particularly deficiencies concerning filing, plus the period of time the re- chemistry, manufacturing, and con- view period was extended (if any), FDA trols issues. The agency will also in- will either: form applicants promptly of its need (i) Approve the application; or for more data or information or for (ii) Issue a notice of opportunity for technical changes in the application or hearing if the applicant asked FDA to the abbreviated application needed to provide it an opportunity for a hearing facilitate the agency’s review. This on an application in response to an ap- early communication is intended to provable letter or a not approvable let- permit applicants to correct such read- ter. ily identified deficiencies relatively (2) Within 180 days after the date of early in the review process and to sub- receipt, plus the period of time the re- mit an amendment before the review view clock was extended (if any), FDA period has elapsed. Such early commu- will either approve or disapprove the nication would not ordinarily apply to abbreviated new drug application. If major scientific issues, which require FDA disapproves the abbreviated new consideration of the entire pending ap- drug application, FDA will issue a no- plication or abbreviated application by tice of opportunity for hearing if the agency managers as well as reviewing applicant asked FDA to provide it an staff. Instead, major scientific issues opportunity for a hearing on an abbre- will ordinarily be addressed in an ac- viated new drug application in response tion letter. to a not approvable letter. (c) Ninety-day conference. Approxi- (3) This paragraph does not apply to mately 90 days after the agency re- applications or abbreviated applica- ceives the application, FDA will pro- tions that have been withdrawn from vide applicants with an opportunity to FDA review by the applicant. meet with agency reviewing officials. [57 FR 17987, Apr. 28, 1992; 57 FR 29353, July The purpose of the meeting will be to 1, 1992, as amended at 59 FR 50366, Oct. 3, inform applicants of the general 1994; 62 FR 40599, July 29, 1997; 64 FR 402, Jan. progress and status of their applica- 5, 1999] tions, and to advise applicants of deficiencies that have been identified by § 314.102 Communications between that time and that have not already FDA and applicants. been communicated. This meeting will (a) General principles. During the be available on applications for all new course of reviewing an application or chemical entities and major new indian abbreviated application, FDA shall cations of marketed drugs. Such meet- communicate with applicants about ings will be held at the applicant’s op- scientific, medical, and procedural tion, and may be held by telephone if issues that arise during the review mutually agreed upon. Such meetings process. Such communication may would not ordinarily be held on abbre- take the form of telephone conversa- viated applications because they are tions, letters, or meetings, whichever not submitted for new chemical enti- is most appropriate to discuss the parties or new indications. ticular issue at hand. Communications (d) End of review conference. At the shall be appropriately documented in conclusion of FDA’s review of an appli- the application in accordance with cation or an abbreviated application as § 10.65 of this chapter. Further details designated by the issuance of an ap- on the procedures for communication provable or not approvable letter, FDA between FDA and applicants are con- will provide applicants with an oppor- tained in a staff manual guide that is tunity to meet with agency reviewing publicly available. officials. The purpose of the meeting (b) Notification of easily correctable de- will be to discuss what further steps ficiencies. FDA reviewers shall make need to be taken by the applicant be- every reasonable effort to commu- fore the application or abbreviated ap- nicate promptly to applicants easily plication can be approved. This meet- correctable deficiencies found in an ap- ing will be available on all applications

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or abbreviated applications, with pri- Further details on this procedure are ority given to applications for new contained in a staff manual guide that chemical entities and major new indi- is publicly available under FDA’s pub- cations for marketed drugs and for the lic information regulations in part 20. first duplicates for such drugs. Re- (c) Scientific and medical disputes. (1) quests for such meetings shall be di- Because major scientific issues are or- rected to the director of the division dinarily communicated to applicants responsible for reviewing the applica- in an approvable or not approvable let- tion or abbreviated application. ter pursuant to § 314.110 or § 314.120, re- (e) Other meetings. Other meetings be- spectively, the ‘‘end-of-review con- tween FDA and applicants may be held, ference’’ described in § 314.102(d) will with advance notice, to discuss sci- provide a timely forum for discussing entific, medical, and other issues that and resolving, if possible, scientific and arise during the review process. Re- medical issues on which the applicant quests for meetings shall be directed to disagrees with the agency. In addition, the director of the division responsible the ‘‘ninety-day conference’’ described for reviewing the application or abbre- in § 314.102(c) will provide a timely viated application. FDA will make forum for discussing and resolving, if every attempt to grant requests for possible, issues identified by that date. meetings that involve important issues and that can be scheduled at mutually (2) When scientific or medical dis- convenient times. However, ‘‘drop-in’’ putes arise at other times during the visits (i.e., an unannounced and un- review process, applicants should dis- scheduled visit by a company rep- cuss the matter directly with the re- resentative) are discouraged except for sponsible reviewing officials. If nec- urgent matters, such as to discuss an essary, applicants may request a meet- important new safety issue. ing with the appropriate reviewing officials and management representatives [57 FR 17988, Apr. 28, 1992; 57 FR 29353, July in order to seek a resolution. Ordi- 1, 1992] narily, such meetings would be held § 314.103 Dispute resolution. first with the Division Director, then with the Office Director, and finally (a) General. FDA is committed to re- with the Center Director if the matter solving differences between applicants is still unresolved. Requests for such and FDA reviewing divisions with re- meetings shall be directed to the direc- spect to technical requirements for ap- tor of the division responsible for re- plications or abbreviated applications viewing the application or abrreviated as quickly and amicably as possible application. FDA will make every at- through the cooperative exchange of tempt to grant requests for meetings information and views. that involve important issues and that (b) Administrative and procedural can be scheduled at mutually conven- issues. When administrative or proce- ient times. dural disputes arise, the applicant should first attempt to resolve the (3) In requesting a meeting designed matter with the division responsible to resolve a scientific or medical dis- for reviewing the application or abbre- pute, applicants may suggest that FDA viated application, beginning with the seek the advice of outside experts, in consumer safety officer assigned to the which case FDA may, in its discretion, application or abbreviated application. invite to the meeting one or more of its If resolution is not achieved, the appli- advisory committee members or other cant may raise the matter with the consultants, as designated by the agen- person designated as ombudsman, cy. Applicants may also bring their whose function shall be to investigate own consultants. For major scientific what has happened and to facilitate a and medical policy issues not resolved timely and equitable resolution. Appro- by informal meetings, FDA may refer priate issues to raise with the ombuds- the matter to one of its standing advi- man include resolving difficulties in sory committees for its consideration scheduling meetings, obtaining timely and recommendations. replies to inquiries, and obtaining [50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, timely completion of pending reviews. 1985, as amended at 57 FR 17989, Apr. 28, 1992]

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§ 314.104 Drugs with potential for exercise its scientific judgment to de- abuse. termine the kind and quantity of data The Food and Drug Administration and information an applicant is re- will inform the Drug Enforcement Ad- quired to provide for a particular drug ministration under section 201(f) of the to meet the statutory standards. FDA Controlled Substances Act (21 U.S.C. makes its views on drug products and classes of drugs available through guid- 801) when an application or abbreviated ance documents, recommendations, application is submitted for a drug and other statements of policy. that appears to have an abuse poten- (d) FDA will approve an abbreviated tial. new drug application and send the ap- [57 FR 17989, Apr. 28, 1992] plicant an approval letter if none of the reasons in § 314.127 for refusing to ap- § 314.105 Approval of an application prove the abbreviated new drug appli- and an abbreviated application. cation applies. The approval becomes (a) The Food and Drug Administra- effective on the date of the issuance of tion will approve an application and the agency’s approval letter unless the send the applicant an approval letter if approval letter provides for a delayed none of the reasons in § 314.125 for re- effective date. An approval with a de- fusing to approve the application ap- layed effective date is tentative and plies. An approval becomes effective on does not become final until the effec- the date of the issuance of the approval tive date. A new drug product approved letter, except with regard to an ap- under this paragraph may not be intro- proval under section 505(b)(2) of the act duced or delivered for introduction into with a delayed effective date. An ap- interstate commerce until approval of proval with a delayed effective date is the abbreviated new drug application is tentative and does not become final effective. Ordinarily, the effective date until the effective date. A new drug of approval will be stated in the ap- product or antibiotic approved under proval letter. this paragraph may not be marketed [57 FR 17989, Apr. 28, 1992, as amended at 64 until an approval is effective. FR 402, Jan. 5, 1999; 65 FR 56479, Sept. 19, (b) FDA will approve an application 2000] and issue the applicant an approval letter (rather than an approvable letter § 314.106 Foreign data. under § 314.110) on the basis of draft la- (a) General. The acceptance of foreign beling if the only deficiencies in the data in an application generally is gov- application concern editorial or similar erned by § 312.120 of this chapter. minor deficiencies in the draft label- (b) As sole basis for marketing approval. ing. Such approval will be conditioned An application based solely on foreign upon the applicant incorporating the clinical data meeting U.S. criteria for specified labeling changes exactly as marketing approval may be approved directed, and upon the applicant sub- if: (1) The foreign data are applicable mitting to FDA a copy of the final to the U.S. population and U.S. med- printed labeling prior to marketing. ical practice; (2) the studies have been (c) FDA will approve an application performed by clinical investigators of after it determines that the drug meets recognized competence; and (3) the the statutory standards for safety and data may be considered valid without effectiveness, manufacturing and con- the need for an on-site inspection by trols, and labeling, and an abbreviated FDA or, if FDA considers such an in- application after it determines that the spection to be necessary, FDA is able drug meets the statutory standards for to validate the data through an on-site manufacturing and controls, labeling, inspection or other appropriate means. and, where applicable, bioequivalence. Failure of an application to meet any While the statutory standards apply to of these criteria will result in the ap- 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.

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(c) Consultation between FDA and ap- § 314.50(i) or § 314.94(a)(12) that the rel- plicants. Applicants are encouraged to evant patent is invalid, unenforceable, meet with agency officials in a ‘‘pre- or will not be infringed, and the patent submission’’ meeting when approval owner or its representative or the ex- based solely on foreign data will be clusive patent licensee brings suit for sought. patent infringement within 45 days of [50 FR 7493, Feb. 22, 1985, as amended at 55 receipt by the patent owner of the no- FR 11580, Mar. 29, 1990] tice of certification from the applicant under § 314.52 or § 314.95, approval may § 314.107 Effective date of approval of be made effective 30 months after the a 505(b)(2) application or abbre- date of the receipt of the notice of cer- viated new drug application under section 505(j) of the act. tification by the patent owner or by the exclusive licensee (or their rep- (a) General. A drug product may be resentatives) unless the court has ex- introduced or delivered for introduc- tended or reduced the period because of tion into interstate commerce when approval of the application or abbre- a failure of either the plaintiff or de- viated application for the drug product fendant to cooperate reasonably in ex- becomes effective. Except as provided pediting the action; or in this section, approval of an applica- (B) If the patented drug product tion or abbreviated application for a qualifies for 5 years of exclusive mar- drug product becomes effective on the keting under § 314.108(b)(2) and the pat- date FDA issues an approval letter ent owner or its representative or the under § 314.105 for the application or ab- exclusive patent licensee brings suit breviated application. for patent infringement during the 1- (b) Effect of patent on the listed drug. If year period beginning 4 years after the approval of an abbreviated new drug date the patented drug was approved application submitted under section and within 45 days of receipt by the 505(j) of the act or of a 505(b)(2) applica- patent owner of the notice of certifi- tion is granted, that approval will be- cation, the approval may be made ef- come effective in accordance with the fective at the expiration of the 71⁄2 following: years from the date of approval of the (1) Date of approval letter. Except as application for the patented drug prod- provided in paragraphs (b)(3), (b)(4), uct. and (c) of this section, approval will be- (ii) If before the expiration of the 30- come effective on the date FDA issues month period, or 71⁄2 years where appli- an approval letter under § 314.105 if the applicant certifies under § 314.50(i) or cable, the court issues a final order § 314.94(a)(12) that: that the patent is invalid, unenforce- (i) There are no relevant patents; or able, or not infringed, approval may be (ii) The applicant is aware of a rel- made effective on the date the court evant patent but the patent informa- enters judgment; tion required under section 505 (b) or (iii) If before the expiration of the 30- (c) of the act has not been submitted to month period, or 71⁄2 years where appli- FDA; or cable, the court issues a final order or (iii) The relevant patent has expired; judgment that the patent has been in- or fringed, approval may be made effec- (iv) The relevant patent is invalid, tive on the date the court determines unenforceable, or will not be infringed. that the patent will expire or otherwise (2) Patent expiration. If the applicant orders; or certifies under § 314.50(i) or (iv) If before the expiration of the 30- § 314.94(a)(12) that the relevant patent month period, or 71⁄2 years where appli- will expire on a specified date, approval cable, the court grants a preliminary will become effective on the specified injunction prohibiting the applicant date. from engaging in the commercial man- (3) Disposition of patent litigation. ufacture or sale of the drug product (i)(A) Except as provided in paragraphs (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this until the court decides the issues of section, if the applicant certifies under patent validity and infringement, and

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if the court later decides that the pat- drug that is both substantially com- ent is invalid, unenforceable, or not in- plete and contains the same certifi- fringed, approval may be made effec- cation. A ‘‘substantially complete’’ ap- tive on the date the court enters a final plication must contain the results of order or judgment that the patent is any required bioequivalence studies, invalid, unenforceable, or not in- or, if applicable, a request for a waiver fringed. of such studies. (v) In order for an approval to be (3) For purposes of paragraph (c)(1) of made effective under paragraph (b)(3) this section, if FDA concludes that the of this section, the applicant must re- applicant submitting the first applica- ceive an approval letter from the agen- tion is not actively pursuing approval cy indicating that the application has of its abbreviated application, FDA received final approval. Tentative ap- will make the approval of subsequent proval of an application does not con- abbreviated applications immediately stitute ‘‘approval’’ of an application effective if they are otherwise eligible and cannot, absent a final approval let- for an immediately effective approval. ter from the agency, result in an effec- (4) For purposes of paragraph (c)(1)(i) tive approval under paragraph (b)(3) of of this section, the applicant submit- this section. ting the first application shall notify (4) Multiple certifications. If the appli- FDA of the date that it commences cant has submitted certifications under commercial marketing of its drug § 314.50(i) or § 314.94(a)(12) for more than product. Commercial marketing com- one patent, the date of approval will be mences with the first date of introduc- calculated for each certification, and tion or delivery for introduction into the approval will become effective on interstate commerce outside the con- the last applicable date. trol of the manufacturer of a drug (c) Subsequent abbreviated new drug product, except for investigational use application submission. (1) If an abbre- under part 312 of this chapter, but does viated new drug application contains a not include transfer of the drug prod- certification that a relevant patent is uct for reasons other than sale within invalid, unenforceable, or will not be the control of the manufacturer or ap- infringed and the application is for a generic copy of the same listed drug for plication holder. If an applicant does which one or more substantially com- not promptly notify FDA of such date, plete abbreviated new drug applica- the effective date of approval shall be tions were previously submitted con- deemed to be the date of the com- taining a certification that the same mencement of first commercial mar- patent was invalid, unenforceable, or keting. would not be infringed, approval of the (d) Delay due to exclusivity. The agen- subsequent abbreviated new drug appli- cy will also delay the effective date of cation will be made effective no sooner the approval of an abbreviated new than 180 days from whichever of the drug application under section 505(j) of following dates is earlier: the act or a 505(b)(2) application if (i) The date the applicant submitting delay is required by the exclusivity the first application first commences provisions in § 314.108. When the effec- commercial marketing of its drug tive date of an application is delayed product; or under both this section and § 314.108, (ii) The date of a decision of the the effective date will be the later of court holding the relevant patent in- the 2 days specified under this section valid, unenforceable, or not infringed. and § 314.108. (2) For purposes of paragraph (c)(1) of (e) Notification of court actions. The this section, the ‘‘applicant submitting applicant shall submit a copy of the the first application’’ is the applicant entry of the order or judgment to the that submits an application that is Office of Generic Drugs (HFD–600), or both substantially complete and con- to the appropriate division in the Of- tains a certification that the patent fice of Drug Evaluation I (HFD–100) or was invalid, unenforceable, or not in- Office of Drug Evaluation II (HFD–500), fringed prior to the submission of any whichever is applicable, within 10 other application for the same listed working days of a final judgment.

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(f) Computation of 45-day time clock. (1) ent infringement. The notice should The 45-day clock described in para- contain the information and be sent to graph (b)(3) of this section begins on the offices or divisions described in the day after the date of receipt of the this paragraph. applicant’s notice of certification by (3) If the patent owner or approved the patent owner or its representative, application holder who is an exclusive and by the approved application holder. patent licensee waives its opportunity When the 45th day falls on Saturday, to file a legal action for patent in- Sunday, or a Federal holiday, the 45th fringement within 45 days of a receipt day will be the next day that is not a of the notice of certification and the Saturday, Sunday, or a Federal holi- patent owner or approved application day. holder who is an exclusive patent li- (2) The abbreviated new drug appli- censee submits to FDA a valid waiver cant or the 505(b)(2) applicant shall no- before the 45 days elapse, approval of tify FDA immediately of the filing of the abbreviated new drug application any legal action filed within 45 days of or the 505(b)(2) application will be receipt of the notice of certification. If made effective upon completion of the the applicant submitting the abbre- agency’s review and approval of the ap- viated new drug application or the plication. FDA will only accept a waiv- 505(b)(2) application or patent owner or er in the following form: its representative does not notify FDA (Name of patent owner or exclusive patent li- in writing before the expiration of the censee) has received notice from (name of ap- 45-day time period or the completion of plicant) under (section 505(b)(3) or 505(j)(2)(B) the agency’s review of the application, of the act) and does not intend to file an ac- whichever occurs later, that a legal action for patent infringement against (name of tion for patent infringement was filed applicant) concerning the drug (name of drug) within 45 days of receipt of the notice before (date on which 45 days elapses. (Name of of certification, approval of the abbre- patent owner or exclusive patent licensee) waives the opportunity provided by (section viated new drug application or the 505(c)(3)(C) or 505(j)(B)(iii) of the act) and does 505(b)(2) application will be made effec- not object to FDA’s approval of (name of ap- tive immediately upon expiration of plicant)’s (505(b)(2) or abbreviated new drug ap- the 45 days or upon completion of the plication) for (name of drug) with an imme- agency’s review and approval of the ap- diate effective date on or after the date of plication, whichever is later. The noti- this letter. fication to FDA of the legal action [59 FR 50367, Oct. 3, 1994, as amended at 63 FR shall include: 59712, Nov. 5, 1998; 65 FR 43235, July 13, 2000] (i) The abbreviated new drug application or 505(b)(2) application number. § 314.108 New drug product exclu- (ii) The name of the abbreviated new sivity. drug or 505(b)(2) application applicant. (a) Definitions. The following defini- (iii) The established name of the drug tions of terms apply to this section: product or, if no established name ex- Active moiety means the molecule or ists, the name(s) of the active ingre- ion, excluding those appended portions dient(s), the drug product’s strength, of the molecule that cause the drug to and dosage form. be an ester, salt (including a salt with (iv) A certification that an action for hydrogen or coordination bonds), or patent infringement identified by num- other noncovalent derivative (such as a ber, has been filed in an appropriate complex, chelate, or clathrate) of the court on a specified date. molecule, responsible for the physio- The applicant of an abbreviated new logical or pharmacological action of drug application shall send the notifi- the drug substance. cation to FDA’s Office of Generic Approved under section 505(b) means Drugs (HFD–600). A 505(b)(2) applicant an application submitted under section shall send the notification to the ap- 505(b) and approved on or after October propriate division in the Center for 10, 1962, or an application that was Drug Evaluation and Research review- ‘‘deemed approved’’ under section ing the application. A patent owner or 107(c)(2) of Pub. L. 87–781. its representative may also notify FDA Clinical investigation means any ex- of the filing of any legal action for pat- periment other than a bioavailability

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study in which a drug is administered to demonstrate substantial evidence of or dispensed to, or used on, human sub- effectiveness of a previously approved jects. drug product for any indication or of Conducted or sponsored by the appli- safety for a new patient population and cant with regard to an investigation do not duplicate the results of another means that before or during the inves- investigation that was relied on by the tigation, the applicant was named in agency to demonstrate the effective- Form FDA–1571 filed with FDA as the ness or safety in a new patient popu- sponsor of the investigational new drug lation of a previously approved drug application under which the investiga- product. For purposes of this section, tion was conducted, or the applicant or data from a clinical investigation pre- the applicant’s predecessor in interest, viously submitted for use in the com- provided substantial support for the in- prehensive evaluation of the safety of a vestigation. To demonstrate ‘‘substan- drug product but not to support the ef- tial support,’’ an applicant must either fectiveness of the drug product would provide a certified statement from a be considered new. certified public accountant that the ap- (b) Submission of and effective date of plicant provided 50 percent or more of approval of an abbreviated new drug ap- the cost of conducting the study or plication submitted under section 505(j) of provide an explanation why FDA the act or a 505(b)(2) application. (1) [Re- should consider the applicant to have served] conducted or sponsored the study if the (2) If a drug product that contains a applicant’s financial contribution to new chemical entity was approved the study is less than 50 percent or the after September 24, 1984, in an applica- applicant did not sponsor the inves- tion submitted under section 505(b) of tigational new drug. A predecessor in the act, no person may submit a interest is an entity, e.g., a corpora- 505(b)(2) application or abbreviated new tion, that the applicant has taken over, drug application under section 505(j) of merged with, or purchased, or from the act for a drug product that con- which the applicant has purchased all tains the same active moiety as in the rights to the drug. Purchase of non- new chemical entity for a period of 5 exclusive rights to a clinical investiga- years from the date of approval of the tion after it is completed is not suffi- first approved new drug application, cient to satisfy this definition. except that the 505(b)(2) application or Date of approval means the date on abbreviated application may be sub- the letter from FDA stating that the mitted after 4 years if it contains a cer- new drug application is approved, tification of patent invalidity or non- whether or not final printed labeling or infringement described in other materials must yet be submitted § 314.50(i)(1)(i)(A)(4) or as long as approval of such labeling or § 314.94(a)(12)(i)(A)(4). materials is not expressly required. (3) The approval of a 505(b)(2) applica- ‘‘Date of approval’’ refers only to a tion or abbreviated application de- final approval and not to a tentative scribed in paragraph (b)(2) of this sec- approval that may become effective at tion will become effective as provided a later date. in § 314.107(b)(1) or (b)(2), unless the Essential to approval means, with re- owner of a patent that claims the drug, gard to an investigation, that there are the patent owner’s representative, or no other data available that could sup- exclusive licensee brings suit for pat- port approval of the application. ent infringement against the applicant FDA means the Food and Drug Ad- during the 1-year period beginning 48 ministration. months after the date of approval of New chemical entity means a drug that the new drug application for the new contains no active moiety that has chemical entity and within 45 days 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:

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(i) Was submitted under section letter may be issued in such cir- 505(b) of the act; cumstances. FDA will send the appli- (ii) Was approved after September 24, cant an approvable letter if the appli- 1984; cation or abbreviated application sub- (iii) Was for a drug product that con- stantially meets the requirements of tains an active moiety that has been this part and the agency believes that previously approved in another appli- it can approve the application or abbre- cation under section 505(b) of the act; viated application if specific additional and information or material is submitted (iv) Contained reports of new clinical or specific conditions (for example, cer- investigations (other than bio- tain changes in labeling) are agreed to availability studies) conducted or spon- by the applicant. The approvable letter sored by the applicant that were essen- will describe the information or mate- tial to approval of the application, the rial FDA requires or the conditions the agency will not make effective for a pe- applicant is asked to meet. As a prac- riod of 3 years after the date of ap- tical matter, the approvable letter will proval of the application the approval serve in most instances as a mecha- of a 505(b)(2) application or an abbre- nism for resolving outstanding issues viated new drug application for the on drugs that are about to be approved conditions of approval of the original and marketed. For an application, the application, or an abbreviated new applicant shall, within 10 days after drug application submitted pursuant to the date of the approvable letter: an approved petition under section (1) Amend the application or notify 505(j)(2)(C) of the act that relies on the FDA of an intent to file an amend- information supporting the conditions ment. The filing of an amendment or of approval of an original new drug ap- notice of intent to file an amendment plication. constitutes an agreement by the appli- (5) If a supplemental application: cant to extend the review period for 45 (i) Was approved after September 24, days after the date FDA receives the 1984; and amendment. The extension is to permit (ii) Contained reports of new clinical the agency to review the amendment; investigations (other than bio- (2) Withdraw the application. FDA availability studies) that were con- will consider the applicant’s failure to ducted or sponsored by the applicant respond within 10 days to an approv- that were essential to approval of the able letter to be a request by the appli- supplemental application, the agency cant to withdraw the application under will not make effective for a period of § 314.65. A decision to withdraw an ap- 3 years after the date of approval of the plication is without prejudice to a re- supplemental application the approval filing; of a 505(b)(2) application or an abbre- (3) For a new drug application, ask viated new drug application for a the agency to provide the applicant an change, or an abbreviated new drug ap- opportunity for a hearing on the ques- plication submitted pursuant to an ap- tion of whether there are grounds for proved petition under section denying approval of the application 505(j)(2)(C) of the act that relies on the under section 505(d) of the act. The ap- information supporting a change applicant shall submit the request to the proved in the supplemental new drug Associate Director for Policy (HFD–5), application. Center for Drug Evaluation and Re- [59 FR 50368, Oct. 3, 1994] search, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. § 314.110 Approvable letter to the ap- Within 60 days of the date of the applicant. provable letter, or within a different (a) In selected circumstances, it is time period to which FDA and the ap- useful at the end of the review period plicant agree, the agency will either for the Food and Drug Administration approve the application under § 314.105 to indicate to the applicant that the or refuse to approve the application application or abbreviated application under § 314.125 and give the applicant is basically approvable providing cer- written notice of an opportunity for a tain issues are resolved. An approvable hearing under § 314.200 and section

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505(c)(2) of the act on the question of § 314.125 or the abbreviated new drug whether there are grounds for denying application may not be approved for approval of the application under sec- one of the reasons given in § 314.127. tion 505(d) of the act; The not approvable letter will describe (4) [Reserved] the deficiencies in the application or (5) Notify FDA that the applicant abbreviated application. Except as pro- agrees to an extension of the review pe- vided in paragraph (b) of this section, riod under section 505(c) of the act, so within 10 days after the date of the not that the applicant can determine approvable letter, the applicant shall: whether to respond further under para- (1) Amend the application or abbre- graph (a)(1), (a)(2), or (a)(3) of this sec- viated application or notify FDA of an tion. The applicant’s notice is required intent to file an amendment. The filing to state the length of the extension. of an amendment or a notice of intent FDA will honor any reasonable request to file an amendment constitutes an for such an extension. FDA will con- agreement by the applicant to extend sider the applicant’s failure to respond the review period under § 314.60 or further within the extended review pe- § 314.96; riod to be a request to withdraw the application under § 314.65. A decision to (2) Withdraw the application or ab- withdraw an application is without breviated application. Except as pro- prejudice to a refiling. vided in paragraph (b) of this section, (b) FDA will send the applicant of an FDA will consider the applicant’s fail- abbreviated new drug application an ure to respond within 10 days to a not approvable letter only if the applica- approvable letter to be a request by the tion substantially meets the require- applicant to withdraw the application ments of this part and the agency be- under § 314.65 or abbreviated applica- lieves that it can approve the abbre- tion under § 314.99. A decision to with- viated application if minor deficiencies draw the application or abbreviated ap- (e.g., labeling deficiencies) are cor- plication is without prejudice to re- rected. The approvable letter will de- filing; scribe the deficiencies and state a time (3) For a new drug application or an period within which the applicant must abbreviated application, ask the agen- respond. Unless the applicant corrects cy to provide the applicant an oppor- the deficiencies by amendment within tunity for a hearing on the question of the specified time period, FDA will whether there are grounds for denying refuse to approve the abbreviated ap- approval of the application under sec- plication under § 314.127. Within 10 days tion 505(d) or (j)(3) of the act. The ap- after the date of the approvable letter, plicant shall submit the request to the the applicant may also ask the agency Associate Director for Policy (HFD–5), to provide the applicant an oppor- Center for Drug Evaluation and Re- tunity for a hearing on the question of search, Food and Drug Administration, whether there are grounds for denying 5600 Fishers Lane, Rockville, MD 20857. approval of the abbreviated new drug Within 60 days of the date of the not application. Applicants who request a approvable letter, or within a different hearing shall submit the request to the time period to which FDA and the ap- Associate Director for Policy (HFD–5), plicant agree, the agency will either Center for Drug Evaluation and Re- approve the application or abbreviated search, Food and Drug Administration, application under § 314.105 or refuse to 5600 Fishers Lane, Rockville, MD 20857. approve the application under § 314.125 [57 FR 17989, Apr. 28, 1992, as amended at 62 or abbreviated new drug application FR 43639, Aug. 15, 1997; 64 FR 402, Jan. 5, 1999] under § 314.127 and give the applicant written notice of an opportunity for a § 314.120 Not approvable letter to the hearing under § 314.200 and section applicant. 505(c)(1)(B) or (j)(4)(C) of the act on the (a) The Food and Drug Administra- question of whether there are grounds tion will send the applicant a not ap- for denying approval of the application provable letter if the agency believes under section 505(d) or (j)(3) of the act; that the application may not be ap- or proved for one of the reasons given in (4) [Reserved]

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(5) Notify FDA that the applicant reasons, in accordance with the proce- agrees to an extension of the review pe- dures in § 314.161. riod under section 505(c)(1) or (j)(4)(A) (c) An abbreviated new drug applica- of the act, so that the applicant can de- tion described in paragraph (a) of this termine whether to respond further section will be disapproved, under under paragraph (a)(1), (a)(2), or (a)(3) § 314.127(a)(11), and a 505(j)(2)(C) peti- of this section. The applicant’s notice tion described in paragraph (a) of this is required to state the length of the section will be disapproved, under extension. FDA will honor any reason- § 314.93(e)(1)(iv), unless the agency de- able request for such an extension. termines that the withdrawal of the FDA will consider the applicant’s fail- listed drug was not for safety or effec- ure to respond further within the ex- tiveness reasons. tended review period to be a request to (d) Certain drug products approved withdraw the application under § 314.65 for safety and effectiveness that were or abbreviated application under no longer marketed on September 24, § 314.99. A decision to withdraw an ap- 1984, are not included in the list. Any plication or abbreviated application is person who wishes to obtain marketing without prejudice to a refiling. approval for such a drug product under (b) With the exception of a request an abbreviated new drug application for an opportunity for a hearing under paragraph (a)(3) of this section, the 10- must petition FDA for a determination day time period in this section for re- whether the drug product was with- sponding to a not approvable letter drawn from the market for safety or ef- does not apply to abbreviated new drug fectiveness reasons and request that applications. FDA may consider the ap- the list be amended to include the drug plicant’s failure to respond within 180 product. A person seeking such a deter- days to a not approvable letter to be a mination shall use the petition proce- request by the applicant to withdraw dures established in § 10.30 of this chap- the abbreviated new drug application ter. The petitioner shall include in the under § 314.99. petition information to show that the drug product was approved for safety [57 FR 17990, Apr. 28, 1992, as amended at 62 and effectiveness and all evidence FR 43639, Aug. 15, 1997; 64 FR 402, Jan. 5, 1999] available to the petitioner concerning § 314.122 Submitting an abbreviated the reason that marketing of the drug application for, or a 505(j)(2)(C) pe- product ceased. tition that relies on, a listed drug that is no longer marketed. [57 FR 17990, Apr. 28, 1992; 57 FR 29353, July 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 was withdrawn for safety or effective- for a hearing under § 314.200 on the ness reasons. The petition must be sub- question of whether there are grounds mitted under §§ 10.25(a) and 10.30 of this for denying approval of the application chapter and must contain all evidence under section 505(d) of the act, if: available to the petitioner concerning (1) FDA sends the applicant an ap- the reasons for the withdrawal from provable or a not approvable letter sale. under § 314.110 or § 314.120; (b) When a petition described in para- (2) The applicant requests an oppor- graph (a) of this section is submitted, tunity for hearing for a new drug on the agency will consider the evidence the question of whether the application in the petition and any other evidence is approvable; and before the agency, and determine (3) FDA finds that any of the reasons whether the listed drug is withdrawn given in paragraph (b) of this section from sale for safety or effectiveness apply.

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(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 an explanation of the omission of a re- the drug is safe for use under the condi- port of any investigation of the drug tions prescribed, recommended, or sug- product sponsored by the applicant, or gested in its proposed labeling. an explanation of the omission of other (3) The results of the tests show that information about the drug pertinent the drug is unsafe for use under the to an evaluation of the application conditions prescribed, recommended, that is received or otherwise obtained or suggested in its proposed labeling or by the applicant from any source. the results do not show that the drug (15) A nonclinical laboratory study product is safe for use under those con- that is described in the application and ditions. that is essential to show that the drug (4) There is insufficient information is safe for use under the conditions pre- about the drug to determine whether scribed, recommended, or suggested in the product is safe for use under the its proposed labeling was not con- conditions prescribed, recommended, ducted in compliance with the good or suggested in its proposed labeling. laboratory practice regulations in part (5) There is a lack of substantial evidence 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. 58 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 § 314.101(d), if the deficiency is not cor- chapter that is contained in the appli- rected. cation refuses to permit an inspection (11) The drug will be manufactured or of facilities or records relevant to the processed in whole or in part in an es- study by a properly authorized officer tablishment that is not registered and or employee of the Department of not exempt from registration under Health and Human Services or refuses section 510 of the act and part 207. to submit reserve samples of the drug (12) The applicant does not permit a products used in the study when re- properly authorized officer or employee quested by FDA.

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

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

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here, with the exception of the require- 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 ap- [50 FR 7493, Feb. 22, 1985, as amended at 50 plication is for a drug product whose FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, route of administration, dosage form, 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. or strength purports to be the same as 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 insuffi- (a) FDA will refuse to approve an ab- cient to show that the route of admin- breviated application for a new drug istration, dosage form, or strength is under section 505(j) of the act for any the same as that of the reference listed of the following reasons: drug; or (1) The methods used in, or the facili- (ii) If the abbreviated new drug appli- ties and controls used for, the manu- cation is for a drug product whose facture, processing, and packing of the route of administration, dosage form, drug product are inadequate to ensure or strength is different from that of the and preserve its identity, strength, listed drug referred to in the applica- quality, and purity. tion, no petition to submit an abbre- (2) Information submitted with the viated new drug application for the abbreviated new drug application is in- drug product with the different route sufficient to show that each of the proof administration, dosage form, or posed conditions of use has been pre- strength was approved under § 314.93. viously approved for the listed drug re- (5) If the abbreviated new drug appli- ferred to in the application. cation was submitted under the ap- (3)(i) If the reference listed drug has proval of a petition under § 314.93, the only one active ingredient, information abbreviated new drug application did submitted with the abbreviated new not contain the information required drug application is insufficient to show by FDA with respect to the active in- that the active ingredient is the same gredient, route of administration, dos- as that of the reference listed drug; age form, or strength that is not the (ii) If the reference listed drug has same as that of the reference listed more than one active ingredient, infor- drug. mation submitted with the abbreviated (6)(i) Information submitted in the new drug application is insufficient to abbreviated new drug application is in- show that the active ingredients are sufficient to show that the drug prod- the same as the active ingredients of uct is bioequivalent to the listed drug the reference listed drug; or referred to in the abbreviated new drug (iii) If the reference listed drug has application; or more than one active ingredient and if (ii) If the abbreviated new drug appli- the abbreviated new drug application is cation was submitted under a petition for a drug product that has an active approved under § 314.93, information ingredient different from the reference submitted in the abbreviated new drug listed drug: application is insufficient to show that (A) Information submitted with the the active ingredients of the drug prod- abbreviated new drug application is in- uct are of the same pharmacological or sufficient to show: therapeutic class as those of the ref- (1) That the other active ingredients erence listed drug and that the drug are the same as the active ingredients product can be expected to have the of the reference listed drug; or same therapeutic effect as the ref- (2) That the different active ingre- erence listed drug when administered dient is an active ingredient of a listed to patients for each condition of use drug or a drug that does not meet the approved for the reference listed drug.

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(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 drug product are unsafe for use, as de- ophthalmic use. scribed in paragraph (a)(8)(ii) of this (5) The use of a delivery or a modified section, under the conditions pre- release mechanism never before ap- scribed, recommended, or suggested in proved for the drug. the labeling proposed for the drug prod- (6) A change in composition to in- uct; or clude a significantly greater content of (B) The composition of the drug prod- one or more inactive ingredients than uct is unsafe, as described in paragraph previously used in the drug product. (a)(8)(ii) of this section, under the con- (7) If the drug product is intended for ditions prescribed, recommended, or topical administration, a change in the suggested in the proposed labeling be- properties of the vehicle or base that cause of the type or quantity of inac- might increase absorption of certain tive ingredients included or the man- potentially toxic active ingredients ner in which the inactive ingredients thereby affecting the safety of the drug are included. product, or a change in the lipophilic (ii)(A) FDA will consider the inactive properties of a vehicle or base, e.g., a ingredients or composition of a drug change from an oleaginous to a water product unsafe and refuse to approve soluble vehicle or base. an abbreviated new drug application (B) FDA will consider an inactive in- under paragraph (a)(8)(i) of this section gredient in, or the composition of, a if, on the basis of information available drug product intended for parenteral to the agency, there is a reasonable use to be unsafe and will refuse to ap- basis to conclude that one or more of prove the abbreviated new drug appli- the inactive ingredients of the pro- cation unless it contains the same in- posed drug or its composition raises se- active ingredients, other than preserv- rious questions of safety or efficacy. atives, buffers, and antioxidants, in the From its experience with reviewing in- same concentration as the listed drug, active ingredients, and from other in- and, if it differs from the listed drug in formation available to it, FDA may a preservative, buffer, or antioxidant, identify changes in inactive ingredi- the application contains sufficient in- ents or composition that may ad- formation to demonstrate that the dif- versely affect a drug product’s safety ference does not affect the safety or ef- or efficacy. The inactive ingredients or ficacy of the drug product. composition of a proposed drug product (C) FDA will consider an inactive in- will be considered to raise serious ques- gredient in, or the composition of, a tions of safety or efficacy if the prod- drug product intended for ophthalmic

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

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the application or abbreviated applica- (3) That on the basis of new information was approved; or tion before FDA, evaluated together (iii) Upon the basis of new informa- with the evidence available when the tion before FDA with respect to the application or abbreviated application drug, evaluated together with the evi- was approved, the labeling of the drug, dence available when the application based on a fair evaluation of all mate- or abbreviated application was ap- rial facts, is false or misleading in any proved, that there is a lack of substan- particular, and the labeling was not tial evidence from adequate and well- corrected by the applicant within a controlled investigations as defined in reasonable time after receipt of writ- § 314.126, that the drug will have the ef- ten notice from the agency. fect it is purported or represented to (4) That the applicant has failed to have under the conditions of use pre- comply with the notice requirements of scribed, recommended, or suggested in section 510(j)(2) of the act. its labeling; or (5) That the applicant has failed to (iv) That the application or abbre- submit bioavailability or bioequiva- viated application contains any untrue lence data required under part 320 of statement of a material fact; or this chapter. (v) That the patent information pre- (6) The application or abbreviated ap- scribed by section 505(c) of the act was plication does not contain an explanation 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 application or abbreviated application chapter or informed consent regula- was approved, the methods used in, or tions in part 50 of this chapter, was not the facilities and controls used for, the conducted in compliance with those manufacture, processing, and packing regulations such that the rights or of the drug are inadequate to ensure safety of human subjects were not ade- and preserve its identity, strength, quately protected. quality, and purity and were not made (9) That the applicant or contract re- adequate within a reasonable time search organization that conducted a after receipt of written notice from the bioavailability or bioequivalence study agency. described in § 320.38 or § 320.63 of this

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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 the market and may ask the applicant holder submits comments on the notice to waive the opportunity for hearing of opportunity for hearing and a hear- otherwise provided for under this sec- ing is granted, the abbreviated new tion, to permit FDA to withdraw ap- drug application holder may partici- proval of the application or abbre- pate in the hearing as a nonparty par- viated application for the product, and ticipant as provided for in § 12.89 of this to remove voluntarily the product from chapter. the market. If the applicant agrees, the (3) Except as provided in paragraphs agency will not make a finding under (c) and (d) of this section, the approval paragraph (b) of this section, but will of an abbreviated new drug application

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

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

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§ 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 removal from the list, upon the agen- [57 FR 17995, Apr. 28, 1992] cy’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; [57 FR 17995, Apr. 28, 1992] (2) Whenever a listed drug is voluntarily 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 ap- (a) FDA will remove a previously approved; and proved new drug product from the list (3) When a person petitions for such a for the period stated when: determination under §§ 10.25(a) and 10.30 (1) The agency withdraws or suspends of this chapter. approval of a new drug application or (b) Any person may petition under an abbreviated new drug application §§ 10.25(a) and 10.30 of this chapter for a under § 314.150(a) or § 314.151 or under determination whether a listed drug the imminent hazard authority of sec- has been voluntarily withdrawn for tion 505(e) of the act, for the same pe- safety or effectiveness reasons. Any riod as the withdrawal or suspension of such petition must contain all evidence the application; or available to the petitioner concerning (2) The agency, in accordance with the reason that the drug is withdrawn the procedures in § 314.153(b) or § 314.161, from sale. issues a final decision stating that the (c) If the agency determines that a listed drug was withdrawn from sale listed drug is withdrawn from sale for for safety or effectiveness reasons, or safety or effectiveness reasons, the suspended under § 314.153(b), until the agency will, except as provided in para- agency determines that the withdrawal graph (d) of this section, publish a no- from the market has ceased or is not tice of the determination in the FED- for safety or effectiveness reasons. ERAL REGISTER. (b) FDA will publish in the FEDERAL (d) If the agency determines under REGISTER a notice announcing the re- paragraph (a) of this section that a moval of a drug from the list. listed drug is withdrawn from sale for (c) At the end of the period specified safety and effectiveness reasons and in paragraph (a)(1) or (a)(2) of this sec- there are approved abbreviated new tion, FDA will relist a drug that has drug applications that are subject to been removed from the list. The agency suspension under section 505(j)(5) of the will publish in the FEDERAL REGISTER a

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notice announcing the relisting of the (2) FDA will publish the notice in the drug. FEDERAL REGISTER and will state that 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 misbranding of an approved drug. 30 days after the date of publication of 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 [50 FR 7493, Feb. 22, 1985. Redesignated at 57 the FEDERAL REGISTER to determine 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 opin- Subpart E—Hearing Procedures for ion of the applicability of a notice to a 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 Drug Labeling Compliance (HFD– otherwise noted. Redesignated at 57 FR 17983, 310), Center for Drug Evaluation and Apr. 28, 1992. Research, Food and Drug Administra- tion, 5600 Fishers Lane, Rockville, MD § 314.200 Notice of opportunity for 20857. A person shall request an opinion hearing; notice of participation and request for hearing; grant or denial within 30 days of the date of publica- of hearing. tion of the notice to be eligible for an opportunity for a hearing under the no- (a) Notice of opportunity for hearing. tice. If a person requests an opinion, The Director of the Center for Drug that person’s time for filing an appear- Evaluation and Research, Food and ance and request for a hearing and sup- Drug Administration, will give the ap- porting studies and analyses begins on plicant, and all other persons who man- the date the person receives the opin- ufacture or distribute identical, re- ion from FDA. lated, or similar drug products as de- (b) FDA will provide the notice of op- fined in § 310.6 of this chapter, notice portunity for a hearing to applicants and an opportunity for a hearing on the and to other persons subject to the no- Center’s proposal to refuse to approve tice under § 310.6, as follows: an application or to withdraw the ap- (1) To any person who has submitted proval of an application or abbreviated an application or abbreviated applica- application under section 505(e) of the tion, by delivering the notice in person act. The notice will state the reasons or by sending it by registered or cer- for the action and the proposed tified mail to the last address shown in grounds for the order. the application or abbreviated applica- (1) The notice may be general (that tion. is, simply summarizing in a general (2) To any person who has not sub- way the information resulting in the mitted an application or abbreviated notice) or specific (that is, either refer- application but who is subject to the ring to specific requirements in the notice under § 310.6 of this chapter, by statute and regulations with which publication of the notice in the FED- there is a lack of compliance, or pro- ERAL REGISTER. viding a detailed description and anal- (c)(1) Notice of participation and re- ysis of the specific facts resulting in quest for a hearing, and submission of the notice). studies and comments. The applicant, or

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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. comments on the proposal to withdraw Any study conducted on the final mar- approval of the application or abbre- keted form of the drug product is re- viated application. The comments are quired to be clearly identified. requested to be submitted within the (3) Each person requesting a hearing time and under the conditions specified shall submit an analysis of the data in this section. upon which the person relies, except (d) The person requesting a hearing is that the required information relating required to submit under paragraph either to safety or to effectiveness may (c)(1)(ii) of this section the studies (in- be omitted if the notice of opportunity

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for hearing does not raise any issue clearly and a waiver obtained under § 314.126 with respect to that aspect of the drug; is required to be submitted. information on compliance with § 300.50 IV. A statement signed by the person responsible 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 components. (c)(1)(i) of this section is required to a. Controlled studies. contain any contention that the prod- b. Partially controlled or uncontrolled uct is not a new drug because it is gen- studies. erally recognized as safe and effective B. Human safety data. within the meaning of section 201(p) of 1. Individual active components. the act, or because it is exempt from a. Controlled studies. part or all of the new drug provisions b. Partially controlled or uncontrolled of the act under the exemption for studies. products marketed before June 25, 1938, c. Documented case reports. contained in section 201(p) of the act or d. Pertinent marketing experiences that may influence a determination about the under section 107(c) of the Drug safety of each individual active component. Amendments of 1962, or for any other 2. Combinations of the individual active reason. Each contention is required to components. be supported by a submission under a. Controlled studies. paragraph (c)(1)(ii) of this section and b. Partially controlled or uncontrolled the Commissioner of Food and Drugs studies. will make an administrative deter- c. Documented case reports. mination on each contention. The fail- d. Pertinent marketing experiences that ure of any person subject to a notice of may influence a determination about the safety of each individual active component. opportunity for a hearing, including II. Effectiveness data. any person who manufactures or dis- A. Individual active components: Con- tributes an identical, related, or simi- trolled studies, with an analysis showing lar drug product as defined in § 310.6, to clearly how each study satisfies, on a point- submit a notice of participation and re- by-point basis, each of the criteria required quest for hearing or to raise all such by § 314.126. contentions constitutes a waiver of any B. Combinations of individual active 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 III. A summary of the data and views set- that is required to obtain approval of ting forth the medical rationale and purpose an application for the product, unless for the drug and its ingredients and the sci- FDA has waived a requirement for ef- entific basis for the conclusion that the drug fectiveness (under § 314.126) or safety, and its ingredients have been proven safe or both. The submission should be in and/or effective for the intended use. If there is an absence of controlled studies in the ma- the format and with the analyses re- terial submitted or the requirements of any quired under paragraph (d) of this sec- element of § 300.50 or § 314.126 have not been tion. A person who fails to submit the fully met, that fact is required to be stated required scientific evidence required

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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. upon published studies which may be A. A copy of each pertinent document or corroborated by unpublished studies record to establish the exact date the drug 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 June 25, 1938, contained in section with a copy of each pertinent document or 201(p) of the act, or under section 107(c) record to establish each such date. of the Drug Amendments of 1962, is re- IV. Verification. quired to be supported by evidence of A statement signed by the person respon- past and present quantitative for- sible for such submission, that all appropriate 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.) I. Formulation. (3) The Food and Drug Administra- 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 inactive ingredients) on the date of initial identical, related, or similar, as de- marketing of the drug. scribed in § 310.6, to a drug product, in- B. A statement whether such formulation cluding any active ingredient for which has at any subsequent time been changed in an application is or at any time has any manner. If any such change has been been effective or deemed approved, or made, the exact date, nature, and rationale approved under section 505 of the act, 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 ingredient, should be stated, together with a (4) A contention that a drug product copy of each pertinent document or record to is not a new drug for any other reason establish the date and nature of each such is required to be supported by submis- change, including, but not limited to, the sion of the factual records, data, and formula which resulted from each such information that are necessary and ap- change. If no such change has been made, a propriate to support the contention. copy of representative documents or records (5) It is the responsibility of every showing the formula at representative points in time should be submitted to support the person who manufactures or distrib- statement. utes a drug product in reliance upon a II. Labeling. ‘‘grandfather’’ provision of the act to A. A copy of each pertinent document or maintain files that contain the data record to establish the identity of each item and information necessary fully to doc- of written, printed, or graphic matter used ument and support that status. as labeling on the date the drug was initially (f) Separation of functions. Separation marketed. of functions commences upon receipt of B. A statement whether such labeling has at any subsequent time been discontinued or a request for hearing. The Director of changed in any manner. If such discontinu- the Center for Drug Evaluation and Re- ance or change has been made, the exact search, Food and Drug Administration, date, nature, and rationale for each dis- will prepare an analysis of the request continuance or change and a copy of each and a proposed order ruling on the pertinent document or record to establish matter. The analysis and proposed each such discontinuance or change should order, the request for hearing, and any be submitted, including, but not limited to, proposed order denying a hearing and the labeling which resulted from each such discontinuance or change. If no such dis- response under paragraph (g) (2) or (3) continuance or change has been made, a copy of this section will be submitted to the of representative documents or records show- Office of the Commissioner of Food and ing labeling at representative points in time Drugs for review and decision. When

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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 the right to a hearing on such an issue. tion, and analyses to demonstrate that Separation of functions on all issues there is a genuine and substantial issue resumes upon issuance of a notice of of fact which justifies a hearing. hearing. The Office of the General (3) When following a general or spe- Counsel, Department of Health and cific notice of opportunity for a hear- Human Services, will observe the same ing a person requesting a hearing sub- separation of functions. mits data or information of a type re- (g) Summary judgment. A person who quired by the statute and regulations, requests a hearing may not rely upon and the Director of the Center for Drug allegations or denials but is required to Evaluation and Research concludes set forth specific facts showing that that summary judgment against the there is a genuine and substantial issue person should be considered, the Direc- of fact that requires a hearing with re- tor will serve upon the person by reg- spect to a particular drug product spec- istered mail a proposed order denying a ified in the request for hearing. hearing. The person has 60 days after (1) Where a specific notice of oppor- receipt of the proposed order to re- tunity for hearing (as defined in para- spond with sufficient data, informa- graph (a)(1) of this section) is used, the tion, and analyses to demonstrate that Commissioner will enter summary there is a genuine and substantial issue judgment against a person who re- of fact which justifies a hearing. quests a hearing, making findings and (4) If review of the data, information, conclusions, denying a hearing, if it and analyses submitted show that the conclusively appears from the face of grounds cited in the notice are not the data, information, and factual valid, for example, that substantial analyses in the request for the hearing evidence of effectiveness exists, the that there is no genuine and substan- Commissioner will enter summary tial issue of fact which precludes the judgment for the person requesting the

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

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

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§ 314.430 Availability for public disclo- for public consideration of a specific sure of data and information in an pending issue; for example, for consid- application or abbreviated applica- eration of an open session of an FDA tion. advisory committee. (a) The Food and Drug Administra- (2) Notwithstanding paragraph (d)(1) tion will determine the public avail- of this section, FDA will make availability of any part of an application or able to the public upon request the in- abbreviated application under this sec- formation in the investigational new tion and part 20 of this chapter. For drug application that was required to purposes of this section, the applica- be filed in Docket Number 95S–0158 in tion or abbreviated application in- the Division of Dockets Management cludes all data and information sub- (HFA–305), Food and Drug Administra- mitted with or incorporated by ref- tion, 5630 Fishers Lane, rm. 1061, Rock- erence in the application or abbre- ville, MD 20852, for investigations in- viated application, including investiga- volving an exception from informed tional new drug applications, drug consent under § 50.24 of this chapter. master files under § 314.420, supple- Persons wishing to request this infor- ments submitted under § 314.70 or mation shall submit a request under § 314.97, reports under § 314.80 or § 314.98, the Freedom of Information Act. and other submissions. For purposes of (e) After FDA sends an approval let- this section, safety and effectiveness ter to the applicant, the following data data include all studies and tests of a and information in the application or drug on animals and humans and all abbreviated application are imme- studies and tests of the drug for iden- diately available for public disclosure, tity, stability, purity, potency, and unless the applicant shows that ex- bioavailability. traordinary circumstances exist. A list (b) FDA will not publicly disclose the of approved applications and abbre- existence of an application or abbreviated applications, entitled ‘‘Approved viated application before an approvable Drug Products with Therapeutic letter is sent to the applicant under Equivalence Evaluations,’’ is available § 314.110, unless the existence of the ap- from the Government Printing Office, plication or abbreviated application Washington, DC 20402. This list is up- has been previously publicly disclosed dated monthly. or acknowledged. The Center for Drug (1) [Reserved] Evaluation and Research will maintain (2) If the application applies to a new and make available for public disclo- drug, all safety and effectiveness data sure a list of applications or abbre- previously disclosed to the public as viated applications for which the agen- set forth in § 20.81 and a summary or cy has sent an approvable letter to the summaries of the safety and effective- applicant. 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 the agency sends an approval letter, and information, after deletion of the but the Commissioner may, in his or following: her discretion, disclose a summary of (a) Names and any information that selected portions of the safety and ef- would identify patients or test subjects fectiveness data that are appropriate or investigators.

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

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(h) The compilations of information not associated with an application specified in § 20.117 are available for should be addressed specifically to the public disclosure. intended office or division and to the [50 FR 7493, Feb. 22, 1985, as amended at 50 person as follows: Center for Drug FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, Evaluation and Research, Food and 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Drug Administration, Attn: [insert Oct. 2, 1996; 64 FR 26698, May 13, 1998; 64 FR name of person], MPN II, HFD–[insert 402, Jan. 5, 1999; 66 FR 1832, Jan. 10, 2001; 68 mail code of office or division], 5600 Fish- FR 24879, May 9, 2003] ers Lane, Rockville, MD 20857. The § 314.440 Addresses for applications mail code for the Office of Generic and abbreviated applications. Drugs is HFD–600, the mail code for the (a) Applicants shall send applica- Division of Chemistry is HFD–630, and tions, abbreviated applications, and the mail code for the Division of Bio- other correspondence relating to mat- equivalence is HFD–650. ters covered by this part, except for products listed in paragraph (b) of this (3) A request for an opportunity for a section, to the Center for Drug Evalua- hearing under § 314.110 or § 314.120 on tion and Research, Food and Drug Ad- the question of whether there are ministration, 5600 Fishers Lane, Rock- grounds for denying approval of an ap- ville, MD 20857, and directed to the application, except an application under propriate office identified below: paragraph (b) of this section, should be directed to the Associate Director for (1) Except as provided in paragraph Policy (HFD–5). (a)(4) of this section, an application under § 314.50 or § 314.54 submitted for (4) The field copy of an application, filing should be directed to the Docu- an abbreviated application, amendment and Records Section, 5901–B ments, supplements, resubmissions, re- Ammendale Rd., Beltsville, MD 20705– quests for waivers, and other cor- 1266. Applicants may obtain folders for respondence about an application and binding applications from the Consoli- an abbreviated application shall be dated Forms and Publications Dis- sent to the applicant’s home FDA distribution Center, Washington Com- trict office, except that a foreign appli- merce Center, 3222 Hubbard Rd., Land- cant shall send the field copy to the ap- over, MD 20785. After FDA has filed the propriate address identified in para- application, the agency will inform the graphs (a)(1) and (a)(2) of this section. applicant which division is responsible for the application. Amendments, sup- (b) Applicants shall send applications plements, resubmissions, requests for and other correspondence relating to waivers, and other correspondence matters covered by this part for the about an application that has been drug products listed below to the Divi- filed should be directed to the appro- sion of Product Certification (HFB– priate division. 240), Center for Biologics Evaluation (2) Except as provided in paragraph and Research, Food and Drug Adminis- (a)(4) of this section, an abbreviated ap- tration, 8800 Rockville Pike, Bethesda, plication under § 314.94, and amend- MD 20892, except applicants shall send ments, supplements, and resubmissions a request for an opportunity for a hear- should be directed to the Office of Ge- ing under § 314.110 or § 314.120 on the neric Drugs (HFD–600), Center for Drug question of whether there are grounds Evaluation and Research, Food and for denying approval of an application Drug Administration, 5600 Fishers to the Director, Center for Biologics Lane, Rockville, MD 20857. Items sent Evaluation and Research (HFB–1), at by parcel post or overnight courier the same address. service should be directed to the Office of Generic Drugs (HFD–600), Center for (1) Ingredients packaged together Drug Evaluation and Research, Food with containers intended for the collec- and Drug Administration, Metro Park tion, processing, or storage of blood North II, 7500 Standish Place, rm. 150, and blood components. Rockville, MD 20855. Correspondence (2) Urokinase products.

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(3) Plasma volume expanders and hy- uct has an effect on a surrogate end- droxyethyl starch for leukapheresis. point that is reasonably likely, based [50 FR 7493, Feb. 22, 1985, as amended at 50 on epidemiologic, therapeutic, patho- FR 21238, May 23, 1985; 55 FR 11581, Mar. 29, physiologic, or other evidence, to pre- 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, dict clinical benefit or on the basis of Sept. 8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR an effect on a clinical endpoint other 13473, Mar. 23, 2004] than survival or irreversible morbidity. Approval under this section will be § 314.445 Guidance documents. subject to the requirement that the ap- (a) FDA has made available guidance plicant study the drug further, to documents under § 10.115 of this chapter verify and describe its clinical benefit, to help you to comply with certain re- where there is uncertainty as to the requirements of this part. lation of the surrogate endpoint to (b) The Center for Drug Evaluation clinical benefit, or of the observed clin- and Research (CDER) maintains a list ical benefit to ultimate outcome. Post- of guidance documents that apply to marketing studies would usually be CDER’s regulations. The list is main- studies already underway. When retained on the Internet and is published quired to be conducted, such studies annually in the FEDERAL REGISTER. A must also be adequate and well-con- request for a copy of the CDER list trolled. The applicant shall carry out should be directed to the Office of any such studies with due diligence. Training and Communications, Divi- sion of Communications Management, § 314.520 Approval with restrictions to Drug Information Branch (HFD–210), assure safe use. Center for Drug Evaluation and Re- search, Food and Drug Administration, (a) If FDA concludes that a drug 5600 Fishers Lane, Rockville, MD 20857. product shown to be effective can be safely used only if distribution or use [65 FR 56480, Sept. 19, 2000] is restricted, FDA will require such postmarketing restrictions as are need- Subpart H—Accelerated Approval ed to assure safe use of the drug prod- of New Drugs for Serious or uct, such as: Life-Threatening Illnesses (1) Distribution restricted to certain facilities or physicians with special SOURCE: 57 FR 58958, Dec. 11, 1992, unless training or experience; or otherwise noted. (2) Distribution conditioned on the performance of specified medical proce- § 314.500 Scope. dures. This subpart applies to certain new (b) The limitations imposed will be drug products that have been studied commensurate with the specific safety for their safety and effectiveness in concerns presented by the drug prod- treating serious or life-threatening ill- uct. nesses and that provide meaningful therapeutic benefit to patients over ex- § 314.530 Withdrawal procedures. isting treatments (e.g., ability to treat (a) For new drugs approved under patients unresponsive to, or intolerant of, available therapy, or improved pa- §§ 314.510 and 314.520, FDA may with- tient response over available therapy). draw approval, following a hearing as provided in part 15 of this chapter, as [57 FR 58958, Dec. 11, 1992, as amended at 64 modified by this section, if: FR 402, Jan. 5, 1999] (1) A postmarketing clinical study § 314.510 Approval based on a surro- fails to verify clinical benefit; gate endpoint or on an effect on a (2) The applicant fails to perform the clinical endpoint other than sur- required postmarketing study with due vival or irreversible morbidity. diligence; FDA may grant marketing approval (3) Use after marketing demonstrates for a new drug product on the basis of that postmarketing restrictions are inadequate and well-controlled clinical adequate to assure safe use of the drug trials establishing that the drug prod- 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 designation; designation of already ap- mation regarding the safety of the di- proved drugs. agnostic radiopharmaceutical, and its 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 designations. studies. FDA will establish categories 316.29 Revocation of orphan-drug designa- of diagnostic radiopharmaceuticals tion. based on defined characteristics rel- 316.30 Annual reports of holder of orphan- evant to risk and will specify the drug designation. amount and type of safety data that are appropriate for each category (e.g., Subpart D—Orphan-drug Exclusive required safety data may be limited for Approval diagnostic radiopharmaceuticals with 316.31 Scope of orphan-drug exclusive ap- a well established, low-risk profile). proval. Upon reviewing the relevant product 316.34 FDA recognition of exclusive ap- characteristics and safety information, proval. FDA will place each diagnostic radio- 316.36 Insufficient quantities of orphan pharmaceutical into the appropriate 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 diag- 316.40 Treatment use of a designated orphan nostic radiopharmaceutical by radi- drug. ation dosimetry evaluations in humans and appropriate animal models. The Subpart F—Availability of Information maximum tolerated dose need not be 316.50 Guidance documents. established. 316.52 Availability for public disclosure of data and information in requests and ap- PART 316—ORPHAN DRUGS plications. AUTHORITY: 21 U.S.C. 360aa, 360bb, 360cc, Subpart A—General Provisions 360dd, 371.

