[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2012 Edition]
[From the U.S. Government Printing Office]



[[Page i]]

          

          Title 21

Food and Drugs


________________________

Parts 300 to 499

                         Revised as of April 1, 2012

          Containing a codification of documents of general 
          applicability and future effect

          As of April 1, 2012
                    Published by the Office of the Federal Register 
                    National Archives and Records Administration as a 
                    Special Edition of the Federal Register

[[Page ii]]

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                            Table of Contents



                                                                    Page
  Explanation.................................................       v

  Title 21:
          Chapter I--Food and Drug Administration, Department 
          of Health and Human Services (Continued)                   3
  Finding Aids:
      Table of CFR Titles and Chapters........................     341
      Alphabetical List of Agencies Appearing in the CFR......     361
      List of CFR Sections Affected...........................     371

[[Page iv]]





                     ----------------------------

                     Cite this Code: CFR
                     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.

                     ----------------------------

[[Page v]]



                               EXPLANATION

    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 subdivided 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 
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Sections Affected (LSA),'' which is issued monthly, and the ``Cumulative 
List of Parts Affected,'' which appears in the Reader Aids section of 
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Register page number of the latest amendment of any given rule.

EFFECTIVE AND EXPIRATION DATES

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citations for the regulations are referred to by volume number and page 
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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.

[[Page vi]]

Many agencies have begun publishing numerous OMB control numbers as 
amendments to existing regulations in the CFR. These OMB numbers are 
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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 eleven separate 
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``[RESERVED]'' TERMINOLOGY

    The term ``[Reserved]'' is used as a place holder within the Code of 
Federal Regulations. An agency may add regulatory information at a 
``[Reserved]'' location at any time. Occasionally ``[Reserved]'' is used 
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INCORPORATION BY REFERENCE

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This material, like any other properly issued regulation, has the force 
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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 
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    (c) The incorporating document is drafted and submitted for 
publication in accordance with 1 CFR part 51.
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    An index to the text of ``Title 3--The President'' is carried within 
that volume.

[[Page vii]]

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the revision dates of the 50 CFR titles.

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    Michael L. White,
    Acting Director,
    Office of the Federal Register.
    April 1, 2012.







[[Page ix]]



                               THIS TITLE

    Title 21--Food and Drugs is composed of nine volumes. The parts in 
these volumes are arranged in the following order: Parts 1-99, 100-169, 
170-199, 200-299, 300-499, 500-599, 600-799, 800-1299 and 1300 to end. 
The first eight volumes, containing parts 1-1299, comprise Chapter I--
Food and Drug Administration, 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, 2012.

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

[[Page 1]]



                        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

[[Page 3]]



CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)




  --------------------------------------------------------------------


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

                    SUBCHAPTER D--DRUGS FOR HUMAN USE
Part                                                                Page
300             General.....................................           5
310             New drugs...................................           5
312             Investigational new drug application........          50
314             Applications for FDA approval to market a 
                    new drug................................          92
315             Diagnostic radiopharmaceuticals.............         177
316             Orphan drugs................................         178
320             Bioavailability and bioequivalence 
                    requirements............................         190
328             Over-the-counter drug products intended for 
                    oral ingestion that contain alcohol.....         206
330             Over-the-counter (OTC) human drugs which are 
                    generally recognized as safe and 
                    effective and not misbranded............         207
331             Antacid products for over-the-counter (OTC) 
                    human use...............................         224
332             Antiflatulent products for over-the-counter 
                    human use...............................         227
333             Topical antimicrobial drug products for 
                    over-the-counter human use..............         229
335             Antidiarrheal drug products for over-the-
                    counter human use.......................         237
336             Antiemetic drug products for over-the-
                    counter human use.......................         239
338             Nighttime sleep-aid drug products for over-
                    the-counter human use...................         240
340             Stimulant drug products for over-the-counter 
                    human use...............................         242

[[Page 4]]

341             Cold, cough, allergy, bronchodilator, and 
                    antiasthmatic drug products for over-
                    the-counter human use...................         243
343             Internal analgesic, antipyretic, and 
                    antirheumatic drug products for over-
                    the-counter human use...................         266
344             Topical otic drug products for over-the-
                    counter human use.......................         274
346             Anorectal drug products for over-the-counter 
                    human use...............................         276
347             Skin protectant drug products for over-the-
                    counter human use.......................         281
348             External analgesic drug products for over-
                    the-counter human use...................         289
349             Ophthalmic drug products for over-the-
                    counter human use.......................         290
350             Antiperspirant drug products for over-the-
                    counter human use.......................         296
352             Sunscreen drug products for over-the-counter 
                    human use [stayed indefinitely].........         298
355             Anticaries drug products for over-the-
                    counter human use.......................         308
357             Miscellaneous internal drug products for 
                    over-the-counter human use..............         313
358             Miscellaneous external drug products for 
                    over-the-counter human use..............         317
361             Prescription drugs for human use generally 
                    recognized as safe and effective and not 
                    misbranded: Drugs used in research......         326
369             Interpretative statements re warnings on 
                    drugs and devices for over-the-counter 
                    sale....................................         331
370-499

[Reserved]

[[Page 5]]



                    SUBCHAPTER D_DRUGS FOR HUMAN USE





PART 300_GENERAL--Table of Contents



Subpart A [Reserved]

                       Subpart B_Combination Drugs

Sec.
300.50 Fixed-combination prescription drugs for humans.

          Subpart C_Substances Generally Prohibited From Drugs

300.100 Chlorofluorocarbon propellants.

    Authority: 21 U.S.C. 331, 351, 352, 355, 360b, 361, 371.

Subpart A [Reserved]



                       Subpart B_Combination Drugs



Sec. 300.50  Fixed-combination prescription drugs for humans.

    The Food and Drug Administration's policy in administering the new-
drug, antibiotic, and other regulatory provisions of the Federal Food, 
Drug, and Cosmetic Act regarding fixed combination dosage form 
prescription drugs for humans is as follows:
    (a) Two or more drugs may be combined in a single dosage form when 
each component makes a contribution to the claimed effects and the 
dosage of each component (amount, frequency, duration) is such that the 
combination is safe and effective for a significant patient population 
requiring such concurrent therapy as defined in the labeling for the 
drug. Special cases of this general rule are where a component is added:
    (1) To enhance the safety or effectiveness of the principal active 
component; and
    (2) To minimize the potential for abuse of the principal active 
component.
    (b) If a combination drug presently the subject of an approved new-
drug application has not been recognized as effective by the 
Commissioner of Food and Drugs based on his evaluation of the 
appropriate National Academy of Sciences-National Research Council panel 
report, or if substantial evidence of effectiveness has not otherwise 
been presented for it, then formulation, labeling, or dosage changes may 
be proposed and any resulting formulation may meet the appropriate 
criteria listed in paragraph (a) of this section.
    (c) A fixed-combination prescription drug for humans that has been 
determined to be effective for labeled indications by the Food and Drug 
Administration, based on evaluation of the NAS-NRC report on the 
combination, is considered to be in compliance with the requirements of 
this section.

[40 FR 13496, Mar. 27, 1975, as amended at 64 FR 401, Jan. 5, 1999]



          Subpart C_Substances Generally Prohibited From Drugs



Sec. 300.100  Chlorofluorocarbon propellants.

    The use of chlorofluorocarbons in human drugs as propellants in 
self-pressurized containers is generally prohibited except as provided 
by Sec. 2.125 of this chapter.

[43 FR 11317, Mar. 17, 1978]



PART 310_NEW DRUGS--Table of Contents



                      Subpart A_General Provisions

Sec.
310.3 Definitions and interpretations.
310.4 Biologics; products subject to license control.
310.6 Applicability of ``new drug'' or safety or effectiveness findings 
          in drug efficacy study implementation notices and notices of 
          opportunity for hearing to identical, related, and similar 
          drug products.

         Subpart B_Specific Administrative Rulings and Decisions

310.100 New drug status opinions; statement of policy.
310.103 New drug substances intended for hypersensitivity testing.

 Subpart C_New Drugs Exempted From Prescription-Dispensing Requirements

310.200 Prescription-exemption procedure.
310.201 Exemption for certain drugs limited by new drug applications to 
          prescription sale.

[[Page 6]]

                      Subpart D_Records and Reports

310.303 Continuation of long-term studies, records, and reports on 
          certain drugs for which new drug applications have been 
          approved.
310.305 Records and reports concerning adverse drug experiences on 
          marketed prescription drugs for human use without approved new 
          drug applications.

        Subpart E_Requirements for Specific New Drugs or Devices

310.501 Patient package inserts for oral contraceptives.
310.502 Certain drugs accorded new drug status through rulemaking 
          procedures.
310.503 Requirements regarding certain radioactive drugs.
310.509 Parenteral drug products in plastic containers.
310.515 Patient package inserts for estrogens.
310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.
310.518 Drug products containing iron or iron salts.
310.519 Drug products marketed as over-the-counter (OTC) daytime 
          sedatives.
310.527 Drug products containing active ingredients offered over-the-
          counter (OTC) for external use as hair growers or for hair 
          loss prevention.
310.528 Drug products containing active ingredients offered over-the-
          counter (OTC) for use as an aphrodisiac.
310.529 Drug products containing active ingredients offered over-the-
          counter (OTC) for oral use as insect repellents.
310.530 Topically applied hormone-containing drug products for over-the-
          counter (OTC) human use.
310.531 Drug products containing active ingredients offered over-the-
          counter (OTC) for the treatment of boils.
310.532 Drug products containing active ingredients offered over-the-
          counter (OTC) to relieve the symptoms of benign prostatic 
          hypertrophy.
310.533 Drug products containing active ingredients offered over-the-
          counter (OTC) for human use as an anticholinergic in cough-
          cold drug products.
310.534 Drug products containing active ingredients offered over-the-
          counter (OTC) for human use as oral wound healing agents.
310.536 Drug products containing active ingredients offered over-the-
          counter (OTC) for use as a nailbiting or thumbsucking 
          deterrent.
310.537 Drug products containing active ingredients offered over-the-
          counter (OTC) for oral administration for the treatment of 
          fever blisters and cold sores.
310.538 Drug products containing active ingredients offered over-the-
          counter (OTC) for use for ingrown toenail relief.
310.540 Drug products containing active ingredients offered over-the-
          counter (OTC) for use as stomach acidifiers.
310.541 Over-the-counter (OTC) drug products containing active 
          ingredients offered for use in the treatment of 
          hypophosphatemia.
310.542 Over-the-counter (OTC) drug products containing active 
          ingredients offered for use in the treatment of 
          hyperphosphatemia.
310.543 Drug products containing active ingredients offered over-the-
          counter (OTC) for human use in exocrine pancreatic 
          insufficiency.
310.544 Drug products containing active ingredients offered over-the-
          counter (OTC) for use as a smoking deterrent.
310.545 Drug products containing certain active ingredients offered 
          over-the-counter (OTC) for certain uses.
310.546 Drug products containing active ingredients offered over-the-
          counter (OTC) for the treatment and/or prevention of nocturnal 
          leg muscle cramps.
310.547 Drug products containing quinine offered over-the-counter (OTC) 
          for the treatment and/or prevention of malaria.
310.548 Drug products containing colloidal silver ingredients or silver 
          salts offered over-the-counter (OTC) for the treatment and/or 
          prevention of disease.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 
361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 263b-263n.



                      Subpart A_General Provisions



Sec. 310.3  Definitions and interpretations.

    As used in this part:
    (a) The term act means the Federal Food, Drug, and Cosmetic Act, as 
amended (secs. 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 
321-392).
    (b) Department means the Department of Health and Human Services.
    (c) Secretary means the Secretary of Health and Human Services.
    (d) Commissioner means the Commissioner of Food and Drugs.
    (e) The term person includes individuals, partnerships, 
corporations, and associations.
    (f) The definitions and interpretations of terms contained in 
section 201 of the act shall be applicable to such terms when used in 
the regulations in this part.

[[Page 7]]

    (g) New drug substance means any substance that when used in the 
manufacture, processing, or packing of a drug, causes that drug to be a 
new drug, but does not include intermediates used in the synthesis of 
such substance.
    (h) The newness of a drug may arise by reason (among other reasons) 
of:
    (1) The newness for drug use of any substance which composes such 
drug, in whole or in part, whether it be an active substance or a 
menstruum, excipient, carrier, coating, or other component.
    (2) The newness for a drug use of a combination of two or more 
substances, none of which is a new drug.
    (3) The newness for drug use of the proportion of a substance in a 
combination, even though such combination containing such substance in 
other proportion is not a new drug.
    (4) The newness of use of such drug in diagnosing, curing, 
mitigating, treating, or preventing a disease, or to affect a structure 
or function of the body, even though such drug is not a new drug when 
used in another disease or to affect another structure or function of 
the body.
    (5) The newness of a dosage, or method or duration of administration 
or application, or other condition of use prescribed, recommended, or 
suggested in the labeling of such drug, even though such drug when used 
in other dosage, or other method or duration of administration or 
application, or different condition, is not a new drug.
    (i) [Reserved]
    (j) The term sponsor means the person or agency who assumes 
responsibility for an investigation of a new drug, including 
responsibility for compliance with applicable provisions of the act and 
regulations. The ``sponsor'' may be an individual, partnership, 
corporation, or Government agency and may be a manufacturer, scientific 
institution, or an investigator regularly and lawfully engaged in the 
investigation of new drugs.
    (k) The phrase related drug(s) includes other brands, potencies, 
dosage forms, salts, and esters of the same drug moiety, including 
articles prepared or manufactured by other manufacturers: and any other 
drug containing a component so related by chemical structure or known 
pharmacological properties that, in the opinion of experts qualified by 
scientific training and experience to evaluate the safety and 
effectiveness of drugs, it is prudent to assume or ascertain the 
liability of similar side effects and contraindications.
    (l) Special packaging as defined in section 2(4) of the Poison 
Prevention Packaging Act of 1970 means packaging that is designed or 
constructed to be significantly difficult for children under 5 years of 
age to open or obtain a toxic or harmful amount of the substance 
contained therein within a reasonable time and not difficult for normal 
adults to use properly, but does not mean packaging which all such 
children cannot open or obtain a toxic or harmful amount within a 
reasonable time.
    (m) [Reserved]
    (n) The term radioactive drug means any substance defined as a drug 
in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act which 
exhibits spontaneous disintegration of unstable nuclei with the emission 
of nuclear particles or photons and includes any nonradioactive reagent 
kit or nuclide generator which is intended to be used in the preparation 
of any such substance but does not include drugs such as carbon-
containing compounds or potassium-containing salts which contain trace 
quantities of naturally occurring radionuclides. The term ``radioactive 
drug'' includes a ``radioactive biological product'' as defined in Sec. 
600.3(ee) of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 39 FR 20484, June 11, 1974; 
40 FR 31307, July 25, 1975; 46 FR 8952, Jan. 27, 1981; 50 FR 7492, Feb. 
22, 1985]



Sec. 310.4  Biologics; products subject to license control.