Sec. SOURCE: 57 FR 62085, Dec. 29, 1992, unless 316.1 Scope of this part. otherwise noted. 316.2 Purpose. EDITORIAL NOTE: Nomenclature changes to 316.3 Definitions. part 316 can be found at 69 FR 13717, Mar. 24, 316.4 Address for submissions. 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 and Cosmetic Act as amended by sec- application 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- to be considered different unless the lic Health Service Act (42 U.S.C. 262). differences were shown to be clinically (10) Orphan drug means a drug in- superior. tended for use in a rare disease or condition as defined in section 526 of the (B) Two polysaccharide drugs would act. be considered the same if they had identical saccharide repeating units, (11) Orphan-drug designation means even if the number of units were to FDA’s act of granting a request for des- vary and even if there were postpolym- ignation under section 526 of the act. erization modifications, unless the sub- (12) Orphan-drug exclusive approval or sequent drug could be shown to be exclusive approval means that, effective clinically superior. on the date of FDA approval as stated in the approval letter of a marketing (C) Two polynucleotide drugs con- application for a sponsor of a des- sisting of two or more distinct nucleo- ignated orphan drug, no approval will tides would be considered the same if be given to a subsequent sponsor of the they had an identical sequence of pu- same drug product for the same indica- rine and pyrimidine bases (or their de- tion for 7 years, except as otherwise rivatives) bound to an identical sugar provided by law or in this part. backbone (ribose, deoxyribose, or modifications 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 same active moiety as a previously ap- (D) Closely related, complex partly proved drug and is intended for the definable drugs with similar thera- same use as the previously approved peutic intent, such as two live viral drug, even if the particular ester or vaccines for the same indication, would salt (including a salt with hydrogen or be considered the same unless the sub- coordination bonds) or other sequent drug was shown to be clini- noncovalent derivative such as a complex, chelate or clathrate has not been cally superior. previously approved, except that if the (14) Sponsor means the entity that as- subsequent drug can be shown to be sumes responsibility for a clinical or clinically superior to the first drug, it nonclinical investigation of a drug, in- will not be considered to be the same cluding the responsibility for compli- drug. ance with applicable provisions of the (ii) If it is a drug composed of large molecules (macromolecules), a drug act and regulations. A sponsor may be that contains the same principal mo- an individual, partnership, corporation, lecular structural features (but not or Government agency and may be a necessarily all of the same structural manufacturer, scientific institution, or features) and is intended for the same an investigator regularly and lawfully use as a previously approved drug, ex- engaged in the investigation of drugs. cept that, if the subsequent drug can be For purposes of the Orphan Drug Act, shown to be clinically superior, it will FDA considers the real party or parties not be considered to be the same drug. in interest to be a sponsor. This criterion will be applied as follows to different kinds of macromolecules: [57 FR 62085, Dec. 29, 1992, as amended at 64 FR 402, Jan. 5, 1999; 64 FR 56449, Oct. 20, 1999] (A) Two protein drugs would be considered the same if the only differences § 316.4 Address for submissions. in structure between them were due to post-translational events or infidelity All correspondence and requests for of translation or transcription or were FDA action pursuant to the provisions minor differences in amino acid se- of this rule should be addressed as fol- quence; other potentially important lows: Office of Orphan Products Devel- differences, such as different glycosyl- opment (HF–35), Food and Drug Admin- ation patterns or different tertiary istration, 5600 Fishers Lane, Rockville, structures, would not cause the drugs MD 20857.

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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 annually in the FEDERAL REGISTER. A orally, or both, at the Director’s dis- request for a copy of the list should be cretion, views and data as to how the directed to the Office of Orphan Prod- holder can assure the availability of ucts Development (HF–35), Food and sufficient quantities of the orphan drug Drug Administration, 5600 Fishers within a reasonable time to meet the Lane, Rockville, MD 20857. needs of patients with the disease or condition for which the drug was des- [65 FR 56480, Sept. 19, 2000] ignated; or (2) Provide the Director in writing § 316.52 Availability for public disclo- the holder’s consent for the approval of sure of data and information in re- other marketing applications for the quests and applications. same drug before the expiration of the (a) FDA will not publicly disclose the 7-year period of exclusive approval. existence of a request for orphan-drug designation under section 526 of the act (b) If, within the time that the Direc- prior to final FDA action on the re- tor specifies, the holder fails to consent quest unless the existence of the re- to the approval of other marketing ap- quest has been previously publicly dis- plications and if the Director finds that closed or acknowledged. the holder has not shown that it can assure the availability of sufficient (b) Whether or not the existence of a quantities of the orphan drug to meet pending request for designation has the needs of patients with the disease been publicly disclosed or acknowl- or condition for which the drug was edged, no data or information in the redesignated, the Director will issue a quest are available for public disclo- written order withdrawing the drug sure prior to final FDA action on the product’s exclusive approval. This request. order will embody the Director’s findings and conclusions and will con- (c) Upon final FDA action on a re- stitute final agency action. An order quest for designation, FDA will deter- withdrawing the sponsor’s exclusive mine the public availability of data marketing rights may issue whether or and information in the request in ac- not there are other sponsors that can cordance with part 20 and § 314.430 of assure the availability of alternative this chapter and other applicable stat- sources of supply. Once withdrawn utes and regulations. under this section, exclusive approval 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. § 316.40 Treatment use of a designated (e) FDA will not publicly disclose the orphan drug. existence of a pending marketing appli- Prospective investigators seeking to cation for a designated orphan drug for obtain treatment use of designated or- the use for which the drug was des- phan drugs may do so as provided in ignated unless the existence of the ap- § 312.34 of this chapter. plication has been previously publicly disclosed or acknowledged.

Subpart F—Availability of (f) FDA will determine the public Information availability of data and information § 316.50 Guidance documents. contained in pending and approved marketing applications for a des- FDA’s Office of Orphan Products De- ignated orphan drug for the use for velopment will maintain and make which the drug was designated in ac- publicly available a list of guidance documents that apply to the regula- cordance with part 20 and § 314.430 of tions in this part. The list is main- this chapter and other applicable stat- tained on the Internet and is published utes and regulations.

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PART 320—BIOAVAILABILITY AND that are not intended to be absorbed BIOEQUIVALENCE REQUIREMENTS into the bloodstream, bioavailability may be assessed by measurements in- Subpart A—General Provisions tended to reflect the rate and extent to which the active ingredient or active Sec. moiety becomes available at the site of 320.1 Definitions. action. Subpart B—Procedures for Determining the (b) Drug product means a finished dos- Bioavailability or Bioequivalence of age form, e.g., tablet, capsule, or solu- Drug Products tion, that contains the active drug ingredient, generally, but not nec- 320.21 Requirements for submission of in essarily, in association with inactive vivo bioavailability and bioequivalence ingredients. 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. modified release dosage forms that re- 320.25 Guidelines for the conduct of an in 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 mul- ingredient over the identical dosing pe- tiple-dose in vivo bioavailability study. riod; do not necessarily contain the 320.28 Correlation of bioavailability with an same inactive ingredients; and meet acute pharmacological effect or clinical 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, where applicable, content uni- and bioequivalence requirements and re- formity, disintegration times, and/or view of protocols by the Food and Drug dissolution rates. Administration. 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 amend- cursor, but not necessarily in the same ing a bioequivalence requirement. amount or dosage form or as the same 320.33 Criteria and evidence to assess actual salt or ester. Each such drug product or potential bioequivalence problems. individually meets either the identical 320.34 Requirements for batch testing and 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 strength, quality, and purity, including each batch. potency and, where applicable, content 320.36 Requirements for maintenance of uniformity, disintegration times and/or records of bioequivalence testing. dissolution rates. 320.38 Retention of bioavailability samples. (e) Bioequivalence means the absence 320.63 Retention of bioequivalence samples. of a significant difference in the rate AUTHORITY: 21 U.S.C. 321, 351, 352, 355, 371. and extent to which the active ingredient or active moiety in pharma- Subpart A—General Provisions ceutical equivalents or pharmaceutical alternatives becomes available at the § 320.1 Definitions. site of drug action when administered (a) Bioavailability means the rate and at the same molar dose under similar extent to which the active ingredient conditions in an appropriately designed or active moiety is absorbed from a study. Where there is an intentional drug product and becomes available at difference in rate (e.g., in certain ex- the site of action. For drug products tended release dosage forms), certain

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pharmaceutical equivalents or alter- FDA to waive the submission of evi- natives may be considered bioequiva- dence demonstrating in vivo bioequivalent if there is no significant difference lence as provided in paragraph (f) of in the extent to which the active ingre- this section. dient or moiety from each product be- (c) Any person submitting a supple- comes available at the site of drug ac- mental application to FDA shall in- tion. This applies only if the difference clude in the supplemental application in the rate at which the active ingre- the evidence or information set forth dient or moiety becomes available at in paragraphs (a) and (b) of this section the site of drug action is intentional if the supplemental application pro- and is reflected in the proposed label- poses any of the following changes: ing, is not essential to the attainment (1) A change in the manufacturing of effective body drug concentrations site or a change in the manufacturing on chronic use, and is considered medi- process, including a change in product cally insignificant for the drug. formulation or dosage strength, beyond (f) Bioequivalence requirement means a the variations provided for in the ap- requirement imposed by the Food and proved application. Drug Administration for in vitro and/or (2) A change in the labeling to pro- in vivo testing of specified drug prod- vide for a new indication for use of the ucts which must be satisfied as a condi- drug product, if clinical studies are re- tion of marketing. quired to support the new indication for use. [42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 17997, Apr. 28, 1992; 67 (3) A change in the labeling to pro- FR 77672, Dec. 19, 2002] vide for a new dosage regimen or for an additional dosage regimen for a special patient population, e.g., infants, if clin- Subpart B—Procedures for Deter- ical studies are required to support the mining the Bioavailability or new or additional dosage regimen. Bioequivalence of Drug Prod- (d) FDA may approve a full new drug ucts application, or a supplemental application proposing any of the changes set SOURCE: 42 FR 1648, Jan. 7, 1977, unless oth- forth in paragraph (c) of this section, erwise noted. that does not contain evidence of in vivo bioavailability or information to § 320.21 Requirements for submission permit waiver of the requirement for in of in vivo bioavailability and bio- vivo bioavailability data, if all of the equivalence data. following conditions are met. (a) Any person submitting a full new (1) The application is otherwise ap- drug application to the Food and Drug provable. Administration (FDA) shall include in (2) The application agrees to submit, the application either: within the time specified by FDA, ei- (1) Evidence measuring the in vivo ther: bioavailability of the drug product that (i) Evidence measuring the in vivo is the subject of the application; or bioavailability and demonstrating the (2) Information to permit FDA to in vivo bioequivalence of the drug waive the submission of evidence meas- product that is the subject of the appli- uring in vivo bioavailability. cation; or (b) Any person submitting an abbre- (ii) Information to permit FDA to viated new drug application to FDA waive measurement of in vivo bio- shall include in the application either: availability. (1) Evidence demonstrating that the (e) Evidence measuring the in vivo drug product that is the subject of the bioavailability and demonstrating the abbreviated new drug application is in vivo bioequivalence of a drug prod- bioequivalent to the reference listed uct shall be obtained using one of the drug (defined in § 314.3(b) of this chap- approaches for determining bio- ter); or availability set forth in § 320.24. (2) Information to show that the drug (f) Information to permit FDA to product is bioequivalent to the ref- waive the submission of evidence meas- erence listed drug which would permit uring the in vivo bioavailability or

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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 gas, e.g., a medicinal or an inhalation (h) The requirements of this section anesthetic; and regarding the submission of evidence (ii) Contains an active ingredient in measuring the in vivo bioavailability the same dosage form as a drug product or demonstrating the in vivo bio- that is the subject of an approved full equivalence apply only to a full or ab- new drug application or abbreviated breviated new drug application or a new drug application. supplemental application for a finished (3) The drug product: dosage formulation. (i) Is a solution for application to the [57 FR 17998, Apr. 28, 1992, as amended at 67 skin, an oral solution, elixir, syrup, FR 77672, Dec. 19, 2002] tincture, a solution for aerosolization or nebulization, a nasal solution, or § 320.22 Criteria for waiver of evidence similar other solubilized form; and of in vivo bioavailability or bio- (ii) Contains an active drug ingre- equivalence. dient in the same concentration and (a) Any person submitting a full or dosage form as a drug product that is abbreviated new drug application, or a the subject of an approved full new supplemental application proposing drug application or abbreviated new any of the changes set forth in drug application; and § 320.21(c), may request FDA to waive (iii) Contains no inactive ingredient the requirement for the submission of or other change in formulation from evidence measuring the in vivo bio- the drug product that is the subject of availability or demonstrating the in the approved full new drug application vivo bioequivalence of the drug product or abbreviated new drug application that is the subject of the application. that may significantly affect absorp- An applicant shall submit a request for tion of the active drug ingredient or waiver with the application. Except as active moiety for products that are provided in paragraph (f) of this sec- systemically absorbed, or that may sig- tion, FDA shall waive the requirement nificantly affect systemic or local for the submission of evidence of in availability for products intended to vivo bioavailability or bioequivalence act locally. if the drug product meets any of the (c) FDA shall waive the requirement provisions of paragraphs (b), (c), (d), or for the submission of evidence meas- (e) of this section. uring the in vivo bioavailability or

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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] availability or bioequivalence of the (2) The drug product is in the same drug product. dosage form, but in a different [57 FR 17998, Apr. 28, 1992, as amended at 67 strength, and is proportionally similar FR 77673, Dec. 19, 2002] in its active and inactive ingredients to another drug product for which the § 320.23 Basis for measuring in vivo same manufacturer has obtained ap- bioavailability or demonstrating proval and the conditions in para- bioequivalence. graphs (d)(2)(i) through (d)(2)(iii) of (a)(1) The in vivo bioavailability of a this section are met: drug product is measured if the prod- (i) The bioavailability of this other uct’s rate and extent of absorption, as drug product has been measured; determined by comparison of measured (ii) Both drug products meet an ap- parameters, e.g., concentration of the propriate in vitro test approved by active drug ingredient in the blood, FDA; and urinary excretion rates, or pharma- (iii) The applicant submits evidence cological effects, do not indicate a sig- showing that both drug products are nificant difference from the reference proportionally similar in their active material’s rate and extent of absorp- and inactive ingredients. tion. For drug products that are not in- (iv) Paragraph (d) of this section does tended to be absorbed into the blood- not apply to delayed release or ex- stream, bioavailability may be as- tended release products. sessed by measurements intended to re- (3) The drug product is, on the basis flect the rate and extent to which the of scientific evidence submitted in the active ingredient or active moiety be- application, shown to meet an in vitro comes available at the site of action. test that has been correlated with in (2) Statistical techniques used shall vivo data. be of sufficient sensitivity to detect

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

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

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

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

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

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

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products, or the method used to meas- (2) General inquiries relating to bio- ure an acute pharmacological effect equivalence requirements and method- shall be demonstrated to be accurate ology shall be submitted to the Food and of sufficient sensitivity to meas- and Drug Administration, Center for ure, with appropriate precision, the ac- Drug Evaluation and Research, Divi- tual concentration of the active drug sion of Bioequivalence (HFD–650), 7500 ingredient or therapeutic moiety, or its Standish Pl., Rockville, MD 20855–2773. active metabolite(s), achieved in the [57 FR 18000, Apr. 28, 1992, as amended at 67 body. FR 77674, Dec. 19, 2002] (b) When the analytical method is 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 (a) Any person planning to conduct fluids or excretory products produced an in vivo bioavailability or bioequiva- by a single dose of the test product, lence study in humans shall submit an two or more single doses may be given ‘‘Investigational New Drug Applica- together to produce higher concentration’’ (IND) if: tion if the requirements of § 320.31 are (1) The test product contains a new met. chemical entity as defined in § 314.108(a) of this chapter; or [42 FR 1648, Jan. 7, 1977, as amended at 67 FR (2) The study involves a radioactively 77674, Dec. 19, 2002] labeled drug product; or (3) The study involves a cytotoxic § 320.30 Inquiries regarding bioavailability and bioequivalence re- drug product. quirements and review of protocols (b) Any person planning to conduct a by the Food and Drug Administra- bioavailability or bioequivalence study tion. in humans using a drug product that contains an already approved, non-new (a) The Commissioner of Food and chemical entity shall submit an IND if Drugs strongly recommends that, to the study is one of the following: avoid the conduct of an improper study (1) A single-dose study in normal sub- and unnecessary human research, any jects or patients where either the max- person planning to conduct a bio- imum single or total daily dose exceeds availability or bioequivalence study that specified in the labeling of the submit the proposed protocol for the drug product that is the subject of an study to FDA for review prior to the approved new drug application or ab- initiation of the study. breviated new drug application. (b) FDA may review a proposed pro- (2) A multiple-dose study in normal tocol for a bioavailability or bioequiva- subjects or patients where either the lence study and will offer advice with single or total daily dose exceeds that respect to whether the following condi- specified in the labeling of the drug tions are met: product that is the subject of an ap- (1) The design of the proposed bio- proved new drug application or abbre- availability or bioequivalence study is viated new drug application. appropriate. (3) A multiple-dose study on a ex- (2) The reference material to be used tended release product on which no sin- in the bioavailability or bioequivalence gle-dose study has been completed. study is appropriate. (c) The provisions of parts 50, 56, and (3) The proposed chemical and statis- 312 of this chapter are applicable to tical analytical methods are adequate. any bioavailability or bioequivalence (c)(1) General inquiries relating to in study in humans conducted under an vivo bioavailability requirements and IND. methodology shall be submitted to the (d) A bioavailability or bioequiva- Food and Drug Administration, Center lence study in humans other than one for Drug Evaluation and Research, Of- described in paragraphs (a) through (c) fice of Clinical Pharmacology and Bio- of this section is exempt from the re- pharmaceutics (HFD–850), 5600 Fishers quirements of part 312 of this chapter if Lane, Rockville, MD 20857. the following conditions are satisfied:

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(1) If the study is one described under formation that was submitted in the § 320.38(b) or § 320.63, the person con- petition as well as other available in- ducting the study, including any con- formation to support the establishment tract research organization, shall re- of a bioequivalence requirement. tain reserve samples of any test article (c) FDA, on its own initiative or in and reference standard used in the response to a petition by an interested study and release the reserve samples person, may propose and promulgate to FDA upon request, in accordance an amendment to a bioequivalence re- with, and for the period specified in, quirement established under this sub- § 320.38; and part. (2) An in vivo bioavailability or bioequivalence study in humans shall be [57 FR 18000, Apr. 28, 1992] conducted in compliance with the re- § 320.33 Criteria and evidence to as- quirements for institutional review set sess actual or potential bioequiva- forth in part 56 of this chapter, and in- lence problems. formed consent set forth in part 50 of this chapter. The Commissioner of Food and Drugs shall consider the following factors, [57 FR 18000, Apr. 28, 1992, as amended at 58 when supported by well-documented FR 25927, Apr. 28, 1993; 67 FR 77674, Dec. 19, evidence, to identify specific pharma- 2002] ceutical equivalents and pharma- § 320.32 Procedures for establishing or ceutical alternatives that are not or amending a bioequivalence require- may not be bioequivalent drug prod- ment. ucts. (a) The Food and Drug Administra- (a) Evidence from well-controlled tion, on its own initiative or in re- clinical trials or controlled observa- sponse to a petition by an interested tions in patients that such drug prod- person, may propose and promulgate a ucts do not give comparable thera- regulation to establish a bioequiva- peutic effects. lence requirement for a product not (b) Evidence from well-controlled subject to section 505(j) of the act if it bioequivalence studies that such prod- finds there is well-documented evi- ucts are not bioequivalent drug prod- dence that specific pharmaceutical ucts. equivalents or pharmaceutical alter- (c) Evidence that the drug products natives intended to be used inter- exhibit a narrow therapeutic ratio, changeably for the same therapeutic e.g., there is less than a 2-fold dif- effect: ference in median lethal dose (LD50) (1) Are not bioequivalent drug prod- and median effective dose (ED50) val- ucts; or ues, or have less than a 2-fold dif- (2) May not be bioequivalent drug ference in the minimum toxic con- products based on the criteria set forth centrations and minimum effective in § 320.33; or concentrations in the blood, and safe (3) May not be bioequivalent drug and effective use of the drug products products because they are members of requires careful dosage titration and a class of drug products that have close patient monitoring. structural similarity and similar phys- (d) Competent medical determination icochemical or pharmacokinetic prop- that a lack of bioequivalence would erties to other drug products in the have a serious adverse effect in the same class that FDA finds are not bio- treatment or prevention of a serious equivalent drug products. disease or condition. (b) FDA shall include in a proposed (e) Physicochemical evidence that: rule to establish a bioequivalence re- (1) The active drug ingredient has a quirement the evidence and criteria set low solubility in water, e.g., less than 5 forth in § 320.33 that are to be consid- milligrams per 1 milliliter, or, if dis- ered in determining whether to issue solution in the stomach is critical to the proposal. If the rulemaking is pro- absorption, the volume of gastric fluids posed in response to a petition, FDA required to dissolve the recommended shall include in the proposal a sum- dose far exceeds the volume of fluids mary and analysis of the relevant in- present in the stomach (taken to be 100

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milliliters for adults and prorated for (5) The active drug ingredient or infants and children). therapeutic moiety is unstable in spe- (2) The dissolution rate of one or cific portions of the gastrointestinal more such products is slow, e.g., less tract and requires special coatings or than 50 percent in 30 minutes when formulations, e.g., buffers, enteric tested using either a general method coatings, and film coatings, to assure specified in an official compendium or adequate absorption. a paddle method at 50 revolutions per (6) The drug product is subject to minute in 900 milliliters of distilled or dose dependent kinetics in or near the deionized water at 37° C, or differs sig- therapeutic range, and the rate and ex- nificantly from that of an appropriate tent of absorption are important to reference material such as an identical bioequivalence. drug product that is the subject of an [42 FR 1635, Jan. 7, 1977. Redesignated and approved full new drug application. amended at 57 FR 18001, Apr. 28, 1992] (3) The particle size and/or surface area of the active drug ingredient is § 320.34 Requirements for batch test- critical in determining its bio- ing and certification by the Food availability. and Drug Administration. (4) Certain physical structural char- (a) If the Commissioner determines acteristics of the active drug ingre- that individual batch testing by the dient, e.g., polymorphic forms, con- Food and Drug Administration is nec- forms, solvates, complexes, and crystal essary to assure that all batches of the modifications, dissolve poorly and this same drug product meet an appropriate poor dissolution may affect absorption. in vitro test, he shall include in the (5) Such drug products have a high bioequivalence requirement a require- ratio of excipients to active ingredi- ment for manufacturers to submit sam- ents, e.g., greater than 5 to 1. ples of each batch to the Food and (6) Specific inactive ingredients, e.g., Drug Administration and to withhold hydrophilic or hydrophobic excipients distribution of the batch until notified and lubricants, either may be required by the Food and Drug Administration for absorption of the active drug ingre- that the batch may be introduced into dient or therapeutic moiety or, alter- interstate commerce. natively, if present, may interfere with (b) The Commissioner will ordinarily such absorption. terminate a requirement for a manu- (f) Pharmacokinetic evidence that: facturer to submit samples for batch (1) The active drug ingredient, thera- testing on a finding that the manufac- peutic moiety, or its precursor is ab- turer has produced four consecutive sorbed in large part in a particular seg- batches that were tested by the Food ment of the gastrointestinal tract or is and Drug Administration and found to absorbed from a localized site. meet the bioequivalence requirement, (2) The degree of absorption of the ac- unless the public health requires that tive drug ingredient, therapeutic moi- batch testing be extended to additional ety, or its precursor is poor, e.g., less batches. than 50 percent, ordinarily in comparison to an intravenous dose, even when [42 FR 1635, Jan. 7, 1977. Redesignated at 57 it is administered in pure form, e.g., in FR 18001, Apr. 28, 1992] solution. § 320.35 Requirements for in vitro test- (3) There is rapid metabolism of the ing of each batch. therapeutic moiety in the intestinal wall or liver during the process of ab- If a bioequivalence requirement sorption (first-class metabolism) so the specifies a currently available in vitro therapeutic effect and/or toxicity of test or an in vitro bioequivalence such drug product is determined by the standard comparing the drug product rate as well as the degree of absorp- to a reference standard, the manufac- tion. turer shall conduct the test on a sam- (4) The therapeutic moiety is rapidly ple of each batch of the drug product to metabolized or excreted so that rapid assure batch-to-batch uniformity. dissolution and absorption are required [42 FR 1635, Jan. 7, 1977. Redesignated at 57 for effectiveness. FR 18001, Apr. 28, 1992]

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§ 320.36 Requirements for mainte- erence standard provided by the appli- nance of records of bioequivalence cant for the testing. testing. (b) Reserve samples shall be retained (a) All records of in vivo or in vitro for the following test articles and ref- tests conducted on any marketed batch erence standards and for the studies de- of a drug product to assure that the scribed: product meets a bioequivalence re- (1) If the formulation of the test arti- quirement shall be maintained by the cle is the same as the formulation(s) manufacturer for at least 2 years after used in the clinical studies dem- the expiration date of the batch and onstrating substantial evidence of safe- submitted to the Food and Drug Ad- ty and effectiveness for the test arti- ministration on request. cle’s claimed indications, a reserve (b) Any person who contracts with sample of the test article used to con- another party to conduct a bioequiva- duct an in vivo bioavailability study lence study from which the data are in- comparing the test article to a ref- tended to be submitted to FDA as part erence oral solution, suspension, or in- of an application submitted under part jection. 314 of this chapter shall obtain from (2) If the formulation of the test arti- the person conducting the study suffi- cle differs from the formulation(s) used cient accurate financial information to in the clinical studies demonstrating allow the submission of complete and substantial evidence of safety and ef- accurate financial certifications or dis- fectiveness for the test article’s closure statements required under part claimed indications, a reserve sample 54 of this chapter and shall maintain of the test article and of the reference that information and all records relat- standard used to conduct an in vivo ing to the compensation given for that bioequivalence study comparing the study and all other financial interest test article to the formulation(s) (ref- information required under part 54 of erence standard) used in the clinical this chapter for 2 years after the date studies. of approval of the application. The per- (3) For a new formulation, new dos- son maintaining these records shall, age form, or a new salt or ester of an upon request for any properly author- active drug ingredient or therapeutic ized officer or employee of the Food moiety that has been approved for mar- and Drug Administration, at reason- keting, a reserve sample of the test ar- able time, permit such officer or em- ticle and of the reference standard used ployee to have access to and copy and to conduct an in vivo bioequivalence verify these records. study comparing the test article to a [42 FR 1635, Jan. 7, 1977. Redesignated at 57 marketed product (reference standard) FR 18001, Apr. 28, 1992, as amended at 63 FR that contains the same active drug in- 5252, Feb. 2, 1998] gredient or therapeutic moiety. (c) Each reserve sample shall consist § 320.38 Retention of bioavailability of a sufficient quantity to permit FDA samples. to perform five times all of the release (a) The applicant of an application or tests required in the application or supplemental application submitted supplemental application. 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

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which the application or supplemental address of the facility to which the re- application is approved, or, if such ap- serve samples have been transferred. plication or supplemental application is not approved, at least 5 years fol- [58 FR 25927, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999] lowing the date of completion of the bioavailability study in which the sam- § 320.63 Retention of bioequivalence ple from which the reserve sample was samples. obtained was used. (f) Authorized FDA personnel will or- The applicant of an abbreviated ap- dinarily collect reserve samples di- plication or a supplemental application rectly from the applicant or contract submitted under section 505 of the Fed- research organization at the storage eral Food, Drug, and Cosmetic Act, or, site during a preapproval inspection. If if bioequivalence testing was per- authorized FDA personnel are unable formed under contract, the contract re- to collect samples, FDA may require search organization shall retain re- the applicant or contract research or- serve samples of any test article and ganization to submit the reserve sam- reference standard used in conducting ples to the place identified in the agen- an in vivo or in vitro bioequivalence cy’s request. If FDA has not collected study required for approval of the ab- or requested delivery of a reserve sam- breviated application or supplemental ple, or if FDA has not collected or re- application. The applicant or contract quested delivery of any portion of a re- research organization shall retain the serve sample, the applicant or contract reserve samples in accordance with, research organization shall retain the and for the period specified in, § 320.38 sample or remaining sample for the 5- and shall release the reserve samples to year period specified in paragraph (e) FDA upon request in accordance with of this section. § 320.38. (g) Upon release of the reserve samples to FDA, the applicant or contract [58 FR 25928, Apr. 28, 1993, as amended at 64 research organization shall provide a FR 402, Jan. 5, 1999] written assurance that, to the best knowledge and belief of the individual PART 328—OVER-THE-COUNTER executing the assurance, the reserve DRUG PRODUCTS INTENDED FOR samples came from the same samples ORAL INGESTION THAT CONTAIN as used in the specific bioavailability or bioequivalence study identified by ALCOHOL the agency. The assurance shall be executed by an individual authorized to Subpart A—General Provisions act for the applicant or contract re- Sec. search organization in releasing the re- 328.1 Scope. serve samples to FDA. 328.3 Definitions. (h) A contract research organization may contract with an appropriate, Subpart B—Ingredients independent third party to provide storage of reserve samples provided 328.10 Alcohol. that the sponsor of the study has been notified in writing of the name and ad- Subpart C—Labeling dress of the facility at which the re- 328.50 Principal display panel of all OTC serve samples will be stored. drug products intended for oral ingestion (i) If a contract research organization that contain alcohol. conducting a bioavailability or bioequivalence study that requires reserve AUTHORITY: Secs. 201, 301, 501, 502, 503, 505, 701 of the Federal Food, Drug, and Cosmetic sample retention under this section or Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 371). § 320.63 goes out of business, it shall transfer its reserve samples to an ap- SOURCE: 60 FR 13595, Mar. 13, 1995, unless propriate, independent third party, and otherwise noted. shall notify in writing the sponsor of EDITORIAL NOTE: Nomenclature changes to the study of the transfer and provide part 328 can be found at 69 FR 13717, Mar. 24, the study sponsor with the name and 2004.

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Subpart A—General Provisions Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. § 328.1 Scope. (f) Ipecac syrup is exempt from the Reference in this part to regulatory provisions of paragraph (d) of this sec- sections of the Code of Federal Regula- tion. (g) The following drugs are tempo- tions are to chapter I of title 21 unless rarily exempt from the provisions of otherwise noted. paragraphs (b), (c), and (d) of this sec- § 328.3 Definitions. tion: (1) Aromatic Cascara Fluidextract. As used in this part: (2) Cascara Sagrada Fluidextract. (a) Alcohol means the substance (3) Orally ingested homeopathic drug known as ethanol, ethyl alcohol, or Al- products. cohol, USP. (b) Inactive ingredient means any com- [60 FR 13595, Mar. 13, 1995, as amended at 61 ponent of a product other than an ac- FR 58630, Nov. 18, 1996; 68 FR 24879, May 9, 2003] tive ingredient as defined in § 210.3(b)(7) of this chapter. Subpart C—Labeling Subpart B—Ingredients § 328.50 Principal display panel of all OTC drug products intended for § 328.10 Alcohol. oral ingestion that contain alcohol. (a) Any over-the-counter (OTC) drug (a) The amount (percentage) of alco- product intended for oral ingestion hol present in a product shall be stated shall not contain alcohol as an inactive in terms of percent volume of absolute ingredient in concentrations that ex- alcohol at 60 °F (15.56 °C) in accordance ceed those established in this part, un- with § 201.10(d)(2) of this chapter. less a specific exemption, as provided (b) A statement expressing the in paragraph (e) or (f) of this section, amount (percentage) of alcohol present has been approved. in a product shall appear prominently (b) For any OTC drug product in- and conspicuously on the ‘‘principal tended for oral ingestion and labeled display panel,’’ as defined in § 201.60 of for use by adults and children 12 years this chapter. For products whose prin- of age and over, the amount of alcohol cipal display panel is on the immediate in the product shall not exceed 10 per- container label and that are not mar- cent. keted in another retail package (e.g., (c) For any OTC drug product in- an outer box), the statement of the per- tended for oral ingestion and labeled centage of alcohol present in the prod- for use by children 6 to under 12 years uct shall appear prominently and con- of age, the amount of alcohol in the spicuously on the ‘‘principal display product shall not exceed 5 percent. panel’’ of the immediate container (d) For any OTC drug product in- label. tended for oral ingestion and labeled (c) For products whose principal dis- for use by children under 6 years of play panel is on the retail package and age, the amount of alcohol in the prod- the retail package is not the imme- uct shall not exceed 0.5 percent. diate container, the statement of the (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

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the package rests as it is designed to be nized as safe and effective and not mis- displayed. branded. (e) For a product to state in its label- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, ing that it is ‘‘alcohol free,’’ it must 360, 371. contain no alcohol (0 percent). (f) For any OTC drug product in- SOURCE: 39 FR 11741, Mar. 29, 1974, unless tended for oral ingestion containing otherwise noted. over 5 percent alcohol and labeled for EDITORIAL NOTE: Nomenclature changes to use by adults and children 12 years of part 330 can be found at 69 FR 13717, Mar. 24, age and over, the labeling shall contain 2004. the following statement in the directions section: ‘‘Consult a physician for Subpart A—General Provisions use in children under 12 years of age.’’ (g) For any OTC drug product in- § 330.1 General conditions for general tended for oral ingestion containing recognition as safe, effective and over 0.5 percent alcohol and labeled for not misbranded. use by children ages 6 to under 12 years An over-the-counter (OTC) drug list- of age, the labeling shall contain the ed in this subchapter is generally rec- following statement in the directions ognized as safe and effective and is not section: ‘‘Consult a physician for use in misbranded if it meets each of the con- children under 6 years of age.’’ ditions contained in this part and each (h) When the direction regarding age in paragraph (e) or (f) of this section of the conditions contained in any ap- differs from an age-limiting direction plicable monograph. Any product contained in any OTC drug monograph which fails to conform to each of the in this chapter, the direction con- conditions contained in this part and taining the more stringent age limita- in an applicable monograph is liable to tion shall be used. regulatory action. (a) The product is manufactured in PART 330—OVER-THE-COUNTER compliance with current good manu- (OTC) HUMAN DRUGS WHICH facturing practices, as established by ARE GENERALLY RECOGNIZED parts 210 and 211 of this chapter. AS SAFE AND EFFECTIVE AND (b) The establishment(s) in which the NOT MISBRANDED drug product is manufactured is registered, and the drug product is listed, Subpart A—General Provisions in compliance with part 207 of this chapter. It is requested but not re- Sec. quired that the number assigned to the 330.1 General conditions for general rec- product pursuant to part 207 of this ognition as safe, effective and not misbranded. chapter appear on all drug labels and in 330.2 Pregnancy–nursing warning. all drug labeling. If this number is 330.3 Imprinting of solid oral dosage form used, it shall be placed in the manner drug products. set forth in part 207 of this chapter. 330.5 Drug categories. (c)(1) The product is labeled in com- Subpart B—Administrative Procedures pliance with chapter V of the Federal Food, Drug, and Cosmetic Act (the act) 330.10 Procedures for classifying OTC drugs and subchapter C et seq. of this chapter, as generally recognized as safe and effec- including the format and content re- tive and not misbranded, and for estab- quirements in § 201.66 of this chapter. lishing monographs. 330.11 NDA deviations from applicable An OTC drug product that is not in monograph. compliance with chapter V and sub- 330.12 Status of over-the-counter (OTC) chapter C, including § 201.66 of this drugs previously reviewed under the chapter, is subject to regulatory ac- Drug Efficacy Study (DESI). tion. For purposes of § 201.61(b) of this 330.13 Conditions for marketing ingredients chapter, the statement of identity of recommended for over-the-counter (OTC) use under the OTC drug review. the product shall be the term or phrase 330.14 Additional criteria and procedures for used in the applicable OTC drug mono- classifying OTC drugs as generally recog- graph established in this part.

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(2) The ‘‘Uses’’ section of the label help or contact a Poison Control Cen- and labeling of the product shall con- ter right away.’’ The Food and Drug tain the labeling describing the ‘‘Indi- Administration will grant an exemp- cations’’ that have been established in tion from these general warnings where an applicable OTC drug monograph or appropriate upon petition, which shall alternative truthful and nonmisleading be maintained in a permanent file for statements describing only those indi- public review by the Division of Dock- cations for use that have been estab- ets Management, Food and Drug Ad- lished in an applicable monograph, sub- ministration, 5630 Fishers Lane, rm. ject to the provisions of section 502 of 1061, Rockville, MD 20852. the act relating to misbranding and the (h) Where no maximum daily dosage prohibition in section 301(d) of the act limit for an active ingredient is estab- against the introduction or delivery for lished in this part, it is used in a prod- introduction into interstate commerce uct at a level that does not exceed the of unapproved new drugs in violation of amount reasonably required to achieve section 505(a) of the act. Any other la- its intended effect. beling under this subchapter and sub- (i) The following terms may be used chapter C et seq. of this chapter shall be interchangeably in the labeling of OTC stated in the exact language where drug products, provided such use does exact language has been established not alter the meaning of the labeling and identified by quotation marks in that has been established and identi- an applicable OTC drug monograph or fied in an applicable monograph or by by regulation (e.g., § 201.63 of this chap- regulation. The following terms shall ter), except as provided in paragraphs not be used to change in any way the (i) and (j) of this section. title, headings, and subheadings re- (d) The advertising for the product quired under § 201.66(c)(1) through (c)(9) prescribes, recommends, or suggests its of this chapter: use only under the conditions stated in (1) ‘‘Abdominal’’ or ‘‘stomach’’ (in the labeling. context only). (e) The product contains only suit- (2) ‘‘Administer’’ or ‘‘give’’. able inactive ingredients which are (3) ‘‘Aggravate(s)’’ or ‘‘make(s) safe in the amounts administered and worse’’. do not interfere with the effectiveness (4) ‘‘Application of this product’’ or of the preparation or with suitable ‘‘applying’’. tests or assays to determine if the (5) ‘‘Are uncertain’’ or ‘‘do not product meets its professed standards know’’. of identity, strength, quality, and pu- (6) ‘‘Ask’’ or ‘‘consult’’ or ‘‘contact’’. rity. Color additives may be used only (7) ‘‘Asking’’ or ‘‘consulting’’. in accordance with section 721 of the (8) ‘‘Assistance’’ or ‘‘help’’ or ‘‘aid’’. act and subchapter A of this chapter. (9) ‘‘Associated with’’ or ‘‘due to’’ or (f) The product container and con- ‘‘caused by’’. tainer components meet the requirements of § 211.94 of this chapter. (10) ‘‘Avoid contact with eyes’’ or ‘‘do (g) The labeling for all drugs contains not get into eyes’’. the general warning: ‘‘Keep out of (11) ‘‘Avoid inhaling’’ or ‘‘do not in- reach of children.’’ [highlighted in bold hale’’. type]. The labeling of drugs shall also (12) ‘‘Before a doctor is consulted’’ or state as follows: For drugs used by oral ‘‘without first consulting your doctor’’ administration, ‘‘In case of overdose, or ‘‘consult your doctor before’’. get medical help or contact a Poison (13) ‘‘Beverages’’ or ‘‘drinks’’. Control Center right away’’; for drugs (14) ‘‘Clean’’ or ‘‘cleanse’’. used topically, rectally, or vaginally (15) ‘‘Consulting’’ or ‘‘advising’’. and not intended for oral ingestion, ‘‘If (16) ‘‘Continue(s)’’ or ‘‘persist(s)’’ or swallowed, get medical help or contact ‘‘is persistent’’ or ‘‘do(es) not go away’’ a Poison Control Center right away’’; or ‘‘last(s)’’. and for drugs used topically and in- (17) ‘‘Daily’’ or ‘‘every day’’. tended for oral use, ‘‘If more than used (18) ‘‘Develop(s)’’ or ‘‘begin(s)’’ or for’’ (insert intended use, e.g., pain) ‘‘is ‘‘occur(s)’’. accidentally swallowed, get medical (19) ‘‘Difficulty’’ or ‘‘trouble’’.

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(20) ‘‘Difficulty in urination’’ or (56) ‘‘Passages’’ or ‘‘passageways’’ or ‘‘trouble urinating’’. ‘‘tubes’’. (21) ‘‘Discard’’ or ‘‘throw away’’. (57) ‘‘Perforation of’’ or ‘‘hole in’’. (22) ‘‘Discontinue’’ or ‘‘stop’’ or (58) ‘‘Persistent’’ or ‘‘that does not go ‘‘quit’’. away’’ or ‘‘that continues’’ or ‘‘that (23) ‘‘Doctor’’ or ‘‘physician’’. lasts’’. (24) ‘‘Drowsiness’’ or ‘‘the drowsiness (59) ‘‘Per day’’ or ‘‘daily’’. effect’’. (60) ‘‘Presently’’ or ‘‘now’’. (25) ‘‘Drowsiness may occur’’ or ‘‘you (61) ‘‘Produce(s)’’ or ‘‘cause(s)’’. may get drowsy’’. (62) ‘‘Prompt(ly)’’ or ‘‘quick(ly)’’ or (26) ‘‘Enlargement of the’’ or ‘‘an en- ‘‘right away’’. larged’’. (63) ‘‘Reduce’’ or ‘‘minimize’’. (27) ‘‘Especially in children’’ or espe- (64) ‘‘Referred to as’’ or ‘‘of’’. cially children’’. (65) ‘‘Sensation’’ or ‘‘feeling’’. (28) ‘‘Exceed’’ or ‘‘use more than’’ or (66) ‘‘Solution’’ or ‘‘liquid’’. ‘‘go beyond’’. (67) ‘‘Specifically’’ or ‘‘definitely’’. (29) ‘‘Exceed recommended dosage’’ (68) ‘‘Take’’ or ‘‘use’’ or ‘‘give’’. or ‘‘use more than directed’’. (69) ‘‘Tend(s) to recur’’ or ‘‘reoc- (30) ‘‘Excessive’’ or ‘‘too much’’. cur(s)’’ or ‘‘return(s)’’ or ‘‘come(s) (31) ‘‘Excitability may occur’’ or back’’. ‘‘you may get excited’’. (70) ‘‘To avoid contamination’’ or (32) ‘‘Experience’’ or ‘‘feel’’. ‘‘avoid contamination’’ or ‘‘do not con- (33) ‘‘For relief of’’ or ‘‘relieves’’. taminate’’. (34) ‘‘For temporary reduction of’’ or (71) ‘‘To help’’ or ‘‘helps’’. ‘‘temporarily reduces’’. (72) ‘‘Unless directed by a doctor’’ or ‘‘except under the advice of a doctor’’ (35) ‘‘For the temporary relief of’’ or or ‘‘unless told to do so by a doctor’’. ‘‘temporarily relieves’’. (73) ‘‘Use caution’’ or ‘‘be careful’’. (36) ‘‘For the treatment of’’ or (74) ‘‘Usually’’ or ‘‘generally’’ (in con- ‘‘treats’’. text only). (37) ‘‘Frequently’’ or ‘‘often’’. (75) ‘‘You’’ (‘‘Your’’) or ‘‘the child’’ (38) ‘‘Give to’’ or ‘‘use in’’. (‘‘the child’s’’). (39) ‘‘Immediately’’ or ‘‘right away’’ (76) ‘‘You also have’’ or ‘‘occurs or ‘‘directly’’. with’’. (40) ‘‘Immediately’’ or ‘‘as soon as’’. (77) ‘‘When practical’’ or ‘‘if pos- (41) ‘‘Immediately following’’ or sible’’. ‘‘right after’’. (78) ‘‘Whether’’ or ‘‘if’’. (42) ‘‘Improve(s)’’ or ‘‘get(s) better’’ (79) ‘‘Worsen(s)’’ or ‘‘get(s) worse’’ or or ‘‘make(s) better’’. ‘‘make(s) worse’’. (43) ‘‘Increased’’ or ‘‘more’’. (j) The following connecting terms (44) ‘‘Increase your risk of’’ or may be deleted from the labeling of ‘‘cause’’. OTC drug products, provided such dele- (45) ‘‘Indication(s)’’ or ‘‘Use(s)’’. tion does not alter the meaning of the (46) ‘‘Inhalation’’ or ‘‘puff’’. labeling that has been established and (47) ‘‘In persons who’’ or ‘‘if you’’ or identified in an applicable monograph ‘‘if the child’’. or by regulation. The following terms (48) ‘‘Instill’’ or ‘‘put’’. shall not be used to change in any way (49) ‘‘Is (are) accompanied by’’ or the specific title, headings, and sub- ‘‘you also have’’ (in context only) or headings required under § 201.66(c)(1) ‘‘(optional: that) occur(s) with’’. through (c)(9) of this chapter: (50) ‘‘Longer’’ or ‘‘more’’. (l) ‘‘And’’. (51) ‘‘Lung’’ or ‘‘pulmonary’’. (2) ‘‘As may occur with’’. (52) ‘‘Medication(s)’’ or ‘‘medicine(s)’’ (3) ‘‘Associated’’ or ‘‘to be associ- or ‘‘drug(s)’’. ated’’. (53) ‘‘Nervousness, dizziness, or sleep- (4) ‘‘Consult a doctor’’. lessness occurs’’ or ‘‘you get nervous, (5) ‘‘Discontinue use’’. dizzy, or sleepless’’. (6) ‘‘Drug Interaction Precaution’’. (54) ‘‘Not to exceed’’ or ‘‘do not ex- (7) ‘‘Due to’’. ceed’’ or ‘‘not more than’’. (8) ‘‘Except under the advice and su- (55) ‘‘Obtain(s)’’ or ‘‘get(s)’’. pervision of a physician’’.

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(9) ‘‘If this occurs’’. (o) Analgesics. (10) ‘‘In case of’’. (p) Sedatives and sleep aids. (11) ‘‘Notice’’. (q) Stimulants. (12) ‘‘Or’’. (r) Antitussives. (13) ‘‘Occurring with’’. (s) Allergy treatment products. (14) ‘‘Or as directed by a doctor’’. (t) Cold remedies. (15) ‘‘Such as’’. (u) Antirheumatic products. (16) ‘‘Such as occurs with’’. (v) Ophthalmic products. (17) ‘‘Tends to’’. (w) Contraceptive products. (18) ‘‘This product’’. (x) Miscellaneous dermatologic prod- (19) ‘‘Unless directed by a doctor’’. ucts. (20) ‘‘While taking this product’’ or (y) Dentifrices and dental products ‘‘before taking this product’’. such as analgesics, antiseptics, etc. (21) ‘‘Within’’. (z) Miscellaneous (all other OTC [39 FR 11741, Mar. 29, 1974, as amended at 40 drugs not falling within one of the FR 11718, Mar. 13, 1975; 40 FR 13496, Mar. 27, above therapeutic categories). 1975; 42 FR 15674, Mar. 22, 1977; 46 FR 8459, Jan. 27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR Subpart B—Administrative 16266, May 1, 1986; 55 FR 11581, Mar. 29, 1990; 59 FR 4000, Jan. 28, 1994; 59 FR 14365, Mar. 28, Procedures 1994; 64 FR 13294, Mar. 17, 1999; 68 FR 24879, May 9, 2003] § 330.10 Procedures for classifying OTC drugs as generally recognized § 330.2 Pregnancy-nursing warning. as safe and effective and not misbranded, and for establishing mono- A pregnancy-nursing warning for graphs. OTC drugs is set forth under § 201.63 of this chapter. For purposes of classifying over-the- counter (OTC) drugs as drugs generally [47 FR 54758, Dec. 3, 1982] recognized among qualified experts as safe and effective for use and as not § 330.3 Imprinting of solid oral dosage misbranded drugs, the following regu- form drug products. lations shall apply: A requirement to imprint an identi- (a) Procedure for establishing OTC drug fication code on solid oral dosage form monographs—(1) Advisory review panels. drug products is set forth under part The Commissioner shall appoint advi- 206 of this chapter. sory review panels of qualified experts [58 FR 47959, Sept. 13, 1993] to evaluate the safety and effectiveness of OTC drugs, to review OTC drug la- § 330.5 Drug categories. beling, and to advise him on the pro- Monographs promulgated pursuant to mulgation of monographs establishing the provisions of this part shall be es- conditions under which OTC drugs are tablished in this part 330 and following generally recognized as safe and effec- parts and shall cover the following des- tive and not misbranded. A single advi- ignated categories: sory review panel shall be established (a) Antacids. for each designated category of OTC (b) Laxatives. drugs and every OTC drug category (c) Antidiarrheal products. will be considered by a panel. The (d) Emetics. members of a panel shall be qualified (e) Antiemetics. experts (appointed by the Commis- (f) Antiperspirants. sioner) and may include persons from (g) Sunburn prevention and treat- lists submitted by organizations rep- ment products. resenting professional, consumer, and (h) Vitamin-mineral products. industry interests. The Commissioner (i) Antimicrobial products. shall designate the chairman of each (j) Dandruff products. panel. Summary minutes of all meet- (k) Oral hygiene aids. ings shall be made. (l) Hemorrhoidal products. (2) Request for data and views. The (m) Hematinics. Commissioner will publish a notice in (n) Bronchodilator and antiasthmatic the FEDERAL REGISTER requesting in- products. terested persons to submit, for review

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and evaluation by an advisory review 3. Documented case reports. Identify ex- panel, published and unpublished data pected or frequently reported side effects. and information pertinent to a des- 4. Pertinent marketing experiences that ignated category of OTC drugs. Data may influence a determination as to the safety of each individual active component. and information submitted pursuant to 5. Pertinent medical and scientific lit- a published notice, and falling within erature. the confidentiality provisions of 18 B. Combinations of the individual active U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. components. 331(j), shall be handled by the advisory 1. Controlled studies. review panel and the Food and Drug 2. Partially controlled or uncontrolled Administration as confidential until studies. 3. Documented case reports. Identify ex- publication of a proposed monograph pected or frequently reported side effects. and the full report(s) of the panel or 4. Pertinent marketing experiences that until the Commissioner places the may influence a determination as to the panel’s recommendations on public dis- safety of combinations of the individual ac- play at the office of the Division of tive components. Dockets Management. Thirty days 5. Pertinent medical and scientific lit- thereafter such data and information erature. C. Finished drug product. shall be made publicly available and 1. Controlled studies. may be viewed at the office of the Divi- 2. Partially controlled or uncontrolled sion of Dockets Management of the studies. Food and Drug Administration, except 3. Documented case reports. Identify ex- to the extent that the person submit- pected or frequently reported side effects. ting it demonstrates that it still falls 4. Pertinent marketing experiences that within the confidentiality provisions of may influence a determination as to the safety of the finished drug product. one or more of those statutes. To be 5. Pertinent medical and scientific lit- considered, eight copies of the data erature. and/or views on any marketed drug V. Efficacy data. within the class must be submitted, A. Individual active components. preferably bound, indexed, and on 1. Controlled studies. standard sized paper (approximately 2. Partially controlled or uncontrolled studies. 81⁄2×11 inches). When requested, abbre- 3. Documented case reports. Identify ex- viated submissions should be sent. All pected or frequently reported side effects. submissions must be in the following 4. Pertinent marketing experiences that format: may influence a determination on the efficacy of each individual active component. OTC DRUG REVIEW INFORMATION 5. Pertinent medical and scientific lit- I. Label(s) and all labeling (preferably erature. mounted and filed with the other data—fac- B. Combinations of the individual active simile labeling is acceptable in lieu of actual components. container labeling). 1. Controlled studies. II. A statement setting forth the quan- 2. Partially controlled or uncontrolled tities of active ingredients of the drug. studies. III. Animal safety data. 3. Documented case reports. Identify ex- A. Individual active components. pected or frequently reported side effects. 1. Controlled studies. 4. Pertinent marketing experiences that 2. Partially controlled or uncontrolled may influence a determination on the effi- studies. cacy of combinations of the individual active B. Combinations of the individual active components. components. 5. Pertinent medical and scientific lit- 1. Controlled studies. erature. 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.