    (a) If a drug has an approved license under section 351 of the 
Public Health Service Act (42 U.S.C. 262 et seq.) or under the animal 
virus, serum, and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it 
is not required to have an approved application under section 505 of the 
act.
    (b) To obtain marketing approval for radioactive biological products 
for human use, as defined in Sec. 600.3(ee) of

[[Page 8]]

this chapter, manufacturers must comply with the provisions of Sec. 
601.2(a) of this chapter.

[64 FR 56448, Oct. 20, 1999, as amended at 70 FR 14981, Mar. 24, 2005]



Sec. 310.6  Applicability of ``new drug'' or safety or effectiveness 
findings in drug efficacy study implementation notices and notices 

of opportunity for hearing to identical, related, and similar 
drug products.

    (a) The Food and Drug Administration's conclusions on the 
effectiveness of drugs are currently being published in the Federal 
Register as Drug Efficacy Study Implementation (DESI) Notices and as 
Notices of Opportunity for Hearing. The specific products listed in 
these notices include only those that were introduced into the market 
through the new drug procedures from 1938-62 and were submitted for 
review by the National Academy of Sciences-National Research Council 
(NAS-NRC), Drug Efficacy Study Group. Many products which are identical 
to, related to, or similar to the products listed in these notices have 
been marketed under different names or by different firms during this 
same period or since 1962 without going through the new drug procedures 
or the Academy review. Even though these products are not listed in the 
notices, they are covered by the new drug applications reviewed and thus 
are subject to these notices. All persons with an interest in a product 
that is identical, related, or similar to a drug listed in a drug 
efficacy notice or a notice of opportunity for a hearing will be given 
the same opportunity as the applicant to submit data and information, to 
request a hearing, and to participate in any hearing. It is not feasible 
for the Food and Drug Administration to list all products which are 
covered by an NDA and thus subject to each notice. However, it is 
essential that the findings and conclusions that a drug product is a 
``new drug'' or that there is a lack of evidence to show that a drug 
product is safe or effective be applied to all identical, related, and 
similar drug products to which they are reasonably applicable. Any 
product not in compliance with an applicable drug efficacy notice is in 
violation of section 505 (new drugs) and/or section 502 (misbranding) of 
the act.
    (b)(1) An identical, related, or similar drug includes other brands, 
potencies, dosage forms, salts, and esters of the same drug moiety as 
well as of any drug moiety related in chemical structure or known 
pharmacological properties.
    (2) Where experts qualified by scientific training and experience to 
evaluate the safety and effectiveness of drugs would conclude that the 
findings and conclusions, stated in a drug efficacy notice or notice of 
opportunity for hearing, that a drug product is a ``new drug'' or that 
there is a lack of evidence to show that a drug product is safe or 
effective are applicable to an identical, related, or similar drug 
product, such product is affected by the notice. A combination drug 
product containing a drug that is identical, related, or similar to a 
drug named in a notice may also be subject to the findings and 
conclusions in a notice that a drug product is a ``new drug'' or that 
there is a lack of evidence to show that a drug product is safe or 
effective.
    (3) Any person may request an opinion on the applicability of such a 
notice to a specific product by writing to the Food and Drug 
Administration at the address shown in paragraph (e) of this section.
    (c) Manufacturers and distributors of drugs should review their 
products as drug efficacy notices are published and assure that 
identical, related, or similar products comply with all applicable 
provisions of the notices.
    (d) The published notices and summary lists of the conclusions are 
of particular interest to drug purchasing agents. These agents should 
take particular care to assure that the same purchasing policy applies 
to drug products that are identical, related, or similar to those named 
in the drug efficacy notices. The Food and Drug Administration applies 
the same regulatory policy to all such products. In many instances a 
determination can readily be made as to the applicability of a drug 
efficacy notice by an individual who is knowledgeable about drugs and 
their indications for use.

[[Page 9]]

Where the relationships are more subtle and not readily recognized, the 
purchasing agent may request an opinion by writing to the Food and Drug 
Administration at the address shown in paragraph (e) of this section.
    (e) Interested parties may submit to the Food and Drug 
Administration, Center for Drug Evaluation and Research, Office of 
Compliance, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002, the 
names of drug products, and of their manufacturers or distributors, that 
should be the subject of the same purchasing and regulatory policies as 
those reviewed by the Drug Efficacy Study Group. Appropriate action, 
including referral to purchasing officials of various government 
agencies, will be taken.
    (f) This regulation does not apply to OTC drugs identical, similar, 
or related to a drug in the Drug Efficacy Study unless there has been or 
is notification in the Federal Register that a drug will not be subject 
to an OTC panel review pursuant to Sec. Sec. 330.10, 330.11, and 330.5 
of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 48 FR 2755, Jan. 21, 1983; 50 
FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 74 FR 13113, Mar. 26, 
2009]



         Subpart B_Specific Administrative Rulings and Decisions



Sec. 310.100  New drug status opinions; statement of policy.

    (a) Over the years since 1938 the Food and Drug Administration has 
given informal advice to inquirers as to the new drug status of 
preparations. These drugs have sometimes been identified only by general 
statements of composition. Generally, such informal opinions were 
incorporated in letters that did not explicitly relate all of the 
necessary conditions and qualifications such as the quantitative formula 
for the drug and the conditions under which it was prescribed, 
recommended, or suggested. This has contributed to misunderstanding and 
misinterpretation of such opinions.
    (b) These informal opinions that an article is ``not a new drug'' or 
``no longer a new drug'' require reexamination under the Kefauver-Harris 
Act (Public Law 87-781; 76 Stat. 788-89). In particular, when approval 
of a new drug application is withdrawn under provisions of section 
505(e) of the Federal Food, Drug, and Cosmetic Act, a drug generally 
recognized as safe may become a ``new drug'' within the meaning of 
section 201(p) of said act as amended by the Kefauver-Harris Act on 
October 10, 1962. This is of special importance by reason of proposed 
actions to withdraw approval of new drug applications for lack of 
substantial evidence of effectiveness as a result of reports of the 
National Academy of Sciences--National Research Council on its review of 
drug effectiveness; for example, see the notice published in the Federal 
Register of January 23, 1968 (33 FR 818), regarding rutin, quercetin, et 
al.
    (c) Any marketed drug is a ``new drug'' if any labeling change made 
after October 9, 1962, recommends or suggests new conditions of use 
under which the drug is not generally recognized as safe and effective 
by qualified experts. Undisclosed or unreported side effects as well as 
the emergence of new knowledge presenting questions with respect to the 
safety or effectiveness of a drug may result in its becoming a ``new 
drug'' even though it was previously considered ``not a new drug.'' Any 
previously given informal advice that an article is ``not a new drug'' 
does not apply to such an article if it has been changed in formulation, 
manufacture control, or labeling in a way that may significantly affect 
the safety of the drug.
    (d) For these reasons, all opinions previously given by the Food and 
Drug Administration to the effect that an article is ``not a new drug'' 
or is ``no longer a new drug'' are hereby revoked. This does not mean 
that all articles that were the subjects of such prior opinions will be 
regarded as new drugs. The prior opinions will be replaced by opinions 
of the Food and Drug Administration that are qualified and current on 
when an article is ``not a new drug,'' as set forth in this subchapter.

[39 FR 11680, Mar. 29, 1974]

[[Page 10]]



Sec. 310.103  New drug substances intended for hypersensitivity testing.

    (a) The Food and Drug Administration is aware of the need in the 
practice of medicine for the ingredients of a new drug to be available 
for tests of hypersensitivity to such ingredients and therefore will not 
object to the shipment of a new drug substance, as defined in Sec. 
310.3(g), for such purpose if all of the following conditions are met:
    (1) The shipment is made as a result of a specific request made to 
the manufacturer or distributor by a practitioner licensed by law to 
administer such drugs, and the use of such drugs for patch testing is 
not promoted by the manufacturer or distributor.
    (2) The new drug substance requested is an ingredient in a marketed 
new drug and is not one that is an ingredient solely in a new drug that 
is legally available only under the investigational drug provisions of 
this part.
    (3) The label bears the following prominently placed statements in 
lieu of adequate directions for use and in addition to complying with 
the other labeling provisions of the act:
    (i) ``Rx only''; and
    (ii) ``For use only in patch testing''.
    (4) The quantity shipped is limited to an amount reasonable for the 
purpose of patch testing in the normal course of the practice of 
medicine and is used solely for such patch testing.
    (5) The new drug substance is manufactured by the same procedures 
and meets the same specifications as the component used in the finished 
dosage form.
    (6) The manufacturer or distributor maintains records of all 
shipments for this purpose for a period of 2 years after shipment and 
will make them available to the Food and Drug Administration on request.
    (b) When the requested new drug substance is intended for 
investigational use in humans or the substance is legally available only 
under the investigational drug provisions of part 312 of this chapter, 
the submission of an ``Investigational New Drug Application'' (IND) is 
required. The Food and Drug Administration will offer assistance to any 
practitioner wishing to submit an Investigational New Drug Application.
    (c) This section does not apply to drugs or their components that 
are subject to the licensing requirements of the Public Health Service 
Act of 1944, as amended. (See subchapter F--Biologics, of this chapter.)

[39 FR 11680, Mar. 29, 1974, as amended at 55 FR 11578, Mar. 29, 1990; 
67 FR 4907, Feb. 1, 2002]



 Subpart C_New Drugs Exempted From Prescription-Dispensing Requirements



Sec. 310.200  Prescription-exemption procedure.

    (a) Duration of prescription requirement. Any drug limited to 
prescription use under section 503(b)(1)(B) of the act remains so 
limited until it is exempted as provided in paragraph (b) or (e) of this 
section.
    (b) Prescription-exemption procedure for drugs limited by a new drug 
application. Any drug limited to prescription use under section 
503(b)(1)(B) of the act shall be exempted from prescription-dispensing 
requirements when the Commissioner finds such requirements are not 
necessary for the protection of the public health by reason of the 
drug's toxicity or other potentiality for harmful effect, or the method 
of its use, or the collateral measures necessary to its use, and he 
finds that the drug is safe and effective for use in self-medication as 
directed in proposed labeling. A proposal to exempt a drug from the 
prescription-dispensing requirements of section 503(b)(1)(B) of the act 
may be initiated by the Commissioner or by any interested person. Any 
interested person may file a petition seeking such exemption, which 
petition may be pursuant to part 10 of this chapter, or in the form of a 
supplement to an approved new drug application.
    (c) New drug status of drugs exempted from the prescription 
requirement. A drug exempted from the prescription requirement under the 
provisions of paragraph (b) of this section is a ``new drug'' within the 
meaning of section 201(p) of the act until it has been used to a 
material extent and for a material time under such conditions except as 
provided in paragraph (e) of this section.

[[Page 11]]

    (d) Prescription legend not allowed on exempted drugs. The use of 
the prescription caution statement quoted in section 503(b) (4) of the 
act, in the labeling of a drug exempted under the provisions of this 
section, constitutes misbranding. Any other statement or suggestion in 
the labeling of a drug exempted under this section, that such drug is 
limited to prescription use, may constitute misbranding.
    (e) Prescription-exemption procedure of OTC drug review. A drug 
limited to prescription use under section 503(b)(1)(B) of the act may 
also be exempted from prescription-dispensing requirements by the 
procedure set forth in Sec. 330.13 of this chapter.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 32582, Aug. 4, 1976; 42 
FR 4714, Jan. 25, 1977; 42 FR 15674, Mar. 22, 1977; 72 FR 15043, Mar. 
30, 2007]



Sec. 310.201  Exemption for certain drugs limited by new-drug 
applications to prescription sale.