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VI. A summary of the data and views set- final monographs, shall apply the fol- ting forth the medical rationale and purpose lowing standards to determine general (or lack thereof) for the drug and its ingredi- recognition that a category of OTC ents and the scientific basis (or lack thereof) for the conclusion that the drug and its in- drugs is safe and effective and not mis- gredients have been proven safe and effective branded: for the intended use. If there is an absence of (i) Safety means a low incidence of controlled studies in the material submitted, adverse reactions or significant side ef- an explanation as to why such studies are fects under adequate directions for use not considered necessary must be included. and warnings against unsafe use as VII. An official United States Pharma- well as low potential for harm which copeia (USP)–National Formulary (NF) drug may result from abuse under condi- monograph for the active ingredient(s) or botanical drug substance(s), or a proposed tions of widespread availability. Proof standard for inclusion in an article to be rec- of safety shall consist of adequate tests ognized in an official USP–NF drug mono- by methods reasonably applicable to graph for the active ingredient(s) or botan- show the drug is safe under the pre- ical drug substance(s). Include information scribed, recommended, or suggested showing that the official or proposed conditions of use. This proof shall in- compendial monograph for the active ingre- clude results of significant human ex- dient or botanical drug substance is consistent with the active ingredient or botan- perience during marketing. General ical drug substance used in the studies estab- recognition of safety shall ordinarily lishing safety and effectiveness and with the be based upon published studies which active ingredient or botanical drug sub- may be corroborated by unpublished stance marketed in the OTC product(s) to a studies and other data. material extent and for a material time. If (ii) Effectiveness means a reasonable differences exist, explain why. expectation that, in a significant pro- (3) Deliberations of an advisory review portion of the target population, the panel. An advisory review panel will pharmacological effect of the drug, meet as often and for as long as is ap- when used under adequate directions propriate to review the data submitted for use and warnings against unsafe to it and to prepare a report containing use, will provide clinically significant its conclusions and recommendations relief of the type claimed. Proof of ef- to the Commissioner with respect to fectiveness shall consist of controlled the safety and effectiveness of the clinical investigations as defined in drugs in a designated category of OTC § 314.126(b) of this chapter, unless this drugs. A panel may consult any indi- requirement is waived on the basis of a vidual or group. Any interested person showing that it is not reasonably appli- may request an opportunity to present cable to the drug or essential to the va- oral views to the panel; such request lidity of the investigation and that an may be granted or denied by the panel. alternative method of investigation is Such requests for oral presentations adequate to substantiate effectiveness. should be in written form including a Investigations may be corroborated by summarization of the data to be pre- partially controlled or uncontrolled sented to the panel. Any interested studies, documented clinical studies by person may present written data and qualified experts, and reports of signifi- views which shall be considered by the cant human experience during mar- panel. This information shall be pre- keting. Isolated case reports, random sented to the panel in the format set experience, and reports lacking the de- forth in paragraph (a)(2) of this section tails which permit scientific evalua- and within the time period established tion will not be considered. General for the drug category in the notice for recognition of effectiveness shall ordi- review by a panel. narily be based upon published studies (4) Standards for safety, effectiveness, which may be corroborated by unpub- and labeling. The advisory review panel, lished studies and other data. in reviewing the data submitted to it (iii) The benefit-to-risk ratio of a and preparing its conclusions and rec- drug shall be considered in determining ommendations, and the Commissioner, safety and effectiveness. in reviewing the conclusions and rec- (iv) An OTC drug may combine two ommendations of the panel and the or more safe and effective active ingre- published proposed, tentative, and the dients and may be generally recognized

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as safe and effective when each active (ii) A statement of active ingredi- ingredient makes a contribution to the ents, labeling claims or other state- claimed effect(s); when combining of ments, or other conditions reviewed the active ingredients does not de- and excluded from the monograph on crease the safety or effectiveness of the basis of the panel’s determination any of the individual active ingredi- that they would result in the drug’s ents; and when the combination, when not being generally recognized as safe used under adequate directions for use and effective or would result in mis- and warnings against unsafe use, pro- branding (Category II). vides rational concurrent therapy for a (iii) A statement of active ingredi- significant proportion of the target ents, labeling claims or other state- population. ments, or other conditions reviewed (v) Labeling shall be clear and truth- and excluded from the monograph on ful in all respects and may not be false the basis of the panel’s determination or misleading in any particular. It that the available data are insufficient shall state the intended uses and re- to classify such condition under either sults of the product; adequate direc- paragraph (a)(5) (i) or (ii) of this sections for proper use; and warnings tion and for which further testing is against unsafe use, side effects, and ad- therefore required (Category III). The verse reactions in such terms as to report may recommend the type of fur- render them likely to be read and un- ther testing required and the time pe- derstood by the ordinary individual, in- riod within which it might reasonably cluding individuals of low comprehen- be concluded. sion, under customary conditions of (6) Proposed monograph. After review- purchase and use. ing the conclusions and recommendations of the advisory review panel, the (vi) A drug shall be permitted for Commissioner shall publish in the FED- OTC sale and use by the laity unless, ERAL REGISTER a proposed order con- because of its toxicity or other poten- taining: tial for harmful effect or because of the (i) A monograph or monographs es- method or collateral measures nec- tablishing conditions under which a essary to its use, it may safely be sold category of OTC drugs or a specific or and used only under the supervision of specific OTC drugs are generally recog- a practitioner licensed by law to ad- nized as safe and effective and not mis- minister such drugs. branded (Category I). (5) Advisory review panel report to the (ii) A statement of the conditions ex- Commissioner. An advisory review panel cluded from the monograph on the may submit to the Commissioner a re- basis of the Commissioner’s determina- port containing its conclusions and tion that they would result in the recommendations with respect to the drug’s not being generally recognized conditions under which OTC drugs fall- as safe and effective or would result in ing within the category covered by the misbranding (Category II). panel are generally recognized as safe (iii) A statement of the conditions and effective and not misbranded. In- excluded from the monograph on the cluded within this report shall be: basis of the Commissioner’s determina- (i) A recommended monograph or tion that the available data are insuffi- monographs covering the category of cient to classify such conditions under OTC drugs and establishing conditions either paragraph (a)(6)(i) or (ii) of this under which the drugs involved are section (Category III). generally recognized as safe and effec- (iv) The full report(s) of the panel to tive and not misbranded (Category I). the Commissioner. The proposed order This monograph may include any con- shall specify a reasonable period of ditions relating to active ingredients, time within which conditions falling labeling indications, warnings and ade- within paragraph (a)(6)(iii) of this sec- quate directions for use, prescription tion may be continued in marketed or OTC status, and any other condi- products while the data necessary to tions necessary and appropriate for the support them are being obtained for safety and effectiveness of drugs cov- evaluation by the Food and Drug Ad- ered by the monograph. ministration. The summary minutes of

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the panel meetings shall be made avail- they would result in a drug product not able to interested persons upon re- being generally recognized as safe and quest. Any interested person may, effective or would result in mis- within 90 days after publication of the branding. This order may be published proposed order in the FEDERAL REG- when no substantive comments in op- ISTER, file with the Division of Dockets position to the panel report or new Management of the Food and Drug Ad- data and information were received by ministration written comments in trip- the Food and Drug Administration licate. Comments may be accompanied under paragraph (a)(6)(iv) of this sec- by a memorandum or brief in support tion or when the Commissioner has thereof. All comments may be reviewed evaluated and concurs with a panel’s at the office of the Division of Dockets recommendation that a condition be Management between the hours of 9 excluded from the monograph. Within a.m. and 4 p.m., Monday through Fri- 90 days, any interested person may file day. Within 30 days after the final day with the Division of Dockets Manage- for submission of comments, reply ment, Food and Drug Administration, comments may be filed with the Divi- written objections specifying with par- sion of Dockets Management; these ticularity the provision of the ten- comments shall be utilized to reply to tative order to which objection is comments made by other interested made. These objections are to be sup- persons and not to reiterate a position. ported by a brief statement of the The Commissioner may satisfy this re- grounds therefor. A request for an oral quirement by publishing in the FED- hearing may accompany such objec- ERAL REGISTER a proposed order sum- tions. marizing the full report of the advisory (iii) Within 12 months after pub- review panel, containing its conclu- lishing a tentative order pursuant to sions and recommendations, to obtain paragraph (a)(7)(i) of this section, any full public comment before under- interested person may file with the Di- taking his own evaluation and decision vision of Dockets Management, Food on the matters involved. and Drug Administration, new data (7) Tentative final monograph. and information to support a condition (i) After reviewing all comments, excluded from the monograph in the reply comments, and any new data and tentative order. information or, alternatively, after re- (iv) Within 60 days after the final day viewing a panel’s recommendations, for submission of new data and infor- the Commissioner shall publish in the mation, comments on the new data and FEDERAL REGISTER a tentative order information may be filed with the Divi- containing a monograph establishing sion of Dockets Management, Food and conditions under which a category of Drug Administration. OTC drugs or specific OTC drugs are (v) New data and information sub- generally recognized as safe and effec- mitted after the time specified in this tive and not misbranded. Within 90 paragraph but prior to the establish- days, any interested person may file ment of a final monograph will be con- with the Division of Dockets Manage- sidered as a petition to amend the ment, Food and Drug Administration, monograph and will be considered by written comments or written objec- the Commissioner only after a final tions specifying with particularity the monograph has been published in the omissions or additions requested. FEDERAL REGISTER unless the These objections are to be supported by Commisisoner finds that good cause a brief statement of the grounds there- has been shown that warrants earlier for. A request for an oral hearing may consideration. accompany such objections. (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

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specify the length of the hearing and report(s), all comments and rebuttal how the time shall be divided among comments submitted on the proposed the parties requesting the hearing. The monograph and all new data and infor- hearing shall be conducted by the Com- mation submitted pursuant to para- missioner and may not be delegated. graph (a)(6) of this section, all objec- (9) Final monograph. After reviewing tions submitted on the tentative final the objections, the entire administra- monograph and all new data and infor- tive record including all new data and mation and comments submitted pur- information and comments, and consid- suant to paragraph (a)(7) of this sec- ering the arguments made at any oral tion, the complete record of any oral hearing, the Commissioner shall pub- public hearing conducted pursuant to lish in the FEDERAL REGISTER a final paragraph (a)(8) of this section, all order containing a monograph estab- other comments requested at any time lishing conditions under which a cat- by the Commissioner, all data and in- egory of OTC drugs or a specific or spe- formation for which the Commissioner cific OTC drugs are generally recog- has reopened the administrative nized as safe and effective and not mis- record, and all other material that the branded. The monograph shall become Commissioner includes in the adminis- effective as specified in the order. trative record as part of the basis for (10) Administrative record. (i) All data the Commissioner’s decision. and information to be considered in (11) Court appeal. The monograph any proceeding pursuant to this sec- contained in the final order constitutes tion shall be submitted in response to final agency action from which appeal the request for data and views pursu- lies to the courts. The Food and Drug ant to paragraph (a)(2) of this section, Administration will request consolida- in response to any other notice pub- tion of all appeals in a single court. lished in the FEDERAL REGISTER, or ac- Upon court appeal, the Commissioner cepted by the panel during its delibera- may, at his discretion, stay the effec- tions pursuant to paragraph (a)(3) of tive date for part or all of the mono- this section or submitted to the Divi- graph pending appeal and final court sion of Dockets Management as part of adjudication. the comments during the 90-day period (12) Amendment of monographs. (i) The and 30-day rebuttal comment period Commissioner may propose on the permitted pursuant to paragraph (a)(6) Commissioner’s own initiative to of this section or submitted to the Di- amend or repeal any monograph estab- vision of Dockets Management during lished pursuant to this section. Any in- the 12-month period or as part of the terested person may petition the Com- comments during the 60-day period per- missioner for such proposal pursuant mitted pursuant to paragraph (a)(7) of to § 10.30 of this chapter. The Commis- this section. sioner may deny the petition if the (ii) The Commissioner shall make all Commissioner finds a lack of safety or decisions and issue all orders pursuant effectiveness employing the standards to this section solely on the basis of in paragraph (a)(4) of this section (in the administrative record, and shall which case the appeal provisions of not consider data or information not paragraph (a)(11) of this section shall included as part of the administrative apply), or the Commissioner may pub- record. lish a proposed amendment or repeal in (iii) The administrative record shall the FEDERAL REGISTER if the Commis- consist solely of the following mate- sioner finds general recognition of safe- rial: All notices and orders published in ty and effectiveness employing the the FEDERAL REGISTER, all data and standards in paragraph (a)(4) of this views submitted in response to the re- section. Any interested person may, quest published pursuant to paragraph within 90 days after publication of the (a)(2) of this section, in response to any proposed order in the FEDERAL REG- other notice published in the FEDERAL ISTER, file with the Division of Dockets REGISTER, or accepted by the panel Management, Food and Drug Adminis- during its deliberations pursuant to tration, written comments in trip- paragraph (a)(3) of this section, all licate. Comments may be accompanied minutes of panel meetings, the panel by a memorandum or brief in support

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thereof. All comments may be reviewed formation and data are derived, that it in the Division of Dockets Management either was conducted in compliance between the hours of 9 a.m. and 4 p.m., with the requirements for institutional Monday through Friday. After review- review set forth in part 56 of this chap- ing the comments, the Commissioner ter, or was not subject to such require- shall publish a final order amending ments in accordance with §§ 56.104 or the monograph established under the 56.105, and that it was conducted in provisions of paragraph (a)(9) of this compliance with the requirements for section or withdraw the proposal if informed consent set forth in part 50 of comments opposing the amendment this chapter. are persuasive. A new drug application (f) Financial certification or disclosure may be submitted in lieu of, or in addi- statement. Any clinical data submitted tion to, a petition under this para- under this section must be accom- graph. panied by financial certifications or (ii) A new drug application may be disclosure statements or both as re- submitted in lieu of a petition to quired by part 54 of this chapter. amend the OTC drug monograh only if [39 FR 11741, Mar. 29, 1974, as amended at 39 the drug product with the condition FR 39556, Nov. 8, 1974; 42 FR 19141, Apr. 12, that is the subject of the new drug ap- 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, plication has not been marketed on an 8955, Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; interim basis (such as under the provi- 46 FR 21360, Apr. 10, 1981; 46 FR 47738, Sept. sions of paragraph (a)(6)(iii) of this sec- 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, tion), all clinical testing has been con- Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR ducted pursuant to a new drug applica- 3073, Jan. 23, 2002] tion plan, and no marketing of the product with the condition for which § 330.11 NDA deviations from applicable monograph. approval is sought is undertaken prior to approval of the new drug applica- A new drug application requesting tion. The Food and Drug Administra- approval of an OTC drug deviating in tion shall handle a new drug applica- any respect from a monograph that has tion as a petition for amendment of a become final shall be in the form re- monograph, and shall review it on that quired by § 314.50 of this chapter, but basis, if the provisions of this para- shall include a statement that the graph preclude approval of a new drug product meets all conditions of the ap- application but permit the granting of plicable monograph except for the devi- such a petition. ation for which approval is requested (b) Regulatory action. Any product and may omit all information except which fails to conform to an applicable that pertinent to the deviation. monograph after its effective date is [39 FR 11741, Mar. 29, 1974, as amended at 55 liable to regulatory action. FR 11581, Mar. 29, 1990] (c) Information and data submitted under this section shall include, with § 330.12 Status of over-the-counter respect to each nonclinical laboratory (OTC) drugs previously reviewed study contained in the application, ei- under the Drug Efficacy Study ther a statement that the study was (DESI). conducted in compliance with the good (a) There were 420 OTC drugs re- laboratory practice regulations set viewed in the Drug Efficacy Study (a 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

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FEDERAL REGISTER concerning pre- the FEDERAL REGISTER of September viously unpublished OTC drugs re- 30, 1972 (37 FR 20525) and has been viewed by the National Academy of stayed by the filing of objections no- Sciences-National Research Council tice of which was published in the FED- Drug Efficacy Study Group. Only the ERAL REGISTER of March 15, 1973 (38 FR evaluations and comments of the pan- 7007). els were published, with no conclusions (2) Deferral of requirements is not ap- of the Commissioner of Food and propriate when an announcement has Drugs. Those publications were for the been published and has been followed purpose of giving interested persons by a final order classifying a drug ei- the benefit of the Academy’s opinions. ther as lacking substantial evidence of For those products, and also for OTC effectiveness or as not shown to be drug products previously published safe. These products will be removed with the Commissioner’s conclusions from the market, if they have not al- (except for the products listed in para- ready been removed. Regulatory action graphs (b) (1) and (2) of this section, all will also be undertaken against iden- requests for data, revised labeling, retical, similar and related products (21 quests for new drug applications, ab- CFR 310.6). Deferral of requirements is breviated new drug applications, updat- not appropriate for the following (the ing supplements, data to support less referenced document may also pertain than effective claims, if any, etc., are to prescription drugs): deferred, and such OTC drug products (i) Certain Sulfonamide-Deconges- are instead subject to the OTC drug re- tant Nasal Preparation (DESI 4850), for view in their appropriate classes pursu- which notice of withdrawal of approval ant to the procedures established in of new drug applications was published this subpart. in the FEDERAL REGISTER of October 24, (1) The requirements of the following 1970 (35 FR 16605, 16606). DESI announcements are not deferred (ii) Eskay’s Theranates, containing (the reference document may also per- strychnine, sodium, and calcium glyc- tain to prescription drugs): erophosphates, thiamine hydro- (i) Certain Surgical Sutures (DESI chloride, alcohol, and phosphoric acid 4725), published in the FEDERAL REG- (DESI 2220), for which notice of with- ISTER of November 11, l971 (36 FR 21612). drawal of approval of the new drug ap- (ii) Absorbable Dusting Powder plication was published in the FEDERAL (DESI 6264), published in the FEDERAL REGISTER of February 18, 1971 (36 FR REGISTER of May 25, 1971 (36 FR 9475). 3152). (iii) Certain Insulin Preparations (iii) The following topical drugs (DESI 4286), published in the FEDERAL (DESI 1726), for which notice of with- REGISTER of April 9, 1971 (36 FR 6842). drawal of new drug applications was (iv) Sulfo-Van Ointment (DESI 2230), published in the FEDERAL REGISTER of published in the FEDERAL REGISTER of August 28, 1971 (36 FR 17368): October 8, 1970 (35 FR 15860). (a) Rhulitol Solution, containing tan- (v) Antiperspirants and Deodorants nic acid, chlorobutanol, phenol, cam- Containing Neomycin Sulfate (DESI phor, alum, and isopropyl alcohol. 11048) for which an order revoking pro- (b) Zirnox Topical Lotion, containing visions for certification or release was phenyitoloxamine citrate and zir- published in the FEDERAL REGISTER of conium oxide. December 5, 1972 (37 FR 25820) and has (iv) Menacyl Tablets, containing as- been stayed by the filing of objections. pirin, menadione, and ascorbic acid (vi) Thorexin Cough Medicine (DESI (DESI 6363), for which notice of with- 11160) for which a notice of opportunity drawal of approval of the new drug ap- for hearing was published in the FED- plication was published in the FEDERAL ERAL REGISTER of February 2, 1973 (38 REGISTER of July 23, 1970 (35 FR 11827). FR 3210). (v) Curad Medicated Adhesive Ban- (vii) Antibiotic susceptibility discs dage containing sulfathiazole (DESI (DESI 90235) for which an order pro- 4964), for which notice of withdrawal of viding for certain discs to be certified approval of the new drug application and removing provisions for certifi- was published in the FEDERAL REG- cation of other discs was published in ISTER of December 31, 1969 (34 FR 20441).

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(vi) Drugs Containing Rutin, Quer- REGISTER of February 2, 1973 (38 FR cetin, Hesperidin, or any Bioflavonoids 3208). (DESI 5960), for which notice of with- (xiv) Those parts of the publication drawal of approval of new drug applica- entitled ‘‘Certain Mouthwash and Gar- tions was published in the FEDERAL gle Preparations’’ (DESI 2855) per- REGISTER of July 3, 1970 (35 FR 10872, taining to Tyrolaris Mouthwash, con- 10873) and October 17, 1970 (35 FR 16332). taining tyrothricin, panthenol, and al- A further notice of opportunity for cohol, for which an order revoking pro- hearing with respect to the drugs cov- vision for certification was published ered by the October 17, 1970 FEDERAL in the FEDERAL REGISTER of February REGISTER notice will be published at a 2, 1967 (32 FR 1172) prior to the drug ef- later date. ficacy study implementation. (vii) Antibiotics in Combination with (c) Manufacturers and distributors Other Drugs for Nasal Use (DESI 7561), should take notice that the informa- for which an order revoking provision tion on OTC drugs provided by the for certification was published in the Drug Efficacy Study review is valuable FEDERAL REGISTER of August 6, 1971 (36 information as to the deficiencies in FR 14469) and confirmed in the FED- the data available to support indica- ERAL REGISTER of October 28, 1971 (36 tions for use. They are encouraged to FR 20686). perform studies to obtain adequate evi- (viii) Antibiotic Troches (DESI 8328), dence of effectiveness for the review of for which an order revoking provision OTC drugs which is already in progress. for certification was published in the In the interim it is in the public inter- FEDERAL REGISTER of July 14, 1971 (36 est that manufacturers and distribu- FR 13089) and confirmed in the FED- tors of all OTC drugs effect changes in ERAL REGISTER of October 9, 1971 (36 FR their formulations and/or labeling to 19695). bring the products into conformity (ix) Certain Drugs Containing Oxy- with current medical knowledge and phenisatin or Oxyphenisatin Acetate experience. (DESI 10732), for which notices of with- (d) Manufacturers and distributors of drawal of approval of new drug applica- OTC drugs may be reluctant to make tions were published in the FEDERAL appropriate formulation and/or label- REGISTER of February 1, 1972 (37 FR ing changes for fear of losing the pro- 2460), and March 9, 1973 (38 FR 6419). tection of the so-called ‘‘grandfather’’ (x) Curad Medicated Adhesive Ban- provisions of the 1938 Federal Food, dage containing tyrothricin-nitrofu- Drug, and Cosmetic Act (sec. 201(p)(1)) razone (DESI 6898), for which an order and the 1962 amendments to the act revoking provision for certification (sec. 107(c) of those amendments). To was published March 14, 1972 (37 FR encourage and facilitate prompt 5294), and confirmed in the FEDERAL changes, the Food and Drug Adminis- REGISTER of July 6, 1972 (37 FR 13254). tration will not take legal action (xi) Candette Cough Gel (DESI 11562), against any OTC drug, other than those for which notice of withdrawal of ap- not deferred, based on a charge that proval of the new drug application was the product is a new drug and not published in the FEDERAL REGISTER of grandfathered under the act as a result November 19, 1972 (37 FR 25249). of the changes if the changes in formu- (xii) Certain OTC Multiple-Vitamin lation and/or labeling are of the fol- Preparations for Oral Use containing lowing kind: excessive amounts of vitamin D and/or (1) The addition to the labeling of vitamin A (DESI 97), for which notice warning, contraindications, side ef- of withdrawal of approval of the new fects, and/or precaution information. drug applications was published in the (2) The deletion from the labeling of FEDERAL REGISTER of November 29, 1972 false, misleading, or unsupported indi- (37 FR 25249). cations for use or claims of effective- (xiii) Certain Sulfonamide-Con- ness. taining Preparations for Topical Oph- (3) Changes in the components or thalmic or Otic Use (DESI 368, for composition of the drug that will give which a notice of withdrawal of ap- increased assurance that the drug will proval was published in the FEDERAL have its intended effect, yet not raise

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or contribute any added safety ques- for which an approved new drug appli- tions. cation is required if marketed for OTC (4) Changes in the components or use prior to the date of publication in composition of the drug which may the FEDERAL REGISTER of a proposed reasonably be concluded to improve the monograph. safety of the drug, without diminishing (2) An OTC drug product covered by its effectiveness. paragraph (b)(1) of this section which is (e) The forbearance from legal action marketed after the date of publication for lack of grandfather protection is an in the FEDERAL REGISTER of a proposed interim procedure designed to encour- monograph but prior to the effective age appropriate change in formulation date of a final monograph shall be sub- and/or labeling during the time period ject to the risk that the Commissioner required to review the various classes may not accept the panel’s rec- of OTC drugs. At such time as an appli- ommendation and may instead adopt a cable OTC drug monograph becomes ef- different position that may require re- fective, the interim procedure will labeling, recall, or other regulatory ac- automatically be terminated and any tion. The Commissioner may state appropriate regulatory action will be such position at any time by notice in initiated. the FEDERAL REGISTER, either separately or as part of another document; § 330.13 Conditions for marketing inappropriate regulatory action will gredients recommended for over- commence immediately and will not the-counter (OTC) use under the await publication of a final monograph. OTC drug review. Marketing of such a product with a for- (a) Before the publication in the FED- mulation or labeling not in accord with ERAL REGISTER of an applicable pro- a proposed monograph or tentative posed monograph, an OTC drug product final monograph also may result in that contains: (1) An active ingredient regulatory action against the product, limited, on or after May 11, 1972, to pre- the marketer, or both. scription use for the indication and (c) An OTC drug product that con- route of administration under consider- tains: (1) An active ingredient limited, ation by an OTC advisory review panel, on or after May 11, 1972, to prescription and not thereafter exempted from such use for the indication and route of ad- limitation pursuant to § 310.200 of this ministration under consideration by an chapter, or OTC advisory review panel, and not (2) An active ingredient at a dosage thereafter exempted from such limita- level higher than that available in an tion pursuant to § 310.200 of this chap- OTC drug product on December 4, 1975, ter, or shall be regarded as a new drug within (2) An active ingredient at a dosage the meaning of section 201(p) of the act level higher than that available in any for which an approved new drug appli- OTC drug product on December 4, 1975, cation is required. which ingredient and/or dosage level is (b)(1) An OTC drug product that con- classified by the panel in category II tains: (i) An active ingredient limited, (conditions subject to § 330.10(a)(6)(ii)), on or after May 11, 1972, to prescription may be marketed only after: use for the indication and route of ad- (i) The Center for Drug Evaluation ministration under consideration by an and Research or the Commissioner ten- OTC advisory review panel, and not tatively determines that the ingredient thereafter exempted from such limita- is generally recognized as safe and ef- tion pursuant to § 310.200 of this chap- fective, and the Commissioner states ter, or by notice in the FEDERAL REGISTER (ii) An active ingredient at a dosage (separately or as part of another docu- level higher than that available in an ment) that marketing under specified OTC drug product on December 4, 1975, conditions will be permitted; which ingredient and/or dosage level is (ii) The ingredient is determined by classified by the panel in category I the Commissioner to be generally rec- (conditions subject to § 330.10(a)(6)(i)) ognized as safe and effective and is in- shall be regarded as a new drug within cluded in the appropriate published the meaning of section 201(p) of the act OTC drug final monograph; or

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(iii) A new drug application for the ered in the OTC drug monograph sys- product has been approved. tem. This section also addresses condi- (d) An OTC drug product that con- tions regulated as a cosmetic or die- tains: (1) An active ingredient limited, tary supplement in a foreign country on or after May 11, 1972, to prescription that would be regulated as OTC drugs use for the indication and route of ad- in the United States. For purposes of ministration under consideration by an this section, ‘‘condition’’ means an ac- OTC advisory review panel, and not tive ingredient or botanical drug sub- thereafter exempted from such limita- stance (or a combination of active in- tion pursuant to § 310.200 of this chap- gredients or botanical drug sub- ter, or stances), dosage form, dosage strength, (2) An active ingredient at a dosage or route of administration, marketed level higher than that available in any for a specific OTC use, except as ex- OTC drug product on December 4, 1975, cluded in paragraph (b)(2) of this sec- which ingredient and/or dosage level is tion. For purposes of this part, ‘‘botan- classified by the panel in category III ical drug substance’’ means a drug sub- (conditions subject to § 330.10(a)(6)(iii)), stance derived from one or more may be marketed only after: plants, algae, or macroscopic fungi, but (i) The Center for Drug Evaluation does not include a highly purified or and Research or the Commissioner ten- chemically modified substance derived tatively determines that the ingredient from such a source. is generally recognized as safe and ef- (b) Criteria. To be considered for infective, and the Commissioner states clusion in the OTC drug monograph by notice in the FEDERAL REGISTER system, the condition must meet the (separately or as part of another docu- following criteria: ment) that marketing under specified (1) The condition must be marketed conditions will be permitted; for OTC purchase by consumers. If the (ii) The ingredient is determined by condition is marketed in another coun- the Commissioner to be generally rec- try in a class of OTC drug products ognized as safe and effective and is in- that may be sold only in a pharmacy, cluded in the appropriate published with or without the personal involve- OTC drug final monograph; or ment of a pharmacist, it must be estab- (iii) A new drug application for the lished that this marketing restriction product has been approved. does not indicate safety concerns about (e) This section applies only to condi- the condition’s toxicity or other poten- tions under consideration as part of the tiality for harmful effect, the method OTC drug review initiated on May 11, of its use, or the collateral measures 1972, and evaluated under the proce- necessary to its use. dures set forth in § 330.10. Section (2) The condition must have been 330.14(h) applies to the marketing of all marketed OTC for a minimum of 5 con- conditions under consideration and tinuous years in the same country and 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 the condition’s extent of marketing in FR 17739, Apr. 23, 1982; 50 FR 8996, Mar. 6, 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

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drug substance(s), pharmacologic with or without the personal involve- class(es), intended OTC use(s), OTC ment of a pharmacist; dietary supple- strength(s) and dosage form(s), route(s) ment; or cosmetic). If the condition has of administration, directions for use, been marketed as a nonprescription and the applicable existing OTC drug pharmacy-only product, establish that monograph(s) under which the condi- this marketing restriction does not in- tion would be marketed or the request dicate safety concerns about its tox- and rationale for creation of a new OTC icity or other potentiality for harmful drug monograph(s). effect, the method of its use, or the col- (i) A detailed chemical description of lateral measures necessary to its use. the active ingredient(s) that includes a (ii) The cumulative total number of full description of the drug substance, dosage units (e.g., tablets, capsules, including its physical and chemical ounces) sold for each dosage form of characteristics, the method of syn- the condition. Manufacturers or sup- thesis (or isolation) and purification of pliers of OTC active ingredients may the drug substance, and any specifica- provide dosage unit information as the tions and analytical methods necessary total weight of active ingredient sold. to ensure the identity, strength, qual- List the various package sizes for each ity, and purity of the drug substance. dosage form in which the condition is (ii) For a botanical drug substance(s), marketed OTC. Provide an estimate of a detailed description of the botanical the minimum number of potential con- ingredient (including proper identifica- sumer exposures to the condition using tion of the plant, plant part(s), alga, or one of the following calculations: macroscopic fungus used; a certificate (A) Divide the total number of dosage of authenticity; and information on the units sold by the number of dosage grower/supplier, growing conditions, units in the largest package size mar- harvest location and harvest time); a keted, or qualitative description (including the (B) Divide the total weight of the ac- name, appearance, physical/chemical tive ingredient sold by the total weight properties, chemical constituents, active constituent(s) (if known), and bio- of the active ingredient in the largest logical activity (if known)); a quan- package size marketed. titative description of the chemical (iii) A description of the population constituents, including the active con- demographics (percentage of various stituent(s) or other chemical marker(s) racial/ethnic groups) and the source(s) (if known and measurable); the type of from which this information has been manufacturing process (e.g., aqueous compiled, to ensure that the condi- extraction, pulverization); and infor- tion’s use(s) can be reasonably extrapo- mation on any further processing of lated to the U.S. population. the botanical substance (e.g., addition (iv) If the use pattern (i.e., how often of excipients or blending). it is to be used (according to the label) (iii) Reference to the current edition and for how long) varies between coun- of the U.S. Pharmacopeia (USP)–Na- tries based on the condition’s pack- tional Formulary (NF) or foreign com- aging and labeling, or changes in use pendiums may help satisfy the require- pattern have occurred over time in one ments in this section. or more countries, describe the use pat- (2) A list of all countries in which the tern for each country and explain why condition has been marketed. Include there are differences or changes. the following information for each (v) A description of the country’s sys- country. (For a condition that has been tem for identifying adverse drug expe- marketed OTC in 5 or more countries riences, especially those found in OTC with a minimum of 5 continuous years marketing experience, including meth- of marketing in at least one country, od of collection if applicable. the sponsor may submit information in (3) A statement of how long the con- accordance with paragraph (c)(4) of this dition has been marketed in each coun- section): try and how long the current product (i) How the condition has been mar- labeling has been in use, accompanied keted (e.g., OTC general sales direct- by a copy of the current product label- to-consumer; sold only in a pharmacy, ing. All labeling that is not in English

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must be translated to English in ac- (d) Submission of information; confiden- cordance with § 10.20(c)(2) of this chap- tiality. The sponsor must submit three ter. State whether the current product copies of the TEA to the Central Docu- labeling has or has not been author- ment Room, 5630 Fishers Lane, rm. ized, accepted, or approved by a regu- 1061, Rockville, MD 20852. The Food and latory body in each country where the Drug Administration will handle the condition is marketed. TEA as confidential until such time as (4) For a condition that has been a decision is made on the eligibility of marketed OTC in five or more coun- the condition for consideration in the tries with a minimum of 5 continuous OTC drug monograph system. If the years of marketing in at least one condition is found eligible, the TEA country, the sponsor may select at will be placed on public display in the least five of these countries from which Division of Dockets Management after to submit information in accord with deletion of information deemed con- paragraphs (c)(2)(i) through (c)(2)(iv) of fidential under 18 U.S.C. 1905, 5 U.S.C. this section. Selected countries must 552(b), or 21 U.S.C. 331(j). Sponsors include the country with a minimum of must identify information that is con- 5 continuous years of OTC marketing, sidered confidential under these statu- countries that have the longest dura- tory provisions. If the condition is not tion of marketing, and countries hav- found eligible, the TEA will not be ing the most support for extent of mar- placed on public display, but a letter keting, i.e., a large volume of sales from the agency to the sponsor stating with cultural diversity among users of why the condition was not found ac- the product. If the condition meets ceptable will be placed on public dis- these criteria in countries listed in sec- play in the Division of Dockets Man- tion 802(b)(1)(A) of the Federal Food, agement. Drug, and Cosmetic Act, some of these (e) Notice of eligibility. If the condition countries should be included among the is found eligible, the agency will pub- five selected. Sponsors should provide lish a notice of eligibility in the FED- information from more than five coun- ERAL REGISTER and provide the sponsor tries if they believe that it is needed to and other interested parties an oppor- support eligibility. Sponsors should ex- tunity to submit data to demonstrate plain the basis for the countries selected in the TEA. safety and effectiveness. When the no- (5) A list of all countries where the tice of eligibility is published, the condition is marketed only as a pre- agency will place the TEA on public scription drug and the reasons why its display in the Division of Dockets Man- marketing is restricted to prescription agement. in these countries. (f) Request for data and views. The no- (6) A list of all countries in which the tice of eligibility shall request inter- condition has been withdrawn from ested persons to submit published and marketing or in which an application unpublished data to demonstrate the for OTC marketing approval has been safety and effectiveness of the condi- denied. Include the reasons for such tion for its intended OTC use(s). These withdrawal or application denial. data shall be submitted to a docket es- (7) The information requested in tablished in the Division of Dockets paragraphs (c)(2), (c)(2)(i) through Management and shall be publicly (c)(2)(iv), and (c)(3) of this section must available for viewing at that office, ex- be provided in a table format. The la- cept data deemed confidential under 18 beling required by paragraph (c)(3) of U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. this section must be attached to the 331(j). Data considered confidential table. under these provisions must be clearly (8) For OTC drugs that have been identified. Any proposed compendial marketed for more than 5 years in the standards for the condition shall not be United States under a new drug appli- considered confidential. The safety and cation, the information requested in effectiveness submissions shall include paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), the following: (c)(3), and (c)(5) of this section need not (1) All data and information listed in be provided. § 330.10(a)(2) under the outline ‘‘OTC

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Drug Review Information,’’ items III Dockets Management. The agency will through VII. publish a notice of proposed rule- (2) All serious adverse drug experi- making to include the condition in ences as defined in §§ 310.305 and 314.80 § 310.502 of this chapter. of this chapter, from each country where the condition has been or is cur- (5) Interested parties will have an op- rently marketed as a prescription drug portunity to submit comments and new or as an OTC drug or product. Provide data. The agency will subsequently individual adverse drug experience re- publish a final rule (or reproposal if ports (FDA Form 3500A or equivalent) necessary) in the FEDERAL REGISTER. along with a summary of all serious ad- (h) Marketing. A condition submitted verse drug experiences and expected or under this section for consideration in frequently reported side effects for the the OTC drug monograph system may condition. Individual reports that are be marketed in accordance with an ap- not in English must be translated to plicable final OTC drug monograph(s) English in accordance with § 10.20(c)(2) only after the agency determines that of this chapter. the condition is generally recognized as (g) Administrative procedures. The safe and effective and includes it in the agency may use an advisory review appropriate OTC drug final mono- panel to evaluate the safety and effec- graph(s), and the condition complies tiveness data in accord with the provi- with paragraph (i) of this section. sions of § 330.10(a)(3). Alternatively, the When an OTC drug monograph has not agency may evaluate the data in con- been finalized and finalization is not junction with the advisory review imminent, after the agency has evalu- panel or on its own without using an ated the comments to a proposed rule advisory review panel. The agency will to include a new condition in a ten- use the safety, effectiveness, and label- tative final monograph as generally ing standards in § 330.10(a)(4)(i) through recognized as safe and effective and the (a)(4)(vi) in evaluating the data. agency has not changed its position as (1) If the agency uses an advisory re- a result of the comments, and the con- view panel to evaluate the data, the dition complies with paragraph (i) of panel may submit its recommendations this section, the agency may publish a in its official minutes of meeting(s) or notice of enforcement policy that al- by a report under the provisions of lows marketing to begin pending com- § 330.10(a)(5). pletion of the final monograph subject (2) The agency may act on an advi- to the risk that the agency may, prior sory review panel’s recommendations to or in the final monograph, adopt a using the procedures in §§ 330.10(a)(2) different position that could require re- and 330.10(a)(6) through (a)(10). labeling, recall, or other regulatory action. (3) If the condition is initially determined to be generally recognized as (i) Compendial monograph. Any active safe and effective for OTC use in the ingredient or botanical drug substance United States, the agency will propose included in a final OTC drug mono- to include it in an appropriate OTC graph or the subject of an enforcement drug monograph(s), either by amending notice described in paragraph (h) of an existing monograph(s) or estab- this section must be recognized in an lishing a new monograph(s), if nec- official USP–NF drug monograph that essary. sets forth its standards of identity, (4) If the condition is initially deter- strength, quality, and purity. Sponsors mined not to be generally recognized as must include an official or proposed safe and effective for OTC use in the compendial monograph as part of the United States, the agency will inform safety and effectiveness data submis- the sponsor and other interested par- sion listed in § 330.10(a)(2) under item ties who have submitted data of its de- VII of the outline entitled ‘‘OTC DRUG termination by letter, a copy of which REVIEW INFORMATION.’’ will be placed on public display in the docket established in the Division of [67 FR 3074, Jan. 23, 2002]

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PART 331—ANTACID PRODUCTS (b) This section does not apply to an FOR OVER-THE-COUNTER (OTC) antacid ingredient specifically added as HUMAN USE a corrective to prevent a laxative or constipating effect. Subpart A—General Provisions [39 FR 19874, June 4, 1974, as amended at 61 FR 4822, Feb. 8, 1996] Sec. 331.1 Scope. § 331.11 Listing of specific active ingredients. Subpart B—Active Ingredients (a) Aluminum-containing active in- 331.10 Antacid active ingredients. gredients: 331.11 Listing of specific active ingredients. (1) Basic aluminum carbonate gel. 331.15 Combination with nonantacid active (2) Aluminum hydroxide (or as alu- ingredients. minum hydroxide-hexitol stabilized Subpart C—Testing Procedures polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum 331.20 Determination of percent contribu- hydroxide-magnesium trisilicate tion of active ingredients. codried gel, aluminum-hydroxide su- 331.21 Test Modifications. crose powder hydrated). Subpart D—Labeling (3) Dihydroxyaluminum amino- acetate and dihydroxyaluminum ami- 331.30 Labeling of antacid products. noacetic acid. 331.80 Professional labeling. (4) Aluminum phosphate gel when AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, used as part of an antacid combination 360, 371. product and contributing at least 25 SOURCE: 39 FR 19874, June 4, 1974, unless percent of the total acid neutralizing otherwise noted. capacity; maximum daily dosage limit is 8 grams. Subpart A—General Provisions (5) Dihydroxyaluminum sodium carbonate. § 331.1 Scope. (b) Bicarbonate-containing active ingredients: Bicarbonate ion; maximum An over-the-counter antacid product daily dosage limit 200 mEq. for persons in a form suitable for oral administra- up to 60 years old and 100 mEq. for per- tion is generally recognized as safe and sons 60 years or older. effective and is not misbranded if it (c) Bismuth-containing active ingre- meets each of the following conditions dients: and each of the general conditions es- (1) Bismuth aluminate. tablished in § 330.1 of this chapter. (2) Bismuth carbonate. (3) Bismuth subcarbonate. Subpart B—Active Ingredients (4) Bismuth subgallate. (5) Bismuth subnitrate. § 331.10 Antacid active ingredients. (d) Calcium-containing active ingre- (a) The active antacid ingredients of dients: Calcium, as carbonate or phos- the product consist of one or more of phate; maximum daily dosage limit 160 the ingredients permitted in § 331.11 mEq. calcium (e.g., 8 grams calcium within any maximum daily dosage carbonate). limit established, each ingredient is in- (e) Citrate-containing active ingredi- cluded at a level that contributes at ents: Citrate ion, as citric acid or salt; least 25 percent of the total acid neu- maximum daily dosage limit 8 grams. tralizing capacity of the product, and (f) Glycine (aminoacetic acid). the finished product contains at least 5 (g) Magnesium-containing active in- meq of acid neutralizing capacity as gredients: measured by the procedure provided in (1) Hydrate magnesium aluminate ac- the United States Pharmacopeia 23/Na- tivated sulfate. tional Formulary 18. The method es- (2) Magaldrate. tablished in § 331.20 shall be used to de- (3) Magnesium aluminosilicates. termine the percent contribution of (4) Magnesium carbonate. each antacid active ingredient. (5) Magnesium glycinate.

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(6) Magnesium hydroxide. acid. No labeling claim of the laxative (7) Magnesium oxide. effect may be used for such a product. (8) Magnesium trisilicate. (b) An antacid may contain any gen- (h) Milk solids, dried. erally recognized as safe and effective (i) Phosphate-containing active in- analgesic ingredient(s), if it is indi- gredients: cated for use solely for the concurrent (1) Aluminum phosphate; maximum symptoms involved, e.g., headache and daily dosage limit 8 grams. acid indigestion, and is marketed in a (2) Mono or dibasic calcium salt; form intended for ingestion as a solu- maximum daily dosage limit 2 grams. tion. (3) Tricalcium phosphate; maximum (c) An antacid may contain any gen- daily dosage limit 24 grams. erally recognized as safe and effective (j) Potassium-containing active in- antiflatulent ingredient if it is indi- gredients: cated for use solely for the concurrent (1) Potassium bicarbonate (or car- symptoms of gas associated with heart- bonate when used as a component of an burn, sour stomach or acid indigestion. effervescent preparation); maximum daily dosage limit 200 mEq. of bicar- Subpart C—Testing Procedures bonate ion for persons up to 60 years old and 100 mEq. of bicarbonate ion for § 331.20 Determination of percent contribution of active ingredients. persons 60 years or older. (2) Sodium potassium tartrate. To determine the percent contribu- (k) Sodium-containing active ingre- tion of an antacid active ingredient, dients: place an accurately weighed amount of (1) Sodium bicarbonate (or carbonate the antacid active ingredient equal to when used as a component of an effer- the amount present in a unit dose of vescent preparation); maximum daily the product into a 250-milliliter (mL) dosage limit 200 mEq. of sodium for beaker. If wetting is desired, add not persons up to 60 years old and 100 mEq. more than 5 mL of alcohol (neutralized of sodium for persons 60 years or older, to an apparent pH of 3.5), and mix to and 200 mEq. of bicarbonate ion for per- wet the sample thoroughly. Add 70 mL sons up to 60 years old and 100 mEq. of of water, and mix on a magnetic stirrer ± bicarbonate ion for persons 60 years or at 300 30 r.p.m. for 1 minute. Analyze older. That part of the warning re- the acid neutralizing capacity of the quired by § 330.1(g), which states, ‘‘Keep sample according to the procedure pro- this and all drugs out of the reach of vided in the United States Pharma- children’’ is not required on a product copeia 23/National Formulary 18 and which contains only sodium bicarbon- calculate the percent contribution of ate powder and which is intended pri- the antacid active ingredient in the marily for other than drug uses. total product as follows: Percent contribution =(Total mEq. (2) Sodium potassium tartrate. Antacid Active Ingredient×100)/(Total (l) Silicates: mEq. Antacid Product). (1) Magnesium aluminosilicates. (2) Magnesium trisilicate. [61 FR 4823, Feb. 8, 1996] (m) Tartrate-containing active ingredients. Tartaric acid or its salts; max- § 331.21 Test modifications. imum daily dosage limit 200 mEq. (15 The formulation or mode of adminis- grams) of tartrate. tration of certain products may require 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, 1990] 18 acid neutralizing capacity test. Any proposed modification and the data to § 331.15 Combination with nonantacid support it shall be submitted as a peti- active ingredients. tion under the rules established in (a) An antacid may contain any gen- § 10.30 of this chapter. All information erally recognized as safe and effective submitted will be subject to the disclo- nonantacid laxative ingredient to cor- sure rules in part 20 of this chapter. rect for constipation caused by the ant- [61 FR 4823, Feb. 8, 1996]

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Subpart D—Labeling and supervision of a physician if you have kidney disease.’’ § 331.30 Labeling of antacid products. (5) For products containing more (a) Statement of identity. The labeling than 25 mEq. potassium in the max- of the product contains the established imum recommended daily dose: ‘‘Do name of the drug, if any, and identifies not use this product except under the the product as an ‘‘antacid.’’ advice and supervision of a physician if (b) Indications. The labeling of the you have kidney disease.’’ product states, under the heading ‘‘In- (6) For products containing more dications,’’ the following: ‘‘For the re- than 5 gm per day lactose in a max- lief of’’ (optional, any or all of the fol- imum daily dosage: ‘‘Do not use this lowing:) ‘‘heartburn,’’ ‘‘sour stomach,’’ product except under advice and super- and/or ‘‘acid indigestion’’ (which may vision of a physician if you are allergic be followed by the optional statement:) to milk or milk products.’’ ‘‘and upset stomach associated with’’ (d) Drug interaction precaution. The (optional, as appropriate) ‘‘this symp- labeling of the product contains the tom’’ or ‘‘these symptoms.’’ Other following statement ‘‘Ask a doctor or truthful and nonmisleading state- pharmacist before use if you are [bul- ments, describing only the indications let]1 presently taking a prescription for use that have been established and drug. Antacids may interact with cer- listed in this paragraph (b), may also tain prescription drugs.’’ be used, as provided in § 330.1(c)(2) of (e) Directions for use. The labeling of this chapter, subject to the provisions the product contains the recommended of section 502 of the act relating to dosage, under the heading ‘‘Direc- misbranding and the prohibition in sections’’, per time interval (e.g., every 4 tion 301(d) of the act against the intro- hours) or time period (e.g., 4 times a duction or delivery for introduction day) broken down by age groups if ap- into interstate commerce of unap- propriate, followed by ‘‘or as directed proved new drugs in violation of sec- by a physician.’’ tion 505(a) of the act. (f) Exemption from the general acci- (c) Warnings. The labeling of the dental overdose warning. The labeling product contains the following warn- for antacid drug products containing ings, under the heading ‘‘Warnings’’, the active ingredients identified in which may be combined but not rear- § 331.11(a), (b), and (d) through (m); per- ranged to eliminate duplicative words mitted combinations of these ingredi- or phrases if the resulting warning is ents provided for in § 331.10; and any of clear and understandable: these ingredients or combinations of (1) ‘‘Do not take more than (max- these ingredients in combination with imum recommended daily dosage, bro- simethicone (identified in § 332.10 of ken down by age groups if appropriate, this chapter and provided for in expressed in units such as tablets or § 331.15(c)), are exempt from the re- teaspoonfuls) in a 24–hour period, or quirement in § 330.1(g) of this chapter use the maximum dosage of this prod- that the labeling bear the general uct for more than 2 weeks, except warning statement ‘‘In case of acci- under the advice and supervision of a dental overdose, seek professional as- physician.’’ sistance or contact a poison control (2) For products which cause con- center immediately.’’ With the excep- stipation in 5 percent or more of per- tion of sodium bicarbonate powder sons who take the maximum rec- products identified in § 331.11(k)(1), the ommended dosage: ‘‘May cause con- labeling must continue to bear the first stipation.’’ part of the general warning in § 330.1(g) (3) For products which cause laxation of this chapter, which states, ‘‘Keep in 5 percent or more of persons who this and all drugs out of the reach of take the maximum recommended dos- children.’’ age: ‘‘May have laxative effect.’’ (g) [Reserved] (4) For products containing more (h) The word ‘‘doctor’’ may be sub- than 50 mEq. of magnesium in the rec- stituted for the word ‘‘physician’’ in ommended daily dosage: ‘‘Do not use this product except under the advice 1 See § 201.66(b)(4) of this chapter.

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any of the labeling statements in this minum is deposited in bone, and dialy- section. sis osteomalacia may develop when large amounts of aluminum are in- [39 FR 19874, June 4, 1974, as amended at 47 FR 38484, Aug. 31, 1982; 51 FR 16266, May 1, gested orally by patients with impaired 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, renal function. Mar. 13, 1987; 55 FR 11581, Mar. 29, 1990; 58 FR (ii) Aluminum forms insoluble com- 45208, Aug. 26, 1993; 59 FR 60556, Nov. 25, 1994; plexes with phosphate in the gastro- 61 FR 17806, Apr. 22, 1996; 64 FR 13295, Mar. 17, intestinal tract, thus decreasing phos- 1999] phate absorption. Prolonged use of alu- EFFECTIVE DATE NOTE: At 69 FR 13734, Mar. minum-containing antacids by normo- 24, 2004, § 331.30 was amended by removing phosphatemic patients may result in paragraphs (c)(4) and (c)(5) and redesignating hypophosphatemia if phosphate intake paragraph (c)(6) as paragraph (c)(4), effective is not adequate. In its more severe Apr. 23, 2004. forms, hypophosphatemia can lead to anorexia, malaise, muscle weakness, § 331.80 Professional labeling. and osteomalacia. (a) The labeling of the product pro- (b) Professional labeling for an ant- vided to health professionals (but not acid-antiflatulent combination may to the general public): contain the information allowed for (1) Shall contain the neutralizing ca- health professionals for antacids and pacity of the product as calculated antiflatulents. using the procedure set forth in United [39 FR 19874, June 4, 1974. Redesignated and States Pharmacopeia 23/National For- amended at 55 FR 19859, May 11, 1990] mulary 18 expressed in terms of the dosage recommended per minimum time interval or, if the labeling rec- PART 332—ANTIFLATULENT PROD- ommends more than one dosage, in UCTS FOR OVER-THE-COUNTER terms of the minimum dosage rec- HUMAN USE ommended per minimum time interval. (2) May contain an indication for the Subpart A—General Provisions symptomatic relief of hyperacidity as- Sec. sociated with the diagnosis of peptic 332.1 Scope. ulcer, gastritis, peptic esophagitis, gas- 332.3 Definitions. tric hyperacidity, and hiatal hernia. (3) For products containing basic alu- Subpart B—Active Ingredients minum carbonate gel identified in 332.10 Antiflatulent active ingredients. § 331.11(a)(1)—Indication. ‘‘For the 332.15 Combination with non-antiflatulent treatment, control, or management of active ingredients. hyperphosphatemia, or for use with a low phosphate diet to prevent forma- Subpart C—Labeling tion of phosphate urinary stones, 332.30 Labeling of antiflatulent products. through the reduction of phosphates in 332.31 Professional labeling. the serum and urine.’’ (4) For products containing aluminum AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. identified in § 331.11(a)—Warnings. (i) Prolonged use of aluminum-containing SOURCE: 39 FR 19877, June 4, 1974, unless antacids in patients with renal failure otherwise noted. may result in or worsen dialysis osteomalacia. Elevated tissue aluminum Subpart A—General Provisions levels contribute to the development of the dialysis encephalopathy and osteo- § 332.1 Scope. malacia syndromes. Small amounts of An over-the-counter antiflatulent aluminum are absorbed from the gas- product in a form suitable for oral ad- trointestinal tract and renal excretion ministration is generally recognized as of aluminum is impaired in renal fail- safe and effective and is not mis- ure. Aluminum is not well removed by branded if it meets each of the fol- dialysis because it is bound to albumin lowing conditions and each of the gen- and transferrin, which do not cross di- eral conditions established in § 330.1 of alysis membranes. As a result, alu- this chapter.

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§ 332.3 Definitions. (2) (Select one of the following: ‘‘Al- leviates’’ or ‘‘Relieves’’) (select one or As used in this part: more of the following: ‘‘bloating,’’ Antigas. A term that may be used ‘‘pressure,’’ ‘‘fullness,’’ or ‘‘stuffed feel- interchangeably with the term anti- ing’’) ‘‘commonly referred to as gas.’’ flatulent. Neither term should be con- (c) Exemption from the general acci- sidered as describing the mechanism of dental overdose warning. The labeling action of the active ingredient con- for antiflatulent drug products contained in the product. taining simethicone identified in [61 FR 8838, Mar. 5, 1996] § 332.10 and antacid/antiflatulent combination drug products provided for in Subpart B—Active Ingredients § 332.15, containing the active ingredients identified in § 331.11(a), (b), and (d) § 332.10 Antiflatulent active ingredi- through (m) of this chapter are exempt ents. from the requirement in § 330.1(g) of Simethicone; maximum daily dose this chapter that the labeling bear the 500 mg. There is no dosage limitation general warning statement ‘‘In case of at this time for professional labeling. accidental overdose, seek professional assistance or contact a poison control § 332.15 Combination with non-anti- center immediately.’’ The labeling flatulent active ingredients. must continue to bear the first part of the general warning in § 330.1(g) of this An antiflatulent may contain any chapter, which states, ‘‘Keep this and generally recognized as safe and effec- all drugs out of the reach of children.’’ tive antacid ingredient(s) if it is indicated for use solely for the concurrent [39 FR 19877, June 4, 1974, as amended at 40 symptoms of gas associated with heart- FR 11719, Mar. 13, 1975; 51 FR 16266, May 1, burn, sour stomach or acid indigestion. 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar. 13, 1987; 61 FR 8838, Mar. 5, 1996]

Subpart C—Labeling § 332.31 Professional labeling. § 332.30 Labeling of antiflatulent drug (a) The labeling of the product pro- products. vided to health professionals (but not to the general public) may contain as (a) Statement of identity. The labeling additional indications postoperative of the product contains the established gas pain or for use in endoscopic exam- name of the drug, if any, and identifies ination. the product as an ‘‘antiflatulent,’’ (b) Professional labeling for an anti- ‘‘antigas,’’ or ‘‘antiflatulent (antigas).’’ flatulent-antacid combination may (b) Indications. The labeling of the contain information allowed for health product states, under the heading ‘‘In- professionals for antacids and anti- dications,’’ one or more of the phrases flatulents. listed in this paragraph (b), as appropriate. Other truthful and nonmisleading statements, describing only the PART 333—TOPICAL ANTI- indications for use that have been es- MICROBIAL DRUG PRODUCTS tablished and listed in this paragraph FOR OVER-THE-COUNTER (b), may also be used, as provided in HUMAN USE § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Fed- Subpart A [Reserved] eral Food, Drug, and Cosmetic Act (the act) relating to misbranding and the Subpart B—First Aid Antibiotic Drug prohibition in section 301(d) of the act Products against the introduction or delivery for introduction into interstate commerce Sec. 333.101 Scope. of unapproved new drugs in violation of 333.103 Definitions. section 505(a) of the act. 333.110 First aid antibiotic active ingredi- (1) (Select one of the following: ‘‘Al- ents. leviates or Relieves’’) ‘‘the symptoms 333.120 Permitted combinations of active in- referred to as gas.’’ gredients.

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333.150 Labeling of first aid antibiotic drug each ingredient and in the specified products. dosage form: 333.160 Labeling of permitted combinations (a) Bacitracin ointment containing, of active ingredients. in each gram, 500 units of bacitracin in Subpart C—Topical Antifungal Drug a suitable ointment base. Products (b) Bacitracin zinc ointment containing, in each gram, 500 units of baci- 333.201 Scope. tracin zinc in a suitable ointment base. 333.203 Definitions. (c) Chlortetracycline hydrochloride 333.210 Antifungal active ingredients. ointment containing, in each gram, 30 333.250 Labeling of antifungal drug products. milligrams of chlortetracycline hydro- 333.280 Professional labeling. chloride in a suitable ointment base. (d) Neomycin sulfate ointment con- Subpart D—Topical Acne Drug Products taining, in each gram, 3.5 milligrams of neomycin in a suitable water soluble or 333.301 Scope. 333.303 Definitions. oleaginous ointment base. 333.310 Acne active ingredients. (e) Neomycin sulfate cream con- 333.320 Permitted combinations of active in- taining, in each gram, 3.5 milligrams of gredients. neomycin in a suitable cream base. 333.350 Labeling of acne drug products. (f) Tetracycline hydrochloride oint- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, ment containing, in each gram, 30 mil- 360, 371. ligrams of tetracycline hydrochloride in a suitable ointment base. SOURCE: 52 FR 47322, Dec. 11, 1987, unless otherwise noted. [52 FR 47322, Dec. 11, 1987, as amended at 53 FR 18838, May 25, 1988; 64 FR 403, Jan. 5, 1999] Subpart A [Reserved] § 333.120 Permitted combinations of active ingredients. Subpart B—First Aid Antibiotic The following combinations are per- Drug Products mitted provided each active ingredient § 333.101 Scope. is present within the established concentration and in the specified dosage (a) An over-the-counter first aid anti- form, and the product is labeled in ac- biotic drug product in a form suitable cordance with § 333.160. for topical administration is generally (a) Combinations of antibiotic active in- recognized as safe and effective and is gredients. (1) Bacitracin-neomycin sul- not misbranded if it meets each of the fate ointment containing, in each conditions in this subpart and each of gram, 500 units of bacitracin and 3.5 the general conditions established in milligrams of neomycin in a suitable § 330.1. ointment base. (b) References in this subpart to reg- (2) Bacitracin-neomycin sulfate-poly- ulatory sections of the Code of Federal myxin B sulfate ointment containing, Regulations are to chapter I of title 21 in each gram, in a suitable ointment unless otherwise noted. base the following: § 333.103 Definitions. (i) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 units of As used in this subpart: polymyxin B; or First aid antibiotic. An antibiotic-con- (ii) 400 units of bacitracin, 3.5 milli- taining drug product applied topically grams of neomycin, and 5,000 units of to the skin to help prevent infection in polymyxin B; minor cuts, scrapes, and burns. (3) Bacitracin-polymyxin B sulfate [52 FR 47322, Dec. 11, 1987, as amended at 64 topical aerosol containing, in each FR 403, Jan. 5, 1999] gram, 500 units of bacitracin and 5,000 units of polymyxin B in a suitable ve- § 333.110 First aid antibiotic active in- hicle, packaged in a pressurized con- gredients. tainer with suitable inert gases. The product consists of any of the (4) Bacitracin zinc-neomycin sulfate following active ingredients within the ointment containing, in each gram, 500 specified concentration established for units of bacitracin and 3.5 milligrams

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of neomycin in a suitable ointment (1) Bacitracin ointment containing, base. in each gram, 500 units of bacitracin (5) Bacitracin zinc-neomycin sulfate- and any single generally recognized as polymyxin B sulfate ointment con- safe and effective amine or ‘‘caine’’- taining, in each gram, in a suitable type local anesthetic active ingredient ointment base the following: in a suitable ointment base. (i) 400 units of bacitracin, 3 milli- (2) Bacitracin-neomycin sulfate-poly- grams of neomycin, and 8,000 units of myxin B sulfate ointment containing, polymyxin B; or in each gram, in a suitable ointment (ii) 400 units of bacitracin, 3.5 milli- base the following: grams of neomycin, and 5,000 units of (i) 500 units of bacitracin, 3.5 milli- polymyxin B; or grams of neomycin, 5,000 units of poly- (iii) 500 units of bacitracin, 3.5 milli- myxin B, and any single generally rec- grams of neomycin, and 5,000 units of ognized as safe and effective amine or polymyxin B; or ‘‘caine’’-type local anesthetic active (iv) 500 units of bacitracin, 3.5 milli- ingredient; or grams of neomycin, and 10,000 units of (ii) 400 units of bacitracin, 3.5 milli- polymyxin B; grams of neomycin, 5,000 units of poly- (6) Bacitracin zinc-polymyxin B sul- myxin B, and any single generally rec- fate ointment containing, in each ognized as safe and effective amine or gram, 500 units of bacitracin and 10,000 ‘‘caine’’-type local anesthetic active units of polymyxin B in a suitable oint- ingredient. ment base. (3) Bacitracin-polymyxin B sulfate (7) Bacitracin zinc-polymyxin B sul- topical aerosol containing, in each fate topical aerosol containing, in each gram, 500 units of bacitracin and 5,000 gram, 120 units of bacitracin and 2,350 units of polymyxin B and any single units of polymyxin B in a suitable ve- generally recognized as safe and effec- hicle, packaged in a pressurized con- tive amine or ‘‘caine’’-type local anes- tainer with suitable inert gases. thetic active ingredient in a suitable (8) Bacitracin zinc-polymyxin B sul- vehicle, packaged in a pressurized con- fate topical powder containing, in each tainer with suitable inert gases. gram, 500 units of bacitracin and 10,000 (4) Bacitracin zinc-neomycin sulfate- units of polymyxin B in a suitable polymyxin B sulfate ointment con- base. taining, in each gram, in a suitable (9) Neomycin sulfate-polymyxin B ointment base the following: sulfate ointment containing, in each (i) 400 units of bacitracin, 3 milligram, 3.5 milligrams of neomycin and grams of neomycin, 8,000 units of poly- 5,000 units of polymyxin B in a suitable myxin B, and any single generally rec- water miscible base. ognized as safe and effective amine or (10) Neomycin sulfate-polymyxin B ‘‘caine’’-type local anesthetic active sulfate cream containing, in each ingredient; or gram, 3.5 milligrams of neomycin and (ii) 400 units of bacitracin, 3.5 milli- 10,000 units of polymyxin B in a suit- grams of neomycin, 5,000 units of poly- able vehicle. myxin B, and any single generally rec- (11) Oxytetracycline hydrochloride- ognized as safe and effective amine or polymyxin B sulfate ointment con- ‘‘caine’’-type local anesthetic active taining, in each gram, 30 milligrams of ingredient; or oxytetracycline and 10,000 units of (iii) 500 units of bacitracin, 3.5 milli- polymyxin B in a suitable ointment grams of neomycin, 5,000 units of poly- base. myxin B, and any single generally rec- (12) Oxytetracycline hydrochloride- ognized as safe and effective amine or polymyxin B sulfate topical powder ‘‘caine’’-type local anesthetic active containing, in each gram, 30 milli- ingredient; or grams of oxytetracycline and 10,000 (iv) 500 units of bacitracin, 3.5 milli- units of polymyxin B with a suitable grams of neomycin, 10,000 units of poly- filler. myxin B, and any single generally rec- (b) Combinations of first aid antibiotic ognized as safe and effective amine or active ingredients and local anesthetic ac- ‘‘caine’’-type local anesthetic active tive ingredients. ingredient;

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(5) Bacitracin zinc-polymyxin B sul- wounds, animal bites, or serious burns, fate ointment containing, in each consult a doctor.’’ gram, 500 units of bacitracin, 10,000 (2) For products containing chlortetra- units of polymyxin B, and any single cycline hydrochloride or tetracycline hy- generally recognized as safe and effec- drochloride.‘‘Stop use and consult a tive amine or ‘‘caine’’-type local anes- doctor if the condition persists or gets thetic active ingredient in a suitable worse. Do not use longer than 1 week ointment base. unless directed by doctor.’’ (6) Neomycin sulfate-polymyxin B (3) For any product containing baci- sulfate cream containing, in each tracin, bacitracin zinc, neomycin, neomy- gram, 3.5 milligrams of neomycin, cin sulfate, polymyxin B, and/or poly- 10,000 units of polymyxin B, and any myxin B sulfate. ‘‘Stop use and consult single generally recognized as safe and a doctor if the condition persists or effective amine or ‘‘caine’’-type local gets worse, or if a rash or other allergic anesthetic active ingredient in a suit- reaction develops. Do not use if you are able vehicle. allergic to any of the ingredients. Do not use longer than 1 week unless di- [52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. rected by a doctor.’’ 24, 1987, as amended at 53 FR 18838, May 25, (d) Directions. The labeling of the 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, product contains the following state- Oct. 3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR ments under the heading ‘‘Directions’’: 403, Jan. 5, 1999] (1) For ointment and cream products. ‘‘Clean the affected area. Apply a small § 333.150 Labeling of first aid antibiotic drug products. amount of this product (an amount equal to the surface area of the tip of (a) Statement of identity. The labeling a finger) on the area 1 to 3 times daily. of the product contains the established May be covered with a sterile ban- name of the drug, if any, and identifies dage.’’ the product as a ‘‘first aid antibiotic.’’ (2) For powder products. ‘‘Clean the af- (b) Indications. The labeling of the fected area. Apply a light dusting of product states, under the heading ‘‘In- the powder on the area 1 to 3 times dications,’’ the following: ‘‘First aid to daily. May be covered with a sterile help’’ [select one of the following: bandage.’’ ‘‘prevent,’’ (‘‘decrease’’ (‘‘the risk of’’ (3) For aerosol products. ‘‘Clean the af- or ‘‘the chance of’’)), (‘‘reduce’’ (‘‘the fected area. Spray a small amount of risk of’’ or ‘‘the chance of’’)), ‘‘guard this product on the area 1 to 3 times against,’’ or ‘‘protect against’’] [select daily. May be covered with a sterile one of the following: ‘‘infection,’’ bandage.’’ ‘‘bacterial contamination,’’ or ‘‘skin (e) The word ‘‘doctor’’ may be sub- infection’’] ‘‘in minor cuts, scrapes, stituted for the word ‘‘physician’’ in and burns.’’ Other truthful and nonmis- any of the labeling statements in this leading statements describing only the subpart. indications for use that have been es- [52 FR 47332, Dec. 11, 1987, as amended at 61 tablished and listed in this paragraph FR 58472, Nov. 15, 1996] (b), may also be used, as provided in § 330.1(c)(2), subject to the provisions of § 333.160 Labeling of permitted com- section 502 of the act relating to mis- binations of active ingredients. branding and the prohibition in section Statements of identity, indications, 301(d) of the act against the introduc- warnings, and directions for use, re- tion or delivery for introduction into spectively, applicable to each ingre- interstate commerce of unapproved dient in the product may be combined new drugs in violation of section 505(a) to eliminate duplicative words or of the act. phrases so that the resulting informa- (c) Warnings. The labeling of the tion is clear and understandable. product contains the following warn- (a) Statement of identity. For a com- ings under the heading ‘‘Warnings’’: bination drug product that has an es- (1) ‘‘For external use only. Do not use tablished name, the labeling of the in the eyes or apply over large areas of product states the established name of the body. In case of deep or puncture the combination drug product, followed

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by the statement of identity for each tions for administrations of the indi- ingredient in the combination, as es- vidual ingredients differ, the directions tablished in the statement of identity for the combination product may not sections of the applicable OTC drug exceed any maximum dosage limits es- monographs. For a combination drug tablished for the individual ingredients product that does not have an estab- in the applicable OTC drug monograph. lished name, the labeling of the product states the statement of identity for Subpart C—Topical Antifungal each ingredient in the combination, as Drug Products established in the statement of identity sections of the applicable OTC drug monographs. SOURCE: 58 FR 49898, Sept. 23, 1993, unless otherwise noted. (b) Indications. The labeling of the product states, under the heading ‘‘In- § 333.201 Scope. dications,’’ the indication(s) for each ingredient in the combination, as es- (a) An over-the-counter antifungal tablished in the ‘‘Indications’’ sections drug product in a form suitable for top- of the applicable OTC drug mono- ical administration is generally recog- graphs, unless otherwise stated in this nized as safe and effective and is not paragraph. Other truthful and nonmis- misbranded if it meets each of the con- leading statements, describing only the ditions in this subpart and each gen- indications for use that have been es- eral condition established in § 330.1 of tablished and listed in this paragraph this chapter. (b), may also be used, as provided in (b) Reference in this subpart to regu- § 330.1(c)(2), subject to the provisions of latory sections of the Code of Federal section 502 of the act relating to mis- Regulations are to chapter I of title 21 branding and the prohibition in section unless otherwise noted. 301(d) of the act against the introduc- § 333.203 Definitions. tion or delivery for introduction into interstate commerce of unapproved As used in this subpart: new drugs in violation of section 505(a) (a) Antifungal. A drug which inhibits of the act. the growth and reproduction of fungal (1) For permitted combinations identi- cells and decreases the number of fungi fied in § 333.120(a). The indications in present. § 333.150 should be used. (b) Athlete’s foot. An infection of the (2) For permitted combinations identi- feet caused by certain dermatophytic fied in § 333.120(b). In addition to the re- fungi. quired indication identified in § 333.150, (c) Dermatophyte. A fungus that in- the labeling of the product may state, vades and lives upon the skin or in the under the heading ‘‘Indications,’’ the hair or nails. following additional indication: ‘‘First (d) Fungus. Any of a large division of aid for the temporary relief of’’ (select plants, including dermatophytes, one of the following: ‘‘pain,’’ ‘‘discom- yeasts, and molds, characterized by a fort,’’ ‘‘pain or discomfort’’ or ‘‘pain simple cell structure and the absence and itching’’) ‘‘in minor cuts, scrapes, of chlorophyll. and burns.’’ (e) Jock itch. A chronic and recurrent (c) Warnings. The labeling of the infection caused by certain product states, under the heading dermatophytic fungi; affects the upper, ‘‘Warnings,’’ the warning(s) for each in- inner thighs and sometimes extends to gredient in the combination, as estab- the groin and the pubic area; the condi- lished in the warnings sections of the tion most frequently occurs in men, applicable OTC drug monographs. but may also occur in women. (d) Directions. The labeling of the (f) Ringworm. A skin infection caused product states, under the heading ‘‘Di- by certain dermatophytic fungi. rections,’’ directions that conform to the directions established for each in- § 333.210 Antifungal active ingredi- gredient in the directions sections of ents. the applicable OTC drug monographs. The active ingredient of the product When the time intervals or age limita- consists of any one of the following

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within the specified concentration es- (B) ‘‘Jock itch,’’ ‘‘jock itch (tinea tablished for each ingredient: cruris),’’ or ‘‘tinea cruris (jock itch)’’; (a) Clioquinol 3 percent. or (b) Haloprogin 1 percent. (C) ‘‘Ringworm,’’ ‘‘ringworm (tinea (c) Miconazole nitrate 2 percent. corporis),’’ or ‘‘tinea corporis (d) Povidone-iodine 10 percent. (ringworm).’’) (e) Tolnaftate 1 percent. (ii) In addition to the information (f) Undecylenic acid, calcium identified in paragraph (b)(1)(i) of this undecylenate, copper undecylenate, section, the labeling of the product and zinc undecylenate may be used in- may contain the following statement: dividually or in any ratio that provides (Select one of the following: ‘‘Re- a total undecylenate concentration of lieves,’’ ‘‘For relief of,’’ ‘‘For effective 10 to 25 percent. relief of,’’ or ‘‘Soothes,’’) (select one or (g) Clotrimazole 1 percent. more of the following: ‘‘Itching,’’ ‘‘scaling,’’ ‘‘cracking,’’ ‘‘burning,’’ [58 FR 49898, Sept. 23, 1993, as amended at 67 ‘‘redness,’’ ‘‘soreness,’’ ‘‘irritation,’’ FR 5943, Feb. 8, 2002] ‘‘discomfort,’’ ‘‘chafing associated with § 333.250 Labeling of antifungal drug jock itch,’’ ‘‘itchy, scaly skin between products. the toes,’’ or ‘‘itching, burning feet’’). (2) For products containing the ingre- (a) Statement of identity. The labeling dient identified in § 333.210(e) labeled for of the product contains the established the prevention of athlete’s foot. (i) (Se- name of the drug, if any, and identifies lect one of the following: ‘‘Clinically the product as an ‘‘antifungal.’’ proven to prevent,’’ ‘‘Prevents,’’ (b) Indications. The labeling of the ‘‘Proven effective in the prevention product states, under the heading ‘‘In- of,’’ ‘‘Helps prevent,’’ ‘‘For the preven- dications,’’ the phrase listed in para- tion of,’’ ‘‘For the prophylaxis (preven- graph (b)(1)(i) of this section and may tion) of,’’ ‘‘Guards against,’’ or ‘‘Pre- contain the additional phrase listed in vents the recurrence of’’) ‘‘most’’ (se- paragraph (b)(1)(ii) of this section. lect one of the following: ‘‘Athlete’s Other truthful and nonmisleading foot,’’ ‘‘athlete’s foot statements, describing only the indica- (dermatophytosis),’’ ‘‘athlete’s foot tions for use that have been established (tinea pedis),’’’ or ‘‘tinea pedis (ath- in paragraph (b) of this section, may lete’s foot)’’) ‘‘with daily use.’’ also be used, as provided in § 330.1(c)(2) of this chapter, subject to the provi- (ii) In addition to the information sions of section 502 of the Federal identified in paragraph (b)(2)(i) of this Food, Drug, and Cosmetic Act (the act) section, the labeling of the product relating to misbranding and the prohi- may contain the following statement: bition in section 301(d) of the act ‘‘Clears up most athlete’s foot infec- against the introduction or delivery for tion and with daily use helps keep it introduction into interstate commerce from coming back.’’ of unapproved new drugs in violation of (c) Warnings. The labeling of the section 505(a) of the act. product contains the following warn- (1) For products containing any ingre- ings under the heading ‘‘Warnings’’: dient identified in § 333.210 labeled for the (1) For products containing any ingre- treatment of athlete’s foot, jock itch, and dient identified in § 330.210. (i) ‘‘Do not ringworm. (i) (Select one of the fol- use on children under 2 years of age un- lowing: ‘‘Treats,’’ ‘‘For the treatment less directed by a doctor.’’ of,’’ ‘‘For effective treatment of,’’ (ii) ‘‘For external use only.’’ ‘‘Cures,’’ ‘‘For the cure of,’’ ‘‘Clears (iii) ‘‘Avoid contact with the eyes.’’ up,’’ or ‘‘Proven clinically effective in (2) For products labeled according to the treatment of’’) ‘‘most’’ (select one paragraph (b)(1) of this section for the condition from any one or more of the treatment of athlete’s foot and ringworm. following groups of conditions: ‘‘If irritation occurs or if there is no (A) ‘‘Athlete’s foot,’’ athlete’s foot improvement within 4 weeks, dis- (dermatophytosis),’’ ‘‘athlete’s foot continue use and consult a doctor.’’ (tinea pedis),’’ or ‘‘tinea pedis (ath- (3) For products labeled according to lete’s foot)’’; paragraph (b)(1) of this section for the

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treatment of jock itch. ‘‘If irritation oc- (e) The word ‘‘physician’’ may be sub- curs or if there is no improvement stituted for the word ‘‘doctor’’ in any within 2 weeks, discontinue use and of the labeling statements in this sec- consult a doctor.’’ tion. (4) For products labeled according to [58 FR 49898, Sept. 23, 1993, as amended at 65 paragraph (b)(2) of this section for the FR 52305, Aug. 29, 2000] prevention of athlete’s foot. ‘‘If irritation occurs, discontinue use and consult a § 333.280 Professional labeling. doctor.’’ The labeling provided to health pro- (5) For products containing the ingre- fessionals (but not to the general pub- dient identified in § 333.210(a) labeled ac- lic) may contain the following addi- cording to paragraph (b)(1) of this sec- tional indication: tion. The following statements must (a) For products containing haloprogin appear in boldface type as the first or miconazole nitrate identified in warnings under the ‘‘Warnings’’ head- § 333.210 (a) and (c). ‘‘For the treatment ing. (i) ‘‘Do not use on children under 2 of superficial skin infections caused by years of age.’’ (This warning is to be yeast (Candida albicans).’’ used in place of the warning in para- (b) [Reserved] graph (c)(1)(i) of this section.) (ii) ‘‘Do not use for diaper rash.’’ (d) Directions. The labeling of the Subpart D—Topical Acne Drug product contains the following state- Products ments under the heading ‘‘Directions’’: (1) For products labeled according to SOURCE: 56 FR 41019, Aug. 16, 1991, unless paragraph (b)(1) of this section for the otherwise noted. treatment of athlete’s foot, jock itch, and ringworm. [Select one of the following: § 333.301 Scope. ‘‘Clean’’ or ‘‘Wash’’] ‘‘the affected area (a) An over-the-counter acne drug and dry thoroughly. Apply’’ (the word product in a form suitable for topical ‘‘spray’’ may be used to replace the application is generally recognized as word ‘‘apply’’ for aerosol products) ‘‘a safe and effective and is not mis- thin layer of the product over affected branded if it meets each of the condi- area twice daily (morning and night) or tions in this subpart and each general as directed by a doctor. Supervise chil- condition established in § 330.1 of this dren in the use of this product. For chapter. athlete’s foot: Pay special attention to (b) References in this subpart to reg- spaces between the toes; wear well-fit- ulatory sections of the Code of Federal ting, ventilated shoes, and change Regulations are to chapter I of title 21 shoes and socks at least once daily. For unless otherwise noted. athlete’s foot and ringworm, use daily for 4 weeks; for jock itch, use daily for § 333.303 Definitions. 2 weeks. If condition persists longer, As used in this subpart: consult a doctor. This product is not (a) Acne. A disease involving the oil effective on the scalp or nails.’’ glands and hair follicles of the skin (2) For products labeled according to which is manifested by blackheads, paragraph (b)(2) of this section for the whiteheads, acne pimples, and acne prevention of athlete’s foot. ‘‘To prevent blemishes. athlete’s foot,’’ (select one of the fol- (b) Acne blemish. A flaw in the skin lowing: ‘‘clean’’ or ‘‘wash’’) ‘‘the feet resulting from acne. and dry thoroughly. Apply’’ (the word (c) Acne drug product. A drug product ‘‘spray’’ may be used to replace the used to reduce the number of acne word ‘‘apply’’ for aerosol products) ‘‘a blemishes, acne pimples, blackheads, thin layer of the product to the feet and whiteheads. once or twice daily (morning and/or (d) Acne pimple. A small, prominent, night). Supervise children in the use of inflamed elevation of the skin result- this product. Pay special attention to ing from acne. spaces between the toes; wear well-fit- (e) Blackhead. A condition of the skin ting, ventilated shoes, and change that occurs in acne and is character- shoes and socks at least once daily.’’ ized by a black tip.

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(f) Whitehead. A condition of the skin introduction into interstate commerce that occurs in acne and is character- of unapproved new drugs in violation of ized by a small, firm, whitish elevation section 505(a) of the act. of the skin. (1) ‘‘For the’’ (select one of the following: ‘‘management’’ or ‘‘treat- § 333.310 Acne active ingredients. ment’’) ‘‘of acne.’’ The active ingredient of the product (2) In addition to the information consists of any of the following when identified in paragraph (b)(1) of this labeled according to § 333.350. section, the labeling of the product (a) Resorcinol 2 percent when com- may contain any one or more of the bined in accordance with § 333.320(a). following statements: (b) Resorcinol monoacetate 3 percent (i) (Select one of the following: when combined in accordance with ‘‘Clears,’’ ‘‘Clears up,’’ ‘‘Clears up § 333.320(b). most,’’ ‘‘Dries,’’ ‘‘Dries up,’’ ‘‘Dries and (c) Salicylic acid 0.5 to 2 percent. clears,’’ ‘‘Helps clear,’’ ‘‘Helps clear (d) Sulfur 3 to 10 percent. up,’’ ‘‘Reduces the number of,’’ or ‘‘Re- (e) Sulfur 3 to 8 percent when com- duces the severity of’’) (select one or bined in accordance with § 333.320. more of the following: ‘‘acne blemishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ § 333.320 Permitted combinations of or ‘‘whiteheads’’) which may be fol- active ingredients. lowed by ‘‘and allows skin to heal.’’ (a) Resorcinol identified in § 333.310(a) (ii) ‘‘Penetrates pores to’’ (select one when combined with sulfur identified of the following: ‘‘eliminate most,’’ in § 333.310(e) provided the product is la- ‘‘control,’’ ‘‘clear most,’’ or ‘‘reduce beled according to § 333.350. the number of’’) (select one or more of (b) Resorcinol monoacetate identified the following: ‘‘acne blemishes,’’ ‘‘acne in § 333.310(b) when combined with sul- pimples,’’ ‘‘blackheads,’’ or fur identified in § 333.310(e) provided the ‘‘whiteheads’’). product is labeled according to § 333.350. (iii) ‘‘Helps keep skin clear of new’’ (select one or more of the following: § 333.350 Labeling of acne drug prod- ‘‘acne blemishes,’’ ‘‘acne pimples,’’ ucts. ‘‘blackheads,’’ or ‘‘whiteheads’’). (a) Statement of identity. The labeling (iv) ‘‘Helps prevent new’’ (select one of the product contains the established or more of the following: ‘‘acne blem- name of the drug, if any, and identifies ishes,’’ ‘‘acne pimples,’’ ‘‘blackheads,’’ the product as an ‘‘acne medication,’’ or ‘‘whiteheads’’) which may be fol- ‘‘acne treatment,’’ ‘‘acne medication’’ lowed by ‘‘from forming.’’ (insert dosage form, e.g., ‘‘cream,’’ (v) ‘‘Helps prevent the development ‘‘gel,’’ ‘‘lotion,’’ or ‘‘ointment’’), or of new’’ (select one or more of the fol- ‘‘acne treatment’’ (insert dosage form, lowing: ‘‘acne blemishes,’’ ‘‘acne pim- e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or ples,’’ ‘‘blackheads,’’ or ‘‘whiteheads’’). ‘‘ointment’’). (c) Warnings. The labeling of the (b) Indications. The labeling of the product contains the following warn- product states, under the heading ‘‘In- ings under the heading ‘‘Warnings’’: dications,’’ the phrase listed in para- (1) For products containing any ingre- graph (b)(1) of this section and may dient identified in § 333.310. (i) ‘‘For ex- contain any of the additional phrases ternal use only.’’ listed in paragraph (b)(2) of this sec- (ii) ‘‘Using other topical acne medi- tion. Other truthful and nonmisleading cations at the same time or imme- statements, describing only the indica- diately following use of this product tions for use that have been established may increase dryness or irritation of and listed in paragraph (b) of this sec- the skin. If this occurs, only one medi- tion, may also be used, as provided in cation should be used unless directed § 330.1(c)(2) of this chapter, subject to by a doctor.’’ the provisions of section 502 of the Fed- (2) For products containing sulfur iden- eral Food, Drug, and Cosmetic Act (the tified in §§ 333.310 (d) and (e). ‘‘Do not act) relating to misbranding and the get into eyes. If excessive skin irrita- prohibition in section 301(d) of the act tion develops or increases, discontinue against the introduction or delivery for use and consult a doctor.’’

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(3) For products containing any com- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, bination identified in § 333.320. ‘‘Apply to 360, 371. affected areas only. Do not use on bro- SOURCE: 68 FR 18881, April 17, 2003, unless ken skin or apply to large areas of the otherwise noted. body.’’ EFFECTIVE DATE NOTE: At 68 FR 18881, (d) Directions. The labeling of the April 17, 2003, Part 335 was added, effective product contains the following infor- April 19, 2004. mation under the heading ‘‘Direc- tions’’: Subpart A—General Provisions (1) ‘‘Cleanse the skin thoroughly before applying medication. Cover the en- § 335.1 Scope. tire affected area with a thin layer one (a) An over-the-counter antidiarrheal to three times daily. Because excessive drug product in a form suitable for oral drying of the skin may occur, start administration is generally recognized with one application daily, then gradu- as safe and effective and is not mis- ally increase to two or three times branded if it meets each condition in daily if needed or as directed by a doc- this part and each general condition es- tor. If bothersome dryness or peeling tablished in § 330.1 of this chapter. occurs, reduce application to once a (b) References in this part to regu- day or every other day.’’ latory sections of the Code of Federal (2) The directions described in para- Regulations are to chapter I of title 21 graph (d)(1) of this section are intended unless otherwise noted. for products that are applied and left on the skin. Other products, such as § 335.3 Definitions. soaps or masks, may be applied and re- As used in this part: moved and should have appropriate di- (a) Antidiarrheal. A drug that can be rections. shown by objective measurement to (3) Optional directions. In addition to treat or control (stop) the symptoms of the required directions in paragraphs diarrhea. (d)(1) and (d)(2) of this section, the (b) Diarrhea. A condition character- product may contain the following op- ized by increased frequency of loose, tional labeling: ‘‘Sensitivity Test for a watery stools (three or more daily) New User. Apply product sparingly to during a limited period (24 to 48 hours), one or two small affected areas during usually with no identifiable cause. the first 3 days. If no discomfort occurs, follow the directions stated: (select one of the following: ‘elsewhere on Subpart B—Active Ingredients this label,’ ‘above,’ or ‘below.’)’’ § 335.10 Antidiarrheal active ingredi- (e) The word ‘‘physician’’ may be sub- ents. stituted for the word ‘‘doctor’’ in any of the labeling statements in this sec- The active ingredient of the product tion. consists of any one of the following when used within the dosage limits established for each ingredient in PART 335—ANTIDIARRHEAL DRUG § 335.50(d): PRODUCTS FOR OVER-THE- (a) Bismuth subsalicylate. COUNTER HUMAN USE (b) Kaolin.

Subpart A—General Provisions Subpart C—Labeling 335.1 Scope. § 335.50 Labeling of antidiarrheal drug 335.3 Definitions. products. Subpart B—Active Ingredients (a) Statement of identity. The labeling of the product contains the established 335.10 Antidiarrheal active ingredients. name of the drug, if any, and identifies the product either as an Subpart C—Labeling ‘‘antidiarrheal’’ or ‘‘for diarrhea.’’ 335.50 Labeling of antidiarrheal drug prod- (b) Indications. The labeling of the ucts. product states, under the heading

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‘‘Use,’’ one or more of the phrases list- [bullet] taking other salicylate prod- ed in this paragraph (b), as appropriate. ucts’’. Other truthful and nonmisleading (ii) ‘‘Do not use if you have [bullet] statements, describing only the indica- an ulcer [bullet] a bleeding problem’’. tions for use that have been established (iii) ‘‘Ask a doctor or pharmacist be- and listed in this paragraph (b) may fore use if you are taking any drug for also be used, as provided in § 330.1(c)(2) [bullet] anticoagulation (thinning the of this chapter, subject to the provi- blood) [bullet] diabetes [bullet] gout sions of section 502 of the Federal [bullet] arthritis’’. Food, Drug, and Cosmetic Act (the act) (iv) ‘‘When using this product a tem- relating to misbranding and the prohi- porary, but harmless, darkening of the bition in section 301(d) of the act stool and/or tongue may occur’’. against the introduction or delivery for (v) ‘‘Stop use and ask a doctor if [bul- introduction into interstate commerce let] symptoms get worse [bullet] ring- of unapproved new drugs in violation of ing in the ears or loss of hearing occurs section 505(a) of the act. [bullet] diarrhea lasts more than 2 (1) For products containing bismuth days’’. subsalicylate identified in § 335.10(a). The (3) For products containing kaolin iden- labeling states [select one of the following: ‘‘controls’’ or ‘‘relieves’’] ‘‘di- tified in § 335.10(b). (i) ‘‘Ask a doctor or arrhea’’. pharmacist before use if you are taking any other drugs. Try to use at least 3 (2) For products containing kaolin iden- hours before or after taking any other tified in § 335.10(b). The labeling states ‘‘helps firm stool within 24 to 48 drugs.’’ hours’’. (ii) ‘‘Stop use and ask a doctor if (3) Additional indications—(i) When [bullet] symptoms get worse [bullet] any additional indications are used, diarrhea lasts more than 2 days’’. the heading ‘‘Uses’’ shall be used and (d) Directions. The labeling of the each listed use shall be preceded by a product contains the following infor- bullet in accord with § 201.66(b)(4) of mation under the heading ‘‘Direc- this chapter. tions’’: (ii) In addition to the indication in (1) For products containing any ingre- paragraph (b)(1) of this section, one or dient identified in § 335.10. The labeling both of the following may be used for states ‘‘[bullet] drink plenty of clear products containing bismuth subsalicy- fluids to help prevent dehydration late in § 335.10(a): ‘‘[bullet] reduces caused by diarrhea’’. number of bowel movements’’ ‘‘[bullet] (2) For products containing bismuth helps firm stool’’. subsalicylate identified in § 335.10(a). The (c) Warnings. The labeling of the labeling states ‘‘[bullet] adults and product contains the following warn- children 12 years and over:’’ 525 milli- ings under the heading ‘‘Warnings’’: grams ‘‘every 1/2 to 1 hour, or’’ 1,050 (1) For products containing any ingre- milligrams ‘‘every hour as needed [bul- dient identified in § 335.10. (i) ‘‘Do not let] do not exceed’’ 4,200 milligrams ‘‘in use if you have [bullet] bloody or black 24 hours [bullet] use until diarrhea stool’’. stops but not more than 2 days [bullet] (ii) ‘‘Ask a doctor before use if you children under 12 years: ask a doctor’’. have [bullet] fever [bullet] mucus in (3) For products containing kaolin iden- the stool’’. tified in § 335.10(b). The labeling states (2) For products containing bismuth ‘‘[bullet] adults and children 12 years subsalicylate identified in § 335.10(a). (i) and over:’’ 26.2 grams ‘‘after each loose The following shall appear in accord- stool [bullet] continue to take every 6 ance with § 201.66(c)(5)(ii) of this chap- hours until stool is firm but not more ter. than 2 days [bullet] do not exceed’’ [262 (A) The Reye’s syndrome warning in grams] ‘‘in 24 hours [bullet] children § 201.314(h) of this chapter. under 12 years of age: ask a doctor’’. (B) ‘‘Allergy alert: Contains salicy- (e) Products that meet the criteria es- late. Do not take if you are [bullet] al- tablished in § 201.66(d)(10) of this chapter. lergic to salicylates (including aspirin), The information described in § 201.66(c)

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

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such as emphysema or chronic bron- in § 336.10(c). ‘‘Do not use [bullet]1 with chitis, or if you have glaucoma or dif- any other product containing ficulty in urination due to enlargement diphenhydramine, including one used of the prostate gland.’’ on skin’’. (ii) For those products that can be and (d) Directions. The labeling of the are labeled only for children under 12 product contains the following infor- years of age. ‘‘Do not give this product mation under the heading ‘‘Direc- to children who have a breathing prob- tions’’: lem such as chronic bronchitis or who (1) For products containing cyclizine have glaucoma, without first con- hydrochloride identified in § 336.10(a). sulting the child’s doctor.’’ Adults and children 12 years of age and (2) For products containing cyclizine over: Oral dosage is 50 milligrams hydrochloride identified in § 336.10(a). every 4 to 6 hours, not to exceed 200 ‘‘Do not give to children under 6 years milligrams in 24 hours, or as directed of age unless directed by a doctor.’’ by a doctor. Children 6 to under 12 (3) For products containing dimenhy- years of age: Oral dosage is 25 milli- drinate identified in § 336.10(b). ‘‘Do not grams every 6 to 8 hours, not to exceed give to children under 2 years of age 75 milligrams in 24 hours, or as di- unless directed by a doctor.’’ rected by a doctor. (4) For products containing (2) For products containing dimenhy- diphenhydramine hydrochloride identified drinate identified in § 336.10(b). Adults in § 336.10(c). ‘‘Do not give to children and children 12 years of age and over: under 6 years of age unless directed by Oral dosage is 50 to 100 milligrams a doctor.’’ every 4 to 6 hours, not to exceed 400 (5) For products containing meclizine milligrams in 24 hours, or as directed hydrochloride identified in § 336.10(d). by a doctor. Children 6 to under 12 ‘‘Do not give to children under 12 years years of age: Oral dosage is 25 to 50 mil- of age unless directed by a doctor.’’ ligrams every 6 to 8 hours, not to ex- (6) For products containing cyclizine ceed 150 milligrams in 24 hours, or as hydrochloride identified in § 336.10(a) or directed by a doctor. Children 2 to meclizine hydrochloride identified in under 6 years of age: Oral dosage is 12.5 § 330.10(d). ‘‘May cause drowsiness; al- to 25 milligrams every 6 to 8 hours, not cohol, sedatives, and tranquilizers may to exceed 75 milligrams in 24 hours, or increase the drowsiness effect. Avoid as directed by a doctor. alcoholic beverages while taking this (3) For products containing product. Do not take this product if diphenhydramine hydrochloride identified you are taking sedatives or tranquil- in § 336.10(c). Adults and children 12 izers, without first consulting your years of age and over: Oral dosage is 25 doctor. Use caution when driving a to 50 milligrams every 4 to 6 hours, not motor vehicle or operating machin- to exceed 300 milligrams in 24 hours, or ery.’’ as directed by a doctor. Children 6 to (7) For products containing dimenhy- under 12 years of age: Oral dosage is drinate identified in § 336.10(b) or 12.5 to 25 milligrams every 4 to 6 hours, diphenhydramine hydrochloride identified not to exceed 150 milligrams in 24 in § 336.10(c). ‘‘May cause marked hours, or as directed by a doctor. drowsiness; alcohol, sedatives, and (4) For products containing meclizine 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 products. interstate commerce of unapproved 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. 341.85 Labeling of permitted combinations feine as a cup of coffee. Limit the use of active ingredients. of caffeine-containing medications, 341.90 Professional labeling. foods, or beverages while taking this product because too much caffeine may AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. cause nervousness, irritability, sleeplessness, and, occasionally, rapid heart EDITORIAL NOTE: Nomenclature changes to beat.’’ part 341 can be found at 69 FR 13717, Mar. 24, (2) ‘‘For occasional use only. Not in- 2004. tended for use as a substitute for sleep. If fatigue or drowsiness persists or con- Subpart A—General Provisions tinues to recur, consult a’’ (select one of the following: ‘‘physician’’ or ‘‘doc- § 341.1 Scope. tor’’). (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. 341.3 Definitions. as in the symptomatic treatment of 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 that relieves cough when inhaled after Subpart C—Labeling being applied topically to the throat or 341.40 Permitted combinations of active in- chest in the form of an ointment or gredients. 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 (a) Oral antitussives. (1) Chlophedianol orally to promote or facilitate the re- hydrochloride. moval of secretions from the res- (2) Codeine ingredients. The following piratory airways. ingredients may be used only in com- (e) Antihistamine drug. A drug used bination in accordance with §§ 290.2 and for the relief of the symptoms of hay 21 CFR 1308.15(c). fever and upper respiratory allergies (i) Codeine. (allergic rhinitis). (ii) Codeine phosphate. (f) Oral nasal decongestant drug. A (iii) Codeine sulfate. drug that is taken by mouth and acts (3) Dextromethorphan. systemically to reduce nasal conges- (4) Dextromethorphan hydrobromide. tion caused by acute or chronic rhi- (5) Diphenhydramine citrate. nitis. (6) Diphenhydramine hydrochloride. (g) Topical nasal decongestant drug. A (b) Topical antitussives. drug that when applied topically inside (1) Camphor. the nose, in the form of drops, jellies, (2) Menthol. or sprays, or when inhaled intranasally reduces nasal congestion caused by [52 FR 30055, Aug. 12, 1987, as amended at 59 FR 29174, June 3, 1994; 67 FR 4907, Feb. 1, 2002] acute or chronic rhinitis. (h) Calibrated dropper. A dropper cali- § 341.16 Bronchodilator active ingredi- brated such that the volume error in- ents. curred in measuring any liquid does The active ingredients of the product not exceed 15 percent under normal use consist of any of the following when conditions. 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, (b) Ephedrine hydrochloride. 1994] (c) Ephedrine sulfate. (d) Epinephrine. Subpart B—Active Ingredients (e) Epinephrine bitartrate. (f) Racephedrine hydrochloride. § 341.12 Antihistamine active ingredi- (g) Racepinephrine hydrochloride. ents. The active ingredient of the product [51 FR 35339, Oct. 2, 1986] 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 (a) Brompheniramine maleate. is guaifenesin when used within the (b) Chlorcyclizine hydrochloride. dosage limits established in § 341.78(d). (c) Chlorpheniramine maleate. [54 FR 8509, Feb. 28, 1989] (d) Dexbrompheniramine maleate. (e) Dexchlorpheniramine maleate. § 341.20 Nasal decongestant active in- (f) Diphenhydramine citrate. gredients. (g) Diphenhydramine hydrochloride. The active ingredient of the product (h) Doxylamine succinate. consists of any of the following when (i) Phenindamine tartrate. used within the dosage limits and in (j) Pheniramine maleate. the dosage forms established for each (k) Pyrilamine maleate. ingredient: (l) Thonzylamine hydrochloride. (a) Oral nasal decongestants. (1) Phen- (m) Triprolidine hydrochloride. ylephrine hydrochloride. [57 FR 58374, Dec. 9, 1992, as amended at 59 (2) Pseudoephedrine hydrochloride. FR 4218, Jan. 28, 1994] (3) Pseudoephedrine sulfate. (b) Topical nasal decongestants. (1) § 341.14 Antitussive active ingredients. Levmetamfetamine. The active ingredients of the product (2) Ephedrine. consist of any of the following when (3) Ephedrine hydrochloride. used within the dosage limits and in (4) Ephedrine sulfate. the dosage forms established for each (5) [Reserved] ingredient in § 341.74(d): (6) Naphazoline hydrochloride.

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

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

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

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oral anesthetic/analgesic active ingre- §§ 341.72(b) and 341.74(b). The warnings dients and any generally recognized as shall be combined from §§ 341.72(c)(1), safe and effective single oral demulcent (c)(2), (c)(4), and (c)(6) and 341.74(c)(1), active ingredient provided that the (c)(2), (c)(3), and (c)(4). Alternatively, product is available in either a liquid all of the warnings in § 341.74(c) shall be (to be swallowed) or a solid dosage used. The directions for OTC labeling form (to be dissolved in the mouth and shall follow §§ 341.74(d)(1)(iv) or swallowed) and provided that the prod- (d)(1)(v), as applicable. The directions uct is labeled according to § 341.85. for professional labeling shall follow (bb) Any single antitussive active in- § 341.90(j) or (k), as applicable. gredient identified in § 341.14(a) or (b)(2) (b) (Reserved) may be combined with any single oral nasal decongestant active ingredient [61 FR 15703, Apr. 9, 1996] identified in § 341.20(a) and any gen- EFFECTIVE DATE NOTE 1: At 67 FR 78170, erally recognized as safe and effective Dec. 23, 2002, § 341.70 was amended by adding single oral anesthetic/analgesic active paragraph (b), effective Dec. 23, 2004. For the ingredient identified or any combina- convenience of the user, the added text is set tion of anesthetic/analgesic active in- forth as follows: gredients and any generally recognized § 341.70 Labeling of OTC drug products con- as safe and effective single oral demul- taining ingredients that are used for cent active ingredient provided that treating concurrent symptoms (in either the product is available in either a liq- a single-ingredient or combination drug uid (to be swallowed) or a solid dosage product). form (to be dissolved in the mouth and swallowed) and provided that the prod- * * * * * uct is labeled according to § 341.85. If (b) For products containing menthol identified the combination contains a topical in §§ 341.14(b)(2) and 356.12(f) of this chapter. antitussive, the product must be for- The product contains 5 to 10 milligrams men- mulated in a solid dosage form to be thol. The labeling of the product contains dissolved in the mouth. the established name of the drug, if any, and identifies the product as a ‘‘cough suppres- [67 FR 78168, Dec. 23, 2002] sant/oral anesthetic’’ or ‘‘antitussive (cough EFFECTIVE DATE NOTE: At 67 FR 78168, Dec. suppressant)/oral anesthetic.’’ The indica- 23, 2002, § 341.40 was added, effective Dec. 23, tions shall be combined from § 341.74(b) and 2004. At 68 FR 17881, Apr. 14, 2003, the amend- part 356 of this chapter. The warnings shall atory instruction was corrected, effective be combined from § 341.74(c)(1), (c)(2), and Dec. 23, 2004. (c)(3) and part 356 of this chapter. The directions shall be: ‘‘Directions [in bold type] § 341.70 Labeling of OTC drug prod- [bullet]1 adults and children 2 years and ucts containing ingredients that are over: dissolve lozenge slowly in the mouth. used for treating concurrent symp- Repeat every hour as needed or as directed toms (in either a single-ingredient by a doctor. [bullet] children under 2 years of or combination drug product). age: ask a doctor’’.

The statements of identity, indica- EFFECTIVE DATE NOTE 2: At 68 FR 17881, tions, warnings, and directions for use, Apr. 14, 2003, the amendment to § 341.70 was respectively, applicable to each ingre- corrected by correcting in paragraph (b) the dient in the product may be combined sentence ‘‘Repeat every hour as needed or as to eliminate duplicative words or directed by a doctor.’’ to read ‘‘Repeat every phrases so that the resulting informa- 2 hours as needed or as directed by a doc- tion is clear and understandable. tor.’’, effective Dec. 23, 2004. (a) For products containing § 341.72 Labeling of antihistamine diphenhydramine citrate and drug products. diphenhydramine hydrochloride identified in § 341.14(a)(5) and (a)(6). The labeling (a) Statement of identity. The labeling of the product contains the established of the product contains the established name of the drug, if any, and identifies name of the drug, if any, and identifies the product as an ‘‘antihistamine/ the product as an ‘‘antihistamine.’’ cough suppressant’’ or ‘‘antihistamine/ antitussive (cough suppressant).’’ The 1See § 201.66(b)(4) of this chapter for defini- indications shall be combined from tion of bullet symbol.

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(b) Indications. The labeling of the tranquilizers may increase the drowsi- product states, under the heading ‘‘In- ness effect. Avoid alcoholic beverages dications,’’ any of the phrases listed in while taking this product. Do not take 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)’’). (2) ‘‘For the temporary relief of only the warnings identified in para- runny nose, sneezing, itching of the graphs (c)(1) and (c)(5) of this section as nose or throat, and itchy, watery eyes well as the following: 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

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

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37.5 milligrams in 24 hours, or as di- age: oral dosage is 1.25 milligrams rected by a doctor. Children under 6 every 4 to 6 hours, not to exceed 5 mil- years of age: consult a doctor. ligrams in 24 hours, or as directed by a (9) For products containing doctor. Children under 6 years of age: phenindamine tartrate identified in consult a doctor. § 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 grams every 4 to 6 hours, not to exceed FR 4218, Jan. 28, 1994; 67 FR 72559, Dec. 6, 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 pheniramine maleate identified in (a) Statement of identity. The labeling § 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’’).

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(3) In addition to the required infor- accompanied by fever, rash, or per- mation identified in paragraphs (b) (1) sistent headache, consult a doctor.’’ and (2) of this section, the labeling of (2) For oral and topical antitussives la- the product may contain any (one or beled for adults or for adults and children more) of the following statements: under 12 years of age. ‘‘Do not take this (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- leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ gredients identified in § 341.14(a)(2) when ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- labeled only for adults. ‘‘Do not take presses’’) (select one of the following: this product if you have a chronic pul- ‘‘Cough,’’ ‘‘the impulse to cough,’’ or monary disease or shortness of breath ‘‘your cough’’) ‘‘to help you’’ (select unless directed by a doctor.’’ one of the following: ‘‘Get to sleep,’’ (iii) For products containing codeine in- ‘‘sleep,’’ or ‘‘rest’’). gredients identified in § 341.14(a)(2) when (vi) For products containing labeled only for children under 12 years of chlophedianol hydrochloride, codeine in- age. ‘‘Do not give this product to chil- gredients, dextromethorphan, or dren who have a chronic pulmonary dextromethorphan hydrobromide identi- disease, shortness of breath, or who are fied in § 341.14(a) (1), (2), (3), and (4). taking other drugs unless directed by a ‘‘Calms the cough control center and doctor.’’ relieves coughing.’’ (iv) For products containing codeine in- (vii) For products containing gredients identified in § 341.14(a)(2) when chlophedianol hydrochloride, labeled for use in adults and children dextromethorphan, dextromethorphan under 12 years of age. ‘‘Adults and chil- hydrobromide, camphor, or menthol iden- dren who have a chronic pulmonary tified in § 341.14(a) (1), (3), (4) and (b) (1) disease or shortness of breath, or chil- and (2). (a) ‘‘Nonnarcotic cough sup- dren who are taking other drugs, pressant for the temporary’’ (select one should not take this product unless di- of the following: ‘‘alleviation,’’ ‘‘con- rected by a doctor.’’ trol,’’ ‘‘decrease,’’ ‘‘reduction,’’ ‘‘re- (v) For products containing lief,’’ or ‘‘suppression’’) ‘‘of cough.’’ dextromethorphan or dextromethorphan (b) (Select one of the following: ‘‘Al- hydrobromide as identified in leviates,’’ ‘‘Controls,’’ ‘‘Decreases,’’ § 341.14(a)(3) and (a)(4) when labeled for ‘‘Reduces,’’ ‘‘Relieves,’’ or ‘‘Sup- adults or for adults and children under 12 presses’’) ‘‘cough impulses without nar- years of age. Drug interaction precaution. cotics.’’ ‘‘Do not use if you are now taking a (c) Warnings. The labeling of the prescription monoamine oxidase inhib- product contains the following warn- itor (MAOI) (certain drugs for depres- ings under the heading ‘‘Warnings’’: sion, psychiatric, or emotional condi- (1) For oral and topical antitussives. ‘‘A tions, or Parkinson’s disease), or for 2 persistent cough may be a sign of a se- weeks after stopping the MAOI drug. If rious condition. If cough persists for you do not know if your prescription more than 1 week, tends to recur, or is drug contains an MAOI, ask a doctor or

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pharmacist before taking this prod- may increase the drowsiness effect. uct.’’ Avoid alcoholic beverages while taking (vi) For products containing this product. Do not take this product dextromethorphan or dextromethorphan if you are taking sedatives or tranquil- hydrobromide as identified in izers, without first consulting your § 341.14(a)(3) and (a)(4) when labeled only doctor. Use caution when driving a for children under 12 years of age. Drug motor vehicle or operating machin- interaction precaution. ‘‘Do not use in a ery.’’ child who is taking a prescription mon- (C) ‘‘Do not use [bullet] with any oamine oxidase inhibitor (MAOI) (cer- other product containing tain drugs for depression, psychiatric, diphenhydramine, even one used on or emotional conditions, or Parkin- skin’’. son’s disease), or for 2 weeks after stop- (5) Topical antitussives—(i) For prod- ping the MAOI drug. If you do not ucts containing camphor or menthol iden- know if your child’s prescription drug tified in § 341.14(b) (1) and (2) in a suit- contains an MAOI, ask a doctor or able ointment vehicle. ‘‘For external use pharmacist before giving this product.’’ only. Do not take by mouth or place in (vii) For products containing nostrils.’’ diphenhydramine citrate or (ii) For products containing camphor or diphenhydramine hydrochloride identified menthol identified in § 341.14(b) (1) and (2) in § 341.14(a)(5) and (a)(6). ‘‘May cause for steam inhalation use. ‘‘For steam in- excitability especially in children.’’ halation only. Do not take by mouth.’’ (viii) For products containing (iii) For any product containing cam- diphenhydramine citrate or phor or menthol in a suitable ointment ve- diphenhydramine hydrochloride identified hicle or for steam inhalation use and in § 341.14(a)(5) and (a)(6) when labeled meets the definition of one of the signal only for children under 12 years of age— words (‘‘extremely flammable,’’ ‘‘flam- (A) ‘‘Do not give this product to chil- mable,’’ ‘‘combustible’’) as described in 16 dren who have a breathing problem CFR 1500.3(b)(10). The labeling contains such as chronic bronchitis, or who have the appropriate flammability signal glaucoma, without first consulting the word(s) followed by a colon and the child’s doctor.’’ 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, (C) ‘‘Do not use [bullet]1 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.

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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‘‘When using this product, do not [bul- in 24 hours, or as directed by a doctor. let] heat [bullet] microwave [bullet] Children 6 to under 12 years of age: use near an open flame [bullet] add to Oral dosage is 5 to 10 milligrams every hot water or any container where heat- 4 hours or 15 milligrams every 6 to 8 ing water except when adding to cold hours, not to exceed 60 milligrams in 24 water only in a hot steam vaporizer. hours, or as directed by a doctor. Chil- 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

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

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

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often than every 3 hours. The use of age. ‘‘Do not give this product for per- 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) unless directed by a doctor.’’ (Collection of information requirement approved by the Office of Management and (d) Directions. The labeling of the Budget under control number 0910–0237) product contains the following information under the heading ‘‘Directions’’ [51 FR 35339, Oct. 2, 1986, as amended at 52 FR for products containing guaifenesin 7126, Mar. 9, 1987; 52 FR 7830, Mar. 13, 1987; 53 identified in § 341.18: Adults and chil- FR 35810, Sept. 15, 1988; 58 FR 54242, Oct. 20, 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,’’ [54 FR 8509, Feb. 28, 1989, as amended at 57 ‘‘drain bronchial tubes,’’ and ‘‘make FR 29177, June 30, 1992] coughs more productive’’). Other truthful 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 (a) Statement of identity. The labeling this paragraph (b), may also be used, as of the product contains the established provided in § 330.1(c)(2) of this chapter, name of the drug, if any, and identifies subject to the provisions of section 502 the product as a ‘‘nasal decongestant.’’ of the act relating to misbranding and (b) Indications. The labeling of the the prohibition in section 301(d) of the product states, under the heading ‘‘In- act against the introduction or deliv- dications,’’ the phrase listed in para- ery for introduction into interstate graph (b)(1) of this section, as appro- commerce of unapproved new drugs in priate, and may contain any additional violation of section 505(a) of the act. phrases listed in paragraph (b)(2) of (c) Warnings. The labeling of the this section. Other truthful and non- product contains the following warn- misleading statements, describing only ings, under the heading ‘‘Warnings’’: the indications for use that have been (1) ‘‘A persistent cough may be a sign established and listed in paragraphs of a serious condition. If cough persists (b)(1) and (b)(2) of this section, may for more than 1 week, tends to recur, also be used, as provided in § 330.1(c)(2) or is accompanied by a fever, rash, or of this chapter, subject to the provi- persistent headache, consult a doctor.’’ sions of section 502 of the Federal (2) For expectorant drug products la- Food, Drug, and Cosmetic Act (the act) beled for adults or for adults and children relating to misbranding and the prohi- under 12 years of age. ‘‘Do not take this bition in section 301(d) of the act product for persistent or chronic cough against the introduction or delivery for such as occurs with smoking, asthma, introduction into interstate commerce chronic bronchitis, or emphysema, or of unapproved new drugs in violation of where cough is accompanied by exces- section 505(a) of the act. sive phlegm (mucus) unless directed by (1) (Select one of the following: ‘‘For a doctor.’’ the temporary relief of nasal conges- (3) For expectorant drug products lation’’ or ‘‘Temporarily relieves nasal beled only for children under 12 years of congestion’’) (which may be followed

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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, or pseudoephedrine sulfate (iii) ‘‘associated with sinusitis.’’ identified in § 341.20 (a)(1), (a)(2), and (2) In addition to the information (a)(3) when labeled for children under 12 identified in paragraph (b)(1) of this years of age. (A) ‘‘Do not exceed rec- section, the labeling of the product ommended dosage. [first sentence in may contain any (one or more) of the boldface type] If nervousness, dizziness, following statements: or sleeplessness occur, discontinue use (i) (Select one of the following: ‘‘For and consult a doctor.’’ the temporary relief of’’ or ‘‘Tempo- (B) ‘‘If symptoms do not improve rarily relieves’’) (select one of the fol- within 7 days or are accompanied by lowing: ‘‘stuffy nose,’’ ‘‘stopped up fever, consult a doctor.’’ nose,’’ ‘‘nasal stuffiness,’’ or ‘‘clogged (C) ‘‘Do not give this product to a up nose.’’) child who has heart disease, high blood (ii) (Select one of the following: ‘‘Re- pressure, thyroid disease, or diabetes duces swelling of,’’ ‘‘Decongests,’’ or unless directed by a doctor.’’ ‘‘Helps clear’’) ‘‘nasal passages; shrinks (D) Drug interaction precaution. ‘‘Do swollen membranes.’’ not use in a child who is taking a pre- (iii) ‘‘Temporarily restores freer scription monoamine oxidase inhibitor breathing through the nose.’’ (MAOI) (certain drugs for depression, (iv) ‘‘Helps decongest sinus openings psychiatric, or emotional conditions, and passages; temporarily relieves or Parkinson’s disease), or for 2 weeks sinus congestion and pressure.’’ after stopping the MAOI drug. If you do (v) ‘‘Promotes nasal and/or sinus not know if your child’s prescription drainage; temporarily relieves sinus drug contains an MAOI, ask a doctor or congestion and pressure.’’ pharmacist before giving this product.’’ (c) Warnings. The labeling of the (iii) For oral nasal decongestant prod- product contains the following warn- ucts labeled for both adults and children ings under the heading ‘‘Warnings’’: under 12 years of age. The labeling of (1) Oral nasal decongestants—(i) For the product contains the warnings products containing phenylephrine hydro- identified in paragraph (c)(1)(i) of this chloride, pseudoephedrine hydrochloride, section. or pseudoephedrine sulfate identified in (2) Topical nasal decongestants—(i) For § 341.20 (a)(1), (a)(2), and (a)(3) when la- products containing any topical nasal de- beled for adults. (A) ‘‘Do not exceed rec- congestant identified in § 341.20(b) when ommended dosage. [first sentence in labeled for adults. (A) ‘‘Do not exceed boldface type] If nervousness, dizziness, recommended dosage.’’ [sentence in or sleeplessness occur, discontinue use boldface type] and consult a doctor.’’ (B) ‘‘This product may cause tem- (B) ‘‘If symptoms do not improve porary discomfort such as burning, within 7 days or are accompanied by stinging, sneezing, or an increase in fever, consult a doctor.’’ nasal discharge.’’ (C) ‘‘Do not take this product if you (C) ‘‘The use of this container by have heart disease, high blood pressure, more than one person may spread in- thyroid disease, diabetes, or difficulty fection.’’ in urination due to enlargement of the (ii) For products containing prostate gland unless directed by a doc- levmetamfetamine identified in tor.’’ § 341.20(b)(1) when used in an inhalant (D) Drug interaction precaution. ‘‘Do dosage form and when labeled for adults. not use if you are now taking a pre- ‘‘Do not use this product for more than

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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 oxymetazoline hydrochloride, phenyl- milligrams in 24 hours. Children 2 to

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under 6 years of age: 15 milligrams give to children under 12 years of age every 4 to 6 hours not to exceed 60 mil- unless directed by a doctor. ligrams in 24 hours. Children under 2 (2) For a 0.025-percent water-based years of age: consult a doctor. jelly. Children 6 to under 12 years of age (2) Topical nasal decongestants—(i) For (with adult supervision): place a small products containing levmetamfetamine amount in each nostril and inhale well identified in § 341.20(b)(1) when used in an back into the nasal passages. Use not inhalant dosage form. The product deliv- more often than every 6 hours. Chil- ers in each 800 milliliters of air 0.04 to dren under 6 years of age: consult a 0.150 milligrams of levmetamfetamine. doctor. Adults: 2 inhalations in each nostril (iv) For products containing not more often than every 2 hours. oxymetazoline hydrochloride identified in Children 6 to under 12 years of age § 341.20(b)(7)—(A) Nasal drops or sprays— (with adult supervision): 1 inhalation (1) For a 0.05-percent aqueous solution. in each nostril not more often than Adults and children 6 to under 12 years every 2 hours. Children under 6 years of of age (with adult supervision): 2 or 3 age: ask a doctor. drops or sprays in each nostril not (ii) For products containing ephedrine, more often than every 10 to 12 hours. ephedrine hydrochloride, or ephedrine Do not exceed 2 doses in any 24-hour sulfate identified in § 341.20(b) (2), (3), period. Children under 6 years of age: and (4)—(A) Nasal drops or sprays—For a consult a doctor. 0.5-percent aqueous solution. Adults and (2) A 0.025-percent aqueous solution in children 12 years of age and over: 2 or a container having either a calibrated 3 drops or sprays in each nostril not dropper or a metered-dose spray that de- more often than every 4 hours. Chil- livers no more than 0.027 milligrams of dren 6 to under 12 years of age (with oxymetazoline per three drops or three adult supervision): 1 or 2 drops or sprays. Children 2 to under 6 years of sprays in each nostril not more often age (with adult supervision): 2 or 3 than every 4 hours. Children under 6 drops or sprays in each nostril not years of age: consult a doctor. more often than every 10 to 12 hours. (B) Nasal jelly—For a 0.5-percent Use only recommended amount. Do not water-based jelly. Adults and children 6 exceed 2 doses in any 24-hour period. to under 12 years of age (with adult su- [previous two sentences in boldface pervision): place a small amount in type] Children under 2 years of age: each nostril and inhale well back into consult a doctor. the nasal passages. Use not more often (B) Nasal jelly—For a 0.05-percent than every 4 hours. water-based jelly. Adults and children 6 (iii) For products containing naphazo- to under 12 years of age (with adult su- line hydrochloride identified in pervision): place a small amount in § 341.20(b)(6)—(A) Nasal drops or sprays— each nostril and inhale well back into (1) For a 0.05-percent aqueous solution. the nasal passages. Use not more often Adults and children 12 years of age and than every 10 to 12 hours. Do not ex- over: 1 or 2 drops or sprays in each nos- ceed 2 doses in any 24-hour period. Chil- tril not more often than every 6 hours. dren under 6 years of age: consult a Do not give to children under 12 years doctor. of age unless directed by a doctor. (v) For products containing phenyl- (2) For a 0.025-percent aqueous solution. ephrine hydrochloride identified in Children 6 to under 12 years of age § 341.20(b)(8)—(A) Nasal drops or sprays— (with adult supervision): 1 or 2 drops or (1) For a 1-percent aqueous solution. sprays in each nostril not more often Adults and children 12 years of age and than every 6 hours. Children under 6 over: 2 or 3 drops or sprays in each nos- years of age: consult a doctor. tril not more often than every 4 hours. (B) Nasal jelly—(1) For a 0.05-percent Do not give to children under 12 years water-based jelly. Adults and children 12 of age unless directed by a doctor. years of age and over: place a small (2) For a 0.5-percent aqueous solution. amount in each nostril and inhale well Adults and children 12 years of age and back into the nasal passages. Use not over: 2 or 3 drops or sprays in each nos- more often than every 6 hours. Do not tril not more often than every 4 hours.

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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. hale well back into the nasal passages. (viii) Other required statements—For Use not more often than every 4 hours. products containing levmetamfetamine or Children under 6 years of age: consult a propylhexedrine identified in § 341.20(b)(1) doctor. or (b)(9) when used in an inhalant dosage (vi) For products containing form. (A) ‘‘This inhaler is effective for a propylhexedrine identified in § 341.20(b)(9) minimum of 3 months after first use.’’ when used in an inhalant dosage form. (B) ‘‘Keep inhaler tightly closed.’’ The product delivers in each 800 milli- [59 FR 43409, Aug. 23, 1994, as amended at 63 liters of air 0.40 to 0.50 milligrams of FR 40650, July 30, 1998; 64 FR 13295, Mar. 17, propylhexedrine. Adults and children 6 1999; 65 FR 8, Jan. 3, 2000] to under 12 years of age (with adult supervision): 2 inhalations in each nostril § 341.85 Labeling of permitted com- not more often than every 2 hours. binations of active ingredients. Children under 6 years of age: consult a The statements of identity, indica- doctor. tions, warnings, and directions for use, (vii) For products containing respectively, applicable to each ingre- xylometazoline hydrochloride identified in dient in the product may be combined § 341.20(b)(10)—(A) Nasal drops or to eliminate duplicative words or

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phrases so that the resulting informa- beled for relief of general cough-cold tion is clear and understandable. symptoms and/or the common cold. (a) Statement of identity. For a com- (i) The labeling for the analgesic- bination drug product that has an es- antipyretic ingredients states ‘‘[bullet] tablished name, the labeling of the temporarily relieves [bullet] minor product states the established name of aches and pains [bullet] headache’’ and the combination drug product, followed ‘‘[bullet] 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 si- drug monographs, unless otherwise nusitis symptoms. stated in this paragraph (a). (i) The labeling for the analgesic- (1) For permitted combinations identi- antipyretic ingredients states ‘‘[bullet] fied in § 341.40(a), (c), (f), (g), (l), (m), (n), temporarily relieves [bullet] minor (o), (q), and (r) containing an analgesic- aches and pains [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) and/or (b)(1)(iii), as ap- fever, then the analgesic-antipyretic propriate, and the labeling for any component is identified as a ‘‘pain re- other cough-cold ingredient present in liever-fever reducer’’ or ‘‘analgesic the combination. This labeling may (pain reliever)-antipyretic (fever re- follow a separate bullet(s) or may be ducer).’’ combined with the indication in para- (2) [Reserved] graph (b)(2)(i) of this section. (b) Indications. The labeling of the (3) For permitted combinations con- product states, under the heading taining an oral analgesic-antipyretic ac- ‘‘Uses,’’ the indication(s) for each in- tive ingredient identified in § 341.40(a), gredient in the combination, as estab- (c), (f), (g), (m), (q), and (r) when labeled lished in the indications sections of the for relief of general cough-cold symptoms applicable OTC drug monographs, un- and/or the common cold and for relief of less otherwise stated in this paragraph hay fever/allergic rhinitis and/or sinusitis (b). Other truthful and nonmisleading symptoms. The labeling states both in- statements, describing only the indica- dications in paragraphs (b)(1) and (b)(2) tions for use that have been established of this section. and listed in the applicable OTC drug (4) For permitted combinations con- monographs or listed in this paragraph taining an oral anesthetic-analgesic ac- (b), may also be used, as provided in tive ingredient identified in § 341.40(k), (s), § 330.1(c)(2) of this chapter, subject to (t), (z), (aa), and (bb). The labeling for the provisions of section 502 of the Fed- the anesthetic-analgesic ingredients in eral Food, Drug, and Cosmetic Act (the part 356 of this chapter should be used. act) relating to misbranding and the (5) For permitted combinations con- prohibition in section 301(d) of the act taining camphor, menthol, and euca- against the introduction or delivery for lyptus oil identified in § 341.40(u). The la- introduction into interstate commerce beling for antitussive ingredients in of unapproved new drugs in violation of § 341.74(b) should be used. section 505(a) of the act. (6) For permitted combinations con- (1) For permitted combinations containing levmetamfetamine with aromatics taining an analgesic-antipyretic active in- identified in § 341.40(v). The labeling for gredient identified in § 341.40(a), (c), (f). nasal decongestant ingredients in (g), (l), (m), (n), (o), (q), and (r) when la- § 341.80(b) should be used.