    (a) The prescription-dispensing requirements of section503(b)(1)(B) 
of the Federal Food, Drug, and Cosmetic Act are not necessary for the 
protection of the public health with respect to the following drugs 
subject to new drug applications:
    (1) N-Acetyl-p-aminophenol (acetaminophen, p-hydroxy-acetanilid) 
preparations meeting all the following conditions:
    (i) The N-acetyl-p-aminophenol is prepared, with or without other 
drugs, in tablet or other dosage form suitable for oral use in self-
medication, and containing no drug limited to prescription sale under 
the provisions of section 503(b)(1) of the act.
    (ii) The N-acetyl-p-aminophenol and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505 (b) of the act is approved for it.
    (iv) The preparation contains not more than 0.325 gram (5 grains) of 
N-acetyl-p-aminophenol per dosage unit, or if it is in liquid form not 
more than 100 milligrams of N-acetyl-p-aminophenol per milliliter.
    (v) The preparation is labeled with adequate directions for use in 
minor conditions as a simple analgesic.
    (vi) The dosages of N-acetyl-p-aminophenol recommended or suggested 
in the labeling do not exceed: For adults, 0.65 gram (10 grains) per 
dose or 2.6 grams (40 grains) per 24-hour period: for children 6 to 12 
years of age, one-half of the maximum adult dose or dosage; for children 
3 to 6 years of age, one-fifth of the maximum adult dose or dosage.
    (vii) The labeling bears, in juxtaposition with the dosage 
recommendations, a clear warning statement against administration of the 
drug to children under 3 years of age and against use of the drug for 
more than 10 days, unless such uses are directed by a physician.
    (viii) If the article is offered for use in arthritis or rheumatism, 
the labeling prominently bears a statement that the beneficial effects 
claimed are limited to the temporary relief of minor aches and pains of 
arthritis and rheumatism and, in juxtaposition with directions for use 
in such conditions, a conspicuous warning statement, such as ``Caution: 
If pain persists for more than 10 days, or redness is present, or in 
conditions affecting children under 12 years of age, consult a physician 
immediately''.
    (2) Sodium gentisate (sodium-2, 5-dihydroxybenzoate) preparations 
meeting all the following conditions:
    (i) The sodium gentisate is prepared, with or without other drugs, 
in tablet or other dosage form suitable for oral use in self-medication, 
and containing no drug limited to prescription sale under the provisions 
of section 503(b)(1) of the act.
    (ii) The sodium gentisate and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 0.5 gram (7.7 grains) of 
anhydrous sodium gentisate per dosage unit.
    (v) The preparation is labeled with adequate directions for use in 
minor conditions as a simple analgesic.

[[Page 12]]

    (vi) The dosages of sodium gentisate recommended or suggested in the 
labeling do not exceed: For adults, 0.5 gram (7.7 grains) per dose of 
2.0 grams (31 grains) per 24-hour period; for children 6 to 12 years of 
age, one-half of the maximum adult dose or dosage.
    (vii) The labeling bears, in juxtaposition with the dosage 
recommendations, a clear warning statement against administration of the 
drug to children under 6 years of age and against use of the drug for a 
prolonged period, except as such uses may be directed by a physician.
    (3) Isoamylhydrocupreine and zolamine hydrochloride (N, N-dimethyl-
N'-2-thiazolyl-N'-p-methoxybenzyl-ethyl- enediamine hydrochloride) 
preparations meeting all the following conditions:
    (i) The isoamylhydrocupreine and zolamine hydrochloride are prepared 
in dosage form suitable for self-medication as rectal suppositories or 
as an ointment and containing no drug limited to prescription sale under 
the provisions of section 503(b)(1) of the act.
    (ii) The isoamylhydrocupreine, zola-amine hydrochloride, and all 
other components of the preparation meet their professed standards of 
identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 0.25 percent of 
isoamylhydrocupreine and 1.0 percent of zolamine hydrochloride.
    (v) If the preparation is in suppository form, it contains not more 
than 5.0 milligrams of isoamylhydrocupreine and not more than 20.0 
milligrams of zolamine hydrochloride per suppository.
    (vi) The preparation is labeled with adequate directions for use in 
the temporary relief of local pain and itching associated with 
hemorrhoids.
    (vii) The directions provide for the use of not more than two 
suppositories or two applications of ointment in a 24-hour period.
    (viii) The labeling bears, in juxtaposition with the dosage 
recommendations, a clear warning statement against use of the 
preparation in case of rectal bleeding, as this may indicate serious 
disease.
    (4) Phenyltoloxamine dihydrogen citrate (N,N-dimethyl-(a-phenyl-O-
toloxy) ethylamine dihydrogen citrate), preparations meeting all the 
following conditions:
    (i) The phenyltoloxamine dihydrogen citrate is prepared, with or 
without other drugs, in tablet or other dosage form suitable for oral 
use in self-medication, and containing no drug limited to prescription 
sale under the provisions of section 503(b)(1) of the act.
    (ii) The phenyltoloxamine dihydrogen citrate and all other 
components of the preparation meet their professed standards of 
identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 88 milligrams of 
phenyltoloxamine dihydrogen citrate (equivalent to 50 milligrams of 
phenyltoloxamine) per dosage unit.
    (v) The preparation is labeled with adequate directions for use in 
the temporary relief of the symptoms of hay fever and/or the symptoms of 
other minor conditions in which it is indicated.
    (vi) The dosages recommended or suggested in the labeling do not 
exceed: For adults, 88 milligrams of phenyltoloxamine dihydrogen citrate 
(equivalent to 50 milligrams of phenyltoloxamine) per dose or 264 
milligrams of phenyltoloxamine dihydrogen citrate (equivalent to 150 
milligrams of phenyltoloxamine) per 24-hour period; for children 6 to 12 
years of age, one-half of the maximum adult dose or dosage.
    (vii) The labeling bears, in juxtaposition with the dosage 
recommendations:
    (a) Clear warning statements against administration of the drug to 
children under 6 years of age, except as directed by a physician, and 
against driving a car or operating machinery while using the drug, since 
it may cause drowsiness.
    (b) If the article is offered for temporary relief of the symptoms 
of colds, a statement that continued administration for such use should 
not exceed 3 days, except as directed by a physician.

[[Page 13]]

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

[[Page 14]]

    (16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations 
meeting all the following conditions:
    (i) The tuaminoheptane sulfate is prepared, with or without other 
drugs, in an aqueous vehicle suitable for administration in self-
medication as nose drops, and containing no drug limited to prescription 
sale under the provisions of section 503(b)(1) of the act.
    (ii) The preparation is packaged with a style of container or 
assembly suited to self-medication by the recommended route of 
administration, and delivering not more than 0.1 milliliter of the 
preparation per drop.
    (iii) The tuaminoheptane sulfate and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iv) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (v) The tuaminoheptane sulfate content of the preparation does not 
exceed 10 milligrams per milliliter.
    (vi) The preparation is labeled with adequate directions for use in 
the temporary relief of nasal congestion.
    (vii) The dosages recommended or suggested in the directions for use 
do not exceed the equivalent: For adults, 5 drops of a 1 percent 
solution per nostril per dose, and 5 doses in a 24-hour period; for 
children 1 to 6 years of age, 3 drops of a 1 percent solution per 
nostril per dose, and 5 doses in a 24-hour period; for infants under 1 
year of age, 2 drops of a 1 percent solution per nostril per dose, and 5 
doses in a 24-hour period.
    (viii) The labeling bears, in juxtaposition with the dosage 
recommendations:
    (a) Clear warning statements against use of more than 5 doses daily, 
and against use longer than 4 days unless directed by a physician.
    (b) A clear warning statement to the effect that frequent use may 
cause nervousness or sleeplessness, and that individuals with high blood 
pressure, heart disease, diabetes, or thyroid disease should not use the 
preparation unless directed by a physician.
    (17) [Reserved]
    (18) Vibesate (a mixture of copolymers of hydroxy-vinyl 
chlorideacetate, sebacic acid, and modified maleic rosin ester) 
preparations meeting all the following conditions.
    (i) The vibesate is prepared and packaged, with or without other 
drugs, solvents, and propellants, in a form suitable for self-medication 
by external application to the skin as a spray, and containing no drug 
limited to prescription sale under the provisions of section 503(b)(1) 
of the act.
    (ii) The vibesate and all other components of the preparation meet 
their professed standards of identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 13 percent by weight of 
vibesate.
    (v) The preparation is labeled with adequate directions for use by 
external application as a dressing for minor burns, minor cuts, or other 
minor skin irritations.
    (vi) The labeling bears in juxtaposition with the directions for use 
clear warning statements against:
    (a) Use on serious burns and on infected, deep, and puncture wounds 
unless directed by a physician.
    (b) Spraying the preparation near the eyes or other mucous 
membranes.
    (c) Inhaling the preparation.
    (d) Use near open flames.
    (e) Puncturing the container or throwing the container into fire.
    (19) Pramoxine hydrochloride (4-N-butoxyphenyl [gamma]-
morpholinopropyl ether hydrochloride) preparations meeting all the 
following conditions:
    (i) The pramoxine hydrochloride is prepared, with or without other 
drugs, in a dosage form suitable for use in self-medication by external 
application to the skin, and containing no drug limited to prescription 
sale under the provisions of section 503(b)(1) of the act.
    (ii) The pramoxine hydrochloride and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 1.0 percent of pramoxine 
hydrochloride.

[[Page 15]]

    (v) The preparation is labeled with adequate directions for use by 
external application to the skin for the temporary relief of pain or 
itching due to minor burns and sunburn, nonpoisonous insect bites, and 
minor skin irritations.
    (vi) The directions for use recommend or suggest not more than four 
applications of the preparation per day, unless directed by a physician.
    (vii) The labeling bears, in juxtaposition with the directions for 
use, clear warning statements against:
    (a) Prolonged use.
    (b) Application to large areas of the body.
    (c) Continued use if redness, irritation, swelling, or pain persists 
or increases, unless directed by a physician.
    (d) Use in the eyes or nose.
    (20) [Reserved]
    (21) Pamabrom (2-amino-2-methylpropanol-1-8-bromotheophyllinate) 
preparations meeting all the following conditions:
    (i) The pamabrom is prepared with appropriate amounts of a suitable 
analgesic and with or without other drugs, in tablet or other dosage 
form suitable for oral use in self-medication, and containing no drug 
limited to prescription sale under the provisions of section 503(b)(1) 
of the act.
    (ii) The pamabrom and all other components of the preparation meet 
their professed standards of identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 50 milligrams of 
pamabrom per dosage unit.
    (v) The preparation is labeled with adequate directions for use in 
the temporary relief of the minor pains and discomforts that may occur a 
few days before and during the menstrual period.
    (vi) The dosages recommended or suggested in the labeling do not 
exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour 
period.
    (22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-
piperidinium methylsulfate) preparations meeting all the following 
conditions:
    (i) The diphemanil methylsulfate is prepared, with or without other 
drugs, in a dosage form suitable for use in self-medication by external 
application to the skin, and containing no drug limited to prescription 
sale under the provisions of section 503(b)(1) of the act.
    (ii) The diphemanil methylsulfate and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 2.0 percent of 
diphemanil methylsulfate.
    (v) The preparation is labeled with adequate directions for use by 
external application to the skin for the relief of symptoms of mild 
poison ivy, oak, and sumac and other minor irritations and itching of 
the skin.
    (vi) The directions for use recommend or suggest not more than four 
applications of the preparation per day, unless directed by a physician.
    (vii) The labeling bears, in juxtaposition with the directions for 
use, a clear warning statement, such as: ``Caution: If redness, 
irritation, swelling, or pain persists or increases, discontinue use and 
consult physician.''
    (23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone 
hydrochloride; 4-n-butoxy-[beta]-piperidonopropiophenone hydrochloride) 
preparations meeting all the following conditions:
    (i) The dyclonine hydrochloride is prepared, with or without other 
drugs, in a dosage form suitable for use as a cream or ointment in self-
medication by external application to the skin, or rectally, and 
contains no drug limited to prescription sale under the provisions of 
section 503(b)(1) of the act.
    (ii) The dyclonine hydrochloride and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 1.0 percent of dyclonine 
hydrochloride.

[[Page 16]]

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

[[Page 17]]

bears, in juxtaposition with the dosage recommendations:
    (a) A clear warning statement against administration of the drug to 
children under 6 years of age, unless directed by a physician.
    (b) A clear warning statement to the effect that frequent or 
prolonged use may cause nervousness, restlessness, or drowsiness, and 
that individuals with high blood pressure, heart disease, diabetes, or 
thyroid disease should not use the preparation unless directed by a 
physician.
    (c) A clear warning statement against use of the drug in the 
presence of high fever or if cough persists, since persistent cough as 
well as high fever may indicate the presence of a serious condition.
    (27) Biphenamine hydrochloride ([beta]-diethylaminoethyl-3-phenyl-2-
hydroxybenzoate hydrochloride) preparations meeting all the following 
conditions:
    (i) The biphenamine hydrochloride is prepared in a form suitable for 
use as a shampoo and contains no drug limited to prescription sale under 
the provisions of section 503(b)(1) of the act.
    (ii) The biphenamine hydrochloride meets its professed standards of 
identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 1 percent of biphenamine 
hydrochloride.
    (v) The preparation is labeled with adequate directions for use for 
the temporary relief of itching and scaling due to dandruff.
    (vi) The label bears a conspicuous warning to keep the drug out of 
the reach of children.
    (28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium 
chloride ophthalmic preparations meeting all the following conditions:
    (i) The tyloxapol and benzalkonium chloride are prepared, with other 
appropriate ingredients which are not drugs limited to prescription sale 
under the provisions of section 503(b)(1) of the act, as a sterile, 
isotonic aqueous solution suitable for use in self-medication on eye 
prostheses.
    (ii) The preparation is so packaged as to volume and type of 
container as to afford adequate protection and be suitable for self-
medication with a minimum risk of contamination of the solution during 
use. Any dispensing unit is sterile and so packaged as to maintain 
sterility until the package is opened.
    (iii) The tyloxapol, benzalkonium chloride, and other ingredients 
used to prepare the isotonic aqueous solution meet their professed 
standards of identity, strength, quality, and purity.
    (iv) An application pursuant to section 505(b) of the act is 
approved for the drug.
    (v) The preparation contains 0.25 percent of tyloxapol and 0.02 
percent of benzalkonium chloride.
    (vi) The label bears a conspicuous warning to keep the drug out of 
the reach of children and the labeling bears, in juxtaposition with the 
dosage recommendations, a clear warning that if irritation occurs, 
persists, or increases, use of the drug should be discontinued and a 
physician consulted. The labeling includes a statement that the dropper 
or other dispensing tip should not touch any surface, since this may 
contaminate the solution.
    (29) [Reserved]
    (b) [Reserved]

[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977; 
52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779, 
Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59 
FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995; 72 FR 15043, Mar. 30, 
2007; 72 FR 67640, Nov. 30, 2007]



                      Subpart D_Records and Reports



Sec. 310.303  Continuation of long-term studies, records, and reports
on certain drugs for which new drug applications have been approved.