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(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 following warnings: (iii) For products labeled for both (i) For products labeled only for adults. adults and for children under 12 years of The following warning should be used age. The warning in paragraph instead of the warnings in § 341.74(c)(1) (c)(1)(iii) of this section should be used and part 343 of this chapter: ‘‘Stop use instead of the warnings in § 341.78(c)(3) and ask a doctor if [in bold type] [bul- and part 343 of this chapter. let] pain or cough gets worse or lasts (3) For permitted combinations con- more than 7 days [bullet] fever gets taining a nasal decongestant and an an- worse or lasts more than 3 days [bullet] algesic-antipyretic identified in § 341.40(c), redness or swelling is present [bullet] (g), (m), (n), (q), and (r). The labeling new symptoms occur [bullet] cough states the following warnings: comes back or occurs with rash or (i) For products labeled only for adults. headache that lasts. These could be The following warning should be used signs of a serious condition.’’ instead of the warnings in (ii) For products labeled only for chil- § 341.80(c)(1)(i)(B) and part 343 of this dren under 12 years of age. The following chapter: ‘‘Stop use and ask a doctor if warning should be used instead of the [in bold type] [bullet] pain or nasal warnings in § 341.74(c)(3) and part 343 of congestion gets worse or lasts more this chapter: ‘‘Stop use and ask a doc- than 7 days [bullet] fever gets worse or tor if [in bold type] [bullet] pain or lasts more than 3 days [bullet] redness cough gets worse or lasts more than 5 or swelling is present [bullet] new days [bullet] fever gets worse or lasts symptoms occur’’. more than 3 days [bullet] redness or (ii) For products labeled for only chil- swelling is present [bullet] new symp- dren under 12 years of age. The following toms occur [bullet] cough comes back warning should be used instead of the or occurs with rash or headache that warnings in § 341.80(c)(1)(ii)(B) and part lasts. These could be signs of a serious 343 of this chapter: ‘‘Stop use and ask a condition.’’ doctor if [in bold type] [bullet] pain or (iii) For products labeled for both nasal congestion gets worse or lasts adults and for children under 12 years of more than 5 days [bullet] fever gets age. The following warning should be worse or lasts more than 3 days [bullet] used instead of the warnings in redness or swelling is present [bullet] § 341.74(c)(2) and part 343 of this chap- new symptoms occur’’.

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(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 [67 FR 78170, Dec. 23, 2002] warning upon petition under the provi- EFFECTIVE DATE NOTE: At 67 FR 78170, Dec. sions of § 10.30 of this chapter provided 23, 2002, § 341.85 was added, effective Dec. 23, adequate data are submitted to dem- 2004. 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 states the warnings for topical nasal hours, not to exceed 2 milligrams per decongestant ingredients in kilogram of body weight in 24 hours. § 341.80(c)(2). (b) For products containing (d) Directions. The labeling of the chlophedianol hydrochloride identified in product states, under the heading ‘‘Di- 341.14(a)(1). Children 2 to under 6 years rections,’’ directions that conform to of age: oral dosage is 12.5 milligrams the directions established for each in- every 6 to 8 hours, not to exceed 50 mil- gredient in the directions sections of ligrams in 24 hours. the applicable OTC drug monographs, (c) For products containing codeine in- unless otherwise stated in paragraph gredients identified in § 341.14(a)(2). (1) (d) of this section. When the time in- Children 2 to under 6 years of age: Oral tervals or age limitations for adminis- dosage is 1 milligram per kilogram tration of the individual ingredients body weight per day administered in differ, the directions for the combina- four equal divided doses. The average tion product may not exceed any max- body weight for each age may also be imum dosage limits established for the used to determine dosage as follows: individual ingredients in the applicable For children 2 years of age (average OTC drug monograph. body weight, 12 kilograms), the oral

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

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(p) For products containing thonzyl- Subpart C—Labeling amine hydrochloride identified in § 341.12(l). Children 2 to under 6 years of 343.50—343.60 [Reserved] 343.80 Professional labeling. age: oral dosage is 12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 Subpart D—Testing Procedures milligrams in 24 hours. (q) For products containing triprolidine 343.90 Dissolution and drug release testing. hydrochloride identified in § 341.12(m). AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, Children 4 to under 6 years of age: oral 360, 371. dosage is 0.938 milligram every 4 to 6 SOURCE: 63 FR 56814, Oct. 23, 1998, unless hours, not to exceed 3.744 milligrams in otherwise noted. 24 hours. Children 2 to under 4 years of age: oral dosage is 0.625 milligram Subpart A—General Provisions every 4 to 6 hours, not to exceed 2.5 milligrams in 24 hours. Infants 4 § 343.1 Scope. months to under 2 years of age: oral dosage is 0.313 milligram every 4 to 6 (a) An over-the-counter analgesic- antipyretic drug product in a form hours, not to exceed 1.252 milligrams in suitable for oral administration is gen- 24 hours. erally recognized as safe and effective (r) For products containing and is not misbranded if it meets each diphenhydramine citrate identified in of the conditions in this part in addi- § 341.14(a)(5). Children 2 to under 6 tion to each of the general conditions years of age: oral dosage is 9.5 milli- established in § 330.1 of this chapter. grams every 4 hours, not to exceed 57 (b) References in this part to regu- milligrams in 24 hours. latory sections of the Code of Federal (s) For products containing Regulations are to chapter I of title 21 diphenhydramine hydrochloride identified unless otherwise noted. in § 341.14(a)(6). Children 2 to under 6 years of age: oral dosage is 6.25 milli- § 343.3 Definitions. grams every 4 hours, not to exceed 37.5 As used in this part: milligrams in 24 hours. Analgesic—antipyretic drug. An agent [51 FR 35339, Oct. 2, 1986, as amended at 52 FR used to alleviate pain and to reduce 30057, Aug. 12, 1987; 54 FR 8509, Feb. 28, 1989; fever. 57 FR 58376, Dec. 9, 1992; 59 FR 4218, Jan. 28, Cardiovascular drug. An agent used to 1994; 59 FR 29174, June 3, 1994; 59 FR 36051, prevent ischemic events. July 15, 1994] Rheumatologic drug. An agent used for the treatment of rheumatologic dis- PART 343—INTERNAL ANALGESIC, orders. ANTIPYRETIC, AND ANTIRHEUMATIC DRUG PROD- Subpart B—Active Ingredients UCTS FOR OVER–THE–COUNTER HUMAN USE § 343.10 [Reserved] § 343.12 Cardiovascular active ingredi- Subpart A—General Provisions ents. Sec. (a) Aspirin. 343.1 Scope. (b) Buffered aspirin. Aspirin identi- 343.3 Definitions. fied in paragraph (a) of this section may be buffered with any antacid in- Subpart B—Active Ingredients gredient(s) identified in § 331.11 of this 343.10 [Reserved] chapter provided that the finished 343.12 Cardiovascular active ingredients. product contains at least 1.9 milli- 343.13 Rheumatologic active ingredients. equivalents of acid-neutralizing capac- 343.20 [Reserved] ity per 325 milligrams of aspirin as 343.22 Permitted combinations of active in- measured by the procedure provided in gredients for cardiovascular- the United States Pharmacopeia 23/Na- rheumatologic use. tional Formulary 18.

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§ 343.13 Rheumatologic active ingredi- ings,’’ ‘‘Precautions,’’ ‘‘Adverse Reac- ents. tions,’’ ‘‘Drug Abuse and Dependence,’’ (a) Aspirin. ‘‘Overdosage,’’ ‘‘Dosage and Adminis- (b) Buffered aspirin. Aspirin identi- tration,’’ and ‘‘How Supplied’’ in the fied in paragraph (a) of this section exact language and the exact order pro- may be buffered with any antacid in- vided as follows: gredient(s) identified in § 331.11 of this COMPREHENSIVE PRESCRIBING chapter provided that the finished INFORMATION product contains at least 1.9 milli- equivalents of acid-neutralizing capac- DESCRIPTION ity per 325 milligrams of aspirin as (Insert the proprietary name and the estab- measured by the procedure provided in lished name (if any) of the drug, type of dosage the United States Pharmacopeia 23/Na- form (followed by the phrase ‘‘for oral adminis- tional Formulary 18. tration’’), the established name(s) and quantity of the active ingredient(s) per dosage unit, the § 343.20 [Reserved] total sodium content in milligrams per dosage unit if the sodium content of a single rec- § 343.22 Permitted combinations of ac- ommended dose is 5 milligrams or more, the es- tive ingredients for cardiovascular- tablished name(s) (in alphabetical order) of any rheumatologic use. inactive ingredient(s) which may cause an aller- Combinations containing aspirin gic hypersensitivity reaction, the pharma- must meet the standards of an accept- cological or therapeutic class of the drug, and able dissolution test, as set forth in the chemical name(s) and structural formula(s) of the drug.) Aspirin is an odorless white, § 343.90. The following combinations are needle-like crystalline or powdery substance. permitted: Aspirin identified in §§ 343.12 When exposed to moisture, aspirin and 343.13 may be combined with any hydrolyzes into salicylic and acetic acids, antacid ingredient identified in § 331.11 and gives off a vinegary-odor. It is highly of this chapter or any combination of lipid soluble and slightly soluble in water. antacids permitted in accordance with § 331.10(a) of this chapter provided that CLINICAL PHARMACOLOGY the finished product meets the require- Mechanism of Action: Aspirin is a more po- ments of § 331.10 of this chapter and is tent inhibitor of both prostaglandin syn- marketed in a form intended for inges- thesis and platelet aggregation than other tion as a solution. salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are thought to be due to the acetyl group on Subpart C—Labeling the aspirin molecule. This acetyl group is responsible for the inactivation of cyclo- §§ 343.50—343.60 [Reserved] oxygenase via acetylation.

§ 343.80 Professional labeling. PHARMACOKINETICS The labeling of an over-the-counter Absorption: In general, immediate release drug product written for health profes- aspirin is well and completely absorbed from sionals (but not for the general public) the gastrointestinal (GI) tract. Following ab- shall consist of the following: sorption, aspirin is hydrolyzed to salicylic (a) For products containing aspirin acid with peak plasma levels of salicylic acid identified in §§ 343.12 and 343.13 or per- occurring within 1–2 hours of dosing (see PHARMACOKINETICS—Metabolism). The rate of mitted combinations identified in § 343.22. absorption from the GI tract is dependent (These products must meet United upon the dosage form, the presence or ab- States Pharmacopeia (USP) standards sence of food, gastric pH (the presence or ab- for dissolution or drug release in sence of GI antacids or buffering agents), and § 343.90.) other physiologic factors. Enteric coated as- (1) The labeling contains the fol- pirin products are erratically absorbed from lowing prescribing information under the GI tract. the heading ‘‘Comprehensive Pre- Distribution: Salicylic acid is widely dis- scribing Information’’ and the sub- tributed to all tissues and fluids in the body including the central nervous system (CNS), headings ‘‘Description,’’ ‘‘Clinical breast milk, and fetal tissues. The highest Pharmacology,’’ ‘‘Clinical Studies,’’ concentrations are found in the plasma, ‘‘Animal Toxicology,’’ ‘‘Indications and liver, renal cortex, heart, and lungs. The pro- Usage,’’ ‘‘Contraindications,’’ ‘‘Warn- tein binding of salicylate is concentration-

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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 (ringing in the ears), occur at plasma con- TIA’s due to fibrin platelet emboli or centrations approximating 200 µg/mL. Severe ischemic stroke, aspirin has been shown to toxic effects are associated with levels > 400 significantly reduce the risk of the combined µg/mL. (See ADVERSE REACTIONS and OVER- endpoint of stroke or death and the com- DOSAGE.) bined endpoint of TIA, stroke, or death by 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 doses, approximately 10 percent is found ex- ized, multi-center, double-blind trial de- creted in the urine as salicylic acid, 75 per- signed to assess the role of aspirin for pre- cent as salicyluric acid, and 10 percent phe- vention of MI in patients with chronic stable nolic and 5 percent acyl glucuronides of sali- angina pectoris, aspirin significantly re- cylic acid. duced the primary combined endpoint of Pharmacodynamics Aspirin affects platelet nonfatal MI, fatal MI, and sudden death by 34 aggregation by irreversibly inhibiting percent. The secondary endpoint for vascular prostaglandin cyclo-oxygenase. This effect events (first occurrence of MI, stroke, or vas- lasts for the life of the platelet and prevents cular death) was also significantly reduced the formation of the platelet aggregating (32 percent). factor thromboxane A2. Nonacetylated Revascularization Procedures: Most patients salicylates do not inhibit this enzyme and who undergo coronary artery have no effect on platelet aggregation. At revascularization procedures have already somewhat higher doses, aspirin reversibly in- had symptomatic coronary artery disease for hibits the formation of prostaglandin I2 which aspirin is indicated. Similarly, pa- (prostacyclin), which is an arterial vaso- tients with lesions of the carotid bifurcation dilator and inhibits platelet aggregation. sufficient to require carotid endarterectomy At higher doses aspirin is an effective anti- are likely to have had a precedent event. As- inflammatory agent, partially due to inhibi- pirin is recommended for patients who un- tion of inflammatory mediators via cyclo- dergo revascularization procedures if there is oxygenase inhibition in peripheral tissues. In a preexisting condition for which aspirin is vitro studies suggest that other mediators of already indicated. inflammation may also be suppressed by as- Rheumatologic Diseases: In clinical studies pirin administration, although the precise in patients with rheumatoid arthritis, juve- mechanism of action has not been eluci- nile rheumatoid arthritis, ankylosing spon- dated. It is this nonspecific suppression of dylitis and osteoarthritis, aspirin has been cyclo-oxygenase activity in peripheral tis- shown to be effective in controlling various sues following large doses that leads to its indices of clinical disease activity.

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ANIMAL TOXICOLOGY should be counseled about the bleeding risks involved with chronic, heavy alcohol use The acute oral 50 percent lethal dose in rats is about 1.5 g/kilogram (kg) and in mice while taking aspirin. 1.1 g/kg. Renal papillary necrosis and de- Coagulation Abnormalities: Even low doses creased urinary concentrating ability occur of aspirin can inhibit platelet function lead- in rodents chronically administered high ing to an increase in bleeding time. This can doses. Dose-dependent gastric mucosal in- adversely affect patients with inherited (he- jury occurs in rats and humans. Mammals mophilia) or acquired (liver disease or vita- may develop aspirin toxicosis associated min K deficiency) bleeding disorders. with GI symptoms, circulatory effects, and GI Side Effects: GI side effects include central nervous system depression. (See stomach pain, heartburn, nausea, vomiting, OVERDOSAGE.) and gross GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are com- INDICATIONS AND USAGE mon and can occur anytime during therapy, Vascular Indications (Ischemic Stroke, TIA, physicians should remain alert for signs of Acute MI, Prevention of Recurrent MI, Unstable ulceration and bleeding, even in the absence Angina Pectoris, and Chronic Stable Angina of previous GI symptoms. Physicians should Pectoris): Aspirin is indicated to: (1) Reduce inform patients about the signs and symp- the combined risk of death and nonfatal toms of GI side effects and what steps to stroke in patients who have had ischemic take if they occur. stroke or transient ischemia of the brain due Peptic Ulcer Disease: Patients with a his- to fibrin platelet emboli, (2) reduce the risk tory of active peptic ulcer disease should of vascular mortality in patients with a sus- avoid using aspirin, which can cause gastric pected acute MI, (3) reduce the combined mucosal irritation and bleeding. risk of death and nonfatal MI in patients with a previous MI or unstable angina pec- PRECAUTIONS toris, and (4) reduce the combined risk of MI and sudden death in patients with chronic General stable angina pectoris. Renal Failure: Avoid aspirin in patients Revascularization Procedures (Coronary Ar- with severe renal failure (glomerular filtra- tery Bypass Graft (CABG), Percutaneous tion rate less than 10 mL/minute). Transluminal Coronary Angioplasty (PTCA), and Carotid Endarterectomy): Aspirin is indi- Hepatic Insufficiency: Avoid aspirin in pa- cated in patients who have undergone tients with severe hepatic insufficiency. revascularization procedures (i.e., CABG, Sodium Restricted Diets: Patients with so- PTCA, or carotid endarterectomy) when dium-retaining states, such as congestive there is a preexisting condition for which as- heart failure or renal failure, should avoid pirin is already indicated. sodium-containing buffered aspirin prepara- Rheumatologic Disease Indications (Rheu- tions because of their high sodium content. matoid Arthritis, Juvenile Rheumatoid Arthritis, Spondyloarthropathies, Osteoarthritis, and the Laboratory Tests Arthritis and Pleurisy of Systemic Lupus Aspirin has been associated with elevated Erythematosus (SLE)): Aspirin is indicated for hepatic enzymes, blood urea nitrogen and the relief of the signs and symptoms of rheu- serum creatinine, hyperkalemia, protein- matoid arthritis, juvenile rheumatoid arthri- uria, and prolonged bleeding time. tis, osteoarthritis, spondyloarthropathies, and arthritis and pleurisy associated with Drug Interactions SLE. Angiotensin Converting Enzyme (ACE) Inhibi- CONTRAINDICATIONS tors: The hyponatremic and hypotensive ef- Allergy: Aspirin is contraindicated in pa- fects of ACE inhibitors may be diminished by tients with known allergy to nonsteroidal the concomitant administration of aspirin anti-inflammatory drug products and in pa- due to its indirect effect on the renin- tients with the syndrome of asthma, rhinitis, angiotensin conversion pathway. and nasal polyps. Aspirin may cause severe Acetazolamide: Concurrent use of aspirin urticaria, angioedema, or bronchospasm and acetazolamide can lead to high serum (asthma). concentrations of acetazolamide (and tox- Reye’s Syndrome: Aspirin should not be used icity) due to competition at the renal tubule in children or teenagers for viral infections, for secretion. with or without fever, because of the risk of Anticoagulant Therapy (Heparin and War- Reye’s syndrome with concomitant use of as- farin): Patients on anticoagulation therapy pirin in certain viral illnesses. are at increased risk for bleeding because of drug-drug interactions and the effect on WARNINGS platelets. Aspirin can displace warfarin from Alcohol Warning: Patients who consume protein binding sites, leading to prolonga- three or more alcoholic drinks every day tion of both the prothrombin time and the

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bleeding time. Aspirin can increase the anti- Pediatric Use: Pediatric dosing rec- coagulant activity of heparin, increasing ommendations for juvenile rheumatoid ar- bleeding risk. thritis are based on well-controlled clinical Anticonvulsants: Salicylate can displace studies. An initial dose of 90–130 mg/kg/day protein-bound phenytoin and valproic acid, in divided doses, with an increase as needed leading to a decrease in the total concentra- for anti-inflammatory efficacy (target plas- tion of phenytoin and an increase in serum ma salicylate levels of 150–300 µg/mL) are ef- valproic acid levels. fective. At high doses (i.e., plasma levels of Beta Blockers: The hypotensive effects of greater than 200 µg/mL), the incidence of tox- beta blockers may be diminished by the con- icity increases. comitant administration of aspirin due to inhibition of renal prostaglandins, leading to ADVERSE REACTIONS 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- ARNINGS.) vascular disease may be diminished by the ported in the literature. (See W concomitant administration of aspirin due to Body as a Whole: Fever, hypothermia, inhibition of renal prostaglandins, leading to thirst. decreased renal blood flow and salt and fluid Cardiovascular: Dysrhythmias, hypo- retention. tension, tachycardia. Methotrexate: Salicylate can inhibit renal Central Nervous System: Agitation, cerebral clearance of methotrexate, leading to bone edema, coma, confusion, dizziness, headache, marrow toxicity, especially in the elderly or subdural or intracranial hemorrhage, leth- renal impaired. argy, seizures. Nonsteroidal Anti-inflammatory Drugs Fluid and Electrolyte: Dehydration, hyper- (NSAID’s): The concurrent use of aspirin with kalemia, metabolic acidosis, respiratory other NSAID’s should be avoided because alkalosis. this may increase bleeding or lead to de- Gastrointestinal: Dyspepsia, GI bleeding, ul- creased renal function. ceration and perforation, nausea, vomiting, Oral Hypoglycemics: Moderate doses of aspi- transient elevations of hepatic enzymes, hep- rin may increase the effectiveness of oral atitis, Reye’s Syndrome, pancreatitis. hypoglycemic drugs, leading to hypo- Hematologic: Prolongation of the pro- glycemia. thrombin time, disseminated intravascular Uricosuric Agents (Probenecid and coagulation, coagulopathy, Sulfinpyrazone): Salicylates antagonize the thrombocytopenia. uricosuric action of uricosuric agents. Hypersensitivity: Acute anaphylaxis, 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. assay, aspirin was not mutagenic; however, aspirin did induce chromosome aberrations Reproductive: Prolonged pregnancy and in cultured human fibroblasts. Aspirin in- labor, stillbirths, lower birth weight infants, hibits ovulation in rats. (See Pregnancy.) antepartum and postpartum bleeding. Respiratory: Hyperpnea, pulmonary edema, Pregnancy: Pregnant women should only tachypnea. take aspirin if clearly needed. Because of the Special Senses: Hearing loss, tinnitus. Pa- known effects of NSAID’s on the fetal cardio- tients with high frequency hearing loss may vascular system (closure of the ductus have difficulty perceiving tinnitus. In these arteriosus), use during the third trimester of patients, tinnitus cannot be used as a clin- pregnancy should be avoided. Salicylate ical indicator of salicylism. products have also been associated with al- Urogenital: Interstitial nephritis, papillary terations in maternal and neonatal hemo- necrosis, proteinuria, renal insufficiency and stasis mechanisms, decreased birth weight, failure. and with perinatal mortality. Labor and Delivery Aspirin should be avoid- DRUG ABUSE AND DEPENDENCE ed 1 week prior to and during labor and delivery because it can result in excessive Aspirin is nonnarcotic. There is no known blood loss at delivery. Prolonged gestation potential for addiction associated with the and prolonged labor due to prostaglandin in- use of aspirin. hibition have been reported. OVERDOSAGE Nursing Mothers: Nursing mothers should avoid using aspirin because salicylate is ex- Salicylate toxicity may result from acute creted in breast milk. Use of high doses may ingestion (overdose) or chronic intoxication. lead to rashes, platelet abnormalities, and The early signs of salicylic overdose bleeding in nursing infants. (salicylism), including tinnitus (ringing in

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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- based on dosage and administration for pre- els above 400 µg/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 after ingestion, even if the patient has vom- Rheumatoid Arthritis: The initial dose is 3 g ited spontaneously. After lavage and/or a day in divided doses. Increase as needed for emesis, administration of activated char- anti-inflammatory efficacy with target plas- µ coal, as a slurry, is beneficial, if less than 3 ma salicylate levels of 150–300 g/mL. At high hours have passed since ingestion. Charcoal doses (i.e., plasma levels of greater than 200 µ adsorption should not be employed prior to g/mL), the incidence of toxicity increases. emesis and lavage. Juvenile Rheumatoid Arthritis: Initial dose is Severity of aspirin intoxication is deter- 90–130 mg/kg/day in divided doses. Increase as mined by measuring the blood salicylate needed for anti-inflammatory efficacy with level. Acid-base status should be closely fol- target plasma salicylate levels of 150–300 µg/ lowed with serial blood gas and serum pH mL. At high doses (i.e., plasma levels of measurements. Fluid and electrolyte balance greater than 200 µg/mL), the incidence of tox- should also be maintained. icity increases. In severe cases, hyperthermia and Spondyloarthropathies: Up to 4 g per day in hypovolemia are the major immediate divided doses. threats to life. Children should be sponged Osteoarthritis: Up to 3 g per day in divided with tepid water. Replacement fluid should doses. be administered intravenously and aug- Arthritis and Pleurisy of SLE: The initial mented with correction of acidosis. Plasma dose is 3 g a day in divided doses. Increase as electrolytes and pH should be monitored to needed for anti-inflammatory efficacy with promote alkaline diuresis of salicylate if target plasma salicylate levels of 150–300 µg/ renal function is normal. Infusion of glucose mL. At high doses (i.e., plasma levels of may be required to control hypoglycemia. greater than 200 mµ/mL), the incidence of Hemodialysis and peritoneal dialysis can toxicity increases. be performed to reduce the body drug content. In patients with renal insufficiency or HOW SUPPLIED in cases of life-threatening intoxication, di- (Insert specific information regarding, alysis is usually required. Exchange trans- strength of dosage form, units in which the dos- fusion may be indicated in infants and young age form is generally available, and information children. to facilitate identification of the dosage form as DOSAGE AND ADMINISTRATION required under § 201.57(k)(1), (k)(2), and (k)(3).) Store in a tight container at 25 °C (77 °F); ex- Each dose of aspirin should be taken with cursions permitted to 15–30 °C (59–86 °F). a full glass of water unless patient is fluid restricted. Anti-inflammatory and analgesic REV: October 23, 1998. dosages should be individualized. When aspi- (2) In addition to, and immediately rin is used in high doses, the development of preceding, the labeling required under tinnitus may be used as a clinical sign of ele- paragraph (a)(1) of this section, the vated plasma salicylate levels except in pa- professional labeling may contain the tients with high frequency hearing loss. Ischemic Stroke and TIA: 50–325 mg once a following highlights of prescribing in- day. Continue therapy indefinitely. formation in the exact language and Suspected Acute MI: The initial dose of 160– exact format provided, but only when 162.5 mg is administered as soon as an MI is accompanied by the comprehensive

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prescribing information required in paragraph (a)(1) of this section.

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(b) [Reserved] PART 344—TOPICAL OTIC DRUG [63 FR 56814, Oct. 23, 1998; 63 FR 66015, 66016, PRODUCTS FOR OVER-THE- Dec. 1, 1998, as amended at 64 FR 49653, Sept. COUNTER HUMAN USE 14, 1999] Subpart A—General Provisions Subpart D—Testing Procedures Sec. 344.1 Scope. § 343.90 Dissolution and drug release 344.3 Definitions. testing. (a) [Reserved] Subpart B—Active Ingredients (b) Aspirin capsules. Aspirin capsules 344.10 Earwax removal aid active ingre- must meet the dissolution standard for dient. aspirin capsules as contained in the 344.12 Ear drying aid active ingredient. United States Pharmacopeia (USP) 23 at page 132. Subpart C—Labeling (c) Aspirin delayed-release capsules and 344.50 Labeling of earwax removal aid drug aspirin delayed-release tablets. Aspirin products. delayed-release capsules and aspirin 344.52 Labeling of ear drying aid drug prod- delayed-release tablets must meet the ucts. drug release standard for aspirin de- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, layed-release capsules and aspirin de- 360, 371. layed-release tablets as contained in SOURCE: 51 FR 28660, Aug. 8, 1986, unless USP 23 at pages 133 and 136 respec- otherwise noted: tively. (d) Aspirin tablets. Aspirin tablets Subpart A—General Provisions must meet the dissolution standard for aspirin tablets as contained in USP 23 § 344.1 Scope. at page 134. (a) An over-the-counter topical otic drug product in a form suitable for top- (e) Aspirin, alumina, and magnesia tab- ical administration is generally recog- lets. Aspirin in combination with alu- nized as safe and effective and is not mina and magnesia in a tablet dosage misbranded if it meets each of the conform must meet the dissolution stand- ditions in this part in addition to each ard for aspirin, alumina, and magnesia of the general conditions established in tablets as contained in USP 23 at page § 330.1. 138. (b) References in this part to regu- (f) Aspirin, alumina, and magnesium latory sections of the Code of Federal oxide tablets. Aspirin in combination Regulations are to chapter I of title 21 with alumina, and magnesium oxide in unless otherwise noted. a tablet dosage form must meet the dissolution standard for aspirin, alu- § 344.3 Definitions. mina, and magnesium tablets as con- As used in this part: tained in USP 23 at page 139. (a) Anhydrous glycerin. An ingredient (g) Aspirin effervescent tablets for oral that may be prepared by heating glyc- ° solution. Aspirin effervescent tablets erin U.S.P. at 150 C for 2 hours to drive off the moisture content. for oral solution must meet the dis- (b) Earwax removal aid. A drug used in solution standard for aspirin effer- the external ear canal that aids in the vescent tablets for oral solution as con- removal of excessive earwax. tained in USP 23 at page 137. (c) Water-clogged ears. The retention (h) Buffered aspirin tablets. Buffered of water in the external ear canal, aspirin tablets must meet the dissolu- thereby causing discomfort and a sen- tion standard for buffered aspirin tab- sation of fullness or hearing impair- lets as contained in USP 23 at page 135. ment.

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

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of unapproved new drugs in violation of ternal (topical) or intrarectal (rectal) section 505(a) of the act. administration is generally recognized (c) Warnings. The labeling of the as safe and effective and is not mis- product contains the following warn- branded if it meets each condition in ings under the heading ‘‘Warnings’’: this part and each general condition es- (1) ‘‘Flammable [in bold type]: Keep tablished in § 330.1 of this chapter. away from fire or flame.’’ (b) References in this part to regu- (2) ‘‘Do not use [in bold type] in the latory sections of the Code of Federal eyes.’’ Regulations are to chapter I of title 212 (3) ‘‘Ask a doctor before use if you unless otherwise noted. have [in bold type] [bullet] ear drainage or discharge [bullet] pain, irrita- § 346.3 Definitions. tion, or rash in the ear [bullet] had ear surgery [bullet] dizziness.’’ As used in this part: (a) Analgesic, anesthetic drug. A topi- (4) ‘‘Stop use and ask a doctor if [in bold type] irritation (too much burn- cally (externally) applied drug that re- ing) or pain occurs.’’ lieves pain by depressing cutaneous sensory receptors. (d) Directions. The labeling of the (b) Anorectal drug. A drug that is used product contains the following statement 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 areas. [65 FR 48905, Aug. 10, 2000] (c) Antipruritic drug. A topically (externally) applied drug that relieves PART 346—ANORECTAL DRUG 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. 346.3 Definitions. (e) External use. Topical application of an anorectal drug product to the Subpart B—Active Ingredients skin of the perianal area and/or the 346.10 Local anesthetic active ingredients. skin of the anal canal. 346.12 Vasoconstrictor active ingredients. (f) Intrarectal use. Topical application 346.14 Protectant active ingredients. of an anorectal drug product to the 346.16 Analgesic, anesthetic, and anti- mucous membrane of the rectum. pruritic active ingredients. 346.18 Astringent active ingredients. (g) Keratolytic drug. A drug that 346.20 Keratolytic active ingredients. causes desquamation (loosening) and 346.22 Permitted combinations of anorectal debridement or sloughing of the sur- active ingredients. face cells of the epidermis. Subpart C—Labeling (h) Local anesthetic drug. A drug that 346.50 Labeling of anorectal drug products. produces local disappearance of pain, 346.52 Labeling of permitted combinations burning, itching, irritation, and/or dis- of anorectal active ingredients. comfort by reversibly blocking nerve AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, conduction when applied to nerve tis- 360, 371. sue in appropriate concentrations. SOURCE: 55 FR 31779, Aug. 3, 1990, unless (i) Protectant drug. A drug that pro- otherwise noted. vides a physical barrier, forming a protective coating over skin or mucous Subpart A—General Provisions membranes. § 346.1 Scope. (j) Vasoconstrictor. A drug that causes (a) An over-the-counter anorectal temporary constriction of blood ves- drug product in a form suitable for ex- sels.

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Subpart B—Active Ingredients contain at least this minimum amount of glycerin. § 346.10 Local anesthetic active ingre- (4) Hard fat. dients. (5) Kaolin. The active ingredient of the product (6) Lanolin. consists of any of the following when (7) Mineral oil. used in the concentration or within the (8) Petrolatum. concentration range established for (9) Topical starch. each ingredient: (10) White petrolatum. (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]

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§ 346.20 Keratolytic active ingredients. may be combined with any single keratolytic identified in § 346.20. The active ingredient of the product consists of any of the following when (i) Any single astringent identified in used within the concentration range § 346.18 may be combined with any sin- established for each ingredient: gle keratolytic identified in § 346.20. (a) Alcloxa 0.2 to 2 percent. (j) Any single local anesthetic identi- (b) Resorcinol 1 to 3 percent. fied in § 346.10 may be combined with any single vasoconstrictor identified in § 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., 0.25 gram of a 2-gram dosage unit), except tringent identified in § 346.18 and with cod liver oil and shark liver oil. If an any single keratolytic identified in ingredient in § 346.14(b) is included in § 346.20. the combination, it must not exceed (n) Any combination of ingredients the concentration limit specified in listed in paragraphs (c) through (m) of § 346.14(b). this section may be combined with up (b) Any single anorectal ingredient to four protectants in accordance with identified in § 346.10, 346.12, 346.16, paragraph (a) of this section. 346.18, or 346.20 may be combined with (o) Any product containing calamine up to four protectants in accordance for use as a protectant and/or as an as- with paragraph (a) of this section. tringent and/or containing zinc oxide (c) Any single local anesthetic identi- for use as a protectant and/or as an as- fied in § 346.10 may be combined with tringent may not have a total weight any single vasoconstrictor identified in of zinc oxide exceeding 25 percent by § 346.12. weight per dosage unit. (d) Any single local anesthetic identified in § 346.10 may be combined with any single astringent identified in Subpart C—Labeling § 346.18. § 346.50 Labeling of anorectal drug (e) Any single local anesthetic identi- products. fied in § 346.10 may be combined with any single keratolytic identified in The labeling of the product contains § 346.20. the following information for anorectal (f) Any single vasoconstrictor identi- ingredients identified in §§ 346.10, 346.12, fied in § 346.12 may be combined with 346.14, 346.16, 346.18, and 346.20, and for any single astringent identified in combinations of anorectal ingredients § 346.18. identified in § 346.22. Unless otherwise (g) Any single analgesic, anesthetic, specified, the labeling in this subpart is and antipruritic identified in § 346.16 applicable to anorectal drug products may be combined with any single as- for both external and intrarectal use. tringent identified in § 346.18. (a) Statement of identity. The labeling (h) Any single analgesic, anesthetic, of the product contains the established and antipruritic identified in § 346.16 name of the drug, if any, and identifies

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

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

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device. ‘‘FOR INTRARECTAL USE: At- the combination drug product, followed tach applicator to tube. Lubricate ap- by the statement of identity estab- plicator well, then gently insert appli- lished in § 346.50(a). For a combination cator into the rectum.’’ drug product that does not have an es- (6) For products for external use only tablished name, the labeling of the containing any of the local anesthetics product states the statement of iden- identified in § 346.10; analgesics, anes- tity established in § 346.50(a). thetics, and antipruritics identified in (b) Indications. The labeling of the § 346.16; or alcloxa or resorcinol identified product states, under the heading ‘‘In- in § 346.20. Apply to the affected area up dications,’’ the indication(s) for each to 6 times daily. ingredient in the combination, as es- (i) For products for external use only tablished in the indications sections of containing dibucaine or dibucaine hydro- this subpart. chloride identified in § 346.10 (c) and (d). (c) Warnings. The labeling of the Apply to the affected area up to 3 or 4 product states, under the heading times daily. ‘‘Warnings,’’ the warning(s) for each in- (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 COUNTER HUMAN USE § 346.14(a)(8) and (10). Apply liberally to the affected area as often as necessary. Subpart A—Astringent Drug Products (e) The word ‘‘physician’’ may be substituted 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. Subpart C—Labeling Indications, warnings, and directions 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 SOURCE: 58 FR 54462, Oct. 21, 1993, unless product states the established name of otherwise noted.

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Subpart A—Astringent Drug EFFECTIVE DATE NOTE: At 68 FR 33377, June 4, 2003, subpart B was added, effective June 4, Products 2004.

EFFECTIVE DATE NOTE: At 68 FR 33376, June § 347.10 Skin protectant active ingredi- 4, 2003, the heading for subpart A was revised ents. to read as follows, effective June 4, 2004. The active ingredients of the product Subpart A—General Provisions consist of any of the following, within the concentration specified for each ingredient: * * * * * (a) Allantoin, 0.5 to 2 percent. (b) Aluminum hydroxide gel, 0.15 to 5 § 347.1 Scope. percent. (a) An over-the-counter skin protect- (c) Calamine, 1 to 25 percent. ant drug product in a form suitable for (d) Cocoa butter, 50 to 100 percent. topical administration is generally rec- (e) Cod liver oil, 5 to 13.56 percent, in ognized as safe and effective and is not accordance with § 347.20(a)(1) or (a)(2), misbranded if it meets each condition provided the product is labeled so that in this part and each general condition the quantity used in a 24-hour period established in § 330.1 of this chapter. does not exceed 10,000 U.S.P. Units vi- (b) References in this part to regu- tamin A and 400 U.S.P. Units cholecal- latory sections of the Code of Federal ciferol. Regulations are to chapter I of title 21 (f) Colloidal oatmeal, 0.007 percent unless otherwise noted. minimum; 0.003 percent minimum in combination with mineral oil in ac- § 347.3 Definitions. cordance with § 347.20(a)(4). As used in this part: (g) Dimethicone, 1 to 30 percent. (a) Astringent drug product means a (h) Glycerin, 20 to 45 percent. drug product that is applied to the skin (i) Hard fat, 50 to 100 percent. or mucous membranes for a local and (j) Kaolin, 4 to 20 percent. limited protein coagulant effect. (k) Lanolin, 12.5 to 50 percent. (b) [Reserved] (l) Mineral oil, 50 to 100 percent; 30 to EFFECTIVE DATE NOTE: At 68 FR 33376, June 35 percent in combination with col- 4, 2003, § 347.3 was revised, effective June 4, loidal oatmeal in accordance with 2004. For the convenience of the user, the re- § 347.20(a)(4). vised text is set forth as follows: (m) Petrolatum, 30 to 100 percent. (n) [Reserved] § 347.3 Definitions. (o) Sodium bicarbonate. As used in this part: (p) [Reserved] Astringent drug product. A drug product applied to the skin or mucous membranes for a (q) Topical starch, 10 to 98 percent. local and limited protein coagulant effect. (r) White petrolatum, 30 to 100 per- Lip protectant drug product. A drug product cent. that temporarily prevents dryness and helps (s) Zinc acetate, 0.1 to 2 percent. relieve chapping of the exposed surfaces of (t) Zinc carbonate, 0.2 to 2 percent. the lips; traditionally called ‘‘lip balm.’’ (u) Zinc oxide, 1 to 25 percent. Poison ivy, oak, sumac dermatitis. An allergic contact dermatitis due to exposure to § 347.12 Astringent active ingredients. plants of the genus Rhus (poison ivy, poison oak, poison sumac), which contain urushiol, The active ingredient of the product a potent skin-sensitizer. consists of any one of the following Skin protectant drug product. A drug prod- within the specified concentration es- uct that temporarily protects injured or ex- tablished for each ingredient: posed skin or mucous membrane surfaces (a) Aluminum acetate, 0.13 to 0.5 per- from harmful or annoying stimuli, and may cent (depending on the formulation and help provide relief to such surfaces. concentration of the marketed product, the manufacturer must provide ade- Subpart B—Active Ingredients quate directions so that the resulting solution to be used by the consumer SOURCE: 68 FR 33377, June 4, 2003, unless contains 0.13 to 0.5 percent aluminum otherwise noted. acetate).

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(b) Aluminum sulfate, 46 to 63 per- (b) Combinations of skin protectant and cent (the concentration is based on the external analgesic active ingredients. Any anhydrous equivalent). one (two when required to be in com- (c) Witch hazel. bination) or more of the active ingredients identified in § 347.10(a), (d), (e), (i), EFFECTIVE DATE NOTE: At 68 FR 33377, June 4, 2003, § 347.10 was redesignated as § 347.12 (k), (l), (m), and (r) may be combined and revised, effective June 4, 2004. For the with any of the following generally rec- convenience of the user, the superseded text ognized as safe and effective external is set forth as follows: analgesic active ingredients: Single amine and caine -type local anes- § 347.10 Astringent active ingredients. ‘‘ ’’ thetics, alcohols and ketones, antihis- The active ingredient of the product consists of any one of the following within the tamines, or any permitted combination specified concentration established for each of these ingredients, but not with hy- ingredient: drocortisone, provided the product is (a) Aluminum acetate, 0.13 to 0.5 percent labeled according to § 347.60(b)(l). (depending on the formulation and con- (c) Combinations of skin protectant and centration of the marketed product, the first aid antiseptic active ingredients. Any manufacturer must provide adequate direc- one (two when required to be in com- tions so that the resulting solution to be used by the consumer contains 0.13 to 0.5 per- bination) or more of the active ingredi- cent aluminum acetate). ents identified in § 347.10(a), (d), (e), (i), (b) Aluminum sulfate, 46 to 63 percent (the (k), (l), (m), and (r) may be combined concentration is based on the anhydrous with any generally recognized as safe equivalent). and effective single first aid antiseptic (c) Witch hazel. active ingredient, or any permitted [58 FR 54462, Oct. 21, 1993, as amended at 59 combination of these ingredients, pro- FR 28768, June 3, 1994] vided the product is labeled according to § 347.60(b)(2). § 347.20 Permitted combinations of ac- (d) Combinations of skin protectant and tive ingredients. sunscreen active ingredients. Any one (a) Combinations of skin protectant ac- (two when required to be in combina- tive ingredients. (1) Any two or more of tion) or more of the skin protectant ac- the ingredients identified in § 347.10(a), tive ingredients identified in § 347.10(a), (d), (e), (i), (k), (l), (m), and (r) may be (d), (e), (g), (h), (i), (k), (l), (m), and (r) combined provided the combination is may be combined with any generally labeled according to § 347.50(b)(1) and recognized as safe and effective single provided each ingredient in the com- sunscreen active ingredient, or any bination is within the concentration permitted combination of these ingre- specified in § 347.10. dients, provided the product meets the (2) Any two or more of the ingredi- conditions in § 352.20(b) of this chapter ents identified in § 347.10(a), (d), (e), (g), and is labeled according to (h), (i), (k), (l), (m), and (r) may be §§ 347.60(b)(3) and 352.60(b) of this chap- combined provided the combination is ter. labeled according to § 347.50(b)(2) and provided each ingredient in the com- EFFECTIVE DATE NOTE: At 68 FR 33377, June bination is within the concentration 4, 2003, § 347.20(d) was stayed until further notice, effective June 4, 2004. specified in § 347.10. (3) Any two or more of the ingredients identified in § 347.10(b), (c), (j), (s), Subpart C—Labeling (t), and (u) may be combined provided the combination is labeled according to SOURCE: 68 FR 33377, June 4, 2003, unless § 347.50(b)(3) and provided each ingre- otherwise noted. dient in the combination is within the EFFECTIVE DATE NOTE: At 68 FR 33377, June concentration specified in § 347.10. 4, 2003, subpart C was added, effective June 4, (4) The ingredients identified in 2004. § 347.10(f) and (l) may be combined provided the combination is labeled ac- § 347.50 Labeling of skin protectant cording to § 347.50(b)(7) and provided drug products. each ingredient in the combination is A skin protectant drug product may within the concentration specified in have more than one labeled use and la- § 347.10. beling appropriate to different uses

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may be combined to eliminate duplica- (which may be followed by: ‘‘and lips’’). tive words or phrases as long as the la- This statement may be followed by the beling is clear and understandable. optional statement: ‘‘helps protect When the labeling of the product con- from the drying effects of wind and tains more than one labeled use, the cold weather’’. [If both statements are appropriate statement(s) of identity, used, each is preceded by a bullet.] indications, warnings, and directions (ii) For products formulated as a lip must be stated in the labeling. protectant. The labeling states ‘‘tempo- (a) Statement of identity. The labeling rarily protects’’ (which may be fol- of the product contains the established lowed by: ‘‘and helps relieve’’) name of the drug, if any, and identifies ‘‘chapped or cracked lips’’. This state- the product with one or more of the ment may be followed by the optional following: statement: ‘‘helps protect lips from the (1) For any product. ‘‘Skin protect- drying effects of wind and cold weath- ant’’ (optional, may add dosage form, er’’. [If both statements are used, each e.g., ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or is preceded by a bullet.] ‘‘ointment’’). (3) For products containing any ingre- (2) For products containing any ingredient in § 347.10(b), (c), (j), (s), (t), and dient in § 347.10(b), (c), (j), (s), (t), and (u). The labeling states ‘‘dries the ooz- (u). ‘‘Poison ivy, oak, sumac drying’’ ing and weeping of poison: [bullet] ivy (optional, may add dosage form, e.g., [bullet] oak [bullet] sumac’’. ‘‘cream,’’ ‘‘gel,’’ ‘‘lotion,’’ or ‘‘oint- (4) For products containing colloidal ment’’). oatmeal identified in § 347.10(f). The la- (3) For products containing any ingre- beling states ‘‘temporarily protects dient in § 347.10(b), (c), (f), (j), (o), (s), (t), and helps relieve minor skin irritation and (u). ‘‘Poison ivy, oak, sumac pro- and itching due to: [select one or more tectant.’’ of the following: ‘[bullet] rashes’ ‘[bul- (b) Indications. The labeling of the let] eczema’ ‘[bullet] poison ivy, oak, product states, under the heading or sumac’ ‘[bullet] insect bites’].’’ ‘‘Uses,’’ one or more of the phrases list- (5) For products containing sodium bi- ed in this paragraph (b), as appropriate. carbonate identified in § 347.10(o). The la- Other truthful and nonmisleading beling states ‘‘temporarily protects statements, describing only the uses and helps relieve minor skin irritation that have been established and listed in and itching due to: [bullet] poison ivy, this paragraph (b), may also be used, as oak, or sumac [bullet] insect bites’’. provided in § 330.1(c)(2) of this chapter, (6) For products containing topical subject to the provisions of section 502 starch identified in § 347.10(q). The label- of the Federal Food, Drug, and Cos- ing states ‘‘temporarily protects and metic Act (the act) relating to mis- helps relieve minor skin irritation’’. branding and the prohibition in section (7) For products containing the com- 301(d) of the act against the introduc- bination of ingredients in § 347.20(a)(4). tion or delivery for introduction into The labeling states ‘‘temporarily pro- interstate commerce of unapproved tects and helps relieve minor skin irri- new drugs in violation of section 505(a) tation and itching due to: [select one of the act. or more of the following: ‘rashes’ or (1) For products containing any ingre- ‘eczema’].’’ [If both conditions are dient in § 347.10(a), (d), (e), (i), (k), (l), used, each is preceded by a bullet.] (m), and (r). The labeling states ‘‘tem- (c) Warnings. The labeling of the porarily protects minor: [bullet]1 cuts product contains the following warn- [bullet] scrapes [bullet] burns’’. ings under the heading ‘‘Warnings’’: (2) For products containing any ingre- (1) ‘‘For external use only’’ in accord dient in § 347.10(a), (d), (e), (g), (h), (i), with § 201.66(c)(5)(i) of this chapter. For (k), (l), (m), and (r)—(i). The labeling products containing only mineral oil in states ‘‘temporarily protects’’ (which § 347.10(l) or sodium bicarbonate in may be followed by: ‘‘and helps re- § 347.10(o), this warning may be omitted lieve’’) ‘‘chapped or cracked skin’’ if labeling for oral use of the product is also provided. 1 See § 201.66(b)(4) of this chapter for defini- (2) ‘‘When using this product [bullet] tion of bullet symbol. do not get into eyes’’.

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(3) ‘‘Stop use and ask a doctor if [bul- ed, or as directed by a doctor [bullet] let] condition worsens [bullet] symp- pat dry (do not rub) to keep a thin toms last more than 7 days or clear up layer on the skin’’. and occur again within a few days’’. (B) For products used as a compress or (4) For products labeled according to wet dressing. The manufacturer must § 347.50(b)(1) or (b)(2): ‘‘Do not use on provide adequate directions to obtain a [bullet] deep or puncture wounds [bul- solution containing a minimum of 0.25 let] animal bites [bullet] serious percent colloidal oatmeal. ‘‘For use as burns’’. a compress or wet dressing: [bullet] (5) For products containing colloidal soak a clean, soft cloth in the mixture oatmeal identified in § 347.10(f) when la- [bullet] apply cloth loosely to affected beled for use as a soak in a tub. ‘‘When area for 15 to 30 minutes [bullet] repeat using this product [bullet] to avoid as needed or as directed by a doctor slipping, use mat in tub or shower’’. [bullet] discard mixture after each (6) For powder products containing use’’. kaolin identified in § 347.10(j) or topical (ii) For topical products intended for di- starch identified in § 347.10(q)—(i) ‘‘Do rect application. The labeling states not use on [bullet] broken skin’’. ‘‘apply as needed’’. (ii) ‘‘When using this product [bullet] (3) For products containing sodium bi- keep away from face and mouth to carbonate identified in § 347.10(o). The la- avoid breathing it’’. beling states ‘‘[bullet] adults and chil- (7) For products containing colloidal dren 2 years of age and over:’’ oatmeal identified in § 347.10(f) or so- (i) The labeling states ‘‘For use as a dium bicarbonate identified in paste: [bullet] add enough water to the § 347.10(o) when labeled for use as a sodium bicarbonate to form a paste soak, compress, or wet dressing. ‘‘When [bullet] apply to the affected area of using this product [bullet] in some skin the skin as needed, or as directed by a conditions, soaking too long may doctor’’. overdry’’. (ii) The labeling states ‘‘For use as a (d) Directions. The labeling of the soak in a bath: [bullet] dissolve 1 to 2 product contains the following state- cupfuls in a tub of warm water [bullet] ments, as appropriate, under the head- soak for 10 to 30 minutes as needed, or ing ‘‘Directions’’: as directed by a doctor [bullet] pat dry (1) For products labeled according to (do not rub) to keep a thin layer on the § 347.50(b)(1), (b)(2), (b)(3), (b)(5), or skin’’. (b)(6). The labeling states ‘‘apply as (iii) The labeling states ‘‘For use as a needed’’. compress or wet dressing: [bullet] add (2) For products containing colloidal sodium bicarbonate to water to make a oatmeal identified in § 347.10(f)—(i) For mixture in a container [bullet] soak a products requiring dispersal in water. The clean, soft cloth in the mixture [bullet] labeling states ‘‘[bullet] turn warm apply cloth loosely to affected area for water faucet on to full force [bullet] 15 to 30 minutes [bullet] repeat as need- slowly sprinkle’’ (manufacturer to in- ed or as directed by a doctor [bullet] sert quantity to be used) ‘‘of colloidal discard mixture after each use’’. oatmeal directly under the faucet into (iv) Any of the directions in para- the tub or container [bullet] stir any graphs (d)(3)(i), (d)(3)(ii), or (d)(3)(iii) of colloidal oatmeal settled on the bot- this section shall be followed by the tom’’. 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

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states ‘‘[bullet] children under 2 years: described in § 201.66(c)(3) and (c)(7) may ask a doctor’’. be omitted, and the headings, sub- (e) Products formulated and labeled as headings, and information described in a lip protectant and that meet the criteria § 201.66(c)(2), (c)(4), and (c)(5) may be established in § 201.66(d)(10) of this chap- presented as follows: ter. The title, headings, subheadings, (i) The active ingredients and information described in § 201.66(c) (§ 201.66(c)(2) of this chapter) shall be of this chapter shall be printed in ac- listed in alphabetical order. cordance with the following specifica- (ii) The heading and the indication tions: required by § 201.66(c)(4) of this chapter (1) The labeling shall meet the re- may be limited to ‘‘Use [in bold type] quirements of § 201.66(c) of this chapter helps protect minor cuts and burns’’ or except that the title, headings, and in- ‘‘Use [in bold type] helps protect formation described in § 201.66(c)(1), chapped skin’’ or ‘‘Use [in bold type] (c)(3), (c)(6), and (c)(7) may be omitted, helps protect minor cuts and burns and and the headings, subheadings, and in- chapped skin’’. formation described in § 201.66(c)(2), (iii) The warning in § 347.50(c)(3) may (c)(4), and (c)(5) may be presented as be revised to read ‘‘See a doctor if con- follows: dition lasts more than 7 days.’’ (i) The active ingredients (iv) The subheadings in (§ 201.66(c)(2) of this chapter) shall be § 201.66(c)(5)(iv) through (c)(5)(vii) of listed in alphabetical order. this chapter may be omitted, provided (ii) The heading and the indication the information after the heading required by § 201.66(c)(4) may be limited ‘‘Warnings’’ contains the warnings in to: ‘‘Use [in bold type] helps protect’’ § 347.50(c)(2), (c)(4), and (f)(1)(iii). (which may be followed by ‘‘and re- (2) The labeling shall be printed in lieve’’) ‘‘chapped lips’’. accordance with the requirements of (iii) The ‘‘external use only’’ warning § 201.66(d) of this chapter except that in § 347.50(c)(1) and in § 201.66(c)(5)(i) of any requirements related to this chapter may be omitted. The § 201.66(c)(3) and (c)(7) may be omitted. warnings in § 347.50(c)(2) and (c)(4) are not required and the warning in EFFECTIVE DATE NOTE: At 68 FR 68511, Dec. § 347.50(c)(3) may be revised to read 9, 2003, § 347.50 was amended by revising paragraphs (b)(2), (e)(1)(ii), and (f)(1)(ii), effective ‘‘Stop use and ask a doctor if condition June 4, 2004. For the convenience of the user, lasts more than 7 days.’’ the revised text is set forth as follows: (iv) The subheadings in § 201.66(c)(5)(iii) through (c)(5)(vi) of § 347.50 Labeling of skin protectant drug this chapter may be omitted, provided products. the information after the heading ‘‘Warning’’ contains the warning in * * * * * § 347.50(e)(1)(iii). (b) Indications. *** (v) The warnings in § 201.66(c)(5)(x) of (2) For products containing any ingredient in this chapter may be omitted. § 347.10(a), (d), (e), (g), (h), (i), (k), (l), (m), and (2) The labeling shall be printed in (r)—(i) The labeling states (optional: ‘‘helps accordance with the requirements of prevent and’’) ‘‘temporarily protects’’ (op- § 201.66(d) of this chapter except that tional: ‘‘and helps relieve’’) (optional: any requirements related to ‘‘chafed,’’) ‘‘chapped or cracked skin’’ (optional: ‘‘and lips’’). This statement may be § 201.66(c)(1), (c)(3), (c)(6), and (c)(7), and followed by the optional statement: ‘‘helps’’ the horizontal barlines and hairlines (optional: ‘‘prevent and’’) ‘‘protect from the described in § 201.66(d)(8), may be omit- drying effects of wind and cold weather’’. [If ted. both statements are used, each is preceded (f) Products containing only cocoa but- by a bullet.] ter, petrolatum, or white petrolatum iden- (ii) For products formulated as a lip protect- tified in § 347.10(d), (m), and (r), singly or ant. The labeling states (optional: ‘‘helps in combination with each other, and mar- prevent and’’) ‘‘temporarily protects’’ (optional: ‘‘and helps relieve’’) (optional: keted other than as a lip protectant. (1) ‘‘chafed,’’) ‘‘chapped or cracked lips’’. This The labeling shall meet the require- statement may be followed by the optional ments of § 201.66(c) of this chapter ex- statement: ‘‘helps’’ (optional: ‘‘prevent and’’) cept that the headings and information ‘‘protect from the drying effects of wind and

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cold weather’’. [If both statements are used, tions due to: [select one or more of the each is preceded by a bullet.] following: ‘poison ivy,’ ‘poison oak,’ ‘poison sumac,’ ‘insect bites,’ ‘athlete’s * * * * * foot,’ or ‘rashes caused by soaps, deter- (e) Products formulated and labeled as a lip gents, cosmetics, or jewelry’].’’ protectant and that meet the criteria established (2) For products containing aluminum in § 201.66(d)(10) of this chapter. *** sulfate identified in § 347.12(b) for use as a (1) * * * styptic pencil. ‘‘Stops bleeding caused (ii) The heading and the indication re- by minor surface cuts and abrasions as quired by § 201.66(c)(4) of this chapter may be may occur during shaving.’’ limited to: ‘‘Use [in bold type] helps’’ (optional: ‘‘prevent and’’) ‘‘protect’’ (optional: (3) For products containing witch hazel ‘‘and relieve’’) ‘‘chapped lips’’. If both op- identified in § 347.12(c). ‘‘Relieves minor tional terms are used, the indication may be skin irritations due to: [select one or limited to: ‘‘Use [in bold type] helps prevent, more of the following: ’insect bites,’ protect, and relieve chapped lips’’. ’minor cuts,’ or ’minor scrapes’].’’ [If more than one condition is used, each * * * * * is preceded by a bullet.] (c) Warnings. The labeling of the (f) Products containing only cocoa butter, petrolatum, or white petrolatum identified in product contains the following warn- § 347.10(d), (m), and (r), singly or in combination ings under the heading ‘‘Warnings’’: with each other, and marketed other than as a (1) ‘‘For external use only. Avoid con- lip protectant. (1) * * * tact with the eyes.’’ (ii) The heading and the indication re- (2) For products containing aluminum quired by § 201.66(c)(4) of this chapter may be acetate identified in § 347.12(a) or witch limited to ‘‘Use [in bold type] helps protect hazel identified in § 347.12(c). ‘‘If condi- minor cuts and burns’’ or ‘‘Use [in bold type] helps’’ (optional: ‘‘prevent and’’) ‘‘protect tion worsens or symptoms persist for chapped skin’’ or ‘‘Use [in bold type] helps more than 7 days, discontinue use of protect minor cuts and burns and’’ (optional: the product and consult a’’ [select one ‘‘prevent and protect’’) ‘‘chapped skin’’. of the following: ’physician’ or ’doctor’].’’ * * * * * (3) For products containing aluminum acetate identified in § 347.12(a) used as a § 347.52 Labeling of astringent drug compress or wet dressing. ‘‘Do not cover products. compress or wet dressing with plastic (a) Statement of identity. The labeling to prevent evaporation.’’ of the product contains the established (d) Directions. The labeling of the name of the drug, if any, and identifies product contains the following infor- the product as an ‘‘astringent.’’ mation under the heading ‘‘Direc- (b) Indications. The labeling of the tions’’: product states, under the heading (1) For products containing aluminum ‘‘Uses’’ any of the phrases listed in this acetate identified in § 347.12(a)—(i) For paragraph (b), as appropriate. Other products used as a soak. ‘‘For use as a truthful and nonmisleading statements soak: Soak affected area in the solu- describing only the indications for use tion for 15 to 30 minutes. Discard solu- that have been established and listed in tion after each use. Repeat 3 times a this paragraph (b) may also be used, as day.’’ provided in § 330.1(c)(2) of this chapter, (ii) For products used as a compress or subject to the provisions of section 502 wet dressing. ‘‘For use as a compress or of the Federal Food, Drug, and Cos- wet dressing: saturate a clean, soft metic Act (the act) relating to mis- white cloth (such as a diaper or torn branding and the prohibition of section sheet) in the solution, gently squeeze, 301(d) of the act against the introduc- and apply loosely to the affected area. tion or delivery for introduction into Saturate the cloth in the solution interstate commerce of unapproved every 15 to 30 minutes and apply to the new drugs in violation of section 505(a) affected area. Discard solution after of the act. each use. Repeat as often as nec- (1) For products containing aluminum essary.’’ acetate identified in § 347.12(a). ‘‘For (2) For products containing aluminum temporary relief of minor skin irrita- sulfate identified in § 347.12(b) for use as a

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styptic pencil. ‘‘Moisten tip of pencil dressing with plastic to prevent evapo- with water and apply to the affected ration.’’ area. Dry pencil after use.’’ (d) Directions. The labeling of the product (3) For products containing witch hazel contains the following information under the identified in § 347.12(c). ‘‘Apply to the af- heading ‘‘Directions’’: (1) For products containing aluminum acetate fected area as often as necessary.’’ identified in § 347.10(a)—(i) For products used EFFECTIVE DATE NOTE 1: At 68 FR 33377, as a soak. ‘‘For use as a soak: Soak affected June 4, 2003, § 347.50 was redesignated as area in the solution for 15 to 30 minutes. Dis- § 347.52 and revised, effective June 4, 2004. For card solution after each use. Repeat 3 times the convenience of the user, the superseded a day.’’ text is set forth as follows: (ii) For products used as a compress or wet dressing. ‘‘For use as a compress or wet dress- § 347.50 Labeling of astringent drug prod- ing: saturate a clean, soft, white cloth (such ucts. as a diaper or torn sheet) in the solution, (a) Statement of identity. The labeling of the gently squeeze, and apply loosely to the af- product contains the established name of the fected area. Saturate the cloth in the solu- drug, if any, and identifies the product as an tion every 15 to 30 minutes and apply to the ‘‘astringent.’’ affected area. Discard solution after each (b) Indications. The labeling of the product use. Repeat as often as necessary.’’ states, under the heading ‘‘Indications’’ any (2) For products containing aluminum sulfate of the phrases listed in this paragraph (b), as identified in § 347.10(b) for use as a styptic pen- appropriate. Other truthful and nonmis- cil. ‘‘Moisten tip of pencil with water and leading statements describing only the indi- apply to the affected area. Dry pencil after cations for use that have been established use.’’ and listed in this paragraph (b) may also be (3) For products containing witch hazel iden- used, as provided in § 330.1(c)(2) of this chap- tified in § 347.10(c). ‘‘Apply to the affected ter, subject to the provisions of section 502 of area as often as necessary.’’ the Federal Food, Drug, and Cosmetic Act (the act) relating to misbranding and the [58 FR 54462, Oct. 21, 1993, as amended at 59 prohibition in section 301(d) of the act FR 28768, June 3, 1994] against the introduction or delivery for introduction into interstate commerce of un- EFFECTIVE DATE NOTE 2: At 68 FR 35293, approved new drugs in violation of section June 13, 2003, § 347.52 was amended by adding 505(a) of the act. paragraphs (c)(4) and (e) and by revising (1) For products containing aluminum acetate paragraphs (d)(1)(i), (d)(1)(ii), and (d)(3), ef- identified in § 347.10(a). ‘‘For temporary relief fective October 27, 2003. However, these of minor skin irritations due to’’ (select one amendments could not be incorporated be- or more of the following: ‘‘poison ivy,’’ ‘‘poi- cause § 347.52 is not effective until June 4, son oak,’’ ‘‘poison sumac,’’ ‘‘insect bites,’’ 2004. At 69 FR 3005, Jan. 22, 2004, the effective ‘‘athlete’s foot,’’ or ‘‘rashes caused by soaps, date of the amendments published at 68 FR detergents, cosmetics, or jewelry’’). 35292, June 13, 2003, was corrected from Octo- (2) For products containing aluminum sulfate ber 27, 2003 to June 13, 2004. For the conven- identified in § 347.10(b) for use as a styptic pen- ience of the user, the revised text is set forth cil. ‘‘Stops bleeding caused by minor surface as follows: cuts and abrasions as may occur during shaving.’’ § 347.52 Labeling of astringent drug products. (3) For products containing witch hazel identified in § 347.10(c). (i) ‘‘For relief of minor skin irritations due to’’ (select one or more * * * * * of the following: ‘‘insect bites,’’ ‘‘minor cuts,’’ or ‘‘minor scrapes’’). (c) * * * (c) Warnings. The labeling of the product (4) For products containing aluminum acetate contains the following warnings under the identified in § 347.12(a) when labeled for use as heading ‘‘Warnings’’: a soak, compress, or wet dressing. ‘‘When using (1) ‘‘For external use only. Avoid contact this product [bullet] in some skin conditions, with the eyes.’’ soaking too long may overdry’’. (2) For products containing aluminum acetate (d) * * * identified in § 347.10(a) or witch hazel identified (1) * * *—(i) For products used as a soak. in § 347.10(c). ‘‘If condition worsens or symp- ‘‘For use as a soak: [bullet] soak affected toms persist for more than 7 days, dis- area for 15 to 30 minutes as needed, or as di- continue use of the product and consult a’’ rected by a doctor [bullet] repeat 3 times a (select one of the following: ‘‘physician’’ or day or as directed by a doctor [bullet] dis- ‘‘doctor’’). card solution after each use’’. (3) For products containing aluminum acetate (ii) For products used as a compress or wet identified in § 347.10(a) used as a compress or dressing. ‘‘For use as a compress or wet dress- wet dressing. ‘‘Do not cover compress or wet ing: [bullet] soak a clean, soft cloth in the

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solution [bullet] apply cloth loosely to af- monographs. For a combination drug fected area for 15 to 30 minutes [bullet] re- product that does not have an estab- peat as needed or as directed by a doctor lished name, the labeling of the prod- [bullet] discard solution after each use’’. uct states the statement of identity for each ingredient in the combination, as * * * * * established in the statement of iden- (3) For products containing witch hazel identity sections of the applicable OTC tified in § 347.12(c). ‘‘Apply as often as need- drug monographs. ed’’. (b) Indications. The labeling of the (e) Products formulated and labeled as a styp- product states, under the heading tic pencil and that meet the criteria established ‘‘Uses,’’ the indication(s) for each in- in § 201.66(d)(10) of this chapter. The title, gredient in the combination as estab- headings, subheadings, and information described in § 201.66(c) of this chapter shall be lished in the indications sections of the printed in accordance with the following applicable OTC drug monographs, un- specifications: less otherwise stated in this paragraph (1) The labeling shall meet the require- (b). Other truthful and nonmisleading ments of § 201.66(c) of this chapter except statements, describing only the indica- that the headings and information described tions for use that have been established in § 201.66(c)(3) and (c)(7) may be omitted, and in the applicable OTC drug monographs the headings, subheadings, and information or listed in this paragraph (b) may also described in § 201.66(c)(4) and (c)(5) may be presented as follows: be used, as provided in § 330.1(c)(2) of (i) The heading and indication required by this chapter, subject to the provisions § 201.66(c)(4) of this chapter may be limited of section 502 of the Federal Food, to: ‘‘Use [in bold type] stops bleeding of Drug, and Cosmetic Act (the act) relat- minor cuts from shaving’’. ing to misbranding and the prohibition (ii) The ‘‘external use only’’ warning in in section 301(d) of the act against the § 347.52(c)(1) and in § 201.66(c)(5)(i) of this introduction or delivery for introduc- chapter may be omitted. The second warning tion into interstate commerce of unap- in § 347.52(c)(1) may state: ‘‘avoid contact with eyes’’. The warning in § 201.66(c)(5)(x) proved new drugs in violation of sec- may be limited to the following: ‘‘Keep out tion 505(a) of the act. In addition to the of reach of children.’’ The subheadings in required information identified in this § 201.66(c)(5)(iii) through (c)(5)(vii) may be paragraph (b), the labeling of the prod- omitted, provided the information after the uct may contain any of the ‘‘other al- heading ‘‘Warning’’ contains the warnings in lowable statements’’ that are identified this paragraph. in the applicable monographs, provided (2) The labeling shall be printed in accord- such statements are neither placed in ance with the requirements of § 201.66(d) of this chapter except that any requirements direct conjunction with information re- related to § 201.66(c)(3) and (c)(7), and the hor- quired to appear in the labeling nor oc- izontal barlines and hairlines described in cupy labeling space with greater prom- § 201.66(d)(8), may be omitted. inence or conspicuousness than the required information. § 347.60 Labeling of permitted com- (1) Combinations of skin protectant and binations of active ingredients. external analgesic active ingredients in The statement of identity, indica- § 347.20(b). In addition to any or all of tions, warnings, and directions for use, the indications for skin protectant respectively, applicable to each ingre- drug products in § 347.50(b)(1), any or all dient in the product may be combined of the allowable indications for exter- to eliminate duplicative words or nal analgesic drug products may be phrases so that the resulting informa- used if the product is labeled for con- tion is clear and understandable. current symptoms. (a) Statement of identity. For a com- (2) Combinations of skin protectant and bination drug product that has an es- first aid antiseptic active ingredients in tablished name, the labeling of the § 347.20(c). In addition to any or all of product states the established name of the indications for skin protectant the combination drug product, followed drug products in § 347.50(b)(1), the re- by the statement of identity for each quired indications for first aid anti- ingredient in the combination, as es- septic drug products should be used. tablished in the statement of identity (3) Combinations of skin protectant and sections of the applicable OTC drug sunscreen active ingredients in § 347.20(d).