    (a) A new drug may not be approved for marketing unless it has been 
shown to be safe and effective for its intended use(s). After approval, 
the applicant is required to establish and maintain records and make 
reports related to clinical experience or other data or information 
necessary to make or facilitate a determination of whether there are or 
may be grounds under section 505(e) of the act for suspending or 
withdrawing approval of the application. Some drugs, because of the 
nature of

[[Page 18]]

the condition for which they are intended, must be used for long periods 
of time--even a lifetime. To acquire necessary data for determining the 
safety and effectiveness of long-term use of such drugs, extensive 
animal and clinical tests are required as a condition of approval. 
Nonetheless, the therapeutic or prophylactic usefulness of such drugs 
may make it inadvisable in the public interest to delay the availability 
of the drugs for widespread clinical use pending completion of such 
long-term studies. In such cases, the Food and Drug Administration may 
approve the new drug application on condition that the necessary long-
term studies will be conducted and the results recorded and reported in 
an organized fashion. The procedures required by paragraph (b) of this 
section will be followed in order to list such a drug in Sec. 310.304.
    (b) A proposal to require additional or continued studies with a 
drug for which a new drug application has been approved may be made by 
the Commissioner on his own initiative or on the petition of any 
interested person, pursuant to part 10 of this chapter. Prior to 
issuance of such a proposal, the applicant will be provided an 
opportunity for a conference with representatives of the Food and Drug 
Administration. When appropriate, investigators or other individuals may 
be invited to participate in the conference. All requirements for 
special studies, records, and reports will be published in Sec. 
310.304.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 4714, Jan. 25, 1976; 42 
FR 15674, Mar. 22, 1977]



Sec. 310.305  Records and reports concerning adverse drug experiences
on marketed prescription drugs for human use without approved new

drug applications.

    (a) Scope. FDA is requiring manufacturers, packers, and distributors 
of marketed prescription drug products that are not the subject of an 
approved new drug or abbreviated new drug application to establish and 
maintain records and make reports to FDA of all serious, unexpected 
adverse drug experiences associated with the use of their drug products. 
Any person subject to the reporting requirements of paragraph (c) of 
this section shall also develop written procedures for the surveillance, 
receipt, evaluation, and reporting of postmarketing adverse drug 
experiences to FDA.
    (b) Definitions. The following definitions of terms apply to this 
section:
    Adverse drug experience. Any adverse event associated with the use 
of a drug in humans, whether or not considered drug related, including 
the following: An adverse event occurring in the course of the use of a 
drug product in professional practice; an adverse event occurring from 
drug overdose whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial reporter, 
at immediate risk of death from the adverse drug experience as it 
occurred, i.e., it does not include an adverse drug experience that, had 
it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.

[[Page 19]]

    Unexpected adverse drug experience. Any adverse drug experience that 
is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event 
because of greater severity or specificity. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the labeling only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the labeling 
only listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1)(i) of this section shall report to FDA adverse drug experience 
information as described in this section and shall submit one copy of 
each report to the Central Document Room, Center for Drug Evaluation and 
Research, Food and Drug Administration, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266.
    (1) Postmarketing 15-day ``Alert reports''. (i) Any person whose 
name appears on the label of a marketed prescription drug product as its 
manufacturer, packer, or distributor shall report to FDA each adverse 
drug experience received or otherwise obtained that is both serious and 
unexpected as soon as possible, but in no case later than 15 calendar 
days of initial receipt of the information by the person whose name 
appears on the label. Each report shall be accompanied by a copy of the 
current labeling for the drug product.
    (ii) A person identified in paragraph (c)(1)(i) of this section is 
not required to submit a 15-day ``Alert report'' for an adverse drug 
experience obtained from a postmarketing study (whether or not conducted 
under an investigational new drug application) unless the applicant 
concludes that there is a reasonable possibility that the drug caused 
the adverse experience.
    (2) Postmarketing 15-day ``Alert reports''--followup. Each person 
identified in paragraph (c)(1)(i) of this section shall promptly 
investigate all serious, unexpected adverse drug experiences that are 
the subject of these postmarketing 15-day Alert reports and shall submit 
followup reports within 15 calendar days of receipt of new information 
or as requested by FDA. If additional information is not obtainable, 
records should be maintained of the unsuccessful steps taken to seek 
additional information. Postmarketing 15-day Alert reports and followups 
to them shall be submitted under separate cover.
    (3) Submission of reports. To avoid unnecessary duplication in the 
submission of, and followup to, reports required in this section, a 
packer's or distributor's obligations may be met by submission of all 
reports of serious adverse drug experiences to the manufacturer of the 
drug product. If a packer or distributor elects to submit these adverse 
drug experience reports to the manufacturer rather than to FDA, it shall 
submit each report to the manufacturer within 5 calendar days of its 
receipt by the packer or distributor, and the manufacturer shall then 
comply with the requirements of this section even if its name does not 
appear on the label of the drug product. Under this circumstance, the 
packer or distributor shall maintain a record of this action which shall 
include:
    (i) A copy of each adverse drug experience report;
    (ii) The date the report was received by the packer or distributor;
    (iii) The date the report was submitted to the manufacturer; and
    (iv) The name and address of the manufacturer.
    (4) Each report submitted to FDA under this section shall bear 
prominent identification as to its contents, i.e., ``15-day Alert 
report,'' or ``15-day Alert report-followup.''
    (5) A person identified in paragraph (c)(1)(i) of this section is 
not required to resubmit to FDA adverse drug experience reports 
forwarded to that person

[[Page 20]]

by FDA; however, the person must submit all followup information on such 
reports to FDA.
    (d) Reporting form. (1) Except as provided in paragraph (d)(3) of 
this section, each person identified in paragraph (c)(1)(i) of this 
section shall submit each report of a serious and unexpected adverse 
drug experience on an FDA Form 3500A (foreign events may be submitted 
either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
    (2) Each completed FDA Form 3500A should pertain only to an 
individual patient.
    (3) Instead of using Form FDA Form 3500A, a manufacturer, packer, or 
distributor may use a computer-generated FDA Form 3500A or other 
alternative format (e.g., a computer-generated tape or tabular listing) 
provided that:
    (i) The content of the alternative format is equivalent in all 
elements of information to those specified in FDA Form 3500A, and
    (ii) The format is agreed to in advance by MedWatch: The FDA Medical 
Products Reporting Program.
    (4) FDA Form 3500A and instructions for completing the form are 
available on the Internet at http://www.fda.gov/medwatch/index.html.
    (e) Patient privacy. Manufacturers, packers, and distributors should 
not include in reports under this section the names and addresses of 
individual patients; instead, the manufacturer, packer, and distributor 
should assign a unique code number to each report, preferably not more 
than eight characters in length. The manufacturer, packer, and 
distributor should include the name of the reporter from whom the 
information was received. Names of patients, individual reporters, 
health care professionals, hospitals, and geographical identifiers in 
adverse drug experience reports are not releasable to the public under 
FDA's public information regulations in part 20 of this chapter.
    (f) Recordkeeping. (1) Each manufacturer, packer, and distributor 
shall maintain for a period of 10 years records of all adverse drug 
experiences required under this section to be reported, including raw 
data and any correspondence relating to the adverse drug experiences, 
and the records required to be maintained under paragraph (c)(4) of this 
section.
    (2) Manufacturers and packers may retain the records required in 
paragraph (f)(1) of this section as part of its complaint files 
maintained under Sec. 211.198 of this chapter.
    (3) Manufacturers, packers, and distributors shall permit any 
authorized FDA employee, at all reasonable times, to have access to and 
copy and verify the records established and maintained under this 
section.
    (g) Disclaimer. A report or information submitted by a manufacturer, 
packer, or distributor under this section (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by 
the manufacturer, packer, or distributor, or by FDA, that the report or 
information constitutes an admission that the drug caused or contributed 
to an adverse effect. The manufacturer, packer, or distributor need not 
admit, and may deny, that the report or information submitted under this 
section constitutes an admission that the drug caused or contributed to 
an adverse effect.

[51 FR 24479, July 3, 1986, as amended at 52 FR 37936, Oct. 13, 1987; 55 
FR 11578, Mar. 29, 1990; 57 FR 17980, Apr. 28, 1992; 62 FR 34167, June 
25, 1997; 62 FR 52249, Oct. 7, 1997; 67 FR 9585, Mar. 4, 2002; 74 FR 
13113, Mar. 26, 2009]



        Subpart E_Requirements for Specific New Drugs or Devices



Sec. 310.501  Patient package inserts for oral contraceptives.

    (a) Requirement for a patient package insert. The safe and effective 
use of oral contraceptive drug products requires that patients be fully 
informed of the benefits and the risks involved in their use. An oral 
contraceptive drug product that does not comply with the requirements of 
this section is misbranded under section 502 of the Federal Food, Drug, 
and Cosmetic Act. Each dispenser of an oral contraceptive drug product 
shall provide a patient package insert to each patient (or to an agent 
of the patient) to whom the product is dispensed, except that the 
dispenser may provide the insert to the

[[Page 21]]

parent or legal guardian of a legally incompetent patient (or to the 
agent of either). The patient package insert is required to be placed in 
or accompany each package dispensed to the patient.
    (b) Distribution requirements. (1) For oral contraceptive drug 
products, the manufacturer and distributor shall provide a patient 
package insert in or with each package of the drug product that the 
manufacturer or distributor intends to be dispensed to a patient.
    (2) Patient package inserts for oral contraceptives dispensed in 
acute-care hospitals or long-term care facilities will be considered to 
have been provided in accordance with this section if provided to the 
patient before administration of the first oral contraceptive and every 
30 days thereafter, as long as the therapy continues.
    (c) Contents of patient package insert. A patient package insert for 
an oral contraceptive drug product is required to contain the following:
    (1) The name of the drug.
    (2) A summary including a statement concerning the effectiveness of 
oral contraceptives in preventing pregnancy, the contraindications to 
the drug's use, and a statement of the risks and benefits associated 
with the drug's use.
    (3) A statement comparing the effectiveness of oral contraceptives 
to other methods of contraception.
    (4) A boxed warning concerning the increased risks associated with 
cigarette smoking and oral contraceptive use.
    (5) A discussion of the contraindications to use, including 
information that the patient should provide to the prescriber before 
taking the drug.
    (6) A statement of medical conditions that are not contraindications 
to use but deserve special consideration in connection with oral 
contraceptive use and about which the patient should inform the 
prescriber.
    (7) A warning regarding the most serious side effects of oral 
contraceptives.
    (8) A statement of other serious adverse reactions and potential 
safety hazards that may result from the use of oral contraceptives.
    (9) A statement concerning common, but less serious side effects 
which may help the patient evaluate the benefits and risks from the use 
of oral contraceptives.
    (10) Information on precautions the patients should observe while 
taking oral contraceptives, including the following:
    (i) A statement of risks to the mother and unborn child from the use 
of oral contraceptives before or during early pregnancy;
    (ii) A statement concerning excretion of the drug in human milk and 
associated risks to the nursing infant;
    (iii) A statement about laboratory tests which may be affected by 
oral contraceptives; and
    (iv) A statement that identifies activities and drugs, foods, or 
other substances the patient should avoid because of their interactions 
with oral contraceptives.
    (11) Information about how to take oral contraceptives properly, 
including information about what to do if the patient forgets to take 
the product, information about becoming pregnant after discontinuing use 
of the drug, a statement that the drug product has been prescribed for 
the use of the patient and should not be used for other conditions or 
given to others, and a statement that the patient's pharmacist or 
practitioner has a more technical leaflet about the drug product that 
the patient may ask to review.
    (12) A statement of the possible benefits associated with oral 
contraceptive use.
    (13) The following information about the drug product and the 
patient package insert:
    (i) The name and place of business of the manufacturer, packer, or 
distributor, or the name and place of business of the dispenser of the 
product.
    (ii) The date, identified as such, of the most recent revision of 
the patient package insert placed prominently immediately after the last 
section of the labeling.
    (d) Other indications. The patient package insert may identify 
indications in addition to contraception that are identified in the 
professional labeling for the drug product.
    (e) Labeling guidance texts. The Food and Drug Administration issues 
informal labeling guidance texts under

[[Page 22]]

Sec. 10.90(b)(9) of this chapter to provide assistance in meeting the 
requirements of this section. A request for a copy of the guidance texts 
should be directed to the Center for Drug Evaluation and Research, 
Division of Reproductive and Urologic Products, Food and Drug 
Administration, 10903 New Hampshire Ave., Silver Spring, MD 20993-0002.
    (f) Requirement to supplement approved application. Holders of 
approved applications for oral contraceptive drug products that are 
subject to the requirements of this section are required to submit 
supplements under Sec. 314.70(c) of this chapter to provide for the 
labeling required by this section. Such labeling may be put into use 
without advance approval by the Food and Drug Administration.