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In addition to any or all of the indica- Subpart B—Active Ingredients tions for skin protectant drug products 348.10 Analgesic, anesthetic, and anti- in § 347.50(b)(2)(i), the required indica- pruritic active ingredients. tions for sunscreen drug products 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 product states, under the heading AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371. ‘‘Warnings,’’ the warning(s) for each ingredient in the combination, as estab- SOURCE: 57 FR 27656, June 19, 1992, unless lished in the warnings section of the otherwise noted. applicable OTC drug monographs unless otherwise stated in this paragraph Subpart A—General Provisions (c). § 348.1 Scope. (1) For combinations containing a skin protectant and a sunscreen identified in (a) An over-the-counter external an- §§ 347.20(d) and 352.20(b). The warnings algesic drug product in a form suitable for sunscreen drug products in for topical administration is generally 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 paragraph (d). When the time intervals or § 348.3 Definitions. 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 may not contain any dosage that ex- penis to help in temporarily slowing ceeds those established for any indi- the onset of ejaculation. vidual ingredient in the applicable OTC (b) [Reserved] drug monograph(s), and may not provide for use by any age group lower Subpart B—Active Ingredients than the highest minimum age limit established for any individual ingre- § 348.10 Analgesic, anesthetic, and dient. antipruritic active ingredients. (1) For combinations containing a skin The active ingredient of the product protectant and a sunscreen identified in consists of any of the following within §§ 347.20(d) and 352.20(b). The directions the specified concentration established for sunscreen drug products in for each ingredient: § 352.60(d) of this chapter are used. (a) Male genital desensitizers. (1) Ben- 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. DRUG PRODUCTS FOR OVER-THE- (b) [Reserved] COUNTER HUMAN USE Subpart C—Labeling Subpart A—General Provisions § 348.50 Labeling of external analgesic Sec. drug products. 348.1 Scope. (a) Statement of identity. The labeling 348.3 Definitions. of the product contains the established

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

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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 Subpart B—Active Ingredients PRODUCTS FOR OVER-THE- § 350.10 Antiperspirant active ingredi- COUNTER HUMAN USE ents. The active ingredient of the product Subpart A—General Provisions consists of any of the following within Sec. the established concentration and dos- 350.1 Scope. age formulation. Where applicable, the 350.3 Definition. ingredient must meet the aluminum to chloride, aluminum to zirconium, and Subpart B—Active Ingredients aluminum plus zirconium to chloride atomic ratios described in the U.S. 350.10 Antiperspirant active ingredients. Pharmacopeia-National Formulary. Subpart C—Labeling The concentration of ingredients in paragraphs (b) through (j) of this sec- 350.50 Labeling of antiperspirant drug prod- tion is calculated on an anhydrous ucts. basis, omitting from the calculation any buffer component present in the Subpart D—Guidelines for Effectiveness compound, in an aerosol or nonaerosol Testing dosage form. The concentration of ingredients in paragraphs (k) through (r) 350.60 Guidelines for effectiveness testing of antiperspirant drug products. of this section is calculated on an anhydrous basis, omitting from the cal- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, culation any buffer component present 360, 371. in the compound, in a nonaerosol dos- SOURCE: 68 FR 34291, June 9, 2003, unless age form. The labeled declaration of otherwise noted. the percentage of the active ingredient should exclude any water, buffer com- EFFECTIVE DATE NOTE: At 68 FR 34291, June ponents, or propellant. 9, 2003, Part 350 was added, effective Dec. 9, 2004. (a) Aluminum chloride up to 15 percent, calculated on the hexahydrate Subpart A—General Provisions form, in an aqueous solution nonaerosol dosage form. § 350.1 Scope. (b) Aluminum chlorohydrate up to 25 percent. (a) An over-the-counter anti- (c) Aluminum chlorohydrex poly- perspirant drug product in a form suit- ethylene glycol up to 25 percent. able for topical administration is gen- (d) Aluminum chlorohydrex pro- erally recognized as safe and effective pylene glycol up to 25 percent. and is not misbranded if it meets each (e) Aluminum dichlorohydrate up to condition in this part and each general 25 percent. condition established in § 330.1 of this (f) Aluminum dichlorohydrex poly- chapter. ethylene glycol up to 25 percent. (g) Aluminum dichlorohydrex pro- (b) References in this part to regu- pylene glycol up to 25 percent. (h) Aluminum sesquichlorohydrate latory sections of the Code of Federal up to 25 percent. Regulations are to chapter I of title 21 (i) Aluminum sesquichlorohydrex unless otherwise noted. polyethylene glycol up to 25 percent. (j) Aluminum sesquichlorohydrex § 350.3 Definition. propylene glycol up to 25 percent. (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 pentachlorohydrex gly up to 20 percent.

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(o) Aluminum zirconium reduction), the labeling may state tetrachlorohydrate up to 20 percent. ‘‘extra effective’’. (p) Aluminum zirconium (5) Products that demonstrate extra tetrachlorohydrex gly up to 20 percent. effectiveness (30 percent sweat reduc- (q) Aluminum zirconium tion) sustained over a 24-hour period trichlorohydrate up to 20 percent. may state the claims in paragraphs (r) Aluminum zirconium (b)(3) and (b)(4) of this section either trichlorohydrex gly up to 20 percent. individually or combined, e.g., ‘‘24 hour extra effective protection’’, ‘‘all day 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 estab- (ii) The warning required by § 369.21 lished and listed in paragraphs (b)(1) of this chapter for drugs in dispensers through (b)(5) of this section, may also pressurized by gaseous propellants. be used, as provided in § 330.1(c)(2) of (d) Directions. The labeling of the this chapter, subject to the provisions product contains the following state- of section 502 of the Federal Food, ment under the heading ‘‘Directions’’: Drug, and Cosmetic Act (the act) relat- ‘‘apply to underarms only’’. ing to misbranding and the prohibition in section 301(d) of the act against the Subpart D—Guidelines for introduction or delivery for introduc- Effectiveness Testing tion into interstate commerce of unapproved new drugs in violation of sec- § 350.60 Guidelines for effectiveness tion 505(a) of the act. testing of antiperspirant drug prod- (1) For any product, the labeling ucts. states [select one of the following: An antiperspirant in finished dosage ‘‘decreases,’’ ‘‘lessens,’’ or ‘‘reduces’’] form may vary in degree of effective- ‘‘underarm’’ [select one of the fol- ness because of minor variations in for- lowing: ‘‘dampness,’’ ‘‘perspiration,’’ mulation. To assure the effectiveness ‘‘sweat,’’ ‘‘sweating,’’ or ‘‘wetness’’]. of an antiperspirant, the Food and (2) The labeling may state ‘‘also [se- Drug Administration is providing lect one of the following: ‘decreases,’ guidelines that manufacturers may use ‘lessens,’ or ‘reduces’] underarm [select in testing for effectiveness. These one of the following: ‘dampness,’ ‘per- guidelines are on file in the Dockets spiration,’ ‘sweat,’ ‘sweating,’ or ‘wet- Management Branch (HFA–305), Food ness’] due to stress’’. and Drug Administration, 5630 Fishers (3) For products that demonstrate Lane, rm. 1061, Rockville, MD 20852. standard effectiveness (20 percent These guidelines are available on the sweat reduction) over a 24-hour period, FDA’s Web site at http://www.fda.gov/ the labeling may state [select one of cder/otc/index.htm or on request for a the following: ‘‘all day protection,’’ nominal charge by submitting a Free- ‘‘lasts all day,’’ ‘‘lasts 24 hours,’’ or ‘‘24 dom of Information (FOI) request in hour protection’’]. (4) For products that demonstrate 1 See § 201.66(b)(4) of this chapter for defini- extra effectiveness (30 percent sweat tion of bullet.

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writing to FDA’s FOI Staff (HFI–35), misbranded if it meets each condition 5600 Fishers Lane, rm. 12A–16, Rock- in this part and each general condition ville, MD 20857. established in § 330.1 of this chapter. (b) References in this part to regu- PART 352—SUNSCREEN DRUG latory sections of the Code of Federal PRODUCTS FOR OVER-THE- Regulations are to Chapter I of Title 21 COUNTER HUMAN USE [STAYED unless otherwise noted. INDEFINITELY] § 352.3 Definitions. Subpart A—General Provisions As used in this part: (a) Minimal erythema dose (MED). The Sec. quantity of erythema-effective energy 352.1 Scope. 352.3 Definitions. (expressed as Joules per square meter) required to produce the first percep- Subpart B—Active Ingredients tible, redness reaction with clearly defined borders. 352.10 Sunscreen active ingredients. (b) Product category designation (PCD). 352.20 Permitted combinations of active ingredients. A labeling designation for sunscreen drug products to aid in selecting the Subpart C—Labeling type of product best suited to an individual’s complexion (pigmentation) 352.50 Principal display panel of all sun- and desired response to ultraviolet screen drug products. 352.52 Labeling of sunscreen drug products. (UV) radiation. 352.60 Labeling of permitted combinations (1) Minimal sun protection product. A of active ingredients. sunscreen product that provides a sun protection factor (SPF) value of 2 to Subpart D—Testing Procedures under 12. 352.70 Standard sunscreen. (2) Moderate sun protection product. A 352.71 Light source (solar simulator). sunscreen product that provides an 352.72 General testing procedures. SPF value of 12 to under 30. 352.73 Determination of SPF value. (3) High sun protection product. A sun- 352.76 Determination if a product is water screen product that provides an SPF resistant or very water resistant. 352.77 Test modifications. value of 30 or above. (c) Sunscreen active ingredient. An ac- AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, tive ingredient listed in § 352.10 that ab- 360, 371. sorbs, reflects, or scatters radiation in SOURCE: 64 FR 27687, May 21, 1999, unless the UV range at wavelengths from 290 otherwise noted. to 400 nanometers. EFFECTIVE DATE NOTE: At 64 FR 27687, May (d) Sun protection factor (SPF) value. 21, 1999, part 352 was added, effective May 21, The UV energy required to produce an 2001. At 65 FR 36319, June 8, 2000, the effec- MED on protected skin divided by the tive date was delayed until Dec. 31, 2002. At 66 FR 67485, Dec. 31, 2001, the effective date UV energy required to produce an MED was stayed until further notice. on unprotected skin, which may also be defined by the following ratio: SPF EFFECTIVE DATE NOTE: At 68 FR 33380, June 4, 2003, the stay on part 352 was lifted and value =MED (protected skin (PS))/MED amendments were made to §§ 352.20, 352.52, (unprotected skin (US)), where MED and 352.60, effective June 4, 2004. At 68 FR (PS) is the minimal erythema dose for 33381, June 4, 2003, part 352 was again stayed protected skin after application of 2 until further notice, effective June 4, 2004. milligrams per square centimeter of the final formulation of the sunscreen Subpart A—General Provisions product, and MED (US) is the minimal erythema dose for unprotected skin, § 352.1 Scope. i.e., skin to which no sunscreen prod- (a) An over-the-counter sunscreen uct has been applied. In effect, the SPF drug product in a form suitable for top- value is the reciprocal of the effective ical administration is generally recog- transmission of the product viewed as a nized as safe and effective and is not UV radiation filter.

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Subpart B—Active Ingredients § 352.20 Permitted combinations of active ingredients. § 352.10 Sunscreen active ingredients. The SPF of any combination product The active ingredient of the product is measured by the testing procedures consists of any of the following, within established in subpart D of this part. the concentration specified for each in- (a) Combinations of sunscreen active ingredient, and the finished product pro- gredients. (1) Two or more sunscreen ac- vides a minimum SPF value of not less tive ingredients identified in § 352.10(a), than 2 as measured by the testing pro- (c), (e), (f), and (h) through (r) may be cedures established in subpart D of this combined with each other in a single part: product when used in the concentra- (a) Aminobenzoic acid (PABA) up to tions established for each ingredient in 15 percent. § 352.10. The concentration of each ac- (b) Avobenzone up to 3 percent. tive ingredient must be sufficient to (c) Cinoxate up to 3 percent. contribute a minimum SPF of not less (d) [Reserved] than 2 to the finished product. The fin- (e) Dioxybenzone up to 3 percent. ished product must have a minimum (f) Homosalate up to 15 percent. SPF of not less than the number of (g) [Reserved] sunscreen active ingredients used in 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)–(c) [Reserved] [64 FR 27687, May 21, 1999] [64 FR 27687, May 21, 1999]

EFFECTIVE DATE NOTE: At 67 FR 41823, June EFFECTIVE DATE NOTE: At 67 FR 41823, June 20, 2002, § 352.10 was amended by revising 20, 2002, § 352.20 was amended by revising paragraphs (f) through (n), effective Sept. 1, paragraphs (a)(1) through (a)(2), effective 2002. This amendment could not be incor- Sept. 1, 2002. This amendment could not be porated because at 66 FR 67485, Dec. 31, 2001 incorporated because at 66 FR 67485, Dec. 31, the effective date was stayed until further 2001 the effective date was stayed until fur- notice. For the convenience of the user, the ther notice. For the convenience of the user, text is set forth as follows: the text is set forth as follows:

§ 352.10 Sunscreen active ingredients. § 352.20 Permitted combinations of active ingredients. * * * * * * * * * * (f) Ensulizole up to 4 percent. (g) Homosalate up to 15 percent. (a) Combinations of sunscreen active ingredi- (h) [Reserved] ents. (1) Two or more sunscreen active ingre- (i) Meradimate up to 5 percent. dients identified in § 352.10(a), (c), (e), (f), (g), (j) Octinoxate up to 7.5 percent. and (i) through (r) may be combined with (k) Octisalate up to 5 percent. each other in a single product when used in (l) Octocrylene up to 10 percent. the concentrations established for each in- (m) Oxybenzone up to 6 percent. gredient in § 352.10. The concentration of each active ingredient must be sufficient to (n) Padimate O up to 8 percent. contribute a minimum SPF of not less than 2 to the finished product. The finished prod- * * * * * uct must have a minimum SPF of not less

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than the number of sunscreen active ingredi- (2) For products with SPF values over ents used in the combination multiplied by 2. 30. ‘‘SPF 30’’ (select one of the fol- (2) Two or more sunscreen active ingredi- lowing: ‘‘plus’’ or ‘‘+’’). Any statement ents identified in § 352.10(b), (c), (e), (g), (j) accompanying the marketed product through (m), (o), and (q) may be combined that states a specific SPF value above with each other in a single product when used in the concentrations established for 30 or similar language indicating a per- each ingredient in § 352.10. The concentration son can stay in the sun more than 30 of each active ingredient must be sufficient times longer than without sunscreen to contribute a minimum SPF of not less will cause the product to be mis- than 2 to the finished product. The finished branded under section 502 of the Fed- product must have a minimum SPF of not eral Food, Drug, and Cosmetic Act (the less than the number of sunscreen active in- act). gredients used in the combination multiplied (b) For products that satisfy the water by 2. resistant sunscreen product testing procedures in § 352.76. (1) (Select one of the * * * * * following: ‘‘Water,’’ ‘‘Water/Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Resistant.’’ EFFECTIVE DATE NOTE: At 68 FR 33380, June (2) ‘‘SPF (insert SPF value of the 4, 2003, § 352.20 was amended by adding paragraph (b), effective June 4, 2004. For the con- product, as stated in paragraph (a)(1) venience of the user, the added text is set or (a)(2) of this section, after it has forth as follows: been tested using the water resistant sunscreen product testing procedures § 352.20 Permitted combinations of active in § 352.76).’’ ingredients. (c) For products that satisfy the very water resistant sunscreen product testing * * * * * procedures in § 352.76. (1) ‘‘Very’’ (select (b) Combinations of sunscreen and skin pro- one of the following: ‘‘Water,’’ ‘‘Water/ tectant active ingredients. Any single sun- Sweat,’’ or ‘‘Water/Perspiration’’) ‘‘Re- screen active ingredient or any permitted sistant.’’ combination of sunscreen active ingredients (2) ‘‘SPF (insert SPF value of the when used in the concentrations established product, as stated in paragraph (a)(1) for each ingredient in § 352.10 may be com- or (a)(2) of this section, after it has bined with one or more skin protectant ac- been tested using the very water resist- tive ingredients identified in § 347.10(a), (d), ant sunscreen product testing proce- (e), (g), (h), (i), (k), (l), (m), and (r) of this chapter. The concentration of each sun- dures in § 352.76).’’ screen active ingredient must be sufficient to contribute a minimum SPF of not less § 352.52 Labeling of sunscreen drug that 2 to the finished product. The finished products. product must have a minimum SPF of not (a) Statement of identity. The labeling less than the number of sunscreen active in- of the product contains the established gredients used in the combination multiplied name of the drug, if any, and identifies by 2, and the product must be labeled accord- the product as a ‘‘sunscreen.’’ ing to § 352.60. (b) Indications. The labeling of the product states, under the heading Subpart C—Labeling ‘‘Uses,’’ all of the phrases listed in paragraph (b)(1) of this section that are § 352.50 Principal display panel of all applicable to the product and may con- sunscreen drug products. tain any of the additional phrases list- In addition to the statement of iden- ed in paragraph (b)(2) of this section, as tity required in § 352.52, the following appropriate. Other truthful and non- labeling statements shall be promi- misleading statements, describing only nently placed on the principal display the uses that have been established and panel: listed in this paragraph (b), may also (a) For products that do not satisfy the be used, as provided in § 330.1(c)(2) of water resistant or very water resistant this chapter, subject to the provisions sunscreen product testing procedures in of section 502 of the act relating to § 352.76. (1) For products with SPF values misbranding and the prohibition in sec- up to 30. ‘‘SPF (insert tested SPF value tion 301(d) of the act against the intro- of the product up to 30).’’ duction or delivery for introduction

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into interstate commerce of unap- (ii) ‘‘Stop use and ask a doctor if proved new drugs in violation of sec- [bullet] rash or irritation develops and tion 505(a) of the act. lasts’’. (1) For products containing any ingre- (2) For products containing any ingredient in § 352.10. (i) ‘‘[bullet]1 helps pre- dient identified in § 352.10 marketed as a vent sunburn [bullet] higher SPF gives lipstick. The external use only warning more sunburn protection’’. in § 201.66(c)(5)(i) of this chapter and (ii) For products that satisfy the water the warning in paragraph (c)(1)(i) of resistant testing procedures identified in this section are not required. § 352.76. ‘‘[bullet] retains SPF after 40 (d) Directions. The labeling of the minutes of’’ (select one or more of the product contains the following state- following: ‘‘activity in the water,’’ ments, as appropriate, under the head- ‘‘sweating,’’ or ‘‘perspiring’’). ing ‘‘Directions.’’ More detailed direc- (iii) For products that satisfy the very tions applicable to a particular product water resistant testing procedures identi- formulation (e.g., cream, gel, lotion, fied in § 352.76. ‘‘[bullet] retains SPF oil, spray, etc.) may also be included. after 80 minutes of’’ (select one or more (1) For products containing any ingre- of the following: ‘‘activity in the dient in § 352.10. (i) ‘‘[bullet] apply’’ (se- water,’’ ‘‘sweating,’’ or ‘‘perspiring’’). lect one or more of the following, as (2) Additional indications. In addition applicable: ‘‘liberally,’’ ‘‘generously,’’ to the indications provided in para- ‘‘smoothly,’’ or ‘‘evenly’’) ‘‘(insert ap- graph (b)(1) of this section, the fol- propriate time interval, if a waiting pe- lowing may be used for products con- riod is needed) before sun exposure and taining any ingredient in § 352.10: as needed’’. (i) For products that provide an SPF of (ii) ‘‘[bullet] children under 6 months 2 to under 12. Select one or both of the of age: ask a doctor’’. following: [‘‘[bullet]’’ (select one of the (2) In addition to the directions pro- following: ‘‘provides minimal,’’ ‘‘provided in § 352.52(d)(1), the following may vides minimum,’’ ‘‘minimal,’’ or ‘‘min- be used for products containing any in- imum’’) ‘‘protection against’’ (select gredient in § 352.10. ‘‘[bullet] reapply as one of the following: ‘‘sunburn’’ or needed or after towel drying, swim- ‘‘sunburn and tanning’’)], or ‘‘[bullet] ming, or’’ (select one of the following: for skin that sunburns minimally’’. ‘‘sweating’’ or ‘‘perspiring’’). (ii) For products that provide an SPF of (3) If the additional directions provided 12 to under 30. Select one or both of the in § 352.52(d)(2) are used, the phrase ‘‘and following: [‘‘[bullet]’’ (select one of the as needed’’ in § 352.52(d)(1) is not re- following: ‘‘provides moderate’’ or quired. ‘‘moderate’’) ‘‘protection against’’ (se- (4) For products marketed as a lipstick. lect one of the following: ‘‘sunburn’’ or The directions in paragraphs (d)(1) and ‘‘sunburn and tanning’’)], or ‘‘[bullet] (d)(2) of this section are not required. for skin that sunburns easily’’. (e) Statement on product performance— (iii) For products that provide an SPF (1) For products containing any ingre- of 30 or above. Select one or both of the dient identified in § 352.10, the following following: [‘‘[bullet]’’ (select one of the PCD labeling claims may be used under following: ‘‘provides high’’ or ‘‘high’’) the heading ‘‘Other information’’ or any- ‘‘protection against’’ (select one of the where outside of the ‘‘Drug Facts’’ box or following: ‘‘sunburn’’ or ‘‘sunburn and enclosure. tanning’’)], or ‘‘[bullet] for skin highly (i) For products containing active ingre- sensitive to sunburn’’. dient(s) that provide an SPF value of 2 to (c) Warnings. The labeling of the under 12. (Select one of the following: product contains the following warn- ‘‘minimal’’ or ‘‘minimum’’) ‘‘sun pro- ings under the heading ‘‘Warnings:’’ tection product.’’ (1) For products containing any ingre- (ii) For products containing active in- dient in § 352.10. (i) ‘‘When using this gredient(s) that provide an SPF value of product [bullet] keep out of eyes. Rinse 12 to under 30. ‘‘moderate sun protec- with water to remove.’’– tion product.’’ (iii) For products containing active in- 1 See § 201.66(b)(4) of this chapter. gredient(s) that provide an SPF value of

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30 or above. ‘‘high sun protection prod- (2) The labeling shall be printed in uct.’’ accordance with the requirements of (2) For products containing any ingre- § 201.66(d) of this chapter except that dient identified in § 352.10, the following any requirements related to labeling statement may be used under the § 201.66(c)(1), (c)(3), and (c)(7), and the heading ‘‘Other information’’ or any- horizontal barlines and hairlines de- where outside of the ‘‘Drug Facts’’ box or scribed in § 201.66(d)(8), may be omitted. enclosure. ‘‘Sun alert: Limiting sun ex- EFFECTIVE DATE NOTE: At 68 FR 33380, June posure, wearing protective clothing, 4, 2003, § 352.52 was amended by revising the and using sunscreens may reduce the heading in paragraphs (c)(2) and (d)(4) and by risks of skin aging, skin cancer, and revising paragraphs (f)(1)(ii) and (f)(1)(vi), ef- other harmful effects of the sun.’’ Any fective June 4, 2004. For the convenience of variation of this statement will cause the user, the revised text is set forth as fol- the product to be misbranded under lows: section 502 of the act. § 352.52 Labeling of sunscreen drug prod- (f) Products labeled for use only on spe- ucts. cific small areas of the face (e.g., lips, nose, ears, and/or around eyes) and that * * * * * meet the criteria established in (c) * * * § 201.66(d)(10) of this chapter. The title, (2) For products containing any ingredient headings, subheadings, and information identified in § 352.10 marketed as a lip protect- described in § 201.66(c) of this chapter ant or lipstick. *** shall be printed in accordance with the (d) * * * following specifications: (4) For products marketed as a lip protectant (1) The labeling shall meet the re- or lipstick. *** quirements of § 201.66(c) of this chapter except that the title, headings, and in- * * * * * formation described in § 201.66(c)(1), (f) * * * (c)(3), and (c)(7) may be omitted, and (1) * * * the headings, subheadings, and infor- (ii) The heading and the indication re- mation described in § 201.66(c)(2), (c)(4), quired by § 201.66(c)(4) of this chapter may be (c)(5), and (c)(6) may be presented as limited to: ‘‘Use [in bold type] helps protect follows:– against sunburn.’’ For a lip protectant product, the heading and the indication required (i) The active ingredients by § 201.66(c)(4) may be limited to: ‘‘Use [in (§ 201.66(c)(2) of this chapter) shall be bold type] helps protect against sunburn and listed in alphabetical order. chapped lips.’’ (ii) The heading and the indication required by § 201.66(c)(4) may be limited * * * * * to: ‘‘Use [in bold type] helps prevent sunburn.’’ (vi) For a lip protectant product or lipstick, the warnings ‘‘Keep out of eyes’’ in (iii) The ‘‘external use only’’ warning § 352.52(f)(1)(iv) and ‘‘Keep out of reach of in § 201.66(c)(5)(i) of this chapter may be children’’ in § 352.52(f)(1)(v) and the direc- omitted. tions in § 352.52(d) may be omitted. (iv) The subheadings in § 201.66(c)(5)(iii) through (c)(5)(vii) of * * * * * this chapter may be omitted, provided the information after the heading § 352.60 Labeling of permitted com- ‘‘Warnings’’ states: ‘‘Keep out of eyes.’’ binations of active ingredients. and ‘‘Stop use if skin rash occurs.’’ Statements of identity, indications, (v) The warning in § 201.66(c)(5)(x) of warnings, and directions for use, re- this chapter may be limited to the fol- spectively, applicable to each ingre- lowing: ‘‘Keep out of reach of chil- dient in the product may be combined dren.’’ to eliminate duplicative words or (vi) For a lipstick, the warnings phrases so that the resulting informa- ‘‘Keep out of eyes’’ in § 352.52(f)(1)(iv) tion is clear and understandable. and ‘‘Keep out of reach of children’’ in (a) Statement of identity. For a com- § 352.52(f)(1)(v) and the directions in bination drug product that has an es- § 352.52(d) may be omitted. tablished name, the labeling of the

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product states the established name of graph. When the time intervals or age the combination drug product, followed limitations for administration of the by the statement of identity for each individual ingredients differ, the direc- ingredient in the combination, as es- tions for the combination product may tablished in the statement of identity not contain any dosage that exceeds sections of the applicable OTC drug those established for any individual in- monographs. For a combination drug gredient in the applicable OTC drug product that does not have an estab- monograph(s), and may not provide for lished name, the labeling of the prod- use by any age group lower than the uct states the statement of identity for highest minimum age limit established each ingredient in the combination, as for any individual ingredient. For per- established in the statement of iden- mitted combinations containing a sun- tity sections of the applicable OTC screen and a skin protectant identified drug monographs. in § 352.20(b). (b) Indications. The labeling of the EFFECTIVE DATE NOTE: At 68 FR 33380, June product states, under the heading 4, 2003, § 352.60 was amended by revising para- ‘‘Uses,’’ the indication(s) for each in- graphs (b)(2), (c), and (d), effective June 4, gredient in the combination as estab- 2004. For the convenience of the user, the re- lished in the indications sections of the vised text is set forth as follows: applicable OTC drug monographs, un- § 352.60 Labeling of permitted combinations less otherwise stated in this paragraph. of active ingredients. Other truthful and nonmisleading statements, describing only the indica- * * * * * tions for use that have been established in the applicable OTC drug monographs (b) * * * (2) For permitted combinations containing or listed in this paragraph (b), may a sunscreen and a skin protectant identified also be used, as provided by § 330.1(c)(2) in § 352.20(b), any or all of the applicable indi- of this chapter, subject to the provi- cations for sunscreens in § 352.52(b) and the sions of section 502 of the Federal indication for skin protectants in Food, Drug, and Cosmetic Act (the act) § 347.50(b)(2)(i) of this chapter should be used. relating to misbranding and the prohi- For products marketed as a lip protectant, bition in section 301(d) of the act the indication in § 352.52(f)(1)(ii) should be used. against the introduction or delivery for (c) Warnings. The labeling of the product introduction into interstate commerce states, under the heading ‘‘Warnings,’’ the of unapproved new drugs in violation of warning(s) for each ingredient in the com- section 505(a) of the act. bination, as established in the warnings sec- (1) In addition, the labeling of the tion of the applicable OTC drug monographs, product may contain any of the ‘‘other except that the warning for skin protectants allowable statements’’ that are identi- in § 347.50(c)(3) of this chapter is not required for permitted combinations containing a fied in the applicable monographs. sunscreen and a skin protectant identified in (2) For permitted combinations con- § 352.20(b). For products marketed as a lip taining a sunscreen and a skin protect- protectant or lipstick, § 352.52(f)(1)(iii), ant identified in § 352.20(b). (f)(1)(iv) (except ‘‘Keep out of eyes,’’ which (c) Warnings. The labeling of the may be omitted), and (f)(1)(vi) apply. product states, under the heading (d) Directions. The labeling of the product ‘‘Warnings,’’ the warning(s) for each in- states, under the heading ‘‘directions,’’ di- gredient in the combination, as estab- rections that conform to the directions established for each ingredient in the direc- lished in the warnings section of the tions sections of the applicable OTC drug applicable OTC drug monographs. For monographs, unless otherwise stated in this permitted combinations containing a paragraph. When the time intervals or age sunscreen and a skin protectant identi- limitations for administration of the indi- fied in § 352.20(b). vidual ingredients differ, the directions for (d) Directions. The labeling of the the combination product may not contain product states, under the heading ‘‘Di- any dosage that exceeds those established for rections,’’ directions that conform to any individual ingredient in the applicable OTC drug monograph(s), and may not pro- the directions established for each in- vide for use by any age group lower than the gredient in the directions sections of highest minimum age limit established for the applicable OTC drug monographs, any individual ingredient. For permitted unless otherwise stated in this para- combinations containing a sunscreen and a

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skin protectant identified in § 352.20(b), the homosalate sunscreen preparation by directions for sunscreens in § 352.52(d) should the following method to ensure proper be used. For products marketed as a lip pro- concentration: tectant or lipstick, § 352.52(d)(4) applies. (1) Preparation of the assay solvent. The solvent consists of 1 percent gla- Subpart D—Testing Procedures cial acetic acid (V/V) in denatured eth- § 352.70 Standard sunscreen. anol. The denatured ethanol should not contain a UV radiation absorbing dena- (a) Laboratory validation. A standard turant. sunscreen shall be used concomitantly (2) in the testing procedures for deter- Preparation of a 1-percent solution mining the SPF value of a sunscreen of the standard homosalate sunscreen drug product to ensure the uniform preparation. Accurately weigh 1 gram of evaluation of sunscreen drug products. the standard homosalate sunscreen The standard sunscreen shall be an 8- preparation into a 100-milliliter volu- percent homosalate preparation with a metric flask. Add 50 milliliters of the mean SPF value of 4.47 (standard devi- assay solvent. Heat on a steam bath ation =1.279). In order for the SPF de- and mix well. Cool the solution to termination of a test product to be room temperature (15 to 30 °C). Then considered valid, the SPF of the stand- dilute the solution to volume with the ard sunscreen must fall within the assay solvent and mix well to make a standard deviation range of the ex- 1-percent solution. pected SPF (i.e., 4.47 ± 1.279) and the 95- (3) Preparation of the test solution (1:50 percent confidence interval for the dilution of the 1-percent solution). Filter mean SPF must contain the value 4. a portion of the 1-percent solution (b) Preparation of the standard through number 1 filter paper. Discard homosalate sunscreen. (1) The standard the first 10 to 15 milliliters of the fil- homosalate sunscreen is prepared from trate. Collect the next 20 milliliters of two different preparations (preparation the filtrate (second collection). Add 1 A and preparation B) with the fol- milliliter of the second collection of lowing compositions: the filtrate to a 50-milliliter volumetric flask. Dilute this solution to COMPOSITION OF PREPARATION A AND volume with assay solvent and mix PREPARATION B OF THE STANDARD SUNSCREEN well. This is the test solution (1:50 dilu- Ingredients––––––– Percent by weight tion of the 1-percent solution). (4) Spectrophotometric determination. Preparation A Lanolin ...... 5.00 The absorbance of the test solution is Homosalate ...... 8.00 measured in a suitable double beam White petrolatum ...... 2.50 spectrophotometer with the assay sol- Stearic acid ...... 4.00 Propylparaben ...... 0.05 vent and reference beam at a wave- Preparation B length near 306 nanometers. Methylparaben ...... 0.10 (5) Calculation of the concentration of Edetate disodium ...... 0.05 Propylene glycol ...... 5.00 homosalate. The concentration of Triethanolamine ...... 1.00 homosalate is determined by the fol- Purified water U.S.P ...... 74.30 lowing formula which takes into consideration the absorbance of the sam- (2) Preparation A and preparation B ple of the test solution, the dilution of are heated separately to 77 to 82 °C, the 1-percent solution (1:50), the weight with constant stirring, until the con- of the sample of the standard tents of each part are solubilized. Add homosalate sunscreen preparation (1 preparation A slowly to preparation B while stirring. Continue stirring until gram), and the standard absorbance the emulsion formed is cooled to room value (172) of homosalate as deter- temperature (15 to 30 °C). Add suffi- mined by averaging the absorbance of a cient purified water to obtain 100 large number of batches of raw grams of standard sunscreen prepara- homosalate: tion. Concentration of homosalate (c) Assay of the standard homosalate =absorbance × 50 × 100 × 172 =percent sunscreen. Assay the standard concentration by weight.

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§ 352.71 Light source (solar simulator). mal responses to sunlight, such as a phototoxic or photoallergic response. A solar simulator used for deter- (b) Test site inspection. The physical mining the SPF of a sunscreen drug examination shall determine the pres- product should be filtered so that it ence of sunburn, suntan, scars, active provides a continuous emission spec- dermal lesions, and uneven skin tones trum from 290 to 400 nanometers simi- on the areas of the back to be tested. lar to sunlight at sea level from the The presence of nevi, blemishes, or sun at a zenith angle of 10° it has less moles will be acceptable if in the phy- than 1 percent of its total energy out- sician’s judgment they will not inter- put contributed by nonsolar wave- fere with the study results. Excess hair lengths shorter than 290 nanometers; on the back is acceptable if the hair is and it has not more than 5 percent of clipped or shaved. its total energy output contributed by (c) Informed consent. Legally effective wavelengths longer than 400 written informed consent must be ob- nanometers. In addition, a solar simu- tained from all individuals. lator should have no significant time- (d) Test site delineation—(1) Test site related fluctuations in radiation emis- area. A test site area serves as an area sions after an appropriate warmup for determining the subject’s MED time, and it should have good beam after application of either the sun- uniformity (within 10 percent) in the screen standard or the test sunscreen exposure plane. To ensure that the product, or for determining the sub- solar simulator delivers the appro- ject’s MED when the skin is unpro- priate spectrum of UV radiation, it tected (control site). The area to be must be measured periodically with an tested shall be the back between the accurately-calibrated beltline and the shoulder blade spectroradiometer system or equiva- (scapulae) and lateral to the midline. lent instrument. Each test site area for applying a prod- § 352.72 General testing procedures. uct or the standard sunscreen shall be a minimum of 50-square centimeters, (a) Selection of test subjects (male and e.g., 5 × 10 centimeters. The test site female). (1) Only fair-skin subjects with areas are outlined with ink. If the per- skin types I, II, and III using the fol- son is to be tested in an upright posi- lowing guidelines shall be selected: tion, the lines shall be drawn on the Selection of Fair-skin Subjects skin with the subject upright. If the Skin Type and Sunburn and Tanning History subject is to be tested while prone, the (Based on first 30 to 45 minutes sun exposure markings shall be made with the sub- after a winter season of no sun exposure.) ject prone. I—Always burns easily; never tans (sen- (2) Test subsite area. Each test site sitive). area shall be divided into at least three II—Always burns easily; tans minimally (sensitive). test subsite areas that are at least 1 III—Burns moderately; tans gradually (light square centimeter. Usually four or five brown) (normal). subsites are employed. Each test IV—Burns minimally; always tans well subsite within a test site area is sub- (moderate brown) (normal). jected to a specified dosage of UV radi- V—Rarely burns; tans profusely (dark ation, in a series of UV radiation expo- brown) (insensitive). sures, in which the test site area is ex- VI—Never burns; deeply pigmented (insensi- posed for the determination of the tive). MED. (2) A medical history shall be ob- (e) Application of test materials. To en- tained from all subjects with emphasis sure standardized reporting and to de- on the effects of sunlight on their skin. fine a product’s SPF value, the applica- Ascertain the general health of the in- tion of the product shall be expressed dividual, the individual’s skin type (I, on a weight basis per unit area which II, or III), whether the individual is establishes a standard film. Both the taking medication (topical or sys- test sunscreen product and the stand- temic) that is known to produce abnor- ard sunscreen application shall be 2 mal sunlight responses, and whether milligrams per square centimeter. For the individual is subject to any abnor- oils and most lotions, the viscosity is

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such that the material can be applied diate responses are noted, each subject with a volumetric syringe. For creams, shall shield the exposed area from fur- heavy gels, and butters, the product ther UV radiation for the remainder of shall be warmed slightly so that it can the test day. The MED is determined 22 be applied volumetrically. On heating, to 24 hours after exposure. The ery- care shall be taken not to alter the thema responses of the test subject product’s physical characteristics, es- should be evaluated under the fol- pecially separation of the formula- lowing conditions: The source of illu- tions. Pastes and ointments shall be mination should be either a tungsten weighed, then applied by spreading on light bulb or a warm white fluorescent the test site area. A product shall be light bulb that provides a level of illu- spread by using a finger cot. If two or mination at the test site within the more sunscreen drug products are range of 450 to 550 lux, and the test sub- being evaluated at the same time, the ject should be in the same position test products and the standard sun- used when the test site was irradiated. screen, as specified in § 352.70, should be Testing depends upon determining the applied in a blinded, randomized man- smallest dose of energy that produces ner. If only one sunscreen drug product redness reaching the borders of the ex- is being tested, the testing subsites posure site at 22 to 24 hours should be exposed to the varying doses postexposure for each series of expo- of UV radiation in a randomized man- sures. To determine the MED, some- ner. what more intense erythemas must (f) Waiting period. Before exposing the also be produced. The goal is to have test site areas after applying a product, some exposures that produce abso- a waiting period of at least 15 minutes lutely no effect, and of those exposures is required. that produce an effect, the maximal ex- (g) Number of subjects. A test panel posure should be no more than twice shall consist of not more than 25 sub- the total energy of the minimal expo- jects with the number fixed in advance sure. by the investigator. From this panel, (i) Rejection of test data. Test data at least 20 subjects must produce valid shall be rejected if the exposure series data for analysis. fails to elicit an MED response on ei- (h) Response criteria. In order that the ther the treated or unprotected skin person who evaluates the MED re- sites, or if the responses on the treated sponses does not know which sunscreen sites are randomly absent (which indi- formulation was applied to which site cates the product was not spread even- or what doses of UV radiation were ad- ly), or if the subject was noncompliant ministered, he/she must not be the (e.g., subject withdraws from the test same person who applied the sunscreen due to illness or work conflicts, subject drug product to the test site or admin- does not shield the exposed testing istered the doses of UV radiation. After sites from further UV radiation until UV radiation exposure from the solar the MED is read, etc.). simulator is completed, all immediate responses shall be recorded. These in- § 352.73 Determination of SPF value. clude several types of typical responses such as the following: An immediate (a)(1) The following erythema action darkening or tanning, typically greyish spectrum shall be used to calculate the or purplish in color, fading in 30 to 60 erythema effective exposure of a solar minutes, and attributed to photo-oxi- simulator: dation of existing melanin granules; Vi (λ)=1.0 (250 < λ < 298 nm) 0.094 (298 - λ immediate reddening, fading rapidly, Vi (λ)=1.0 ) (298 < λ < 328 and viewed as a normal response of nanometers) 0.015 (139 - λ capillaries and venules to heat, visible Vi (λ)=1.0 ) (328 < λ < 400 and infrared radiation; and an imme- nanometers) diate generalized heat response, resem- (2) The data contained in this action bling prickly heat rash, fading in 30 to spectrum are to be used as spectral 60 minutes, and apparently caused by weighting factors to calculate the ery- heat and moisture generally irritating thema effective exposure of a solar to the skin’s surface. After the imme- simulator as follows:

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(b) Determination of MED of the unpro- spectrum calculated according to tected skin. A series of UV radiation ex- § 352.73(a)) is administered to the posures expressed as Joules per square subsite areas on each subject with an meter (adjusted to the erythema action accurately-calibrated solar simulator. spectrum calculated according to A series of seven exposures shall be ad- § 352.73(a)) is administered to the ministered to the protected test sites subsite areas on each subject with an to determine the MED of the protected accurately calibrated solar simulator. skin (MED(PS)). The doses selected A series of five exposures shall be ad- shall consist of a geometric series of ministered to the untreated, unpro- five exposures, where the middle expo- tected skin to determine the subject’s sure is placed to yield the expected inherent MED. The doses selected shall SPF plus two other exposures placed be a geometric series represented by symmetrically around the middle expo- n (1.25 ), wherein each exposure time in- sure. The exact series of exposures to terval is 25 percent greater than the be given to the protected skin shall be previous time to maintain the same determined by the previously estab- relative uncertainty (expressed as a lished MED(US) and the expected SPF constant percentage), independent of of the test sunscreen. For products the subject’s sensitivity to UV radi- with an expected SPF less than 8, the ation, regardless of whether the subject has a high or low MED. Usually, the exposures shall be the MED(US) times MED of a person’s unprotected skin is 0.64X, 0.80X, 0.90X, 1.00X, 1.10X, 1.25X, determined the day prior to testing a and 1.56X, where X equals the expected product. This MED(US) shall be used in SPF of the test product. For products the determination of the series of UV with an expected SPF between 8 and 15, radiation exposures to be administered the exposures shall be the MED(US) to the protected site in subsequent times 0.69X, 0.83X, 0.91X, 1.00X, 1.09X, testing. The MED(US) should be deter- 1.20X, and 1.44X, where X equals the ex- mined again on the same day as the pected SPF of the test product. For standard and test sunscreens and this products with an expected SPF greater MED(US) should be used in calculating that 15, the exposures shall be the the SPF. MED(US) times 0.76X, 0.87X, 0.93X, (c) Determination of individual SPF 1.00X, 1.07X, 1.15X, and 1.32X, where X values. A series of UV radiation expo- equals the expected SPF of the test sures expressed as Joules per square product. The MED is the quantity of meter (adjusted to the erythema action erythema-effective energy required to

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produce the first perceptible, unambig- be the label SPF value determined uous redness reaction with clearly de- after 40 minutes of water immersion fined borders at 22 to 24 hours using the following procedure for the postexposure. The SPF value of the water resistance test: test sunscreen is then calculated from (1) Apply sunscreen product (followed the dose of UV radiation required to by the waiting period after application produce the MED of the protected skin of the sunscreen product indicated on and from the dose of UV radiation re- the product labeling). quired to produce the MED of the un- (2) 20 minutes moderate activity in protected skin (control site) as follows: water. SPF value =the ratio of erythema ef- (3) 20-minute rest period (do not fective exposure (Joules per square towel test sites). meter) (MED(PS)) to the erythema ef- (4) 20 minutes moderate activity in fective exposure (Joules per square water. meter) (MED(US)). (5) Conclude water test (air dry test (d) Determination of the test product’s sites without toweling). SPF value and PCD. Use data from at (6) Begin solar simulator exposure to least 20 test subjects with n rep- test site areas as described in § 352.73. resenting the number of subjects used. (b) Procedure for testing a very water First, for each subject, compute the resistant sunscreen product. For sun- SPF value as stated in § 352.73(b) and screen products making the claim of (c). Second, compute the mean SPF ‘‘very water resistant,’’ the label SPF value, x¯ , and the standard deviation, s, shall be the label SPF value deter- for these subjects. Third, obtain the mined after 80 minutes of water immer- upper 5-percent point from the t dis- sion using the following procedure for tribution table with n-1 degrees of free- the very water resistant test: dom. Denote this value by t. Fourth, (1) Apply sunscreen product (followed compute ts/ √n. Denote this quantity by the waiting period after application by A (i.e., A =ts/ √n). Fifth, calculate of the sunscreen product indicated on the SPF value to be used in labeling as the product labeling). follows: the label SPF equals the larg- (2) 20 minutes moderate activity in est whole number less than x¯ - A. Sixth water. and last, the drug product is classified (3) 20-minute rest period (do not into a PCD as follows: if 30 + A < x¯ , the towel test sites). PCD is High; if 12 + A < x¯ < 30 + A, the (4) 20 minutes moderate activity in PCD is Moderate; if 2 + A < x¯ < 12 + A, water. the PCD is Minimal; if x¯ < 2 + A, the (5) 20-minute rest period (do not product shall not be labeled as a sun- towel test sites). screen drug product and shall not dis- (6) 20 minutes moderate activity in play an SPF value. water. (7) 20-minute rest period (do not § 352.76 Determination if a product is towel test sites). water resistant or very water resist- (8) 20 minutes moderate activity in ant. water. The general testing procedures in (9) Conclude water test (air dry test § 352.72 shall be used as part of the fol- sites without toweling). lowing tests, except where modified in (10) Begin solar simulator exposure this section. An indoor fresh water to test site areas as described in pool, whirlpool, and/or jacuzzi main- § 352.73. tained at 23 to 32 °C shall be used in these testing procedures. Fresh water § 352.77 Test modifications. is clean drinking water that meets the The formulation or mode of adminis- standards in 40 CFR part 141. The pool tration of certain products may require and air temperature and the relative modification of the testing procedures humidity shall be recorded. in this subpart. In addition, alternative (a) Procedure for testing the water re- methods (including automated or in sistance of a sunscreen product. For sun- vitro procedures) employing the same screen products making the claim of basic procedures as those described in ‘‘water resistant,’’ the label SPF shall this subpart may be used. Any proposed

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modification or alternative procedure § 355.3 Definitions. shall be submitted as a petition in ac- As used in this part: cord with § 10.30 of this chapter. The petition should contain data to support (a) Abrasive. Solid materials that are the modification or data dem- added to dentifrices to facilitate me- onstrating that an alternative proce- chanical removal of dental plaque, de- dure provides results of equivalent ac- bris, and stain from tooth surfaces. curacy. All information submitted will (b) Anhydrous glycerin. An ingredient be subject to the disclosure rules in that may be prepared by heating glyc- part 20 of this chapter. erin U.S.P. at 150 –C for 2 hours to drive off the moisture content. PART 355—ANTICARIES DRUG (c) Anticaries drug. A drug that aids in the prevention and prophylactic PRODUCTS FOR OVER-THE- treatment of dental cavities (decay, COUNTER HUMAN USE caries). (d) Dental caries. A disease of calcified Subpart A—General Provisions tissues of teeth characterized by Sec. demineralization of the inorganic por- 355.1 Scope. tion and destruction of the organic ma- 355.3 Definitions. trix. (e) Dentifrice. An abrasive-containing Subpart B—Active Ingredients dosage form (gel, paste, or powder) for 355.10 Anticaries active ingredients. delivering an anticaries drug to the 355.20 Packaging conditions. teeth. (f) Fluoride. The inorganic form of the Subpart C—Labeling chemical element fluorine in combination with other elements. 355.50 Labeling of anticaries drug products. 355.55 Principal display panel of all fluoride (g) Fluoride ion. The negatively rinse drug products. charged atom of the chemical element 335.60 Professional labeling. fluorine. (h) Fluoride supplement. A special Subpart D—Testing Procedures treatment rinse dosage form that is intended to be swallowed, and is pro- 355.70 Testing procedures for fluoride dentifrice drug products. moted to health professionals for use in areas where the water supply contains AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, 0 to 0.7 parts per million (ppm) fluoride 360, 371. ion. SOURCE: 60 FR 52507, Oct. 6, 1995, unless (i) Preventive treatment gel. A dosage otherwise noted. form for delivering an anticaries drug EDITORIAL NOTE: Nomenclature changes to to the teeth. Preventive treatment gels part 355 can be found at 69 FR 13717, Mar. 24, are formulated in an anhydrous glyc- 2004. erin base with suitable thickening agents included to adjust viscosity. Subpart A—General Provisions Preventive treatment gels do not contain abrasives. § 355.1 Scope. (j) Treatment rinse. A liquid dosage (a) An over-the-counter anticaries form for delivering an anticaries drug drug product in a form suitable for top- to the teeth. ical administration to the teeth is gen- (k) Treatment rinse concentrated solu- erally recognized as safe and effective tion. A fluoride treatment rinse in a and is not misbranded if it meets each concentrated form to be mixed with condition in this part and each general water before using to result in the ap- condition established in § 330.1 of this propriate fluoride concentration speci- chapter. fied in the monograph. (b) References in this part to regu- (l) Treatment rinse effervescent tablets. latory sections of the Code of Federal A fluoride treatment rinse prepared by Regulations are to chapter I of title 21 adding an effervescent tablet (a con- unless otherwise noted. centrated solid dosage form) to water

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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 monofluoro- form) to water before using to result in phosphate 0.654 to 0.884 percent with an the appropriate fluoride concentration available fluoride ion concentration = – specified in the monograph. (consisting of PO3 F and F combined) ≥ 800 ppm. [60 FR 52507, Oct. 6, 1995, as amended at 61 FR 52286, Oct. 7, 1996] (2) Dentifrices containing 1,500 ppm theoretical total fluorine in a gel or paste dosage form. Sodium monofluoro- Subpart B—Active Ingredients phosphate 1.153 percent with an avail- § 355.10 Anticaries active ingredients. able fluoride ion concentration (con- = – sisting of PO3 F and F combined) ≥ The active ingredient of the product 1,275 ppm. consists of any of the following when (c) Stannous fluoride—(1) Dentifrices used in the concentration and dosage containing 850 to 1,150 ppm theoretical form established for each ingredient: total fluorine in a gel or paste dosage (a) Sodium fluoride—(1) Dentifrices conform. (i) Stannous fluoride 0.351 to 0.474 taining 850 to 1,150 ppm theoretical total percent with an available fluoride ion fluorine in a gel or paste dosage form. So- concentration ≥ 700 ppm for products dium fluoride 0.188 to 0.254 percent with containing abrasives other than cal- an available fluoride ion concentration cium pyrophosphate. ≥ 650 parts per million (ppm). (ii) Stannous fluoride 0.351 to 0.474 (2) Dentifrices containing 850 to 1,150 percent with an available fluoride ion ppm theoretical total fluorine in a pow- concentration ≥ 290 ppm for products dered dosage form. Sodium fluoride 0.188 containing the abrasive calcium to 0.254 percent with an available fluo- ≥ pyrophosphate. ride ion concentration of 850 ppm for (2) Preventive treatment gel. Stannous products containing the abrasive so- fluoride 0.4 percent in an anhydrous dium bicarbonate and a poured-bulk glycerin gel, made from anhydrous density of 1.0 to 1.2 grams per milli- glycerin and the addition of suitable liter. thickening agents to adjust viscosity. (3) Treatment rinses. (i) An aqueous so- (3) Treatment rinse. Stannous fluoride lution of acidulated phosphate fluoride concentrate marketed in a stable form derived from sodium fluoride and containing adequate directions for acidulated with a mixture of sodium mixing with water immediately before phosphate, monobasic, and phosphoric using to result in a 0.1-percent aqueous acid to a level of 0.1 molar phosphate solution. ion and a pH of 3.0 to 4.5 and which yields an effective fluoride ion con- [60 FR 52507, Oct. 6, 1995, as amended at 61 FR centration of 0.02 percent. 52286, Oct. 7, 1996] (ii) An aqueous solution of acidulated phosphate fluoride derived from so- § 355.20 Packaging conditions. dium fluoride acidulated with a mix- (a) Package size limitation. Due to the ture of sodium phosphate, dibasic, and toxicity associated with fluoride active phosphoric acid to a pH of 3.5 and ingredients, the following package size which yields an effective fluoride ion limitations are required for anticaries concentration of 0.01 percent. drug products: (iii) Sodium fluoride 0.02 percent (1) Dentifrices. Dentifrice (toothpastes aqueous solution with a pH of approxi- and tooth powders) packages shall not mately 7. contain more than 276 milligrams (mg) (iv) Sodium fluoride 0.05 percent total fluorine per package. aqueous solution with a pH of approxi- (2) Preventive treatment gels and treat- mately 7. ment rinses. Preventive treatment gel (v) Sodium fluoride concentrate con- and treatment rinse packages shall not taining adequate directions for mixing contain more than 120 mg total fluo- with water before using to result in a rine per package.

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(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 article, and from efflorescence, deli- Poison Control Center right away.’’ quescence, or evaporation under the or- These warnings shall be used in place dinary or customary conditions of han- of the general warning statements re- dling, shipment, storage, and distribu- quired by § 330.1(g) of this chapter. tion, and is capable of tight reclosure. (2) For all fluoride rinse and preventive treatment gel products. ‘‘Keep out of Subpart C—Labeling reach of children. [highlighted in bold type] If more than used for’’ (select ap- § 355.50 Labeling of anticaries drug propriate word: ‘‘brushing’’ or ‘‘rins- products. ing’’) ‘‘is accidentally swallowed, get (a) Statement of identity. The labeling medical help or contact a Poison Con- of the product contains the established trol Center right away.’’ These warn- name of the drug, if any, and identifies ings shall be used in place of the gen- the product as: (select one or both of eral warning statements required by the following: ‘anticavity’ or ‘fluoride’) § 330.1(g) of this chapter. (select one of the following as appro- (d) Directions. The labeling of the priate: ‘‘dentifrice,’’ ‘‘toothpaste,’’ product contains the following state- ‘‘tooth polish,’’ ‘‘tooth powder;’’ (op- ments under the heading ‘‘Directions’’: tional: ‘‘dental’’) ‘‘preventive treat- (1) For anticaries dentifrice products— ment gel;’’ or (optional: ‘‘treatment’’ (i) Gel or paste dosage form with a theo- or ‘‘dental’’)) (select one of the fol- retical total fluorine concentration of 850 lowing: ‘‘rinse,’’ ‘‘concentrated solu- to 1,150 ppm identified in § 355.10(a)(1), tion,’’ ‘‘rinse powder,’’ or ‘‘rinse effer- (b)(1), and (c)(1). Adults and children 2 vescent tablets’’). The word ‘‘mouth- years of age and older: Brush teeth wash’’ may be substituted for the word thoroughly, preferably after each meal ‘‘rinse’’ in this statement of identity if or at least twice a day, or as directed the product also has a cosmetic use, as by a dentist or doctor. Instruct chil- defined in section 201(i) of the Federal dren under 6 years of age in good Food, Drug, and Cosmetic Act (the act) brushing and rinsing habits (to mini- (21 U.S.C. 321(i)). mize swallowing). Supervise children (b) Indication. The labeling of the as necessary until capable of using product states, under the heading ‘‘In- without supervision. Children under 2 dication,’’ the following: ‘‘Aids in the years of age: Consult a dentist or doc- prevention of dental (select one of the tor. following: ‘‘cavities,’’ ‘‘decay,’’ ‘‘caries (ii) Gel or paste dosage form with a the- (decay),’’ or ‘‘caries (cavities)’’). Other oretical total fluorine concentration of truthful and nonmisleading state- 1,500 ppm identified in § 355.10(b)(2). ments, describing only the indication Adults and children 6 years of age and for use that has been established and older: Brush teeth thoroughly, pref- listed in this paragraph (b), may also erably after each meal or at least twice be used, as provided in § 330.1(c)(2) of a day, or as directed by a dentist or this chapter, subject to the provisions doctor. Instruct children under 12 years of section 502 of the Federal Food, of age in good brushing and rinsing Drug, and Cosmetic Act (the act) relat- habits (to minimize swallowing). Su- ing to misbranding and the prohibition pervise children as necessary until ca- in section 301(d) of the act against the pable of using without supervision. introduction or delivery for introduc- Children under 6 years of age: Do not

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use unless directed by a dentist or doc- Children under 6 years of age: consult a tor. dentist or doctor. (iii) Powdered dosage form with a theo- (3) For stannous fluoride treatment retical total fluorine concentration of 850 rinse products. (i) ‘‘Use immediately to 1,150 ppm identified in § 355.10(a)(2). after preparing the rinse.’’ Adults and children 6 years of age and (ii) For powder or effervescent tablets older: Apply powder to a wet tooth- used to prepare treatment rinses. ‘‘Do not brush; completely cover all bristles. use as a rinse until all the’’ (select one Brush for at least 30 seconds. Reapply of the following: ‘‘powder’’ or ‘‘tablet’’) powder as before and brush again. ‘‘has dissolved.’’ Rinse and spit out thoroughly. Brush (4) For anticaries preventive treatment teeth, preferably after each meal or at gel products. Adults and children 6 least twice a day, or as directed by a years of age and older: Use once a day dentist or doctor. Instruct children after brushing your teeth with a tooth- under 12 years of age in good brushing paste. Apply the gel to your teeth and and rinsing habits (to minimize swal- brush thoroughly. Allow the gel to re- lowing). Supervise children as nec- main on your teeth for 1 minute and essary until capable of using without then spit out. Do not swallow the gel. supervision. Children under 6 years of Do not eat or drink for 30 minutes after age: Do not use unless directed by a brushing. Instruct children under 12 dentist or doctor. years of age in the use of this product (2) For anticaries treatment rinse prod- (to minimize swallowing). Supervise ucts—(i) For acidulated phosphate fluo- children as necessary until capable of ride solution containing 0.02 percent fluo- using without supervision. Children ride ion, sodium fluoride 0.05 percent, so- under 6 years of age: consult a dentist dium fluoride concentrate, and stannous or doctor. fluoride concentrate identified in (5) For all concentrated treatment rinse § 355.10(a)(3)(i), (a)(3)(iv), (a)(3)(v), and solutions, powders, and effervescent tab- (c)(3). Adults and children 6 years of lets. The following statement shall ap- age and older: Use once a day after pear as the first statement under direc- brushing your teeth with a toothpaste. tions: ‘‘Do not use before mixing with Vigorously swish 10 milliliters of rinse water.’’ between your teeth for 1 minute and (e) Additional labeling statements for then spit out. Do not swallow the rinse. anticaries drug products. The following Do not eat or drink for 30 minutes after statements need not appear under rinsing. Instruct children under 12 warnings, but are required to appear on years of age in good rinsing habits (to the label of anticaries drugs products minimize swallowing). Supervise chil- as applicable. dren as necessary until capable of (1) For all preventive treatment gels. using without supervision. Children ‘‘This is a(n)’’ (select one or both of the under 6 years of age: Consult a dentist following: ‘‘anticavity’’ or ‘‘fluoride’’) or doctor. ‘‘preventive treatment gel, not a tooth- (ii) For acidulated phosphate fluoride paste. Read directions carefully before solution containing 0.01 percent fluoride using.’’ ion and sodium fluoride 0.02 percent aque- (2) For all stannous fluoride treatment ous solution identified in § 355.10(a)(3)(ii) rinse, preventive treatment gel, and den- and (a)(3)(iii). Adults and children 6 tifrice products. ‘‘This product may years of age and older: Use twice a day produce surface staining of the teeth. after brushing your teeth with a tooth- Adequate toothbrushing may prevent paste. Vigorously swish 10 milliliters of these stains which are not harmful or rinse between your teeth for 1 minute permanent and may be removed by and then spit out. Do not swallow the your dentist.’’ rinse. Do not eat or drink for 30 min- (f) Optional additional labeling state- utes after rinsing. Instruct children ments—(1) For fluoride treatment rinses under 12 years of age in good rinsing and preventive treatment gels. The fol- habits (to minimize swallowing). Su- lowing labeling statement may appear pervise children as necessary until ca- in the required boxed area designated pable of using without supervision. ‘‘APPROVED USES’’: ‘‘The combined

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daily use of a fluoride preventive treat- Subpart D—Testing Procedures ment’’ (select one of the following: ‘‘rinse’’ or ‘‘gel’’) ‘‘and a fluoride tooth- § 355.70 Testing procedures for fluo- paste can help reduce the incidence of ride dentifrice drug products. dental cavities.’’ (a) A fluoride dentifrice drug product (2) For dentifrice products containing shall meet the biological test require- 1,500 ppm theoretical total fluorine. ments for animal caries reduction and ‘‘Adults and children over 6 years of age one of the following tests: Enamel solu- may wish to use this extra-strength bility reduction or fluoride enamel up- fluoride dentifrice if they reside in a take. The testing procedures for these nonfluoridated area or if they have a biological tests are labeled Biological greater tendency to develop cavities.’’ Testing Procedures for Fluoride Dentifrices; these testing procedures are [60 FR 52507, Oct. 6, 1995; 60 FR 57927, Nov. 24, on file under Docket No. 80N–0042 in 1995; 61 FR 51187, Oct. 7, 1996; 64 FR 13296, the Division of Dockets Management Mar. 17, 1999] (HFA–305), Food and Drug Administra- tion, 5630 Fishers Lane, rm. 1061, Rock- § 355.55 Principal display panel of all fluoride rinse drug products. ville, MD 20852, and are available on request to that office. In addition to the statement of iden- (b) The United States Pharmacopeia tity required in § 355.50, the following fluoride dentifrice reference standards statement shall be prominently placed along with reference standard stability on the principal display panel: ‘‘IM- profiles (total fluoride, available fluo- PORTANT: Read directions for proper ride ion, pH, and specific gravity) reuse.’’ quired to be used in the biological tests are available to any purchaser upon § 355.60 Professional labeling. written request to the United States (a) The labeling for anticaries fluo- Pharmacopeial Convention, Inc., 1260 ride treatment rinses identified in Twinbrook Parkway, Rockville, MD § 355.10(a)(3) and (c)(3) that are spe- 20852. cially formulated so they may be swal- (c) Alternative testing procedures lowed (fluoride supplements) and are may be used. Any proposed modifica- provided to health professionals (but tion or alternative testing procedures not to the general public) may contain shall be submitted as a petition in ac- the following additional dosage infor- cord with § 10.30 of this chapter. The petition should contain data to support mation: Children 3 to under 14 years of the modification or data dem- age: As a supplement in areas where onstrating that an alternative testing the water supply is nonfluoridated (less procedure provides results of equiva- than 0.3 parts per million (ppm)), clean lent accuracy. All information sub- the teeth with a toothpaste and rinse mitted will be subjected to the disclo- with 5 milliliters (mL) of 0.02 percent sure rules in part 20 of this chapter. or 10 mL of 0.01 percent fluoride ion rinse daily, then swallow. When the [60 FR 52507, Oct. 6, 1995, as amended at 68 FR water supply contains 0.3 to 0.7 ppm 24879, May 9, 2003] fluoride ion, reduce the dose to 2.5 mL of 0.02 percent or 5 mL of 0.01 percent PART 357—MISCELLANEOUS INTER- fluoride ion rinse daily. NAL DRUG PRODUCTS FOR (b) The labeling for products mar- OVER-THE-COUNTER HUMAN keted to health to health professionals USE in package sizes larger than those specified in § 355.20 shall include the state- Subpart A [Reserved] ments: ‘‘For Professional Office Use Only’’ and ‘‘This product is not intended Subpart B—Anthelmintic Drug Products for home or unsupervised consumer Sec. use.’’ 357.101 Scope. 357.103 Definition. 357.110 Anthelmintic active ingredient.

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357.150 Labeling of anthelmintic drug prod- the dosage limits established in ucts. § 357.150(d)(1). 357.152 Package inserts for anthelmintic drug products. § 357.150 Labeling of anthelmintic 357.180 Professional labeling. drug products. Subpart C—Cholecystokinetic Drug (a) Statement of identity. The labeling Products of the product contains the established name of the drug, if any, and identifies 357.201 Scope. the product as a ‘‘pinworm treatment.’’ 357.203 Definition. (b) Indication. The labeling of the 357.210 Cholecystokinetic active ingredi- product states, under the heading ‘‘In- ents. dication,’’ the following: ‘‘For the 357.250 Labeling of cholecystokinetic drug products. treatment of pinworms.’’ Other truth- 357.280 Professional labeling. ful and nonmisleading statements, describing only the indications for use Subparts D–H [Reserved] that have been established and listed in this paragraph (b), may also be used, as Subpart I—Deodorant Drug Products for provided in § 330.1(c)(2), subject to the Internal Use provisions of section 502 of the act re- 357.801 Scope. lating to misbranding and the prohibi- 357.803 Definitions. tion in section 301(d) of the act against 357.810 Active ingredients for deodorant the introduction or delivery for intro- drug products for internal use. duction into interstate commerce of 357.850 Labeling of deodorant drug products unapproved new drugs in violation of for internal use. section 505(a) of the act. AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (c) Warnings. The labeling of the 360, 371. product contains the following warnings under the heading ‘‘Warnings’’: Subpart A [Reserved] (1) ‘‘Abdominal cramps, nausea, vomiting, diarrhea, headache, or dizziness sometimes occur after taking this Subpart B—Anthelmintic Drug drug. If any of these conditions persist Products consult a doctor.’’ (2) ‘‘If you are pregnant or have liver SOURCE: 51 FR 27759, Aug. 1, 1986, unless disease, do not take this product unless otherwise noted. directed by a doctor.’’ (d) Directions. The labeling of the § 357.101 Scope. product contains the following infor- (a) An over-the-counter anthelmintic mation under the heading ‘‘Direc- drug product in a form suitable for oral tions’’: administration is generally recognized (1) Adults, children 12 years of age as safe and effective and is not mis- and over, and children 2 years to under branded if it meets each condition in 12 years of age: Oral dosage is a single this subpart and each general condition dose of 5 milligrams of pyrantel base established in § 330.1. per pound, or 11 milligrams per kilo- (b) References in this subpart to reg- gram, of body weight not to exceed 1 ulatory sections of the Code of Federal gram. Dosing information should be Regulations are to chapter I of title 21 converted to easily understood direc- unless otherwise noted. tions for the consumer using the following dosage schedule: § 357.103 Definition. Weight Dosage (taken as a single As used in this subpart: dose) 1 Anthelmintic. An agent that is destructive to worms. Less than 25 pounds or Do not use unless directed under 2 years old. by a doctor. 25 to 37 pounds ...... 125 milligrams. § 357.110 Anthelmintic active ingre- 38 to 62 pounds ...... 250 milligrams. dient. 63 to 87 pounds ...... 375 milligrams. 88 to 112 pounds ...... 500 milligrams. The active ingredient of the product 113 to 137 pounds ...... 625 milligrams. is pyrantel pamoate when used within 138 to 162 pounds ...... 750 milligrams.

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person to person and hygienic proce- Weight Dosage (taken as a single dose) 1 dures to follow to avoid such spreading. 163 to 187 pounds ...... 875 milligrams. (e) The appropriate labeling informa- 188 pounds and over ...... 1,000 milligrams. tion contained in § 357.150 1 Depending on the product, the label should state the (Collection of information requirement ap- quantity of drug as a liquid measurement (e.g., teaspoonsful) or as the number of dosage units (e.g., tablets) to be taken proved by the Office of Management and for the varying body weights. (If appropriate, it is rec- Budget under control number 0910–0232) ommended that a measuring cup graduated by body weight and/or liquid measurement be provided with the product.) [51 FR 27759, Aug. 1, 1986, as amended at 52 Manufacturers should present this information as appropriate FR 2515, Jan 23, 1987] for their product and may vary the format of this chart as necessary. § 357.180 Professional labeling. (2) ‘‘Read package insert carefully The labeling provided to health pro- before taking this medication. Take fessionals (but not to the general pub- only according to directions and do not lic) may contain an additional indica- exceed the recommended dosage unless tion: ‘‘For the treatment of common directed by a doctor. Medication should roundworm infestation.’’ only be taken on time as a single dose; do not repeat treatment unless directed by a doctor. When one indi- Subpart C—Cholecystokinetic vidual in a household has pinworms, Drug Products the entire household should be treated unless otherwise advised. See Warn- § 357.201 Scope. ings. If any worms other than (a) An over-the-counter pinworms are present before or after cholecystokinetic drug product in a treatment, consult a doctor. If any form suitable for oral administration is symptoms or pinworms are still generally recognized as safe and effec- present after treatment, consult a doc- tive and is not misbranded if it meets tor. each of the conditions in this subpart (3) ‘‘This product can be taken any in addition to each of the general con- time of day, with or without meals. It ditions established in § 330.1. may be taken alone or with milk or (b) References in this subpart to reg- fruit juice. Use of a laxative is not nec- ulatory sections of the Code of Federal essary prior to, during, or after medi- Regulations are to chapter I of title 21 cation.’’ unless otherwise noted. (e) Optional wording. The word ‘‘phy- [48 FR 27005, June 10, 1983] sician’’ may be substituted for the word ‘‘doctor’’ in any of the labeling § 357.203 Definition. statements in this section. As used in this subpart: [51 FR 27759, Aug. 1, 1986; 52 FR 7831, Mar. 13, Cholecystokinetic drug product. A drug 1987, as amended at 53 FR 35810, Sept. 15, product that causes contraction of the 1988] gallbladder and is used during the course of diagnostic gallbladder studies § 357.152 Package inserts for anthel- (cholecystography). mintic drug products. [48 FR 27005, June 10, 1983] The labeling of the product contains a consumer package insert which in- § 357.210 Cholecystokinetic active includes the following information: gredients. (a) A discussion of the symptoms sug- The active ingredient of the product gestive of pinworm infestation, includ- consists of any of the following when ing a statement that pinworms must be used within the specified concentration visually identified before taking this and dosage form established for each medication. ingredient: (b) A detailed description of how to (a) 50-percent aqueous emulsion of find and identify the pinworm. corn oil. (c) A commentary on the life cycle of (b) Hydrogenated soybean oil in a the pinworm. suitable, water-dispersible powder. The (d) A commentary on the ways in hydrogenated soybean oil is food-grade, which pinworms may be spread from partially hydrogenated with a melting

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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 Palmitoleic acid ...... 0.1 FR 16267, May 1, 1986; 52 FR 7830, Mar. 13, Stearic acid ...... 13.5 1987; 54 FR 8321, Feb. 28, 1989] Oleic acid ...... 72.0 Linoleic acid ...... 3.8 § 357.280 Professional labeling. Linolenic acid ...... 0.1 Arachidic acid ...... 0.5 The labeling provided to health pro- Behenic acid ...... 0.2 fessionals (but not to the general public) may contain the following informa- [54 FR 8321, Feb. 28, 1989] tion for ingredients identified in § 357.210: Indication. ‘‘For visualization § 357.250 Labeling of cholecystokinetic of biliary ducts during cholecys- drug products. tography.’’ (a) Statement of identity. The labeling of the product contains the established [54 FR 8321, Feb. 28, 1989] name of the drug, if any, and identifies the product as a ‘‘gallbladder diag- Subparts D–H [Reserved] nostic agent.’’ (b) Indications. The labeling of the Subpart I—Deodorant Drug product states, under the heading ‘‘In- Products for Internal Use dications,’’ the following: ‘‘For the contraction of the gallbladder during diagnostic gallbladder studies.’’ Other SOURCE: 55 FR 19865, May 11, 1990, unless truthful and nonmisleading state- otherwise noted. ments, describing only the indications § 357.801 Scope. for use that have been established and listed in this paragraph (b), may also (a) An over-the-counter deodorant be used, as provided in § 330.1(c)(2), sub- drug product for internal use in a form ject to the provisions of section 502 of suitable for oral administration is gen- the act relating to misbranding and the erally recognized as safe and effective prohibition in section 301(d) of the act and is not misbranded if it meets each against the introduction or delivery for condition in this subpart and each gen- introduction into interstate commerce eral condition established in § 330.1 of of unapproved new drugs in violation of this chapter. section 505(a) of the act. (b) References in this subpart to reg- (c) Warnings. [Reserved] ulatory sections of the Code of Federal (d) Directions. The labeling of the Regulations are to chapter I of title 21 product contains the following state- unless otherwise noted. ments under the heading ‘‘Directions’’: (1) ‘‘Take only when instructed by a § 357.803 Definitions. doctor:’’ As used in this subpart: (2) For products containing 50-percent aqueous emulsion of corn oil. (a) Colostomy. An external operative (i) ‘‘Shake well before using.’’ opening of the colon. (ii) Oral dosage is 60 milliliters 20 (b) Deodorant for internal use. An in- minutes before diagnostic gallbladder gredient taken internally to reduce x-ray or as directed by a doctor. odors arising from conditions such as (3) For products containing colostomies, ileostomies, or fecal in- hydrogeneated soybean oil. Oral dosage continence. is 12.4 grams in a suitable, water-dis- (c) Ileostomy. An external operative persible powder in 2 to 3 ounces of opening from the ileum. water. Stir briskly to prepare a suspen- (d) Incontinence. An inability to re- sion before using. Drink 20 minutes be- tain urine or feces.

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§ 357.810 Active ingredients for deo- chlorophyllin copper complex identi- dorant drug products for internal fied in § 357.810(b). use. (2) [Reserved] The active ingredient of the product (d) Directions. The labeling of the consists of either of the following when product contains the following infor- used within the dosage limits estab- mation under the heading ‘‘Direc- lished for each ingredient in § 357.850(d): tions.’’ (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 products for internal use. grams up to 4 times daily. Children 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 (b) Indications. The labeling of the up to an additional 100 milligrams product states, under the heading ‘‘In- daily in divided doses as required. The dications,’’ any of the phrases listed in smallest effective dose should be used. paragraph (b) of this section as appro- Do not exceed 300 milligrams daily. priate. Other truthful and nonmis- Children under 12 years of age: consult leading statements, describing only the a doctor. indications for use that have been established and listed in paragraph (b) of PART 358—MISCELLANEOUS EXTER- this section may also be used, as pro- NAL DRUG PRODUCTS FOR vided in § 330.1(c)(2) of this chapter, subject to the provisions of section 502 OVER-THE-COUNTER HUMAN of the Federal Food, Drug, and Cos- USE metic Act (the act) relating to misbranding and the prohibition in section Subpart A [Reserved] 301(d) of the act against the introduc- Subpart B—Wart Remover Drug Products tion or delivery for introduction into interstate commerce of unapproved Sec. new drugs in violation of section 505(a) 358.101 Scope. of the act. 358.103 Definitions. 358.110 Wart remover active ingredients. (1) For products containing bismuth 358.150 Labeling of wart remover drug prod- subgallate identified in § 357.810(a). ‘‘An ucts. aid to reduce odor from a colostomy or ileostomy.’’ Subpart C [Reserved] (2) For products containing chlorophyllin copper complex identified in Subpart D—Ingrown Toenail Relief Drug § 357.810(b). (i) ‘‘An aid to reduce odor Products from a colostomy or ileostomy.’’ 358.301 Scope. (ii) ‘‘An aid to reduce fecal odor due 358.303 Definitions. to incontinence.’’ 358.310 Ingrown toenail relief active ingre- (c) Warnings. The labeling of the dient. 358.350 Labeling of ingrown toenail relief product contains the following warn- drug products. ings under the heading ‘‘Warnings’’: (1) For products containing chlorophyllin Subpart E [Reserved] copper complex identified in § 357.810(b). (i) ‘‘If cramps or diarrhea occurs, re- Subpart F—Corn and Callus Remover Drug duce the dosage. If symptoms persist, Products consult your doctor.’’ 358.501 Scope. (ii) The warning required by § 330.1(g) 358.503 Definitions. of this chapter concerning overdose is 358.510 Corn and callus remover active in- not required on products containing gredients.

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358.550 Labeling of corn and callus remover (c) Plaster vehicle. A fabric, plastic, or drug products. other suitable backing material in which medication is usually incor- Subpart G—Pediculicide Drug Products porated for topical application to the 358.601 Scope. skin. 358.603 Definition. 358.610 Pediculicide active ingredients. § 358.110 Wart remover active ingredi- 358.650 Labeling of pediculicide drug prod- ents. ucts. The product consists of any of the Subpart H—Drug Products for the Control following active ingredients within the of Dandruff, Seborrheic Dermatitis, and specified concentration and in the dos- Psoriasis age form established for each ingredient. 358.701 Scope. (a) Salicylic acid 12 to 40 percent in a 358.703 Definitions. plaster vehicle. 358.710 Active ingredients for the control of dandruff, seborrheic dermatitis, or psori- (b) Salicylic acid 5 to 17 percent in a asis. collodion-like vehicle. 358.720 Permitted combinations of active in- (c) Salicylic acid 15 percent in a gredients. karaya gum, glycol plaster vehicle. 358.750 Labeling of drug products for the control of dandruff, seborrheic derma- § 358.150 Labeling of wart remover titis, or psoriasis. drug products. AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, (a) Statement of identity. The labeling 360, 371. of the product contains the established SOURCE: 55 FR 33255, Aug. 14, 1990, unless name of the drug, if any, and identifies otherwise noted. the product as a ‘‘wart remover.’’ (b) Indications. The labeling of the Subpart A [Reserved] product states, under the heading ‘‘In- dications,’’ any of the phrases listed in Subpart B—Wart Remover Drug paragraph (b) of this section. Other Products truthful and nonmisleading statements, describing only the indications § 358.101 Scope. for use that have been established in (a) An over-the-counter wart remover paragraph (b) of this section, may also drug product in a form suitable for top- be used, as provided in § 330.1(c)(2) of ical application is generally recognized this chapter, subject to the provisions as safe and effective and is not mis- of section 502 of the Federal Food, branded if it meets each of the condi- Drug, and Cosmetic Act (the act) relat- tions in this subpart and each of the ing to misbranding and the prohibition general conditions established in § 330.1 in section 301(d) of the act against the of this chapter. introduction or delivery for introduc- (b) References in this subpart to reg- tion into interstate commerce of unap- ulatory sections of the Code of Federal proved new drugs in violation of sec- Regulations are to chapter I of title 21 tion 505(a) of the act. unless otherwise noted. (1) ‘‘For the removal of common warts. The common wart is easily rec- § 358.103 Definitions. ognized by the rough ‘cauliflower-like’ As used in this subpart: appearance of the surface.’’ (a) Wart remover drug product. A top- (2) ‘‘For the removal of plantar warts ical agent used for the removal of com- on the bottom of the foot. The plantar mon or plantar warts. wart is recognized by its location only (b) Collodion-like vehicle. A solution on the bottom of the foot, its tender- containing pyroxylin (nitrocellulose) ness, and the interruption of the foot- in an appropriate nonaqueous solvent print pattern.’’ that leaves a transparent cohesive film (c) Warnings. The labeling of the when applied to the skin in a thin product contains the following warn- layer. ings under the heading ‘‘Warnings’’:

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(1) For products containing any ingre- wart in warm water for 5 minutes.’’) dient identified in § 358.110. (i) ‘‘For ex- ‘‘Dry area thoroughly. Gently smooth ternal use only.’’ wart surface with emery file supplied.’’ (ii) ‘‘Do not use this product on irri- (If appropriate: ‘‘Cut plaster to fit tated skin, on any area that is infected wart.’’) ‘‘Apply a drop of warm water to or reddened, if you are a diabetic, or if the wart, keeping the surrounding skin you have poor blood circulation.’’ dry. Apply medicated plaster at bed- (iii) ‘‘If discomfort persists, see your time and leave in place for at least 8 doctor.’’ hours. In the morning, remove plaster (iv) ‘‘Do not use on moles, birth- and discard. Repeat procedure every 24 marks, warts with hair growing from hours as needed (until wart is removed) them, genital warts, or warts on the for up to 12 weeks.’’ face or mucous membranes.’’ (e) The word ‘‘physician’’ may be sub- (2) For any product formulated in a stituted for the word ‘‘doctor’’ in any flammable vehicle. (i) The labeling of the labeling statements in this sec- should contain an appropriate flamma- tion. bility signal word, e.g. ‘‘extremely (f) The phrase ‘‘or podiatrist’’ may be flammable,’’ ‘‘flammable,’’ ‘‘combus- used in addition to the word ‘‘doctor’’ tible,’’ consistent with 16 CFR in any of the labeling statements in 1500.3(b)(10). this section when a product is labeled (ii) ‘‘Keep away from fire or flame.’’ with the indication identified in (3) For any product formulated in a § 358.150(b)(2). volatile vehicle. ‘‘Cap bottle tightly and [55 FR 33255, Aug. 14, 1990; 55 FR 37403, Sept. store at room temperature away from 11, 1990, as amended at 57 FR 44495, Sept. 28, heat.’’ 1992; 59 FR 60317, Nov. 23, 1994] (4) For any product formulated in a collodion-like vehicle. (i) ‘‘If product gets Subpart C [Reserved] into the eye, flush with water for 15 minutes.’’ (ii) ‘‘Avoid inhaling vapors.’’ Subpart D—Ingrown Toenail Relief (d) Directions. The labeling of the Drug Products product contains the following information under the heading ‘‘Direc- SOURCE: 68 FR 24348, May 7, 2003, unless tions’’: otherwise noted. (1) For products containing salicylic acid identified in § 358.110(a). ‘‘Wash af- § 358.301 Scope. fected area.’’ (Optional: ‘‘May soak (a) An over-the-counter ingrown toe- wart in warm water for 5 minutes.’’) nail relief drug product in a form suit- ‘‘Dry area thoroughly.’’ (If appropriate: able for topical administration is gen- ‘‘Cut plaster to fit wart.’’) ‘‘Apply erally recognized as safe and effective medicated plaster. Repeat procedure and is not misbranded if it meets each every 48 hours as needed (until wart is condition in this subpart and each gen- removed) for up to 12 weeks.’’ eral condition established in § 330.1 of (2) For products containing salicylic this chapter. acid identified in § 358.110(b). ‘‘Wash af- (b) References in this subpart to reg- fected area.’’ (Optional: ‘‘May soak ulatory sections of the Code of Federal wart in warm water for 5 minutes.’’) Regulations are to chapter 1 of title 21 ‘‘Dry area thoroughly. Apply’’ (select unless otherwise noted. one of the following, as appropriate: ‘‘one drop’’ or ‘‘small amount’’) ‘‘at a § 358.303 Definitions. time with’’ (select one of the following, As used in this subpart: as appropriate: ‘‘applicator’’ or (a) Ingrown toenail relief drug product. ‘‘brush’’) ‘‘to sufficiently cover each A drug product applied to an ingrown wart. Let dry. Repeat this procedure toenail that relieves pain or discomfort once or twice daily as needed (until either by softening the nail or by hard- wart is removed) for up to 12 weeks.’’ ening the nail bed. (3) For products containing salicylic (b) Retainer ring. A die cut poly- acid identified in § 358.110(c). ‘‘Wash af- ethylene foam pad coated on one side fected area.’’ (Optional: ‘‘May soak with medical grade acrylic pressure-

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sensitive adhesive. The retainer ring (4) ‘‘When using this product [bullet] has slots, center-cut completely use with a retainer ring’’. through the foam with the cut of suffi- (5) ‘‘Stop use and ask a doctor if [bul- cient size to allow for localization of an let] redness or swelling of your toe inactive ingredient in a gel vehicle to a creases [bullet] discharge is present specific target area. The retainer ring around the nail [bullet] symptoms last is used with adhesive bandage strips to more than 7 days or clear up and occur place over the retainer ring to hold it again within a few days’’. in place. (d) Directions. The labeling of the § 358.310 Ingrown toenail relief active product contains the following state- ingredient. ments under the heading ‘‘Directions’’: (1) ‘‘[Bullet] adults and children 12 The active ingredient of the product years and over:’’ is sodium sulfide 1 percent in a gel vehicle. The gel vehicle is an aqueous, (i) ‘‘[Bullet] wash the affected area semisolid system with large organic and dry thoroughly [bullet] place re- molecules interpenetrated with a liq- tainer ring on toe with slot over the uid. area where the ingrown nail and the skin meet. Smooth ring down firmly. § 358.350 Labeling of ingrown toenail [bullet] apply enough gel product to fill relief drug products. the slot in the ring [bullet] place round (a) Statement of identity. The labeling center section of bandage strip directly of the product contains the established over the gel-filled ring to seal the gel name of the product, if any, and identi- in place. Smooth ends of bandage strip fies the product as an ‘‘ingrown toenail around toes.’’ relief product’’ or as an ‘‘ingrown toe- (ii) ‘‘[Bullet] repeat twice daily nail discomfort reliever.’’ (morning and night) for up to 7 days (b) Indications. The labeling of the until discomfort is relieved or until the product states, under the heading nail can be lifted out of the nail groove ‘‘Use,’’ the following: ‘‘for temporary and easily trimmed’’. relief of’’ [select one or both of the fol- (2) ‘‘[Bullet] children under 12 years: lowing: ’pain’ or ’discomfort’] ‘‘from in- ask a doctor’’. grown toenails’’. Other truthful and nonmisleading statements, describing Subpart E [Reserved] only the use that has been established and listed in this paragraph (b), may also be used, as provided in § 330.1(c)(2) Subpart F—Corn and Callus of this chapter, subject to the provi- Remover Drug Products sions of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) SOURCE: 55 FR 33261, Aug. 14, 1990, unless relating to misbranding and the prohi- otherwise noted. bition in section 301(d) of the act against the introduction or delivery for § 358.501 Scope. introduction into interstate commerce (a) An over-the-counter corn and cal- of unapproved new drugs in violation of lus remover drug product in a form section 505(a) of the act. suitable for topical application is gen- (c) Warnings. The labeling of the erally recognized as safe and effective product contains the following warn- and is not misbranded if it meets each ings under the heading ‘‘Warnings’’: of the conditions in this subpart and (1) ‘‘For external use only’’ in accord each of the general conditions estab- with § 201.66(c)(5)(i) of this chapter. lished in § 330.1 of this chapter. (2) ‘‘Do not use [bullet]1 on open sores’’. (b) References in this subpart to reg- (3) ‘‘Ask a doctor before use if you ulatory sections of the Code of Federal have [bullet] diabetes [bullet] poor cir- Regulations are to chapter I of title 21 culation [bullet] gout’’. unless otherwise noted. § 358.503 Definitions. 1See § 201.66(b)(4) of this chapter for definition of bullet. As used in this subpart:

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(a) Corn and callus remover drug prod- may contain the following statement: uct. A topical agent used for the re- ‘‘Relieves pain by removing corns and moval of corns and calluses. calluses.’’ (b) Collodion-like vehicle. A solution (c) Warnings. The labeling of the containing pyroxylin (nitrocellulose) product contains the following warn- in an appropriate nonaqueous solvent ings under the heading ‘‘Warnings’’: that leaves a transparent cohesive film (1) For products containing any ingre- when applied to the skin in a thin dient identified in § 358.510. (i) ‘‘For ex- layer. ternal use only.’’ (c) Plaster vehicle. A fabric, plastic, or (ii) ‘‘Do not use this product on irri- other suitable backing material in tated 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.’’ § 358.510 Corn and callus remover ac- (2) For any product formulated in a tive ingredients. flammable vehicle. (i) The labeling The product consists of any of the should contain an appropriate flamma- following active ingredients within the bility signal word, e.g., ‘‘extremely specified concentrations and in the dos- flammable,’’ ‘‘flammable,’’ ‘‘combus- age form established for each ingre- tible,’’ consistent with 16 CFR dient. 1500.3(b)(10). (a) Salicylic acid 12 to 40 percent in a (ii) ‘‘Keep away from fire or flame.’’ plaster vehicle. (3) For any product formulated in a (b) Salicylic acid 12 to 17.6 percent in volatile vehicle. ‘‘Cap bottle tightly and a collodion-like vehicle. store at room temperature away from heat.’’ § 358.550 Labeling of corn and callus (4) For any product formulated in a col- remover drug products. lodion-like vehicle. (i) ‘‘If product gets (a) Statement of identity. The labeling into the eye, flush with water for 15 of the product contains the established minutes.’’ name of the drug, if any, and identifies (ii) ‘‘Avoid inhaling vapors.’’ the product as a ‘‘corn and callus re- (d) Directions. The labeling of the mover.’’ product contains the following infor- (b) Indications. The labeling of the mation under the heading ‘‘Direc- product states, under the heading ‘‘In- tions’’: dications,’’ the phrase listed in para- (1) For products containing salicylic graph (b)(1) of this section and may acid identified in § 358.510(a). ‘‘Wash af- contain the additional phrase listed in fected area and dry thoroughly.’’ (If ap- paragraph (b)(2) of this section. Other propriate: ‘‘Cut plaster to fit corn/cal- truthful and nonmisleading state- lus.’’) ‘‘Apply medicated plaster. After ments, describing only the indications 48 hours remove the medicated plaster. for use that have been established in Repeat this procedure every 48 hours as paragraph (b) of this section, may also needed for up to 14 days (until corn/cal- be used, as provided in § 330.1(c)(2) of lus is removed).’’ (Optional: ‘‘May soak this chapter, subject to the provisions corn/callus in warm water for 5 min- of section 502 of the Federal Food, utes to assist in removal.’’) Drug, and Cosmetic Act (the act) relat- (2) For products containing salicylic ing to misbranding and the prohibition acid identified in § 358.510(b). ‘‘Wash af- in section 301(d) of the act against the fected area and dry thoroughly. Apply’’ introduction or delivery for introduc- (select one of the following, as appro- tion into interstate commerce of unap- priate: ‘‘one drop’’ or ‘‘small amount’’) proved new drugs in violation of sec- ‘‘at a time with’’ (select one of the fol- tion 505(a) of the act. lowing, as appropriate: ‘‘applicator’’ or (1) ‘‘For the removal of corns and cal- ‘‘brush’’) ‘‘to sufficiently cover each luses.’’ corn/callus. Let dry. Repeat this proce- (2) In addition to the information dure once or twice daily as needed for identified in paragraph (b)(1) of this up to 14 days (until corn/callus is re- section, the labeling of the product moved).’’ (Optional: ‘‘May soak corn/

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callus in warm water for 5 minutes to indications for use that have been es- assist in removal.’’) tablished and listed in paragraph (b) of (e) The word ‘‘physician’’ may be sub- this section, may also be used, as pro- stituted for the word ‘‘doctor’’ in any vided in § 330.1(c)(2) of this chapter, of the labeling statements in this sec- subject to the provisions of section 502 tion. of the Federal Food, Drug, and Cos- [55 FR 33261, Aug. 14, 1990, as amended at 57 metic Act (the act) relating to mis- FR 44494, Sept. 28, 1992] branding and the prohibition in section 301(d) of the act against the introduc- Subpart G—Pediculicide Drug tion or delivery for introduction into interstate commerce of unapproved Products new drugs in violation of section 505(a) of the act. SOURCE: 58 FR 65455, Dec. 14, 1993, unless (c) Warnings. The labeling of the otherwise noted. product contains the following warn- § 358.601 Scope. ings under the heading ‘‘Warnings’’: (1) ‘‘Use with caution on persons al- (a) An over-the-counter pediculicide lergic to ragweed.’’ drug product in a form suitable for top- (2) ‘‘For external use only. Do not use ical application is generally recognized near the eyes or permit contact with as safe and effective and is not mis- mucous membranes, such as inside the branded if it meets each condition in nose, mouth, or vagina, as irritation this subpart and each general condition may occur. Keep out of eyes when rins- established in § 330.1 of this chapter. ing hair. Adults and children: Close (b) References in this subpart to reg- eyes tightly and do not open eyes until ulatory sections of the Code of Federal product is rinsed out. Also, protect Regulations are to chapter I of title 21 children’s eyes with washcloth, towel unless otherwise noted. or other suitable material, or by a similar method. If product gets into § 358.603 Definition. the eyes, immediately flush with As used in this subpart: water.’’ Pediculicide drug product. A drug (3) ‘‘If skin irritation or infection is product for the treatment of head, present or develops, discontinue use pubic (crab), and body lice. and consult a doctor. Consult a doctor if infestation of eyebrows or eyelashes § 358.610 Pediculicide active ingredients. occurs.’’ (4) The word ‘‘physician’’ may be sub- The active ingredients of the product stituted for the word ‘‘doctor’’ in any consist of the combination of pyre- of the warning statements in this para- thrum extract (providing a concentra- graph. tion of pyrethrins of 0.17 to 0.33 per- (d) Directions. The labeling of the cent) with piperonyl butoxide (2 to 4 product contains the following infor- percent) in a nonaerosol dosage formu- mation under the heading ‘‘Direc- lation. tions’’: [63 FR 43303, Aug. 13, 1998] (1) For all products. ‘‘Important: Read warnings before using.’’ [statement in § 358.650 Labeling of pediculicide drug boldface type] products. (2) For nonshampoo products. ‘‘Apply (a) Statement of identity. The labeling to affected area until all the hair is of the product contains the established thoroughly wet with product. Allow name of the drug, if any, and identifies product to remain on area for 10 min- the product as a ‘‘pediculicide (lice utes but no longer. Wash area thor- treatment)’’ or ‘‘lice treatment.’’ oughly with warm water and soap or (b) Indications. The labeling of the shampoo. A fine-toothed comb or a spe- product states, under the heading ‘‘In- cial lice/nit removing comb may be dications,’’ the following: ‘‘For the used to help remove dead lice or their treatment of head, pubic (crab), and eggs (nits) from hair. A second treat- body lice.’’ Other truthful and nonmis- ment must be done in 7 to 10 days to leading statements, describing only the kill any newly hatched lice.’’

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(3) For products formulated for use as a by the same procedure as described for shampoo. ‘‘Apply to affected area until head lice, except that sealing clothing all the hair is thoroughly wet with in a plastic bag is not recommended for product. Allow product to remain on body lice because the nits (eggs) from area for 10 minutes but no longer. Add these lice can remain dormant for a pe- sufficient warm water to form a lather riod of up to 30 days.’’ and shampoo as usual. Rinse thor- [58 FR 65455, Dec. 14, 1993, as amended at 64 oughly. A fine-toothed comb or a spe- FR 13296, Mar. 17, 1999] cial lice/nit removing comb may be used to help remove dead lice or their EFFECTIVE DATE NOTE: At 68 FR 75417, Dec. eggs (nits) from hair. A second treat- 31, 2003, § 358.60 was revised, effective June 30, 2005. For the convenience of the user, the re- ment must be done in 7 to 10 days to vised text is set forth as follows: kill any newly hatched lice.’’ (e) Other required statements. § 358.650 Labeling of pediculicide drug (1) ‘‘Head Lice: Head lice live on the products. scalp and lay small white eggs (nits) on (a) Statement of identity. The labeling of the the hair shaft close to the scalp. The product contains the established name of the nits are most easily found on the nape drug, if any, and identifies the product as a ‘‘lice treatment.’’ of the neck or behind the ears. All per- (b) Indications. The labeling of the product sonal headgear, scarfs, coats, and bed states, under the heading ‘‘Uses,’’ the fol- linen should be disinfected by machine lowing: ‘‘treats head, pubic (crab), and body washing in hot water and drying, using lice.’’ Other truthful and nonmisleading the hot cycle of a dryer for at least 20 statements, describing only the uses that minutes. Personal articles of clothing have been established and listed in this para- or bedding that cannot be washed may graph (b), may also be used, as provided in be dry-cleaned, sealed in a plastic bag § 330.1(c)(2) of this chapter, subject to the provisions of section 502 of the Federal Food, for a period of about 2 weeks, or Drug, and Cosmetic Act (the act) relating to sprayed with a product specifically de- misbranding and the prohibition in section signed for this purpose. Personal combs 301(d) of the act against the introduction or and brushes may be disinfected by delivery for introduction into interstate soaking in hot water (above 130 °F) for commerce of unapproved new drugs in viola- 5 to 10 minutes. Thorough vacuuming tion of section 505(a) of the act. of rooms inhabited by infected patients (c) Warnings. The labeling of the product is recommended.’’ contains the following warnings under the heading ‘‘Warnings’’: (2) ‘‘Pubic (Crab) Lice: Pubic lice may (1) ‘‘For external use only’’ in accord with be transmitted by sexual contact; § 201.66(c)(5)(i) of this chapter. therefore, sexual partners should be (2) ‘‘Do not use [bullet]1/≤ near eyes [bullet] treated simultaneously to avoid re- inside nose, mouth, or vagina [bullet] on lice infestation. The lice are very small and in eyebrows or eyelashes. See a doctor if lice look almost like brown or grey dots on are present in these areas.’’ the skin. Pubic lice usually cause in- (3) ‘‘Ask a doctor before use if you are [bul- tense itching and lay small white eggs let] allergic to ragweed. May cause breathing difficulty or an asthmatic attack.’’ (nits) on the hair shaft generally close (4) ‘‘When using this product [bullet] keep to the skin surface. In hairy individ- eyes tightly closed and protect eyes with a uals, pubic lice may be present on the washcloth or towel [bullet] if product gets in short hairs of the thighs and trunk, eyes, flush with water right away [bullet] underarms, and occasionally on the scalp itching or redness may occur’’. beard and mustache. Underwear should (5) ‘‘Stop use and ask a doctor if [bullet] be disinfected by machine washing in breathing difficulty occurs [bullet] eye irri- hot water; then drying, using the hot tation occurs [bullet] skin or scalp irritation continues or infection occurs’’. cycle for at least 20 minutes.’’ (d) Directions. The labeling of the product (3) ‘‘Body Lice: Body lice and their contains the following information under the eggs are generally found in the seams heading ‘‘Directions’’: of clothing, particularly in the waist- (1) The labeling states ‘‘[bullet] Important: line and armpit area. They move to the Read warnings before use’’ [statement shall skin to feed, then return to the seams appear first and in bold type]. of the clothing where they lay their eggs. Clothing worn and not laundered 1 See § 201.66(b)(4) of this chapter for defini- before treatment should be disinfected tion of bullet symbol.

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(2) The labeling states ‘‘adults and children outer carton or container label shall include 2 years and over:’’ [in bold type]. a statement referring to the package insert (3) For head lice treatment products ‘‘In- for additional information. spect [in bold type] [bullet] check (1) ‘‘Head lice [highlighted in bold type] eachhousehold member with a magnifying [bullet] lay small white eggs (nits) on hair glass in bright light for lice/nits (eggs) [bul- shaft close to scalp [bullet] nits are most let]look for tiny nits near scalp, beginning at easily found on back of neck or behind ears back of neck and behind ears [bullet] [bullet] disinfect hats, hair ribbons, scarves, examinesmall sections of hair at a time [bul- coats, towels, and bed linens by machine let] unlike dandruff which moves when washing in hot water (above 54 °C (130 °F)), touched, nitsstick to the hair [bullet] if ei- then using hottest dryer cycle for at least 20 ther lice or nits are found, treat with this minutes [bullet] items that cannot be product’’. washed (bedspreads, blankets, pillows, (4) Select one of the following: stuffed toys, etc.) should be dry-cleaned or (i) For shampoo products ‘‘Treat [in bold sealed in a plastic bag for 4 weeks, then re- type] [bullet] apply thoroughly to (optional, moved outdoors and shaken out very hard may add ‘‘dry’’) hair or other affected area. before using again [bullet] items that cannot For head lice, first apply behind ears and to be washed, dry-cleaned, or stored may be back of neck. [bullet] allow product to re- sprayed with a product designed for this pur- main for 10 minutes, but no longer [bullet] pose [bullet] soak all combs and brushes in use warm water to form a lather, shampoo, hot water (above 54 °C (130 °F)) for at least 10 then thoroughly rinse [bullet] for head lice, minutes [bullet] vacuum all carpets, mat- towel dry hair and comb out tangles’’. tresses, upholstered furniture, and car seats (ii) For nonshampoo products ‘‘Treat [in that may have been used by affected people’’. bold type] [bullet] apply thoroughly to (op- (2) ‘‘Pubic (crab) lice [highlighted in bold tional, may add ‘‘dry’’) hair or other affected type] [bullet] may be transmitted by sexual area. For head lice, first apply behind ears contact. Sexual partners should be treated and to back of neck. [bullet] allow product to simultaneously to avoid reinfestation [bul- remain for 10 minutes, but no longer [bullet] let] lice are very small and look like brown wash area thoroughly with warm water and or grey dots on skin [bullet] usually cause soap or shampoo [bullet] for head lice, towel intense itching and lay small white eggs dry hair and comb out tangles’’. (nits) on the hair shaft generally close to the (5) ‘‘Remove lice and their eggs (nits) [in skin surface [bullet] may be present on the bold type] [bullet] use a fine-tooth or special short hairs of groin, thighs, trunk, and lice/nit comb. Remove any remaining nits by underarms, and occasionally on the beard hand (using a throw-away glove). [bullet] and mustache [bullet] disinfect underwear by hair should remain slightly damp while re- machine washing in hot water (above 54 °C moving nits [bullet] if hair dries during (130 °F)), then using hottest dryer cycle for combing, dampen slightly with water [bul- at least 20 minutes’’. let] for head lice, part hair into sections. Do (3) ‘‘Body lice [highlighted in bold type] one section at a time starting on top of head. [bullet] body lice and their eggs (nits) are Longer hair may take 1 to 2 hours. [bullet] generally found in the seams of clothing par- lift a 1- to 2-inch wide strand of hair. Place ticularly in waistline and armpit area [bul- comb as close to scalp as possible and comb let] body lice feed on skin then return to with a firm, even motion away from scalp. clothing to lay their eggs [bullet] disinfect [bullet] pin back each strand of hair after clothing by machine washing in hot water combing [bullet] clean comb often. Wipe nits (above 54 °C (130 °F)), then using hottest away with tissue and discard in a plastic dryer cycle for at least 20 minutes [bullet] do bag. Seal bag and discard to prevent lice not seal clothing in a plastic bag because from coming back. [bullet] after combing, nits can remain dormant for up to 30 days’’. thoroughly recheck for lice/nits. Repeat combing if necessary. [bullet] check daily for any lice/nits that you missed’’. Subpart H—Drug Products for the (6) The labeling states ‘‘[bullet] a second Control of Dandruff, treatment must be done in 7 to 10 days to Seborrheic Dermatitis, and kill any newly hatched lice’’. (7) The labeling states ‘‘[bullet] if infesta- Psoriasis tion continues, see a doctor for othertreatments’’. SOURCE: 56 FR 63568, Dec. 4, 1991, unless (8) The labeling states ‘‘children under 2 otherwise noted. years:’’ [in bold type] ‘‘ask a doctor’’. (e) Other information. The labeling of the § 358.701 Scope. product contains the following statements, as appropriate, under the heading ‘‘Other in- (a) An over-the-counter dandruff, formation.’’ This information may appear in seborrheic dermatitis, or psoriasis drug a package insert. If a package insert is used, product in a form suitable for topical the ‘‘Other information’’ section on the application is generally recognized as

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safe and effective and is not mis- of the coal tar present in the final branded if it meets each of the condi- product. tions in this subpart and each general (2) Pyrithione zinc, 0.3 to 2 percent condition established in § 330.1 of this when formulated to be applied and then chapter. washed off after brief exposure. (b) References in this subpart to reg- (3) Pyrithione zinc, 0.1 to 0.25 percent ulatory sections of the Code of Federal when formulated to be applied and left Regulations are to chapter I of title 21 on the skin or scalp. unless otherwise noted. (4) Salicylic acid, 1.8 to 3 percent. (5) Selenium sulfide, 1 percent. § 358.703 Definitions. (6) Selenium sulfide, micronized, 0.6 As used in this subpart: percent. (a) Coal tar. The tar used for medic- (7) Sulfur, 2 to 5 percent. inal purposes that is obtained as a by- (b) Active ingredients for the control of product during the destructive distilla- seborrheic dermatitis. (1) Coal tar, 0.5 to tion of bituminous coal at tempera- 5 percent. When a coal tar solution, de- ° ° tures in the range of 900 C to 1,100 C. rivative, or fraction is used as the It may be further processed using ei- source of the coal tar, the labeling ther extraction with alcohol and suit- shall specify the identity and con- able dispersing agents and maceration centration of the coal tar source used times or fractional distillation with or and the concentration of the coal tar without the use of suitable organic sol- present in the final product. vents. (2) Pyrithione zinc, 0.95 to 2 percent (b) Dandruff. A condition involving when formulated to be applied and then an increased rate of shedding of dead washed off after brief exposure. epidermal cells of the scalp. (3) Pyrithione zinc, 0.1 to 0.25 percent (c) Psoriasis. A condition of the scalp when formulated to be applied and left or body characterized by irritation, on the skin or scalp. itching, redness, and extreme excess (4) Salicylic acid, 1.8 to 3 percent. shedding of dead epidermal cells. (d) Seborrheic dermatitis. A condition (5) Selenium sulfide, 1 percent. of the scalp or body characterized by (c) Active ingredients for the control of irritation, itching, redness, and excess psoriasis. (1) Coal tar, 0.5 to 5 percent. shedding of dead epidermal cells. When a coal tar solution, derivative, or (e) Selenium sulfide, micronized. Se- fraction is used as the source of the lenium sulfide that has been finely coal tar, the labeling shall specify the ground and that has a median particle identity and concentration of the coal size of approximately 5 micrometers tar source used and the concentration (µm), with not more than 0.1 percent of of the coal tar present in the final the particles greater than 15 µm and product. not more than 0.1 percent of the par- (2) Salicylic acid, 1.8 to 3 percent. ticles less than 0.5 µm. [56 FR 63568, Dec. 4, 1991, as amended at 59 [56 FR 63568, Dec. 4, 1991, as amended at 59 FR 4001, Jan. 28, 1994] FR 4001, Jan. 28, 1994] § 358.720 Permitted combinations of § 358.710 Active ingredients for the active ingredients. control of dandruff, seborrheic der- Salicylic acid identified in § 358.710(a) matitis, or psoriasis. (4) may be combined with sulfur identi- The active ingredient of the product fied in § 358.710(a)(6) provided each in- consists of any of the following within gredient is present within the estab- the specified concentration established lished concentration and the product is for each ingredient: labeled for the control of dandruff. (a) Active ingredients for the control of dandruff. (1) Coal tar, 0.5 to 5 percent. § 358.750 Labeling of drug products for When a coal tar solution, derivative, or the control of dandruff, seborrheic fraction is used as the source of the dermatitis, or psoriasis. coal tar, the labeling shall specify the (a) Statement of identity. The labeling identity and concentration of the coal of the product contains the established tar source used and the concentration name of the drug, if any, and identifies

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the product with one or more of the (ii) ‘‘Avoid contact with the eyes. If following, as appropriate: contact occurs, rinse eyes thoroughly (1) ‘‘Dandruff (insert product form)’’ with water.’’ or ‘‘antidandruff (insert product (iii) ‘‘If condition worsens or does not form)’’. improve after regular use of this prod- (2) ‘‘Seborrheic dermatitis (insert uct as directed, consult a doctor.’’ product form)’’. (2) For any product containing coal tar (3) ‘‘Psoriasis (insert product form)’’. identified in § 358.710(a), (b), or (c). (i) (b) Indications. The labeling of the ‘‘Use caution in exposing skin to sun- product states, under the heading ‘‘In- light after applying this product. It dications,’’ the phrase listed in para- may increase your tendency to sunburn graph (b)(1) of this section and may for up to 24 hours after application.’’ contain any of the terms listed in para- (ii) ‘‘Do not use for prolonged periods graph (b)(2) or (b)(3) of this section. without consulting a doctor.’’ Other truthful and nonmisleading (3) For products containing coal tar statements, describing only the indica- when formulated to be applied and left on tions for use that have been established the skin (e.g., creams, ointments, lotions). and listed in paragraph (b) of this sec- ‘‘Do not use this product in or around tion, may also be used, as provided in the rectum or in the genital area or § 330.1(c)(2) of this chapter, subject to groin except on the advice of a doctor.’’ the provisions of section 502 of the Fed- eral Food, Drug, and Cosmetic Act (the (4) For products containing coal tar act) relating to misbranding and the identified in § 358.710(c) for the control of prohibition in section 301(d) of the act psoriasis. ‘‘Do not use this product with against the introduction or delivery for other forms of psoriasis therapy such introduction into interstate commerce as ultraviolet radiation or prescription of unapproved new drugs in violation of drugs unless directed to do so by a doc- section 505(a) of the act. tor.’’ (1) (‘‘For relief of’’ or ‘‘Controls’’) (5) For products containing any ingre- ‘‘the symptoms of’’ (select one or more dient identified in § 358.710(b) or (c) for of the following, as appropriate: ‘‘dan- the control of seborrheic dermatitis or pso- druff,’’ ‘‘seborrheic dermatitis,’’ and/or riasis. ‘‘If condition covers a large area ‘‘psoriasis.’’) of the body, consult your doctor before (2) The following terms or phrases using this product.’’ may be used in place of or in addition (d) Directions. The labeling of the to the words ‘‘For the relief of’’ or product contains the following infor- ‘‘Controls’’ in the indications in para- mation under the heading ‘‘Direc- graph (b)(1) of this section: ‘‘fights,’’ tions.’’ More detailed directions appli- ‘‘reduces,’’ ‘‘helps eliminate,’’ ‘‘helps cable to a particular product formula- stop,’’ ‘‘controls recurrence of,’’ ‘‘fights tion may also be included. recurrence of,’’ ‘‘helps prevent recur- (1) For products containing active in- rence of,’’ ‘‘reduces recurrence of,’’ gredients for the control of dandruff, ‘‘helps eliminate recurrence of,’’ ‘‘helps seborrheic dermatitis, or psoriasis when stop recurrence of.’’ formulated to be applied and then washed (3) The following terms may be used off after brief (a few minutes) exposure in place of the words ‘‘the symptoms (e.g, shampoos, preshampoo rinses, of’’ in the indications in paragraph postshampoo rinses). ‘‘For best results (b)(1) of this section: (‘‘skin’’ and/or ‘‘scalp,’’ as appropriate) (select one or use at least twice a week or as directed more of the following: ‘‘itching,’’ ‘‘irri- by a doctor.’’ tation,’’ ‘‘redness,’’ ‘‘flaking,’’ ‘‘scal- (2) For products containing active in- ing,’’) ‘‘associated with.’’ gredients for the control of dandruff, (c) Warnings. The labeling of the seborrheic dermatitis, or psoriasis when product contains the following warn- formulated so as to be applied and left on ings under the heading ‘‘Warnings’’: the skin or scalp (e.g., creams, ointments, (1) For products containing any ingre- lotions, hairgrooms). ‘‘Apply to affected dient identified in § 358.710. (i) ‘‘For ex- areas one to four times daily or as di- ternal use only.’’ rected by a doctor.’’