[54 FR 22587, May 25, 1989, as amended at 74 FR 13113, Mar. 26, 2009]



Sec. 310.502  Certain drugs accorded new drug status through rulemaking
procedures.

    (a) The drugs listed in this paragraph have been determined by 
rulemaking procedures to be new drugs within the meaning of section 
201(p) of the act. An approved new drug application under section 505 of 
the act and part 314 of this chapter is required for marketing the 
following drugs:
    (1) Aerosol drug products for human use containing 1,1,1-
trichloroethane.
    (2) Aerosol drug products containing zirconium.
    (3) Amphetamines (amphetamine, dextroamphetamine, and their salts, 
and levamfetamine and its salts) for human use.
    (4) Camphorated oil drug products.
    (5) Certain halogenated salicylanilides (tribromsalan (TBS, 3,4',5-
tribromosalicylanilide), dibromsalan (DBS, 4', 5-dibromosalicylanilide), 
metabromsalan (MBS, 3, 5-dibromosalicylanilide), and 3,3', 4,5'-
tetrachlorosalicylanilide (TC-SA)) as an ingredient in drug products.
    (6) Chloroform used as an ingredient (active or inactive) in drug 
products.
    (7) Cobalt preparations intended for use by man.
    (8) Intrauterine devices for human use for the purpose of 
contraception that incorporate heavy metals, drugs, or other active 
substances.
    (9) Oral prenatal drugs containing fluorides intended for human use.
    (10) Parenteral drug products in plastic containers.
    (11) Sterilization of drugs by irradiation.
    (12) Sweet spirits of nitre drug products.
    (13) Thorium dioxide for drug use.
    (14) Timed release dosage forms.
    (15) Vinyl chloride as an ingredient, including propellant, in 
aerosol drug products.
    (b) [Reserved]

[62 FR 12084, Mar. 14, 1997, as amended at 64 FR 401, Jan. 5, 1999]



Sec. 310.503  Requirements regarding certain radioactive drugs.

    (a) On January 8, 1963 (28 FR 183), the Commissioner of Food and 
Drugs exempted investigational radioactive new drugs from part 312 of 
this chapter provided they were shipped in complete conformity with the 
regulations issued by the Nuclear Regulatory Commission. This exemption 
also applied to investigational radioactive biologics.
    (b) It is the opinion of the Nuclear Regulatory Commission, and the 
Food and Drug Administration that this exemption should not apply for 
certain specific drugs and that these drugs should be appropriately 
labeled for uses for which safety and effectiveness can be demonstrated 
by new drug applications or through licensing under the Public Health 
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. Continued 
distribution under the investigational exemption when the drugs are 
intended for established uses will not be permitted.
    (c) Based on its experience in regulating investigational 
radioactive pharmaceuticals, the Nuclear Regulatory Commission has 
compiled a list of reactor-produced isotopes for which it considers that 
applicants may reasonably be expected to submit adequate evidence of 
safety and effectiveness for use as recommended in appropriate labeling. 
Such use may include, among others, the uses in this tabulation:

------------------------------------------------------------------------
        Isotope              Chemical form                 Use
------------------------------------------------------------------------
Chromium 51...........  Chromate...............  Spleen scans.

[[Page 23]]

 
 Do...................  ......do...............  Placenta localization.
 Do...................  ......do...............  Red blood cell labeling
                                                  and survival studies.
 Do...................  Labeled human serum      Gastrointestinal
                         albumin.                 protein loss studies.
 Do...................  ......do...............  Placenta localization.
 Do...................  Labeled red blood cells   Do.
Cobalt 58 or Cobalt 60  Labeled cyanocobalamin.  Intestinal absorption
                                                  studies.
Gold 198..............  Colloidal..............  Liver scans.
 Do...................  ......do...............  Intracavitary treatment
                                                  of pleural effusions
                                                  and/or ascites.
 Do...................  ......do...............  Interstitial treatment
                                                  of cancer.
Iodine 131............  Iodide.................  Diagnosis of thyroid
                                                  functions.
 Do...................  ......do...............  Thyroid scans.
 Do...................  ......do...............  Treatment of
                                                  hyperthyroidism and/or
                                                  cardiac dysfunction.
 Do...................  ......do...............  Treatment of thyroid
                                                  carcinoma.
 Do...................  Iodinated human serum    Blood volume
                         albumin.                 determinations.
 Do...................  ......do...............  Cisternography.
 Do...................  ......do...............  Brain tumor
                                                  localization.
 Do...................  ......do...............  Placenta localization.
 Do...................  ......do...............  Cardiac scans for
                                                  determination of
                                                  pericardial effusions.
 Do...................  Rose Bengal............  Liver function studies.
 Do...................  ......do...............  Liver scans.
 Do...................  Iodopyracet, sodium      Kidney function studies
                         iodohippurate, sodium    and kidney scans.
                         diatrizoate,
                         diatrizoate
                         methylglucamine,
                         sodium diprotrizoate,
                         sodium acetrizoate, or
                         sodium iothalamate.
 Do...................  Labeled fats and/or      Fat absorption studies.
                         fatty acids.
 Do...................  Cholografin............  Cardiac scans for
                                                  determination of
                                                  pericardial effusions.
 Do...................  Macroaggregated          Lung scans.
                         iodinated human serum
                         albumin.
 Do...................  Colloidal                Liver scans.
                         microaggregated human
                         serum albumin.
Iodine 125............  Iodide.................  Diagnosis of thyroid
                                                  function.
 Do...................  Iodinated human serum    Blood volume
                         albumin.                 determinations.
 Do...................  Rose Bengal............  Liver function studies.
 Do...................  Iodopyracet, sodium      Kidney function
                         iodohippurate, sodium    studies.
                         diatrizoate,
                         diatrizoate methyl-
                         glucamine, sodium
                         diprotrizoate, sodium
                         acetrizoate, or sodium
                         iothalamate.
 Do...................  Labeled fats and/or      Fat absorption studies.
                         fatty acids.
Iron 59...............  Chloride, citrate and/   Iron turnover studies.
                         or sulfate.
Krypton 85............  Gas....................  Diagnosis of cardiac
                                                  abnormalities.
Mercury 197...........  Chlormerodrin..........  Kidney scans.
 Do...................  ......do...............  Brain scans.
Mercury 203 \1\.......  ......do...............  Kidney scans.
 Do...................  ......do...............  Brain scans.
Phosphorus 32.........  Soluble phosphate......  Treatment of
                                                  polycythemia vera.
 Do...................  ......do...............  Treatment of leukemia
                                                  and bone metastasis.
 Do...................  Colloidal chromic        Intracavitary treatment
                         phosphate.               of pleural effusions
                                                  and/or ascites.
 Do...................  ......do...............  Interstitial treatment
                                                  of cancer.
Potassium 42..........  Chloride...............  Potassium space
                                                  studies.
Selenium 75...........  Labeled methionine.....  Pancreas scans.
Strontium 85..........  Nitrate or chloride....  Bone scans on patients
                                                  with diagnosed cancer.
Technetium 99m........  Pertechnetate..........  Brain scans.
 Do...................  ......do...............  Thyroid scans.
 Do...................  Sulfur colloid.........  Liver and spleen scans.
 Do...................  Pertechnetate..........  Placenta localization.
 Do...................  ......do...............  Blood pool scans.
 Do...................  ......do...............  Salivary gland scans.
 Do...................  Diethylenetri-amine      Kidney scans.
                         pentaacetic acid
                         (DTPA).
Xenon 133.............  Gas....................  Diagnosis of cardia
                                                  abnormalities.
                                                  Cerebral bloodflow
                                                  studies. Pulmonary
                                                  function studies.
                                                  Muscle bloodflow
                                                  studies.
------------------------------------------------------------------------
\1\ This item has been removed from the AEC list for kidney scans but is
  included as the requirements of this order are applicable.

    (d)(1) In view of the extent of experience with the isotopes listed 
in paragraph (c) of this section, the Nuclear Regulatory Commission and 
the Food and Drug Administration conclude that such isotopes should not 
be distributed under investigational-use labeling when they are actually 
intended for use in medical practice.
    (2) The exemption referred to in paragraph (a) of this section, as 
applied to

[[Page 24]]

any drug or biologic containing any of the isotopes listed in paragraph 
(c) of this section, in the ``chemical form'' and intended for the uses 
stated, is terminated on March 3, 1972, except as provided in paragraph 
(d)(3) of this section.
    (3) The exemption referred to in paragraph (a) of this section, as 
applied to any drug or biologic containing any of the isotopes listed in 
paragraph (c) of this section, in the ``chemical form'' and intended for 
the uses stated, for which drug a new drug application or a 
``Investigational New Drug Application'' was submitted prior to March 3, 
1972, or for which biologic an application for product license or 
``Investigational New Drug Application'' was submitted prior to March 3, 
1972, is terminated on August 20, 1976, unless an approvable notice was 
issued on or before August 20, 1976, in which case the exemption is 
terminated either upon the subsequent issuance of a nonapprovable notice 
for the new drug application or on November 20, 1976, whichever occurs 
first.
    (e) No exemption from section 505 of the act or from part 312 of 
this chapter is in effect or has been in effect for radioactive drugs 
prepared from accelerator-produced radioisotopes, naturally occurring 
isotopes, or nonradioactive substances used in conjunction with 
isotopes.
    (f)(1) Based on its experience in regulating investigational 
radioactive pharmaceuticals, the Nuclear Regulatory Commission has 
compiled a list of reactor-produced isotopes for which it considers that 
applicants may reasonably be expected to submit adequate evidence of 
safety and effectiveness for use as recommended in appropriate labeling; 
such use may include, among others, the uses in this tabulation:

------------------------------------------------------------------------
        Isotope              Chemical form                 Use
------------------------------------------------------------------------
Fluorine 18...........  Fluoride...............  Bone imaging.
Indium-113m...........  Diethylenetriamine       Brain imaging; kidney
                         pentaacetic acid         imaging.
                         (DTPA).
 Do...................  Chloride...............  Placenta imaging; blood
                                                  pool imaging.
Technetium 99m........  Human serum albumin      Lung imaging.
                         microspheres.
 Do...................  Diethylenetriamine       Kidney imaging; kidney
                         pentaacetic acid (Sn).   function studies.
 Do...................  ......do...............  Brain imaging.
 Do...................  Polyphosphates.........  Bone imaging.
 Do...................  Technetated aggregated   Lung imaging.
                         albumin (human).
 Do...................  Disodium etidronate....  Bone imaging.
------------------------------------------------------------------------

    (2) In view of the extent of experience with the isotopes listed in 
paragraph (f)(1) of this section, the Nuclear Regulatory Commission and 
the Food and Drug Administration conclude that they should not be 
distributed under investigational-use labeling when they are actually 
intended for use in medical practice.
    (3) Any manufacturer or distributor interested in continuing to ship 
in interstate commerce drugs containing the isotopes listed in paragraph 
(f)(1) of this section for any of the indications listed, shall submit, 
on or before August 25, 1975 to the Center for Drug Evaluation and 
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857, a new drug application or a ``Investigational New Drug 
Application'' for each such drug for which the manufacturer or 
distributor does not have an approved new drug application pursuant to 
section 505(b) of the act. If the drug is a biologic, a 
``Investigational New Drug Application'' or an application for a license 
under section 351 of the Public Health Service Act shall be submitted to 
the Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20014, in lieu of any 
submission to the Center for Drug Evaluation and Research.
    (4) The exemption referred to in paragraph (a) of this section, as 
applied to any drug or biologic containing any of the isotopes listed in 
paragraph (f)(1) of this section, in the ``chemical form'' and intended 
for the uses stated, is terminated on August 26, 1975 except as provided 
in paragraph (f)(5) of this section.
    (5)(i) Except as provided in paragraph (f)(5)(ii) of this section, 
the exemption referred to in paragraph (a) of this section, as applied 
to any drug containing any of the isotopes listed in paragraph (f)(1) of 
this section, in the ``chemical form'' and intended for the uses stated, 
for which drug a new drug application

[[Page 25]]

or ``Investigational New Drug Application'' was submitted to the Center 
for Drug Evaluation and Research on or before August 25, 1975 is 
terminated on August 20, 1976, unless an approvable notice was issued on 
or before August 20, 1976, in which case the exemption is terminated 
either upon the subsequent issuance of a nonapprovable notice for the 
new drug application or on November 20, 1976, whichever occurs first.
    (ii) The exemption referred to in paragraph (a) of this section, as 
applied to any biologic containing any of the isotopes listed in 
paragraph (f)(1) of this section in the ``chemical form'' and intended 
for the uses stated, for which biologic an application for product 
license or ``Investigational New Drug Application'' was submitted to the 
Center for Biologics Evaluation and Research on or before August 25, 
1975 is terminated on October 20, 1976, unless an approvable notice was 
issued on or before October 20, 1976, in which case the exemption is 
terminated either upon the subsequent issuance of a nonapprovable notice 
for the new drug application or on January 20, 1977, whichever occurs 
first.
    (g) The exemption referred to in paragraph (a) of this section, as 
applied to any drug intended solely for investigational use as part of a 
research project, which use had been approved on or before July 25, 1975 
in accordance with 10 CFR 35.11 (or equivalent regulation of an 
Agreement State) is terminated on February 20, 1976 if the manufacturer 
of such drug or the sponsor of the investigation of such drug submits on 
or before August 25, 1975 to the Food and Drug Administration, Bureau of 
Drugs, HFD-150, 5600 Fishers Lane, Rockville, MD 20857, the following 
information:
    (1) The research project title;
    (2) A brief description of the purpose of the project;
    (3) The name of the investigator responsible;
    (4) The name and license number of the institution holding the 
specific license under 10 CFR 35.11 (or equivalent regulation of an 
Agreement State);
    (5) The name and maximum amount per subject of the radionuclide 
used;
    (6) The number of subjects involved; and
    (7) The date on which the administration of the radioactive drugs is 
expected to be completed.
    (h) The exemption referred to in paragraph (a) of this section, as 
applied to any drug not referred to in paragraphs (d), (f), and (g) of 
this section, is terminated on August 26, 1975.

[39 FR 11680, Mar. 29, 1974, as amended at 40 FR 31307, July 25, 1975; 
40 FR 44543, Sept. 29, 1975; 41 FR 35171, Aug. 20, 1976; 41 FR 42947, 
Sept. 29, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990; 64 
FR 56449, Oct. 20, 1999]



Sec. 310.509  Parenteral drug products in plastic containers.

    (a) Any parenteral drug product packaged in a plastic immediate 
container is not generally recognized as safe and effective, is a new 
drug within the meaning of section 201(p) of the act, and requires an 
approved new drug application as a condition for marketing. An 
``Investigational New Drug Application'' set forth in part 312 of this 
chapter is required for clinical investigations designed to obtain 
evidence of safety and effectiveness.
    (b) As used in this section, the term ``large volume parenteral drug 
product'' means a terminally sterilized aqueous drug product packaged in 
a single-dose container with a capacity of 100 milliliters or more and 
intended to be administered or used intravenously in a human.
    (c) Until the results of compatibility studies are evaluated, a 
large volume parenteral drug product for intravenous use in humans that 
is packaged in a plastic immediate container on or after April 16, 1979, 
is misbranded unless its labeling contains a warning that includes the 
following information:
    (1) A statement that additives may be incompatible.
    (2) A statement that, if additive drugs are introduced into the 
parenteral system, aseptic techniques should be used and the solution 
should be thoroughly mixed.
    (3) A statement that a solution containing an additive drug should 
not be stored.
    (d) This section does not apply to a biological product licensed 
under the

[[Page 26]]

Public Health Service Act of July 1, 1944 (42 U.S.C. 201).

[62 FR 12084, Mar. 14, 1997]



Sec. 310.515  Patient package inserts for estrogens.

    (a) Requirement for a patient package insert. FDA concludes that the 
safe and effective use of drug products containing estrogens requires 
that patients be fully informed of the benefits and risks involved in 
the use of these drugs. Accordingly, except as provided in paragraph (e) 
of this section, each estrogen drug product restricted to prescription 
distribution, including products containing estrogens in fixed 
combinations with other drugs, shall be dispensed to patients with a 
patient package insert containing information concerning the drug's 
benefits and risks. An estrogen drug product that does not comply with 
the requirements of this section is misbranded under section 502(a) of 
the Federal Food, Drug, and Cosmetic Act.
    (b) Distribution requirements. (1) For estrogen drug products, the 
manufacturer and distributor shall provide a patient package insert in 
or with each package of the drug product that the manufacturer or 
distributor intends to be dispensed to a patient.
    (2) In the case of estrogen drug products in bulk packages intended 
for multiple dispensing, and in the case of injectables in multiple-dose 
vials, a sufficient number of patient labeling pieces shall be included 
in or with each package to assure that one piece can be included with 
each package or dose dispensed or administered to every patient. Each 
bulk package shall be labeled with instructions to the dispensor to 
include one patient labeling piece with each package dispensed or, in 
the case of injectables, with each dose administered to the patient. 
This section does not preclude the manufacturer or labeler from 
distributing additional patient labeling pieces to the dispensor.
    (3) Patient package inserts for estrogens dispensed in acute-care 
hospitals or long-term care facilities will be considered to have been 
provided in accordance with this section if provided to the patient 
before administration of the first estrogen and every 30 days 
thereafter, as long as the therapy continues.
    (c) Patient package insert contents. A patient package insert for an 
estrogen drug product is required to contain the following information:
    (1) The name of the drug.
    (2) The name and place of business of the manufacturer, packer, or 
distributor.
    (3) A statement regarding the benefits and proper uses of estrogens.
    (4) The contraindications to use, i.e., when estrogens should not be 
used.
    (5) A description of the most serious risks associated with the use 
of estrogens.
    (6) A brief summary of other side effects of estrogens.
    (7) Instructions on how a patient may reduce the risks of estrogen 
use.
    (8) The date, identified as such, of the most recent revision of the 
patient package insert.
    (d) Guidance language. The Food and Drug Administration issues 
informal labeling guidance texts under Sec. 10.90(b)(9) of this chapter 
to provide assistance in meeting the requirements of paragraph (c) of 
this section. Requests for a copy of the guidance text should be 
directed to the Center for Drug Evaluation and Research, Division of 
Reproductive and Urologic Products, Food and Drug Administration, 10903 
New Hampshire Ave., Silver Spring, MD 20993-0002.
    (e) Exemptions. This section does not apply to estrogen-progestogen 
oral contraceptives. Labeling requirements for these products are set 
forth in Sec. 310.501.
    (f) Requirement to supplement approved application. Holders of 
approved applications for estrogen drug products that are subject to the 
requirements of this section must submit supplements under Sec. 
314.70(c) of this chapter to provide for the labeling required by 
paragraph (a) of this section. Such labeling may be put into use without 
advance approval by the Food and Drug Administration.

[55 FR 18723, May 4, 1990, as amended at 74 FR 13113, Mar. 26, 2009]

[[Page 27]]



Sec. 310.517  Labeling for oral hypoglycemic drugs of the sulfonylurea
class.

    (a) The University Group Diabetes Program clinical trial has 
reported an association between the administration of tolbutamide and 
increased cardiovascular mortality. The Food and Drug Administration has 
concluded that this reported association provides adequate basis for a 
warning in the labeling. In view of the similarities in chemical 
structure and mode of action, the Food and Drug Administration also 
believes it is prudent from a safety standpoint to consider that the 
possible increased risk of cardiovascular mortality from tolbutamide 
applies to all other sulfonylurea drugs as well. Therefore, the labeling 
for oral hypoglycemic drugs of the sulfonylurea class shall include a 
warning concerning the possible increased risk of cardiovascular 
mortality associated with such use, as set forth in paragraph (b) of 
this section.
    (b) Labeling for oral hypoglycemic drugs of the sulfonylurea class 
shall include in boldface type at the beginning of the ``Warnings'' 
section of the labeling the following statement:

      Special Warning on Increased Risk of Cardiovascular Mortality

    The administration of oral hypoglycemic drugs has been reported to 
be associated with increased cardiovascular mortality as compared to 
treatment with diet alone or diet plus insulin. This warning is based on 
the study conducted by the University Group Diabetes Program (UGDP), a 
long-term prospective clinical trial designed to evaluate the 
effectiveness of glucose-lowering drugs in preventing or delaying 
vascular complications in patients with non-insulin-dependent diabetes. 
The study involved 823 patients who were randomly assigned to one of 
four treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970).
    UGDP reported that patients treated for 5 to 8 years with diet plus 
a fixed dose of tolbutamide (1.5 grams per day) had a rate of 
cardiovascular mortality approximately 2\1/2\ times that of patients 
treated with diet alone. A significant increase in total mortality was 
not observed, but the use of tolbutamide was discontinued based on the 
increase in cardiovascular mortality, thus limiting the opportunity for 
the study to show an increase in overall mortality. Despite controversy 
regarding the interpretation of these results, the findings of the UGDP 
study provide an adequate basis for this warning. The patient should be 
informed of the potential risks and advantages of (name of drug) and of 
alternative modes of therapy.
    Although only one drug in the sulfonylurea class (tolbutamide) was 
included in this study, it is prudent from a safety standpoint to 
consider that this warning may also apply to other oral hypoglycemic 
drugs in this class, in view of their close similarities in mode of 
action and chemical structure.

[49 FR 14331, Apr. 11, 1984]



Sec. 310.518  Drug products containing iron or iron salts.

    Drug products containing elemental iron or iron salts as an active 
ingredient in solid oral dosage form, e.g., tablets or capsules shall 
meet the following requirements:
    (a) Labeling. (1) The label of any drug in solid oral dosage form 
(e.g., tablets or capsules) that contains iron or iron salts for use as 
an iron source shall bear the following statement:

    WARNING: Accidental overdose or iron-containing products is a 
leading cause of fatal poisoning in children under 6. Keep this product 
out of reach of children. In case of accidental overdose, call a doctor 
or poison control center immediately.

    (2)(i) The warning statement required by paragraph (a)(1) of this 
section shall appear prominently and conspicuously on the information 
panel of the immediate container label.
    (ii) If a drug product is packaged in unit-dose packaging, and if 
the immediate container bears labeling but not a label, the warning 
statement required by paragraph (a)(1) of this section shall appear 
prominently and conspicuously on the immediate container labeling in a 
way that maximizes the likelihood that the warning is intact until all 
of the dosage units to which it applies are used.
    (3) Where the immediate container is not the retail package, the 
warning statement required by paragraph (a)(1) of this section shall 
also appear prominently and conspicuously on the information panel of 
the retail package label.
    (4) The warning statement shall appear on any labeling that contains 
warnings.
    (5) The warning statement required by paragraph (a)(1) of this 
section shall be set off in a box by use of hairlines.

[[Page 28]]

    (b) The iron-containing inert tablets supplied in monthly packages 
of oral contraceptives are categorically exempt from the requirements of 
paragraph (a) of this section.

[68 FR 59715, Oct. 17, 2003]



Sec. 310.519  Drug products marketed as over-the-counter (OTC) daytime
sedatives.

    (a) Antihistamines, bromides, and scopolamine compounds, either 
singly or in combinations, have been marketed as ingredients in over-
the-counter (OTC) drug products for use as daytime sedatives. The 
following claims have been made for daytime sedative products: 
``occasional simple nervous tension,'' ``nervous irritability,'' 
``nervous tension headache,'' ``simple nervousness due to common every 
day overwork and fatigue,'' ``a relaxed feeling,'' ``calming down and 
relaxing,'' ``gently soothe away the tension,'' ``calmative,'' 
``resolving that irritability that ruins your day,'' ``helps you 
relax,'' ``restlessness,'' ``when you're under occasional stress . . . 
helps you work relaxed.'' Based on evidence presently available, there 
are no ingredients that can be generally recognized as safe and 
effective for use as OTC daytime sedatives.
    (b) Any OTC drug product that is labeled, represented, or promoted 
as an OTC daytime sedative (or any similar or related indication) is 
regarded as a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act for which an approved new drug 
application under section 505 of the act and part 314 of this chapter is 
required for marketing.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted as an OTC daytime 
sedative (or any similar or related indication) is safe and effective 
for the purpose intended must comply with the requirements and 
procedures governing the use of investigational new drugs set forth in 
part 312 of this chapter.
    (d) Any OTC daytime sedative drug product introduced into interstate 
commerce after December 24, 1979, that is not in compliance with this 
section is subject to regulatory action.

[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at 
55 FR 11579, Mar. 29, 1990]



Sec. 310.527  Drug products containing active ingredients offered 
over-the-counter (OTC) for external use as hair growers or for hair 

loss prevention.

    (a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid, 
biotin and all other B-vitamins, dexpanthenol, estradiol and other 
topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20, 
polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction 
of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat 
germ oil have been marketed as ingredients in OTC drug products for 
external use as hair growers or for hair loss prevention. There is a 
lack of adequate data to establish general recognition of the safety and 
effectiveness of these or any other ingredients intended for OTC 
external use as a hair grower or for hair loss prevention. Based on 
evidence currently available, all labeling claims for OTC hair grower 
and hair loss prevention drug products for external use are either 
false, misleading, or unsupported by scientific data. Therefore, any OTC 
drug product for external use containing an ingredient offered for use 
as a hair grower or for hair loss prevention cannot be considered 
generally recognized as safe and effective for its intended use.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for external use as a hair grower or for hair loss prevention is 
regarded as a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act), for which an approved 
new drug application under section 505 of the act and part 314 of this 
chapter is required for marketing. In the absence of an approved new 
drug application, such product is also misbranded under section 502 of 
the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC external use as a 
hair grower or for hair loss prevention is safe and effective for the 
purpose intended must

[[Page 29]]

comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After January 8, 1990, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[54 FR 28777, July 7, 1989]



Sec. 310.528  Drug products containing active ingredients offered
over-the-counter (OTC) for use as an aphrodisiac.