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(3) For products containing active in- forth in paragraph (d) of this section, gredients for the control of seborrheic der- that: matitis or psoriasis of the skin when for- (i) The pharmacological dose is with- mulated as soaps. ‘‘Use on affected areas in the limits set forth in paragraph in place of your regular soap.’’ (b)(2) of this section; (e) The word ‘‘physician’’ may be sub- (ii) The radiation dose is within the stituted for the word ‘‘doctor’’ in any limits set forth in paragraph (b)(3) of of the labeling statements in this sec- this section; tion. (iii) The radiation exposure is justified by the quality of the study being PART 361—PRESCRIPTION DRUGS undertaken and the importance of the FOR HUMAN USE GENERALLY information it seeks to obtain; RECOGNIZED AS SAFE AND EF- (iv) The study meets the other re- FECTIVE AND NOT MISBRANDED: quirements set forth in paragraph (d) DRUGS USED IN RESEARCH of this section regarding qualifications of the investigator, proper licensure for AUTHORITY: 21 U.S.C. 321, 351, 352, 353, 355, handling radioactive materials, selec- 371; 42 U.S.C. 262. tion and consent of research subjects, quality of radioactive drugs used, re- § 361.1 Radioactive drugs for certain search protocol design, reporting of ad- research uses. verse reactions, and approval by an ap- (a) Radioactive drugs (as defined in propriate Institutional Review Com- § 310.3(n) of this chapter) are generally mittee; and recognized as safe and effective when (v) The use of the radioactive drug in administered, under the conditions set human subjects has the approval of the forth in paragraph (b) of this section, Radioactive Drug Research Committee. to human research subjects during the (2) Limit on pharmacological dose. The course of a research project intended to amount of active ingredient or com- obtain basic information regarding the bination of active ingredients to be ad- metabolism (including kinetics, dis- ministered shall be known not to cause tribution, and localization) of a radioactively labeled drug or regarding any clinically detectable pharma- human physiology, pathophysiology, or cological effect in human beings. If the biochemistry, but not intended for im- same active ingredients (exclusive of mediate therapeutic, diagnostic, or the radionuclide) are to be adminis- similar purposes or to determine the tered simultaneously, e.g., under a safety and effectiveness of the drug in ‘‘Investigational New Drug Applica- humans for such purposes (i.e., to carry tion’’ or for a therapeutic use in ac- out a clinical trial). Certain basic re- cordance with labeling for a drug ap- search studies, e.g., studies to deter- proved under part 314 of this chapter, mine whether a drug localizes in a par- the total amount of active ingredients ticular organ or fluid space and to de- including the radionuclide shall be scribe the kinetics of that localization, known not to exceed the dose limita- may have eventual therapeutic or diag- tions applicable to the separate admin- nostic implications, but the initial istration of the active ingredients ex- studies are considered to be basic re- cluding the radionuclide. search within the meaning of this sec- (3) Limit on radiation dose. The tion. amount of radioactive material to be (b) The conditions under which use of administered shall be such that the radioactive drugs for research are con- subject receives the smallest radiation sidered safe and effective are: dose with which it is practical to per- (1) Approval by Radioactive Drug Re- form the study without jeopardizing search Committee. A Radioactive Drug Research Committee, composed and ap- the benefits to be obtained from the proved by the Food and Drug Adminis- study. tration in accordance with paragraph (i) Under no circumstances may the (c) of this section, has determined, in radiation dose to an adult research accordance with the standards set

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subject from a single study or cumula- qualified in various disciplines perti- tively from a number of studies con- nent to the field of nuclear medicine ducted within 1 year be generally rec- (e.g., radiology, internal medicine, ognized as safe if such dose exceeds the clinical pathology, hematology, endo- following: crinology, radiation therapy, radiation Whole body, active blood-forming or- physics, radiation biophysics, health gans, lens of the eye, and gonads: physics, and radiopharmacy). Member- ship shall be sufficiently diverse to per- Rems mit expert review of the technical and Single dose ...... 3 scientific aspects of proposals sub- Annual and total dose commitment ...... 5 mitted to the committee. The addition Other organs: Single dose ...... 5 of consultants in other pertinent med- Annual and total dose commitment ...... 15 ical disciplines is encouraged. A Radio- active Drug Research Committee shall (ii) For a research subject under 18 be either associated with a medical in- years of age at his last birthday, the stitution operated for care of patients radiation dose shall not exceed 10 per- and with sufficient scientific expertise cent of that set forth in paragraph to allow for selection of committee (b)(3)(i) of this section. members from its faculty, or with a (iii) All radioactive material included committee established by a State au- in the drug either as essential material thority to provide advice on radiation or as a significant contaminant or im- health matters. Joint committees in- purity shall be included when deter- volving more than one medical institu- mining the total radiation doses and tion which have been established in dose commitments. Radiation doses order to achieve a high level and diver- from x-ray procedures that are part of sity of experience will be acceptable. the research study (i.e., would not have The Director of the Center for Drug occurred but for the study) shall also Evaluation and Research may modify be included. The possibility of followup any of the foregoing requirements in a studies shall be considered for inclu- particular situation where alternative sion in the dose calculations. factors provide substantially the same (iv) Numerical definitions of dose composition and association. shall be based on an absorbed fraction method of radiation absorbed dose cal- (2) Function. Each Radioactive Drug culation, such as the system set forth Research Committee shall select a by the Medical Internal Radiation Dose chairman, who shall sign all applica- Committee of the Society of Nuclear tions, minutes, and reports of the com- Medicine, or the system set forth by mittee. Each committee shall meet at the International Commission on Radi- least once each quarter in which re- ological Protection. search activity has been authorized or (c) A Radioactive Drug Research conducted. A quorum consisting of Committee, in order to comply with more than 50 percent of the member- paragraph (b)(1) of this section, shall be ship must be present with appropriate composed, shall function, and shall ob- representation of the required fields of tain and maintain approval of the Food specialization. Minutes shall be kept and Drug Administration in con- and shall include the numerical results formity with the following: of votes on protocols involving use in (1) Membership. A Radioactive Drug human subjects. No member shall vote Research Committee shall consist of at on a protocol in which he is an investi- least five individuals. Each committee gator. shall include the following three indi- (3) Reports. Each Radioactive Drug viduals: (i) A physician recognized as a Research Committee shall submit an specialist in nuclear medicine, (ii) a annual report on or before January 31 person qualified by training and experi- of each year to the Food and Drug Ad- ence to formulate radioactive drugs, ministration, Center for Drug Evalua- and (iii) a person with special com- tion and Research, HFD–160, 5600 Fish- petence in radiation safety and radi- ers Lane, Rockville, MD 20857. The an- ation dosimetry. The remainder of the nual report shall include the names committee shall consist of individuals and qualifications of the members of,

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and of any consultants used by, the Ra- llllllllllll dioactive Drug Research Committee, Chairman, Radioactive Drug and, for each study conducted during Research Committee the preceding year, a summary of in- At any time a proposal is approved formation presented in the following which involves exposure either of more format: than 30 research subjects, or of any research subject under 18 years of age, REPORT ON RESEARCH USE OF RADIOACTIVE the committee shall immediately sub- DRUG mit to the Food and Drug Administra- 1. Title of the research project. tion a special summary of information 2. Brief description of the purpose of the in the format shown in this paragraph. research project. 3. Name of the investigator responsible. Contents of these reports are available 4. Pharmacological dose: for public disclosure, unless confiden- a. Active ingredients. tiality is requested by the investigator b. Maximum amount administered per sub- and it is adequately shown by the in- ject. vestigator that the report constitutes a 5. Name of the radionuclide(s) used, includ- trade secret or confidential commer- ing any present, as significant contaminants cial information as defined in § 20.61 of or impurities. 6. Radiation absorbed dose. Provide the this chapter. maximum dose commitement to the whole (4) Approval. Each Radioactive Drug body and each organ specified in 21 CFR Research Committee shall be specifi- 361.1(b)(3)(i) that was received by a rep- cally approved by the Center for Drug resentative subject and the calculations or Evaluation and Research of the Food references that were used to estimate these and Drug Administration. Applications maximum dose commitments. The report shall be submitted to the Food and shall include the dose contribution of both the administered radionuclide(s) and any X- Drug Administration, Center for Drug ray procedures associated with the study. If Evaluation and Research, HFD–160, 5600 the study elicits data on the uptake or excre- Fishers Lane, Rockville, MD 20857, and tion of the radioactive drug pertinent to the shall contain the names and qualifica- estimation of dose commitment, report the tions of the members of the committee, mean value and range of values. For each and a statement that the committee subject provide: agrees to comply with the require- (a) Age, sex, and approximate weight. (b) Total activity of each radionuclide ad- ments set forth in this section. Ap- ministered for each radioactive drug used in proval shall be based upon an assess- the study. Report each X-ray procedure used ment of the qualifications of the mem- in conjunction with the study. bers of the committee, and the assur- (c) If the subject has participated in other ance that all necessary fields of exper- radioactive drug research studies, report the tise are covered. Approval of a com- name of the radioactive drug used in these mittee may be withdrawn at any time other studies, the date of administration, and the total activity of each radionuclide for failure of the committee to comply administered. If any X-ray procedures were with any of the requirements of this used, identify the X-ray procedure(s) and in- section. Approval of a committee shall clude an estimate of the absorbed radiation remain effective unless and until the doses. FDA withdraws such approval. Changes (d) If more than one administration of a ra- in membership and applications for dioactive drug per subject, cumulative radi- new members shall be submitted to the ation dose and dose commitment, expressed Food and Drug Administration as soon as whole body, active blood-forming organs, lens of the eye, gonads, and other organ as, or before, vacancies occur on the doses from the administered radionuclides. committee. 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 confidential commercial information as defined in 21 view of its annual report, through re- CFR 20.61. view of minutes and full protocols for llllllllllll certain studies, and through on-site in- Investigator spections.

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(d) In making the determination re- thorities, when required by State or quired in paragraph (b)(1) of this sec- local law, to possess and use the spe- tion, a Radioactive Drug Research cific radionuclides for research use. Committee shall consider the following (5) Human research subjects. Each in- requirements and assure that each is vestigator shall select appropriate met: human subjects and shall obtain the re- (1) Radiation dose to subjects. To as- view and approval of an institutional sure that the radiation dose to re- review committee that conforms to the search subjects is as low as practicable requirements of part 56 of this chapter, to perform the study and meet the cri- and shall obtain the consent of the sub- teria of § 361.1(b)(3), the Radioactive jects or their legal representatives in Drug Research Committee shall require accordance with part 50 of this chapter. that: The research subjects shall be at least (i) The investigator provide absorbed 18 years of age and legally competent. dose calculations based on biologic dis- Exceptions are permitted only in those tribution data available from published literature or from other valid studies. special situations when it can be dem- (ii) The investigator provide for an onstrated to the committee that the acceptable method of radioassay of the study presents a unique opportunity to radioactive drug prior to its use to as- gain information not currently avail- sure that the dose calculations actu- able, requires the use of research sub- ally reflect the administered dose. jects less than 18 years of age, and is (iii) The radioactive drug chosen for without significant risk to the subject. the study has that combination of half- Studies involving minors shall be sup- life, types of radiations, radiation en- ported with review by qualified pedi- ergy, metabolism, chemical properties, atric consultants to the Radioactive etc., which results in the lowest dose to Drug Research Committee. Each fe- the whole body or specific organs with male research subject of childbearing which it is possible to obtain the nec- potential shall state in writing that essary information. she is not pregnant, or, on the basis of (iv) The investigator utilize adequate a pregnancy test be confirmed as not and appropriate instrumentation for pregnant, before she may participate in the detection and measurement of the any study. specific radionuclide. (6) Quality of radioactive drug. The ra- (2) Pharmacological dosage. To deter- dioactive drug used in the research mine that the amount of active ingre- study shall meet appropriate chemical, dients to be administered does not ex- pharmaceutical, radiochemical, and ceed the limitations set forth in para- radionuclidic standards of identity, graph (b)(2) of this section, the com- strength, quality, and purity as needed mittee shall require that the investi- for safety and be of such uniform and gator provide pharmacological dose reproducible quality as to give signifi- calculations based on data available cance to the research study conducted. from published literature or from other The Radioactive Drug Research Com- valid human studies. mittee shall determine that radio- (3) Qualifications of investigators. Each active materials for parenteral use are investigator shall be qualified by training and experience to conduct the pro- prepared in sterile and pyrogen-free posed research studies. form. (4) License to handle radioactive mate- (7) Research protocol. No matter how rials. The responsible investigator or small the amount of radioactivity, no institutions shall, in the case of reac- study involving administration of a ra- tor-produced isotopes, be licensed by dioactive drug, as defined in § 310.3(n) of the Nuclear Regulatory Commission or this chapter, to research subjects under Agreement State to possess and use the this section, shall be permitted unless specific radionuclides for research use the Radioactive Drug Research Com- or be a listed investigator under a mittee concludes, in its judgment, that broad license, or in the case of non-re- scientific knowledge and benefit is actor-produced isotopes, be licensed by likely to result from that study. There- other appropriate State or local au- fore, the protocol shall be based upon a

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sound rationale derived from appro- dioactive materials by the Nuclear priate animal studies or published lit- Regulatory Commission or by State or erature and shall be of sound design local radiological health authorities such that information of scientific bear the following: value may result. The radiation dose (1) The statement ‘‘Rx only’’; shall be both sufficient and no greater than necessary to obtain valid meas- (2) The statement ‘‘To be adminis- urement. The projected number of sub- tered in compliance with the require- jects shall be sufficient but no greater ments of Federal regulations regarding than necessary for the purpose of the radioactive drugs for research use (21 study. The number of subjects shall CFR 361.1)’’; also reflect the fact that the study is (3) The established name of the drug, intended to obtain basic research infor- if any; mation referred to in paragraph (a) of this section and not intended for imme- (4) The established name and quan- diate therapeutic, diagnostic or similar tity of each active ingredient; purposes or to determine the safety and effectiveness of the drug in humans (5) The name and half-life of the for such purposes (i.e., to carry out a radionuclide, total quantity of radioac- clinical trial). tivity in the drug product’s immediate container, and amount of radioactivity (8) Adverse reactions. The investigator per unit volume or unit mass at a des- shall immediately report to the Radio- ignated referenced time; active Drug Research Committee all (6) The route of administration, if it adverse effects associated with the use is for the other than oral use; of the radioactive drug in the research study. All adverse reactions probably (7) The net quantity of contents; attributable to the use of the radio- (8) An identifying lot or control num- active drug in the research study shall ber from which it is possible to deter- be immediately reported by the Radio- mine the complete manufacturing his- active Drug Research Committee to tory of the package of the drug; the Food and Drug Administration, Center for Drug Evaluation and Re- (9) The name and address of the man- search, HFD–160, 5600 Fishers Lane, ufacturer, packer, or distributor; Rockville, MD 20857. (10) The expiration date, if any; (9) Approval by an institutional review (11) If the drug is intended for paren- board. The investigator shall obtain the teral use, a statement as to whether review and approval of an institutional the contents are sterile; review board that conforms to the requirements of part 56 of this chapter. (12) If the drug is for other than oral use, the names of all inactive ingredi- (e) The results of any research con- ents, except that: ducted pursuant to this section as part of the evaluation of a drug pursuant to (i) Trace amounts of harmless subpart 312 of this chapter shall be instances added solely for individual cluded in the submissions required product identification need not be under part 312 of this chapter. named. (f) A radioactive drug prepared, pack- (ii) If the drug is intended for paren- aged, distributed, and primarily in- teral use, the quantity or proportion of tended for use in accordance with the all inactive ingredients, except that in- requirements of this section shall be gredients added to adjust pH or to exempt from section 502(f)(1) of the act make the drug isotonic may be de- and §§ 201.5 and 201.100 of this chapter if clared by name and a statement of the packaging, label, and labeling are their effect; if the vehicle is water for in compliance with Federal, State, and injection, it need not be named. Pro- local law regarding radioactive mate- vided, however, That in the case of con- rials and if the label of the immediate tainers too small or otherwise unable container and shielded container, if to accommodate a label with sufficient any, either separate from or as part of space to bear all such information, the any label and labeling required for ra- information required by paragraphs (f)

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(1) and (12) of this section may be paring proper labeling for these arti- placed on the shielded container only. cles for over-the-counter sale and in [40 FR 31308, July 25, 1975, as amended at 40 meeting the legal requirements of the FR 44543, Sept. 29, 1975; 42 FR 15674, Mar. 22, act that the label or labeling of drugs 1977; 43 FR 14646, Apr. 7, 1978; 46 FR 8955, Jan. and devices bear adequate warnings, in 27, 1981; 49 FR 44460, Nov. 7, 1984; 50 FR 8996, such manner and form as are necessary Mar. 6, 1985; 55 FR 11582, Mar. 29, 1990; 56 FR for the protection of users. Only sec- 10806, Mar. 14, 1991; 67 FR 4907, Feb. 1, 2002] tion 502(d) of the act requires use of the specific language included in these sug- PART 369—INTERPRETATIVE STATE- gested warning and caution state- MENTS RE WARNINGS ON DRUGS ments. These suggested warning or AND DEVICES FOR OVER-THE- caution statements are illustrative of COUNTER SALE those that may be necessary or desirable. It is the responsibility of the Subpart A—Definitions and Interpretations manufacturer, packer, shipper, or dis- Sec. tributor in interstate commerce to see 369.1 Purpose of issuance. that such statements are adequate for 369.2 Definitions. compliance with the provisions of the 369.3 Warnings required on drugs exempted law. Omission of any article from this from prescription-dispensing require- suggested list does not relieve drugs ments of section 503(b)(1)(C). 369.4 Warnings suggested for drugs by for- and devices subject to provisions of the mal or informal statements of policy. act from bearing adequate warning or 369.6 [Reserved] caution statements where such state- 369.7 Warnings required by official comments are necessary or desirable for pendia. the protection of the user. 369.8 Warning statements in relation to conditions for use. § 369.2 Definitions. 369.9 General warnings re accidental ingestion by children. (a) As used in this part, the term act 369.10 Conspicuousness of warning state- means the Federal Food, Drug, and ments. Cosmetic Act. Subpart B—Warning and Caution (b) The terms drugs and devices are Statements for Drugs defined in section 201(g) and (k) of the act. 369.20 Drugs; recommended warning and (c) Official compendia are defined in caution statements. 369.21 Drugs; warning and caution state- section 201(j) of the act. ments required by regulations. § 369.3 Warnings required on drugs ex- AUTHORITY: 21 U.S.C. 321, 331, 351, 352, 353, empted from prescription-dis- 355, 371. pensing requirements of section SOURCE: 39 FR 11745, Mar. 29, 1974, unless 503(b)(1)(C). otherwise noted. Drugs exempted from prescription- EDITORIAL NOTE: Nomenclature changes to dispensing requirements under section part 369 can be found at 69 FR 13717, Mar. 24, 503(b)(1)(C) of the act are subject to the 2004. labeling requirements prescribed in § 310.201(a) of this chapter. Although, Subpart A—Definitions and for convenience, warning and caution Interpretations statements for a number of the drugs named in § 310.201 of this chapter § 369.1 Purpose of issuance. (cross-referenced in the text of this The warning and caution statements part) are included in subpart B of this suggested in subparts B and C of this part, the inclusion of such drugs in part, for inclusion in the label or label- §§ 369.20, 369.21, 369.22 in no way affects ing of drugs and devices subject to sec- the requirements for compliance with tion 502(d) and (f)(2) and other relevant § 310.201(a) of this chapter, or the provi- provisions of the Federal Food, Drug, sions of an effective application pursu- and Cosmetic Act are issued for the ant to section 505(b) of the act. purpose of assisting industry in pre-

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§ 369.4 Warnings suggested for drugs § 369.10 Conspicuousness of warning by formal or informal statements of statements. policy. Necessary warning statements should The warning and caution statements appear in the labeling prominently and included in subpart B of this part in no conspicuously as compared to other way affect any warning statement sug- words, statements, designs, and de- gested for such drugs or devices by any vices, and in bold type on clearly con- statement of policy or interpretation trasting background, in order to com- in subchapter C of this chapter. ply with the provisions of section 502(c) [39 FR 11745, Mar. 29, 1974, as amended at 40 and (f)(2) of the act. The warning state- FR 13496, Mar. 27, 1975] ments should be placed in the labeling in juxtaposition with the directions for § 369.6 [Reserved] use and, in any case, should appear on the label when there is sufficient label § 369.7 Warnings required by official space in addition to mandatory label compendia. information. Any drug included in the official compendia defined by the act shall Subpart B—Warning and Caution bear such warning or caution state- Statements for Drugs ment as may be required by such compendia, and no statement in subpart B § 369.20 Drugs; recommended warning or subpart C of this part is intended to and caution statements. alter, modify, or permit the omission of any such statement required by such ACETANILID. compendia. Warning—Do not exceed recommended dosage. Overdosage or con- § 369.8 Warning statements in relation tinued use may result in serious blood to conditions for use. disturbances. The mention in any warning or cau- ACETOPHENETIDIN CONTAINING tion statement included in subparts A, PREPARATIONS. (See § 201.309 of this B, and C of this part, of a disease condi- chapter.) tion does not imply a finding on the part of the Food and Drug Administra- Warning—This medication may dam- tion that any drug or device is effica- age the kidneys when used in large cious in such condition; nor is any drug amounts or for a long period of time. or device bearing labeling referring to Do not take more than the rec- such disease condition precluded from ommended dosage, nor take regularly regulatory action under the applicable for longer than 10 days without con- provisions of the act if such claim is sulting your physician. considered to be misbranding. ANESTHETICS FOR EXTERNAL USE (LOCAL ANESTHETICS). (See also § 369.9 General warnings re accidental § 310.201(a)(19) and (23) of this chapter.) ingestion by children. Section 369.20 includes under certain Caution—Do not use in the eyes. Not items, but not all medicines, the state- for prolonged use. If the condition for ment: ‘‘Keep this and all medicines out which this preparation is used persists of children’s reach. In case of overdose, or if a rash or irritation develops, dis- get medical help or contact a Poison continue use and consult physician. Control Center right away,’’ or ‘‘Keep ANTIHISTAMINICS FOR EXTERNAL out of reach of children.’’ However, in USE (EXCEPT PREPARATIONS FOR view of the possibility of accidental in- OPHTHALMIC USE). gestion of drugs, it is not only sug- Caution—Do not use in the eyes. If gested but is recommended that one of the condition for which this prepara- these statements be used on the label tion is used persists or if a rash or irri- of all drug products. tation develops, discontinue use and [64 FR 13296, Mar. 17, 1999] consult physician.

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ANTIHISTAMINICS, ORAL. (See also dosage. If eye pain occurs, discontinue § 310.201(a)(4) and (a)(24) of this chap- use and see your physician imme- ter.) diately as this may indicate undiagnosed glaucoma. Caution—This preparation may cause drowsiness. Do not drive or operate In the case of scopolamine or scopol- machinery while taking this medica- amine aminoxide preparations indi- tion. Do not give to children under 6 cated for insomnia, the portion of the years of age or exceed the rec- above warning that reads ‘‘children ommended dosage unless directed by under 6 years of age’’ should read in- physician. stead ‘‘children under 12 years of age’’. The reference to drowsiness is not re- BORIC ACID (POWDERED, CRYS- quired on preparations for the pro- TALLINE, OR GRANULAR). motion of sleep or on preparations that Warning—Do not use as a dusting are shown not to produce drowsiness. powder, especially on infants, or take ANTIPERSPIRANTS. internally. Use only as a solution. Do Do not apply to broken skin. If a rash not apply to badly broken or raw skin, develops, discontinue use. or to large areas of the body. ANTIPYRINE. BROMIDES. Warning—Do not exceed rec- Caution—Use only as directed. Do not ommended dosage. If skin rash appears, give to children or use in the presence discontinue use and consult physician. of kidney disease. If skin rash appears or if nervous symptoms persist, recur ANTISEPTICS FOR EXTERNAL USE. frequently, or are unusual, discontinue Caution—In case of deep or puncture use and consult physician. wounds or serious burns, consult physi- CARBOLIC ACID (PHENOL) PREP- cian. If redness, irritation, swelling, or ARATIONS (MORE THAN 0.5 PER- pain persists or increases or if infection CENT) FOR EXTERNAL USE. occurs discontinue use and consult physician. Warning—Use according to direc- The reference to wounds and burns is tions. Do not apply to large areas of not required on preparations intended the body. If applied to fingers or toes, solely for diaper rash. do not bandage. ARSENIC PREPARATIONS. CATHARTICS AND LAXATIVES—IR- RITANTS AND OTHER PERISTALTIC Warning—Frequent or prolonged use STIMULANTS. may cause serious injury. Do not exceed recommended dosage. Keep out of Warning—Do not use when abdominal the reach of children. pain, nausea, or vomiting are present. Frequent or prolonged use of this prep- BELLADONNA PREPARATIONS AND aration may result in dependence on PREPARATIONS OF ITS ALKALOIDS laxatives. (ATROPINE, HYOSCYAMINE, AND Mercury preparations should have SCOPOLAMINE (HYOSCINE); added to the ‘‘frequent use’’ statement, HYOSCYAMUS, STRAMONIUM, the words ‘‘and serious mercury poi- THEIR DERIVATIVES, AND RE- soning’’. LATED DRUG PREPARATIONS. Phenolphthalein preparations should Warning—Not to be used by persons bear, in addition to the general warn- having glaucoma or excessive pressure ing, the following statement: within the eye, by elderly persons Caution—If skin rash appears, do not (where undiagnosed glaucoma or exces- use this or any other preparation con- sive pressure within the eye occurs taining phenolphthalein. most frequently), or by children under See also Mineral Oil Laxatives. 6 years of age, unless directed by a phy- CHLORATES: MOUTH WASH OR GAR- sician. Discontinue use if blurring of GLE. vision, rapid pulse, or dizziness occurs. Do not exceed recommended dosage. Avoid swallowing. Not for frequent or prolonged use. If COBALT PREPARATIONS (See also dryness of the mouth occurs, decrease § 250.106 of this chapter.)

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Warning—Do not exceed the rec- Warning—For temporary use only. ommended dosage. Do not administer Long-term use of this product may lead to children under 12 years of age unless to faster bone loss, continuing irrita- directed by physician. Do not use for tion, sores, and tumors. For Use Only more than 2 months unless directed by Until a Dentist Can Be Seen. physician. DENTURE REPAIR KITS. This warning is not required on arti- Warning—For emergency repairs only. cles containing not more than 0.5 milli- Long-term use of home-repaired den- gram of cobalt as a cobalt salt per dos- tures may cause faster bone loss, con- age unit and which recommend admin- tinuing irritation, sores, and tumors. istration of not more than 0.5 milli- This kit for emergency use only. See gram per dose and not more than 2 mil- Dentist Without Delay. ligrams per 24-hour period. DIARRHEA PREPARATIONS. ‘‘COUGH-DUE-TO-COLD’’ PREPARA- TIONS. (See also § 310.201(a)(20) of this Warning—Do not use for more than 2 chapter.) days or in the presence of high fever or in infants or children under 3 years of Warning—Persons with a high fever age unless directed by a physician. or persistent cough should not use this DOUCHE PREPARATIONS. preparation unless directed by physician. Warning—Do not use more often than twice weekly unless directed by physi- COUNTERIRRITANTS AND cian. RUBEFACIENTS. See also Creosote * * * Douche for Caution—Do not apply to irritated additional warning. skin or if excessive irritation develops. DRESSINGS, PROTECTIVE SPRAY- Avoid getting into the eyes or on mu- ON TYPE. (See also § 310.201(a) (11) and cous membranes. (18) of this chapter.) If offered for use in arthritis or rheu- Warning—In case of deep or puncture matism, in juxtaposition therewith, wounds or serious burns consult physi- the statement: cian. If redness, irritation, swelling or Caution—If pain persists for more pain persists or increases or if infection than 10 days, or redness is present, or occurs consult physician. Keep away in conditions affecting children under from eyes or other mucous membranes. 12 years of age consult a physician im- Avoid inhaling. mediately. See also Dispensers Pressurized by See also ‘‘Salicylates’’ in this section Gaseous Propellants * * * for addi- for additional warnings for prepara- tional warnings to be included for prod- tions containing methyl salicylate. ucts under pressure. CREOSOTE, CRESOLS, GUAIACOL, IODINE AND IODIDES (ORAL). AND SIMILAR SUBSTANCES IN Caution—If a skin rash appears, dis- PREPARATIONS FOR EXTERNAL continue use and consult physician. USE. MERCURY PREPARATIONS FOR EX- Caution—Do not apply to large areas TERNAL USE. of the body. Warning—Discontinue use if rash or CREOSOTE, CRESOLS, GUAIACOL, irritation develops or if condition for AND SIMILAR SUBSTANCES IN which used persists. Frequent or pro- DOUCHE PREPARATIONS. longed use, or application to large Warning—The use of solutions areas may cause serious mercury poi- stronger than those recommended may soning. result in severe local irritation, burns, MINERAL OIL LAXATIVES. (See also or serious poisoning. Mix as directed § 201.302 of this chapter.) before pouring into douche bag. Do not Caution—Take only at bedtime. use more often than twice weekly un- Avoid prolonged use. Do not administer less directed by physician. to infants or young children, in preg- DENTURE RELINERS, PADS, AND nancy, or to bedridden or aged patients CUSHIONS. unless directed by physician.

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NASAL PREPARATIONS: VASO- Caution—Excessive use of this prepa- CONSTRICTORS (PHENYL- ration may temporarily discolor blond, PROPANOLAMINE). white, or red hair. Caution—Do not exceed recommended SALICYLATES, INCLUDING ASPIRIN dosage. AND SALICYLAMIDE (EXCEPT METHYL SALICYLATE, EFFER- NUX VOMICA AND STRYCHNINE VESCENT SALICYLATE PREPARA- PREPARATIONS. TIONS, AND PREPARATIONS OF ‘‘Do not use more than the rec- AMINOSALICYLIC ACID AND ITS ommended dosage. Keep out of reach of SALTS). (See also § 201.314 of this chap- children. In case of overdose, get med- ter.) ical help or contact a Poison Control ‘‘Keep out of reach of children. In Center right away.’’ case of overdose, get medical help or OPHTHALMIC PREPARATIONS. (See contact a Poison Control Center right also § 200.50 of this chapter.) away;’’ or ‘‘Keep out of reach of children.’’ Boric acid offered for use in the prep- If the article is an aspirin prepara- aration of ophthalmic solutions should tion, it should bear the first of the bear the statement: Prepare solution above two warning statements. In ei- by boiling in water. Store in a sterile ther case, the above information container. Prepare sufficient for one should appear on the label. day’s use and discard unused portion. Caution—For children under 3 years PHENACETIN-CONTAINING PREPA- of age, consult your physician; or RATION. (See acetophenetidin.) Caution—For younger children, con- PHENYLPROPANOLAMINE HY- sult your physician. DROCHLORIDE PREPARATIONS, One of the two immediately pre- ORAL. ceding caution statements is required on the label of all aspirin tablets, but Caution—Individuals with high blood such a statement is not required on the pressure, heart disease, diabetes, or labels of other salicylates clearly of- thyroid disease should use only as di- fered for administration to adults only. rected by physician. If offered for use in arthritis or rheu- POTASSIUM PERMANGANATE matism, in juxtaposition therewith, AQUEOUS SOLUTIONS (CONTAINING the statement: NOT MORE THAN 0.04 PERCENT PO- Caution—If pain persists for more TASSIUM PERMANGANATE). (See than 10 days, or redness is present, or § 250.108 of this chapter.) in conditions affecting children under 12 years of age, consult a physician im- Warning—For external use on the mediately. skin only. Severe injury may result from use internally or as a douche. SALICYLATES: METHYL SALICY- Avoid contact with mucous mem- LATE (WINTERGREEN OIL). (See also branes. §§ 201.303 and 201.314 of this chapter.) ‘‘Do not use otherwise than as di- QUININE AND OTHER CINCHONA DE- rected. Keep out of reach of children to RIVATIVES (EXCEPT FOR USE IN avoid accidental poisoning. If swal- MALARIA). lowed, get medical help or contact a Caution—Discontinue use if ringing Poison Control Center right away.’’ in the ears, deafness, skin rash, or vis- If the preparation is a counter-irri- ual disturbances occur. tant or rubefacient the statement: RESINS, OLEORESINS, AND VOLA- Caution—Discontinue use if excessive TILE OILS. irritation of the skin develops. Avoid getting into the eyes or on mucous Caution—If nausea, vomiting, abdom- membranes. inal discomfort, diarrhea, or skin rash If offered for use in arthritis or rheu- occurs, discontinue use and consult matism, in juxtaposition therewith, physician. the statement: RESORCINOL (NOT THE Caution—If pain persists for more MONOACETATE) HAIR PREPARA- than 10 days, or redness is present, or TIONS. in conditions affecting children under

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12 years of age consult a physician im- EFFECTIVE DATE NOTE 2: At 68 FR 34293, mediately. June 9, 2003, § 369.20 was amended by removing the entry for ‘‘ANTIPERSPIRANTS.’’, SILVER. effective Dec. 9, 2004. Caution—Frequent or prolonged use § 369.21 Drugs; warning and caution of this preparation may result in per- statements required by regulations. manent discoloration of skin and mucous membranes. ACETAMINOPHEN (N-ACETYL-p- SODIUM PERBORATE MOUTHWASH AMINOPHENOL) (See § 310.201(a)(1) of AND GARGLE AND TOOTHPASTE. this chapter.) Warning—Do not give to children Caution—Discontinue use if irritation under 3 years of age or use for more or inflammation develops, or increases. than 10 days unless directed by a physi- Avoid swallowing. cian. SULFONAMIDE NOSE DROPS. If offered for use in arthritis, or rheumatism, in juxtaposition therewith, —Do not use if a known al- Caution the statement: lergy to sulfonamide drugs exists. Caution—If pain persists for more SULFUR PREPARATION FOR EX- than 10 days, or redness is present, or TERNAL USE. in conditions affecting children under Caution—If undue skin irritation de- 12 years of age consult a physician im- velops or increases, discontinue use mediately. and consult physician. ALCOHOL RUBBING COMPOUND. (See 26 CFR 182.855(a)(5); The National THROAT PREPARATIONS FOR TEM- Formulary, Tenth Edition 1955, pp. 27– PORARY RELIEF OF MINOR SORE 28; and section 502(g) of the act). THROAT: LOZENGES, TROCHES, WASHES, GARGLES, ETC. (See also Warning—For external use only. If § 201.315 of this chapter.) taken internally serious gastric distrubances will result. Warning—Severe or persistent sore throat or sore throat accompanied by ANTIHISTAMINICS, ORAL (PHENYL- high fever, headache, nausea, and vom- TOLOXAMINE DIHYDROGEN CIT- iting may be serious. Consult physician RATE AND CHLOROTHEN CITRATE promptly. Do not use more than 2 days PREPARATIONS). (See § 310.201(a)(4) or administer to children under 3 years and (a)(24) of this chapter.) of age unless directed by physician. Caution—This preparation may cause TOOTHACHE PREPARATIONS. drowsiness. Do not drive or operate machinery while taking this medica- For temporary use only until a den- tion. Do not give to children under 6 tist can be consulted. years of age or exceed the rec- ZINC STEARATE DUSTING POW- ommended dosage unless directed by DERS. physician. ‘‘Keep out of reach of children; avoid If offered for symptoms of colds, the inhaling. If swallowed, get medical statement: help or contact a Poison Control Cen- Caution—If relief does not occur ter right away.’’ within 3 days, discontinue use and consult physician. [39 FR 11745, Mar. 29, 1974, as amended at 40 FR 8917, Mar. 3, 1975; 40 FR 13496, Mar. 27, CARBETAPENTANE CITRATE PREP- 1975; 41 FR 10885, Mar. 15, 1976; 51 FR 27760, ARATIONS. (See Cough-Due-to-Cold Aug. 1, 1986; 51 FR 35340, Oct. 2, 1986; 52 FR Preparations.) 15893, Apr. 30, 1987; 52 FR 30057, Aug. 12, 1987; ‘‘COUGH–DUE–TO–COLD’’ PREPARA- 52 FR 47324, Dec. 11, 1987; 53 FR 7093, Mar. 4, TIONS (CARBETAPENTANE CIT- 1988; 55 FR 31783, Aug. 3, 1990; 57 FR 58376, RATE). (See § 310.201(a)(20) of this chap- Dec. 9, 1992; 59 FR 43412, Aug. 23, 1994; 64 FR 13296, Mar. 17, 1999] ter.)

EFFECTIVE DATE NOTE 1: At 68 FR 18882, ‘‘Keep out of reach of children. In April 17, 2003, § 369.20 was amended by remov- case of overdose, get medical help or ing the entry for ‘‘DIARRHEA PREPARA- contact a Poison Control Center right TIONS’’, effective April 19, 2004. away.’’

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DICYCLOMINE HYDROCHLORIDE trating and inhaling the contents can WITH AN ANTACID. (See § 310.201(a)(8) be harmful or fatal. of this chapter.) The warning is not required for the 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; DIPHEMANIL METHYLSULFATE (c) Products of a net quantity of con- FOR EXTERNAL USE. (See tents of less than 2 ozs. that are de- § 310.201(a)(22) of this chapter.) signed to release a measured amount of Caution—If redness, irritation, swell- product with each valve actuation; ing, or pain persists or increases, dis- (d) Products of a net quantity of con- continue use and consult physician. tents of less than 1⁄2 oz. DRUGS IN DISPENSERS PRESSUR- DYCLONINE HYDROCHLORIDE. (See IZED BY GASEOUS PROPELLANTS. § 310.201(a)(23) of this chapter.) (See also § 310.201(a) (11) and (18) of this Caution—Do not use in the eyes. Not chapter.) for prolonged use. Do not apply to The warnings herein shall appear large areas of the body. If redness, irri- prominently and conspicuously, but in tation, swelling, or pain persists or in- no case may the letters be less than 1⁄16 creases, discontinue use unless directed inch in height. by physician. Do not use, but consult If the label of any package is too physician for deep or puncture wounds small to accommodate the warnings, or serious burns. Do not use in case of the Commissioner may establish by rectal bleeding, as this may indicate regulation an acceptable alternative serious disease. method, e.g., a type size smaller than HEXADENOL. (See § 310.201(a)(11) of 1⁄16 inch in height. A petition request- this chapter.) ing such a regulation, as an amend- Caution—Do not use for treatment of ment to this paragraph, shall be sub- serious burns or skin conditions or for mitted to the Division of Dockets Man- conditions which persist for prolonged agement in the form established in periods. In such cases, consult your part 10 of this chapter. physician. Do not spray in vicinity of Warning—Avoid spraying in eyes. eyes, mouth, nose, or ears. Do not store Contents under pressure. Do not punc- above 120° F. ture or incinerate. Do not store at temperature above 120° F. Keep out of IPECAC SYRUP IN ONE-FLUID reach of children. OUNCE CONTAINERS FOR EMER- In the case of products packaged in GENCY TREATMENT OF POISONING, glass containers, the word ‘‘break’’ TO INDUCE VOMITING. (See § 201.308 may be substituted for the word of this chapter.) ‘‘puncture.’’ Ipecac syrup packaged for over-the- The words ‘‘Avoid spraying in eyes’’ counter sale must bear statements to may be deleted from the warning in the the following effect, in a prominent case of a product not expelled as a and conspicuous manner: spray, or that is intended to be used in The following statement (boxed and the eyes. in red letters): In addition to the above warning, the ‘‘For emergency use to cause vom- label of a drug packaged in a self-pres- iting in poisoning. Before using, call surized container in which the propel- physician, the Poison Control Center, lant consists in whole or in part of a or hospital emergency room imme- halocarbon or hydrocarbon shall bear diately for advice.’’ the following warning: The following warning: Warning— Warning—Use only as directed. Inten- Keep out of reach of children. Do not tional misuse by deliberately concen- use in unconscious persons. Ordinarily,

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this drug should not be used if strych- If offered for use in arthritis or rheu- nine, corrosives such as alkalies (lye) matism, in juxtaposition therewith, and strong acids, or petroleum dis- the statement: tillates such as kerosene, gasoline, coal Caution—If pain persists for more oil, fuel oil, paint thinner, or cleaning than 10 days, or redness is present, or fluid have been ingested. in conditions affecting children under 12 years of age, consult a physician im- ISOAMYLHYRDOCUPREINE AND ZO- mediately. LAMINE HYDROCHLORIDE RECTAL PREPARATIONS FOR EXTERNAL TUAMINOHEPTANE SULFATE USE (See § 310.201(a)(3) of this chapter.) NASAL PREPARATIONS. (See § 310.201(a)(16) of this chapter.) Warning—Do not use this preparation in case of rectal bleeding, as this may Caution—Do not exceed recommended dosage. Overdosage may cause nervous- indicate serious disease. ness, restlessness, or sleeplessness. In- NEOMYCIN SULFATE WITH A VASO- dividuals with high blood pressure, CONSTRICTOR, IN NASAL PREPARA- heart disease, diabetes, or thyroid dis- TIONS (SPRAY OR DROPS). ease should use only as directed by Caution—Do not exceed recommended physician. Do not use for more than 3 dosage. Do not administer to children or 4 consecutive days unless directed by physician. under 3 years of age unless directed by physician. VIBESATE PREPARATIONS. (See § 310.201(a)(18) of this chapter.) PRAMOXINE HYDROCHLORIDE FOR EXTERNAL USE. (See § 310.201(a)(19) of Caution—Do not use but consult phy- this chapter.) sician for deep or puncture wounds or serious burns. If redness, irritation, Caution—Do not use in the eyes or swelling, or pain persists or increases, nose. Not for prolonged use. Do not discontinue use and consult physician. apply to large areas of the body. If red- Warning—Contents under pressure. ness, irritation, swelling, or pain per- Do not puncture. Do not use or store sists or increases, discontinue use un- near heat or open flame. Exposure to less directed by a physician. temperatures above 130° Fahrenheit SODIUM GENTISATE. (See §§ 201.314 may cause bursting. Never throw con- and 310.301(a)(2) of this chapter.) tainer into fire or incinerator. Warning—Do not use in children [39 FR 11745, Mar. 29, 1974] under 6 years of age or use for pro- EDITORIAL NOTE: For FEDERAL REGISTER ci- longed period unless directed by physi- tations affecting § 369.21, see the List of CFR cian. Sections Affected, which appears in the ‘‘Keep out of reach of children. In Finding Aids section of the printed volume case of overdose, get medical help or and on GPO Access. contact a Poison Control Center right away.’’ PARTS 370–499 [RESERVED]

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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. Material Approved for Incorporation by Reference Table of CFR Titles and Chapters Alphabetical List of Agencies Appearing in the CFR List of CFR Sections Affected

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The Director of the Federal Register has approved under 5 U.S.C. 552(a) and 1 CFR Part 51 the incorporation by reference of the following publications. This list contains only those incorporations by reference effective as of the revision date of this volume. Incorporations by reference found within a regulation are effective upon the effective date of that regulation. For more information on incorporation by reference, see the preliminary pages of this volume.

21 CFR (PARTS 300 TO 499) FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES 21 CFR AOAC International (Association of Official Analytical Chemists) 481 N. Frederick Ave., Suite 500, Gaithersburg, MD 20877-2417 Telephone: (301) 924–7077 Official Methods of Analysis of the Association of Official Analytical 331.22 Chemists, 11th Ed., 1970.

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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) IV Miscellaneous Agencies (Parts 400—500)

Title 2 [Reserved]

Title 3—The President

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

Title 4—Accounts

I General Accounting Office (Parts 1—99)

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 (Part 2100) 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 (Part 3201) XXIII Department of Energy (Part 3301) XXIV Federal Energy Regulatory Commission (Part 3401) XXV Department of the Interior (Part 3501) XXVI Department of Defense (Part 3601)

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XXVIII Department of Justice (Part 3801) 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 (Part 4301) XXXV Office of Personnel Management (Part 4501) XL Interstate Commerce Commission (Part 5001) XLI Commodity Futures Trading Commission (Part 5101) XLII Department of Labor (Part 5201) XLIII National Science Foundation (Part 5301) XLV Department of Health and Human Services (Part 5501) XLVI Postal Rate Commission (Part 5601) XLVII Federal Trade Commission (Part 5701) XLVIII Nuclear Regulatory Commission (Part 5801) L Department of Transportation (Part 6001) LII Export-Import Bank of the United States (Part 6201) LIII Department of Education (Parts 6300—6399) LIV Environmental Protection Agency (Part 6401) LV National Endowment for the Arts (Part 6501) LVI National Endowment for the Humanities (Part 6601) LVII General Services Administration (Part 6701) LVIII Board of Governors of the Federal Reserve System (Part 6801) LIX National Aeronautics and Space Administration (Part 6901) LX United States Postal Service (Part 7001) LXI National Labor Relations Board (Part 7101) LXII Equal Employment Opportunity Commission (Part 7201) LXIII Inter-American Foundation (Part 7301) LXV Department of Housing and Urban Development (Part 7501) LXVI National Archives and Records Administration (Part 7601) LXVII Institute of Museum and Library Services (Part 7701) LXIX Tennessee Valley Authority (Part 7901) LXXI Consumer Product Safety Commission (Part 8101) LXXIII Department of Agriculture (Part 8301) LXXIV Federal Mine Safety and Health Review Commission (Part 8401) LXXVI Federal Retirement Thrift Investment Board (Part 8601) LXXVII Office of Management and Budget (Part 8701)

Title 6—Homeland Security

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

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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) 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, Department of Agriculture (Parts 2900—2999) XXX Office of the Chief Financial Officer, Department of Agriculture (Parts 3000—3099)

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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 Cooperative State Research, Education, and Extension Service, Department of 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)

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)

Title 10—Energy

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

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I Federal Election Commission (Parts 1—9099)

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) 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, Department of Com- merce (Parts 400—499) V Emergency Oil and Gas Guaranteed Loan Board, Department of Commerce (Parts 500—599)

Title 14—Aeronautics and Space

I Federal Aviation Administration, Department of Transportation (Parts 1—199) II Office of the Secretary, Department of Transportation (Aviation Proceedings) (Parts 200—399) III Commercial Space Transportation, Federal Aviation Adminis- tration, Department of Transportation (Parts 400—499) V National Aeronautics and Space Administration (Parts 1200— 1299) VI Air Transportation System Stabilization (Parts 1300—1399)

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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)

Title 17—Commodity and Securities Exchanges

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

Title 18—Conservation of Power and Water Resources

I Federal Energy Regulatory Commission, Department of Energy (Parts 1—399) III Delaware River Basin Commission (Parts 400—499) VI Water Resources Council (Parts 700—799)

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VIII Susquehanna River Basin Commission (Parts 800—899) XIII Tennessee Valley Authority (Parts 1300—1399)

Title 19—Customs Duties

I Bureau of Customs and Border Protection, Department of Home- land 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 Bureau of 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 Employment Standards Administration, 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, Department of Labor (Parts 1000—1099)

Title 21—Food and Drugs

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

Title 22—Foreign Relations

I Department of State (Parts 1—199) II Agency for International Development (Parts 200—299) III Peace Corps (Parts 300—399) IV International Joint Commission, United States and Canada (Parts 400—499) V Broadcasting Board of Governors (Parts 500—599) VII Overseas Private Investment Corporation (Parts 700—799) IX Foreign Service Grievance Board Regulations (Parts 900—999)

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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) 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 Housing Com- missioner, Department of Housing and Urban Development (Parts 200—299) III Government National Mortgage Association, Department of Housing and Urban Development (Parts 300—399) IV Office of Housing and Office of Multifamily Housing Assistance Restructuring, Department of Housing and Urban Develop- ment (Parts 400—499) V Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 500—599) VI Office of Assistant Secretary for Community Planning and De- velopment, Department of Housing and Urban Development (Parts 600—699) [Reserved] VII Office of the Secretary, Department of Housing and Urban Devel- opment (Housing Assistance Programs and Public and Indian Housing Programs) (Parts 700—799)

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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) XX Office of Assistant Secretary for Housing—Federal Housing Commissioner, Department of Housing and Urban Develop- ment (Parts 3200—3899) 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 (Part 1200)

Title 26—Internal Revenue

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)

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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) 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 Minerals Management Service, Department of the Interior (Parts 200—299) III Board of Surface Mining and Reclamation Appeals, Department of the Interior (Parts 300—399) IV Geological Survey, Department of the Interior (Parts 400—499)

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VII Office of Surface Mining Reclamation and Enforcement, Depart- ment of the Interior (Parts 700—999)

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)

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) 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)

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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) XI National Institute for Literacy (Parts 1100—1199) SUBTITLE C—REGULATIONS RELATING TO EDUCATION XII National Council on Disability (Parts 1200—1299)

Title 35—Panama Canal

I Panama Canal Regulations (Parts 1—299)

Title 36—Parks, Forests, and Public Property

I National Park Service, Department of the Interior (Parts 1—199) II Forest Service, Department of Agriculture (Parts 200—299) III Corps of Engineers, Department of the Army (Parts 300—399) IV American Battle Monuments Commission (Parts 400—499) V Smithsonian Institution (Parts 500—599) 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 (Part 1501) XVI Morris K. Udall Scholarship and Excellence in National Environ- mental Policy Foundation (Parts 1600—1699)

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I United States Patent and Trademark Office, Department of Commerce (Parts 1—199) II Copyright Office, Library of Congress (Parts 200—299) 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)

Title 39—Postal Service

I United States Postal Service (Parts 1—999) III Postal Rate 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)

Title 41—Public Contracts and Property Management

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) 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) 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)

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128 Department of Justice (Parts 128–1—128–99) SUBTITLE D—OTHER PROVISIONS RELATING TO PROPERTY MANAGE- MENT [RESERVED] SUBTITLE E—FEDERAL INFORMATION RESOURCES MANAGEMENT REGULATIONS SYSTEM 201 Federal Information Resources Management Regulation (Parts 201–1—201–99) [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 303–70) 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 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—10010)

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

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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) 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) 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)

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III National Telecommunications and Information Administration, Department of Commerce (Parts 300—399)

Title 48—Federal Acquisition Regulations System

1 Federal Acquisition Regulation (Parts 1—99) 2 Department of Defense (Parts 200—299) 3 Department of Health and Human Services (Parts 300—399) 4 Department of Agriculture (Parts 400—499) 5 General Services Administration (Parts 500—599) 6 Department of State (Parts 600—699) 7 United States Agency for International Development (Parts 700—799) 8 Department of Veterans Affairs (Parts 800—899) 9 Department of Energy (Parts 900—999) 10 Department of the Treasury (Parts 1000—1099) 12 Department of Transportation (Parts 1200—1299) 13 Department of Commerce (Parts 1300—1399) 14 Department of the Interior (Parts 1400—1499) 15 Environmental Protection Agency (Parts 1500—1599) 16 Office of Personnel Management, Federal Employees Health Benefits Acquisition Regulation (Parts 1600—1699) 17 Office of Personnel Management (Parts 1700—1799) 18 National Aeronautics and Space Administration (Parts 1800— 1899) 19 Broadcasting Board of Governors (Parts 1900—1999) 20 Nuclear Regulatory Commission (Parts 2000—2099) 21 Office of Personnel Management, Federal Employees Group Life Insurance Federal Acquisition Regulation (Parts 2100—2199) 23 Social Security Administration (Parts 2300—2399) 24 Department of Housing and Urban Development (Parts 2400— 2499) 25 National Science Foundation (Parts 2500—2599) 28 Department of Justice (Parts 2800—2899) 29 Department of Labor (Parts 2900—2999) 30 Department of Homeland Security, Homeland Security Acquisi- tion Regulation (HSAR) (Parts 3000—3099) 34 Department of Education Acquisition Regulation (Parts 3400— 3499) 35 Panama Canal Commission (Parts 3500—3599) 44 Federal Emergency Management Agency (Parts 4400—4499) 51 Department of the Army Acquisition Regulations (Parts 5100— 5199) 52 Department of the Navy Acquisition Regulations (Parts 5200— 5299) 53 Department of the Air Force Federal Acquisition Regulation Supplement (Parts 5300—5399)

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54 Defense Logistics Agency, Department of Defense (Parts 5400— 5499) 57 African Development Foundation (Parts 5700—5799) 61 General Services Administration Board of Contract Appeals (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 Research and Special Programs Administration, Department of Transportation (Parts 100—199) II Federal Railroad Administration, Department of Transportation (Parts 200—299) III Federal Motor Carrier Safety Administration, Department of Transportation (Parts 300—399) IV Coast Guard, Department of Homeland Security (Parts 400—499) V National Highway Traffic Safety Administration, Department of Transportation (Parts 500—599) VI Federal Transit Administration, Department of Transportation (Parts 600—699) VII National Railroad Passenger Corporation (AMTRAK) (Parts 700—799) VIII National Transportation Safety Board (Parts 800—999) X Surface Transportation Board, Department of Transportation (Parts 1000—1399) XI Bureau of Transportation Statistics, Department of Transpor- tation (Parts 1400—1499) XII Transportation Security Administration, Department of Home- land Security (Parts 1500—1599)

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)

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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 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, United States 22, II Federal Acquisition Regulation 48, 7 Agricultural Marketing Service 7, I, IX, X, XI Agricultural Research Service 7, V Agriculture Department 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 Cooperative State Research, Education, and Extension 7, XXXIV Service Economic Research Service 7, XXXVII Energy, Office of 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 Natural Resources Conservation Service 7, VI Operations, Office of 7, XXVIII Procurement and Property Management, Office of 7, XXXII Rural Business-Cooperative Service 7, XVIII, XLII Rural Development Administration 7, XLII Rural Housing Service 7, XVIII, XXXV Rural Telephone Bank 7, XVI Rural Utilities Service 7, XVII, XVIII, XLII Secretary of Agriculture, Office of 7, Subtitle A Transportation, Office of 7, XXXIII World Agricultural Outlook Board 7, XXXVIII Air Force Department 32, VII Federal Acquisition Regulation Supplement 48, 53 Air Transportation Stabilization Board 14, VI Alcohol and Tobacco Tax and Trade Bureau 27, I Alcohol, Tobacco, Firearms, and Explosives, Bureau of 27, II AMTRAK 49, VII American Battle Monuments Commission 36, IV American Indians, Office of the Special Trustee 25, VII 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 Chapter I—Continued 21 CFR 68 FR Page 320.22 (a), (b)(1)(ii), (2)(ii), (3)(i), (ii), (iii), (c), (d) introductory Chapter I 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 320.23 Heading revised; (a)(1) (d)(17) added; (d)(1) revised; eff. amended...... 77673 4–19–04 ...... 18881 320.24 Heading, (b)(5), (6) and (c) (a)(18)(i), (v), (vi), and (d)(1) re- introductory text revised; (a) vised; (d)(32) added; eff. 6–4–04 and (b)(4) amended ...... 77673 ...... 33376 320.25 (a)(2) removed; (a)(3) redes- (a)(4) redesignated as (a)(4)(i); ignated as (a)(2); new (a)(2), new (a)(4)(i) heading, (ii) and (d)(1), (e)(1) introductory text, (d)(34) added; (d)(1) revised; eff. (i) and (f) heading revised; (f) 12–9–04...... 34291 amended...... 77674 (a)(26)(xi) and (d)(37) added; (d) 320.26 Heading and (a)(1) re- introductory text and (13) revised...... 77674 vised ...... 51170 320.27 (a)(3)(iv), (d)(1) and (2) re- (d)(1) corrected; eff. 4–19–04 ...... 37963 vised; (b)(2) and (3)(i) amend- 312 Nomenclature change ...... 24879 ed ...... 77674 314 Nomenclature change ...... 24879 320.28 Amended...... 77674 314.50 (l)(1) revised; (l)(4) heading 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 320.31 (b) introductory text and 314.53 (b), (c)(1), (2) and (3) re- (3) amended ...... 77674 vised...... 36703 329 Removed ...... 4907 314.65 Amended...... 25287 330 Compliance date extension...... 16304 314.72 (a)(2)(iii) amended...... 25287 330.10 Amended ...... 3073 314.81 (b)(2)(iii) revised; eff. 6–8– 330.13 (e) added...... 3074 04...... 69019 330.14 Added ...... 3074 314.94 (d)(1) revised; eff. 6–8–04 ...... 69019 331 Compliance date extension...... 16304 314.95 (a)(3) redesignated as (a)(4); 333 Technical correction...... 11571 new (a)(3) added ...... 36705 333.210 (g) added...... 5943 328 Nomenclature change ...... 24879 336.50 (c)(8) added; eff. 12–8–03 ...... 72559 330 Nomenclature change ...... 24879 338.50 (c)(5) added; eff. 12–8–03 ...... 72559 335 Added; eff. 4–19–04...... 18881 341 Compliance date extension...... 16304 341.40 Corrected; eff. 12–23–04...... 17881 341.14 (a)(2) amended...... 4907 341.70 (b) corrected; eff. 12–23– 341.40 Added; eff. 12–23–04 ...... 78168 04...... 17881 341.70 (b) added; eff. 12–23–04 ...... 78170 347.1—347.50 (Subpart A) Heading 341.72 (c)(6)(iv) and (7) added; eff. revised; eff. 6–4–04 ...... 33376 12–8–03 ...... 72559 347.3 Revised; eff. 6–4–04 ...... 33376 341.74 (c)(4)(viii)(C) and (ix)(C) 347.10—347.20 (Subpart B) Des- added; eff. 12–8–03 ...... 72559 ignation and heading added; eff. 6–4–04 ...... 33377 341.85 Added; eff. 12–23–04 ...... 78170 347.10 Redesignated as 347.12; new 346 Compliance date extension...... 16304 347.10 added; eff. 6–4–04...... 33377 352.10 (f) through (n) revised...... 41823 347.12 Redesignated from 347.10; 352.20 (a)(1) and (2) revised...... 41823 eff. 6–4–04 ...... 33377 355 Compliance date extension...... 16304 347.20 Added; (d) suspended; eff. 6– 358 Compliance date extension...... 16304 4–04...... 33377 361.1 (f)(1) amended...... 4907 347.50—347.60 (Subpart C) Des- 369 Compliance date extension...... 16304 ignation and heading added; 369.22 Removed ...... 4907 eff. 6–4–04 ...... 33377

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21 CFR—Continued 68 FR 2004 Page Chapter I—Continued (Regulations published from January 1, 347.50 Redesignated as 347.52; new 2004, through April 1, 2004) 347.50 added; eff. 6–4–04...... 33377 (b)(2), (e)(1)(ii) and (f)(1)(ii) re- 21 CFR 69 FR vised; eff. 6–4–04 ...... 68511 Page 347.52 Redesignated from 347.50; Chapter I eff. 6–4–04 ...... 33377 312 Nomenclature change ...... 13717 (c)(4) and (e) added; (d)(1)(i), (ii) 312.140 (a) amended ...... 13473 and (3) revised ...... 35293 314 Nomenclature change ...... 13717 Regulation at 68 FR 35293 con- 314.52 (a)(3) removed; (a)(4) redes- firmed...... 58273 ignated as (a)(3) ...... 11310 347.60 Added; eff. 6–4–04 ...... 33377 314.53 (d)(4) amended...... 13473 349.12 (a)(3) amended...... 32982 349.20 Revised ...... 7921 314.80 (c) introductory text 349.78 (a) revised...... 7921 amended...... 13473 350 Added; eff. 12–9–04...... 34291 314.95 (a)(3) removed; (a)(4) redes- 352 Regulation at 66 FR 67485 rein- ignated as (a)(3) ...... 11310 stated; eff. 6–4–04...... 33380 314.420 (a)(5) amended ...... 13473 Suspended; eff. 6–4–04 ...... 33381 314.440 (a)(1) amended ...... 13473 352.20 (b) added; eff. 6–4–04 ...... 33380 316 Nomenclature change ...... 13717 352.52 (c)(2) heading, (d)(4) head- 328 Nomenclature change ...... 13717 ing, (f)(1)(ii) and (vi) revised; 330 Nomenclature change ...... 13717 eff. 6–4–04 ...... 33380 331.30 (c)(4) and (5) removed; (c)(6) 352.60 (b)(2), (c) and (d) revised; redesignated as new (c)(4)...... 13734 eff. 6–4–04 ...... 33380 355 Nomenclature change ...... 24879 341 Nomenclature change ...... 13717 358.301—358.350 (Subpart D) 347 Technical correction ...... 3005 Added ...... 24348 355 Nomenclature change ...... 13717 358.650 Revised; eff. 6–30–05...... 75417 369 Nomenclature change ...... 13717 369.20 Amended; eff. 4–19–04 ...... 18882 Amended; eff. 12–9–04...... 34293 Æ

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