    (a) Any product that bears labeling claims that it will arouse or 
increase sexual desire, or that it will improve sexual performance, is 
an aphrodisiac drug product. Anise, cantharides, don qual, estrogens, 
fennel, ginseng, golden seal, gotu kola, Korean ginseng, licorice, 
mandrake, methyltestosterone, minerals, nux vomica, Pega Palo, 
sarsaparilla, strychnine, testosterone, vitamins, yohimbine, yohimbine 
hydrochloride, and yohimbinum have been present as ingredients in such 
drug products. Androgens (e.g., testosterone and methyltestosterone) and 
estrogens are powerful hormones when administered internally and are not 
safe for use except under the supervision of a physician. There is a 
lack of adequate data to establish general recognition of the safety and 
effectiveness of any of these ingredients, or any other ingredient, for 
OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use 
are either false, misleading, or unsupported by scientific data. The 
following claims are examples of some that have been made for 
aphrodisiac drug products for OTC use: ``acts as an aphrodisiac;'' 
``arouses or increases sexual desire and improves sexual performance;'' 
``helps restore sexual vigor, potency, and performance;'' ``improves 
performance, staying power, and sexual potency;'' and ``builds virility 
and sexual potency.'' Based on evidence currently available, any OTC 
drug product containing ingredients for use as an aphrodisiac cannot be 
generally recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, or prompted 
for use as an aphrodisiac is regarded as a new drug within the meaning 
of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the 
act), for which an approved new drug application under section 505 of 
the act and part 314 of this chapter is required for marketing. In the 
absence of an approved new drug application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as an 
aphrodisiac is safe and effective for the purpose intended must comply 
with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After January 8, 1990, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[54 FR 28786, July 7, 1989]



Sec. 310.529  Drug products containing active ingredients offered 
over-the-counter (OTC) for oral use as insect repellents.

    (a) Thiamine hydrochloride (vitamin B-1) has been marketed as an 
ingredient in over-the-counter (OTC) drug products for oral use as an 
insect repellent (an orally administered drug product intended to keep 
insects away). There is a lack of adequate data to establish the 
effectiveness of this, or any other ingredient for OTC oral use as an 
insect repellent. Labeling claims for OTC orally administered insect 
repellent drug products are either false, misleading, or unsupported by 
scientific data. The following claims are examples of some that have 
been made for orally administered OTC insect repellent drug products: 
``Oral mosquito repellent,'' ``mosquitos avoid you,'' ``bugs stay 
away,'' ``keep mosquitos away for 12 to 24 hours,'' and ``the newest way 
to fight mosquitos.'' Therefore, any drug product containing ingredients 
offered for oral use as an insect repellent cannot be generally 
recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for oral use as an insect repellent is regarded as

[[Page 30]]

a new drug within the meaning of section 201(p) of the Federal Food, 
Drug and Cosmetic Act for which an approved new drug application under 
section 505 of the act and part 314 of this chapter is required for 
marketing. In the absence of an approved new drug application, such 
product is also misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted OTC for oral use as an 
insect repellent is safe and effective for the purpose intended must 
comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) Any such drug product in interstate commerce after December 17, 
1985, that is not in compliance with this section is subject to 
regulatory action.

[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]



Sec. 310.530  Topically applied hormone-containing drug products for 
over-the-counter (OTC) human use.

    (a) The term ``hormone'' is used broadly to describe a chemical 
substance formed in some organ of the body, such as the adrenal glands 
or the pituitary, and carried to another organ or tissue, where it has a 
specific effect. Hormones include, for example, estrogens, progestins, 
androgens, anabolic steroids, and adrenal corticosteroids, and synthetic 
analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate 
have been present as ingredients in OTC drug products marketed for 
topical use as hormone creams. However, there is a lack of adequate data 
to establish effectiveness for any OTC drug use of these ingredients. 
Therefore, with the exception of those hormones identified in paragraph 
(e) of this section, any OTC drug product containing an ingredient 
offered for use as a topically applied hormone cannot be considered 
generally recognized as safe and effective for its intended use. The 
intended use of the product may be inferred from the product's labeling, 
promotional material, advertising, and any other relevant factor. The 
use of the word ``hormone'' in the text of the labeling or in the 
ingredient statement is an implied drug claim. The claim implied by the 
use of this term is that the product will have a therapeutic or some 
other physiological effect on the body. Therefore, reference to a 
product as a ``hormone cream'' or any statement in the labeling 
indicating that ``hormones'' are present in the product, or any 
statement that features or emphasizes the presence of a hormone 
ingredient in the product, will be considered to be a therapeutic claim 
for the product, or a claim that the product will affect the structure 
or function of the body, and will consequently cause the product to be a 
drug.
    (b) Any OTC drug product that is labeled, represented, or promoted 
as a topically applied hormone-containing product for drug use, with the 
exception of those hormones identified in paragraph (e) of this section, 
is regarded as a new drug within the meaning of section 201(p) of the 
act, for which an approved application or abbreviated application under 
section 505 of the act and part 314 of this chapter is required for 
marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as a 
topically applied hormone-containing drug product is safe and effective 
for the purpose intended must comply with the requirements and 
procedures governing the use of investigational new drugs set forth in 
part 312 of this chapter.
    (d) After March 9, 1994, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.
    (e) This section does not apply to hydrocortisone and hydrocortisone 
acetate labeled, represented, or promoted for OTC topical use in 
accordance with part 348 of this chapter.

[58 FR 47610, Sept. 9, 1993]

[[Page 31]]



Sec. 310.531  Drug products containing active ingredients offered 
over-the-counter (OTC) for the treatment of boils.

    (a) Aminacrine hydrochloride, benzocaine, bismuth subnitrate, 
calomel, camphor, cholesterol, ergot fluid extract, hexachlorophene, 
ichthammol, isobutamben, juniper tar (oil of cade), lanolin, magnesium 
sulfate, menthol, methyl salicylate, oxyguinoline sulfate, petrolatum, 
phenol, pine tar, rosin, rosin cerate, sassafras oil, sulfur, thymol, 
triclosan, and zinc oxide have been present in OTC boil treatment drug 
products. There is a lack of adequate data to establish general 
recognition of the safety and effectiveness of these or any other 
ingredient for OTC use for the treatment of boils. Treatment is defined 
as reducing the size of a boil or reducing an infection related to a 
boil. Treatment has involved the use of ``drawing salves'' for these 
purposes. These ``drawing salves'' contained various ingredients. Based 
on evidence currently available, any OTC drug product offered for the 
treatment of boils cannot be considered generally recognized as safe and 
effective.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for the treatment of boils is regarded as a new drug within the meaning 
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), 
for which an approved application or abbreviated application under 
section 505 of the act and part 314 of this chapter is required for 
marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any OTC 
boil treatment drug product is safe and effective for the purpose 
intended must comply with the requirements and procedures governing the 
use of investigational new drugs set forth in part 312 of this chapter.
    (d) After May 7, 1991, any such OTC drug product that contains 
aminacrine hydrochloride, bismuth subnitrate, calomel, camphor, 
cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper 
tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl 
salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin, 
rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced 
or initially delivered for introduction into interstate commerce that is 
not in compliance with this section is subject to regulatory action.
    (e) After May 16, 1994, any such OTC drug product that contains 
benzocaine, ichthammol, sulfur, or triclosan initially introduced or 
initially delivered for introduction into interstate commerce that is 
not in compliance with this section is subject to regulatory action.
    (f) This section does not apply to drug products that contain 
benzocaine labeled, represented, or promoted for OTC topical use in 
accordance with part 348 of this chapter.

[58 FR 60336, Nov. 15, 1993]



Sec. 310.532  Drug products containing active ingredients offered
over-the-counter (OTC) to relieve the symptoms of benign prostatic

hypertrophy.

    (a) The amino acids glycine, alanine, and glutamic acid (alone or in 
combination) and the ingredient sabal have been present in over-the-
counter (OTC) drug products to relieve the symptoms of benign prostatic 
hypertrophy, e.g., urinary urgency and frequency, excessive urinating at 
night, and delayed urination. There is a lack of adequate data to 
establish general recognition of the safety and effectiveness of these 
or any other ingredients for OTC use in relieving the symptoms of benign 
prostatic hypertrophy. In addition, there is no definitive evidence that 
any drug product offered for the relief of the symptoms of benign 
prostatic hypertrophy would alter the obstructive or inflammatory signs 
and symptoms of this condition. Therefore, self-medication with OTC drug 
products might unnecessarily delay diagnosis and treatment of 
progressive obstruction and secondary infections. Based on evidence 
currently available, any OTC drug product containing ingredients offered 
for use in relieving the symptoms of benign prostatic hypertrophy cannot 
be generally recognized as safe and effective.

[[Page 32]]

    (b) Any OTC drug product that is labeled, represented, or promoted 
to relieve the symptoms of benign prostatic hypertrophy is regarded as a 
new drug within the meaning of section 201(p) of the Federal Food, Drug, 
and Cosmetic Act (the act), for which an approved application under 
section 505 of the act and part 314 of this chapter is required for 
marketing. In the absence of an approved application, such product is 
also misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use to relieve 
the symptoms of benign prostatic hypertrophy is safe and effective for 
the purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After August 27, 1990, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[55 FR 6930, Feb. 27, 1990]



Sec. 310.533  Drug products containing active ingredients offered 
over-the-counter (OTC) for human use as an anticholinergic in

cough-cold drug products.

    (a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids 
as contained in Atropa belladonna and Datura stramonium have been 
present as ingredients in cough-cold drug products for use as an 
anticholinergic. Anticholinergic drugs have been marketed OTC in cough-
cold drug products to relieve excessive secretions of the nose and eyes, 
symptoms that are commonly associated with hay fever, allergy, rhinitis, 
and the common cold. Atropine sulfate for oral use as an anticholinergic 
is probably safe at dosages that have been used in marketed cough-cold 
products (0.2 to 0.3 milligram); however, there are inadequate data to 
establish general recognition of the effectiveness of this ingredient. 
The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and 
scopolamine (l- hyoscine), are probably safe for oral use at dosages 
that have been used in marketed cough-cold products (0.2 milligram) but 
there are inadequate data to establish general recognition of the 
effectiveness of these ingredients as an anticholinergic for cough-cold 
use. Belladonna alkaloids for inhalation use, as contained in Atropa 
belladonna and Datura stramonium, are neither safe nor effective as an 
OTC anticholinergic. There are inadequate safety and effectiveness data 
to establish general recognition of the safety and/or effectiveness or 
any of these ingredients, or any other ingredient, for OTC use as an 
anticholinergic in cough-cold drug products.
    (b) Any OTC cough-cold drug product that is labeled, represented, or 
promoted for use as an anticholinergic is regarded as a new drug within 
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic 
Act, for which an approved new drug application under section 505 of the 
act and part 314 of this chapter is required for marketing. In the 
absence of an approved new drug application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
cough-cold drug product labeled, represented, or promoted for OTC use as 
an anticholinergic is safe and effective for the purpose intended must 
comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After the effective date of the final regulation, any such OTC 
cough-cold drug product that is labeled, represented, or promoted for 
use as an anticholinergic may not be initially introduced or initially 
delivered for introduction into interstate commerce unless it is the 
subject of an approved new drug application.

[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]



Sec. 310.534  Drug products containing active ingredients offered
over-the-counter (OTC) for human use as oral wound healing agents.

    (a) Allantoin, carbamide peroxide in anhydrous glycerin, water 
soluble chlorophyllins, and hydrogen peroxide in aqueous solution have 
been present in oral mucosal injury drug products

[[Page 33]]

for use as oral wound healing agents. Oral wound healing agents have 
been marketed as aids in the healing of minor oral wounds by means other 
than cleansing and irrigating, or by serving as a protectant. Allantoin, 
carbamide peroxide in anhydrous glycerin, water soluble chlorophyllins, 
and hydrogen peroxide in aqueous solution are safe for use as oral wound 
healing agents, but there are inadequate data to establish general 
recognition of the effectiveness of these ingredients as oral wound 
healing agents.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for use as an oral wound healing agent is regarded as a new drug within 
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic 
Act, for which an approved new drug application under section 505 of the 
act and part 314 of this chapter is required for marketing. In the 
absence of an approved new drug application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as an oral 
wound healing agent is safe and effective for the purpose intended must 
comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After the effective date of the final regulation, any OTC drug 
product that is labeled, represented, or promoted for use as an oral 
wound healing agent may not be initially introduced or initially 
delivered for introduction into interstate commerce unless it is the 
subject of an approved new drug application.

[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]



Sec. 310.536  Drug products containing active ingredients offered 
over-the-counter (OTC) for use as a nailbiting or thumbsucking 

deterrent.

    (a) Denatonium benzoate and sucrose octaacetate have been present in 
OTC nailbiting and thumbsucking deterrent drug products. There is a lack 
of adequate data to establish general recognition of the safety and 
effectiveness of these and any other ingredients (e.g., cayenne pepper) 
for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence 
currently available, any OTC drug product containing ingredients offered 
for use as a nailbiting or thumbsucking deterrent cannot be generally 
recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, and promoted 
as a nailbiting or thumbsucking deterrent is regarded as a new drug 
within the meaning of section 201(p) of the Federal Food, Drug, and 
Cosmetic Act (the act) for which an approved application or abbreviated 
application under section 505 of the act and part 314 of this chapter is 
required for marketing. In the absence of an approved new drug 
application or abbreviated new drug application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as a 
nailbiting or thumbsucking deterrent is safe and effective for the 
purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After March 2, 1994, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[58 FR 46754, Sept. 2, 1993]



Sec. 310.537  Drug products containing active ingredients offered 
over-the-counter (OTC) for oral administration for the treatment 

of fever blisters and cold sores.

    (a) l-lysine (lysine, lysine hydrochloride), Lactobacillus 
acidophilus, and Lactobacillus bulgaricus have been present in orally 
administered OTC drug products to treat fever blisters and cold sores. 
There is a lack of adequate data to establish general recognition of the 
safety and effectiveness of these or any other orally administered 
ingredients for OTC use to treat or relieve the symptoms or discomfort 
of fever blisters and cold sores. Based on evidence currently available, 
any

[[Page 34]]

OTC drug product for oral administration containing ingredients offered 
for use in treating or relieving the symptoms or discomfort of fever 
blisters and cold sores cannot be generally recognized as safe and 
effective.
    (b) Any OTC drug product for oral administration that is labeled, 
represented, or promoted to treat or relieve the symptoms or discomfort 
of fever blisters and cold sores is regarded as a new drug within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
(the act), for which an approved application under section 505 of the 
act and part 314 of this chapter is required for marketing. In the 
absence of an approved application, such product is also misbranded 
under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product for oral administration labeled, represented, or promoted 
for OTC use to treat or relieve the symptoms or discomfort of fever 
blisters and cold sores is safe and effective for the purpose intended 
must comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After December 30, 1992, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[57 FR 29173, June 30, 1992]



Sec. 310.538  Drug products containing active ingredients offered 
over-the-counter (OTC) for use for ingrown toenail relief.

    (a) Any product that bears labeling claims such as for ``temporary 
relief of discomfort from ingrown toenails,'' or ``ingrown toenail 
relief product,'' or ``ingrown toenail reliever,'' or similar claims is 
considered an ingrown toenail relief drug product. Benzocaine, 
chlorobutanol, chloroxylenol, dibucaine, tannic acid, and urea have been 
present as ingredients in such products. There is lack of adequate data 
to establish general recognition of the safety and effectiveness of 
these or any other ingredients for OTC use for ingrown toenail relief. 
Based on evidence currently available, any OTC drug product containing 
ingredients offered for use for ingrown toenail relief cannot be 
generally recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for ingrown toenail relief is regarded as a new drug within the meaning 
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act), 
for which an approved application or abbreviated application under 
section 505 of the act and part 314 of this chapter is required for 
marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use for ingrown 
toenail relief is safe and effective for the purpose intended must 
comply with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After March 9, 1994, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.
    (e) This section does not apply to sodium sulfide labeled, 
represented, or promoted for OTC topical use for ingrown toenail relief 
in accordance with part 358, subpart D of this chapter, after June 6, 
2003.

[58 FR 47605, Sept. 9, 1993, as amended at 68 FR 24348, May 7, 2003]



Sec. 310.540  Drug products containing active ingredients offered 
over-the-counter (OTC) for use as stomach acidifiers.

    (a) Betaine hydrochloride, glutamic acid hydrochloride, diluted 
hydrochloric acid, and pepsin have been present as ingredients in over-
the-counter (OTC) drug products for use as stomach acidifiers. Because 
of the lack of adequate data to establish the effectiveness of these or 
any other ingredients for use in treating achlorhydria and 
hypochlorhydria, and because such conditions are asymptomatic, any OTC 
drug product containing ingredients offered for use as a stomach 
acidifier

[[Page 35]]

cannot be considered generally recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for use as a stomach acidifier is regarded as a new drug within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act, 
for which an approved new drug application under section 505 of the act 
and part 314 of this chapter is required for marketing. In the absence 
of an approved new drug application, such product is also misbranded 
under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted as a stomach acidifier 
for OTC use is safe and effective for the purpose intended must comply 
with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After the effective date of the final regulation, any such OTC 
drug product initially introduced or initially delivered for 
introduction into interstate commerce that is not in compliance with 
this section is subject to regulatory action.

[53 FR 31271, Aug. 17, 1988]



Sec. 310.541  Over-the-counter (OTC) drug products containing 
active ingredients offered for use in the treatment of 

hypophosphatemia.

    (a) Hypophosphatemia is a condition in which an abnormally low 
plasma level of phosphate occurs in the blood. This condition is not 
amenable to self-diagnosis or self-treatment. Treatment of this 
condition should be restricted to the supervision of a physician. For 
this reason, any drug product containing ingredients offered for OTC use 
in the treatment of hypophosphatemia cannot be considered generally 
recognized as safe and effective.
    (b) Any drug product that is labeled, represented, or promoted for 
OTC use in the treatment of hypophosphatemia is regarded as a new drug 
within the meaning of section 201(p) of the Federal Food, Drug, and 
Cosmetic Act (the act), for which an approved application under section 
505 of the act and part 314 of this chapter is required for marketing. 
In the absence of an approved application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use in the 
treatment of hypophosphatemia is safe and effective for the purpose 
intended must comply with the requirements and procedures governing the 
use of investigational new drugs set forth in part 312 of his chapter.
    (d) After November 12, 1990, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[55 FR 19858, May 11, 1990]



Sec. 310.542  Over-the-counter (OTC) drug products containing active 
ingredients offered for use in the treatment of hyperphosphatemia.

    (a) Hyperphosphatemia is a condition in which an abnormally high 
plasma level of phosphate occurs in the blood. This condition in not 
amenable to self-diagnosis or self-treatment. Treatment of this 
condition should be restricted to the supervision of a physician. For 
this reason, any drug product containing ingredients offered for OTC use 
in the treatment of hyperphosphatemia cannot be considered generally 
recognized as safe and effective.
    (b) Any drug product that is labeled, represented, or promoted for 
OTC use in the treatment of hyperphosphatemia is regarded as a new drug 
within the meaning of section 201(p) of the Federal Food, Drug, and 
Cosmetic Act (the act), for which an approved application under section 
505 of the act and part 314 of this chapter is required for marketing. 
In the absence of an approved application, such product is also 
misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for use in the treatment 
of hyperphosphatemia is safe and effective for the purpose intended must 
comply with the requirements and procedures governing use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After November 12, 1990, any such OTC drug product initially 
introduced

[[Page 36]]

or initially delivered for introduction into interstate commerce that is 
not in compliance with this section is subject to regulatory action.

[55 FR 19858, May 11, 1990]



Sec. 310.543  Drug products containing active ingredients offered
over-the-counter (OTC) for human use in exocrine pancreatic 

insufficiency.

    (a) Hemicellulase, pancreatin, and pancrelipase have been present as 
ingredients in exocrine pancreatic insufficiency drug products. 
Pancreatin and pancrelipase are composed of enzymes: amylase, trypsin 
(protease), and lipase. Significant differences have been shown in the 
bioavailability of marketed exocrine pancreatic insufficiency drug 
products produced by different manufacturers. These differences raise a 
potential for serious risk to patients using these drug products. The 
bioavailability of pancreatic enzymes is dependent on the process used 
to manufacture the drug products. Information on this process is not 
included in an OTC drug monograph. Therefore, the safe and effective use 
of these enzymes for treating exocrine pancreatic insufficiency cannot 
be regulated adequately by an OTC drug monograph. Information on the 
product's formulation, manufacture, quality control procedures, and 
final formulation effectiveness testing are necessary in an approved 
application to ensure that a company has the ability to manufacture a 
proper bioactive formulation. In addition, continuous physician 
monitoring of patients who take these drug products is a collateral 
measure necessary to the safe and effective use of these enzymes, 
causing such products to be available by prescription only.
    (b) Any drug product that is labeled, represented, or promoted for 
OTC use in the treatment of exocrine pancreatic insufficiency is 
regarded as a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act), for which an approved 
application under section 505 of the act and part 314 of this chapter is 
required for marketing. In the absence of an approved application, such 
product is also misbranded under section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use in the 
treatment of exocrine pancreatic insufficiency is safe and effective for 
the purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After May 7, 1991, any such OTC drug product that contains 
hemicellulase initially introduced or initially delivered for 
introduction into interstate commerce that is not in compliance with 
this section is subject to regulatory action.
    (e) After October 24, 1995, any such OTC drug product that contains 
pancreatin or pancrelipase initially introduced or initially delivered 
for introduction into interstate commerce that is not in compliance with 
this section is subject to regulatory action.

[60 FR 20165, Apr. 24, 1995]



Sec. 310.544  Drug products containing active ingredients offered 
over-the-counter (OTC) for use as a smoking deterrent.

    (a) Any product that bears labeling claims that it ``helps stop or 
reduce the cigarette urge,'' ``helps break the cigarette habit,'' 
``helps stop or reduce smoking,'' or similar claims is a smoking 
deterrent drug product. Cloves, coriander, eucalyptus oil, ginger 
(Jamaica), lemon oil (terpeneless), licorice root extract, lobeline (in 
the form of lobeline sulfate or natural lobelia alkaloids or Lobelia 
inflata herb), menthol, methyl salicylate, povidone-silver nitrate, 
quinine ascorbate, silver acetate, silver nitrate, and thymol have been 
present as ingredients in such drug products. There is a lack of 
adequate data to establish general recognition of the safety and 
effectiveness of these or any other ingredients for OTC use as a smoking 
deterrent. Based on evidence currently available, any OTC drug product 
containing ingredients offered for use as a smoking deterrent cannot be 
generally recognized as safe and effective.
    (b) Any OTC drug product that is labeled, represented, or promoted 
as a smoking deterrent is regarded as a new drug within the meaning of 
section

[[Page 37]]

201(p) of the Federal Food, Drug, and Cosmetic Act (the act), for which 
an approved application or abbreviated application under section 505 of 
the act and part 314 of this chapter is required for marketing. In the 
absence of an approved new drug application or abbreviated new drug 
application, such product is also misbranded under section 502 of the 
act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use as a smoking 
deterrent is safe and effective for the purpose intended must comply 
with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) After May 7, 1991, any such OTC drug product containing cloves, 
coriander, eucalyptus oil, ginger (Jamaica), lemon oil (terpeneless), 
licorice root extract, menthol, methyl salicylate, quinine ascorbate, 
silver nitrate, and/or thymol initially introduced or initially 
delivered for introduction into interstate commerce that is not in 
compliance with this section is subject to regulatory action. After 
December 1, 1993, any such OTC drug product containing lobeline (in the 
form of lobeline sulfate or natural lobelia alkaloids or Lobelia inflata 
herb), povidone-silver nitrate, silver acetate, or any other ingredients 
initially introduced or initially delivered for introduction into 
interstate commerce that is not in compliance with this section is 
subject to regulatory action.

[58 FR 31241, June 1, 1993]



Sec. 310.545  Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.

    (a) A number of active ingredients have been present in OTC drug 
products for various uses, as described below. However, based on 
evidence currently available, there are inadequate data to establish 
general recognition of the safety and effectiveness of these ingredients 
for the specified uses:
    (1) Topical acne drug products.

Alcloxa
Alkyl isoquinolinium bromide
Aluminum chlorohydrex
Aluminum hydroxide
Benzocaine
Benzoic acid
Boric acid
Calcium polysulfide
Calcium thiosulfate
Camphor
Chloroxylenol
Cloxyquin
Coal tar
Dibenzothiophene
Estrone
Magnesium aluminum silicate
Magnesium sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Povidone-iodine
Pyrilamine maleate
Resorcinol (as single ingredient)
Resorcinol monoacetate (as single ingredient)
Salicylic acid (over 2 up to 5 percent)
Sodium borate
Sodium thiosulfate
Tetracaine hydrochloride
Thymol
Vitamin E
Zinc oxide
Zinc stearate
Zinc sulfide

    (2) Anticaries drug products--(i) Approved as of May 7, 1991.

Hydrogen fluoride
Sodium carbonate
Sodium monofluorophosphate (6 percent rinse)
Sodium phosphate

    (ii) Approved as of October 7, 1996.

Calcium sucrose phosphate
Dicalcium phosphate dihydrate
Disodium hydrogen phosphate \1\
---------------------------------------------------------------------------

    \1\ These ingredients are nonmonograph except when used to prepare 
acidulated phosphate fluoride treatment rinses identified in Sec. 
355.10(a)(3) of this chapter.
---------------------------------------------------------------------------

Phosphoric acid \1\
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent \1\

    (3) Antidiarrheal drug products--(i) Approved as of May 7, 1991.

Aluminum hydroxide
Atropine sulfate
Calcium carbonate
Carboxymethylcellulose sodium
Glycine
Homatropine methylbromide
Hyoscyamine sulfate
Lactobacillus acidophilus
Lactobacillus bulgaricus

[[Page 38]]

Opium, powdered
Opium tincture
Paregoric
Phenyl salicylate
Scopolamine hydrobromide
Zinc phenolsulfonate

    (ii) Approved as of April 19, 2004; April 18, 2005, for products 
with annual sales less than $25,000.

Attapulgite, activated
Bismuth subnitrate
Calcium hydroxide
Calcium polycarbophil
Charcoal (activated)
Pectin
Polycarbophil
Potassium carbonate
Rhubarb fluidextract

    (4) Antiperspirant drug products--(i) Ingredients--Approved as of 
May 7, 1991.

Alum, potassium
Aluminum bromohydrate
Aluminum chloride (alcoholic solutions)
Aluminum chloride (aqueous solution) (aerosol only)
Aluminum sulfate
Aluminum sulfate, buffered (aerosol only)
Sodium aluminum chlorohydroxy lactate

    (ii) Approved as of December 9, 2004; June 9, 2005, for products 
with annual sales less than $25,000.

Aluminum sulfate buffered with sodium aluminum lactate

    (5) [Reserved]
    (6) Cold, cough, allergy, bronchodilator, and antiasthmatic drug 
products--(i) Antihistamine drug products--(A) Ingredients.

Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride

    (B) Ingredients.

Phenyltoloxamine dihydrogen citrate
Methapyrilene hydrochloride
Methapyrilene fumarate
Thenyldiamine hydrochloride

    (ii) Nasal decongestant drug products--(A) Approved as of May 7, 
1991.

Allyl isothiocyanate
Camphor (lozenge)
Creosote, beechwood (oral)
Eucalyptol (lozenge)
Eucalyptol (mouthwash)
Eucalyptus oil (lozenge)
Eucalyptus oil (mouthwash)
Menthol (mouthwash)
Peppermint oil (mouthwash)
Thenyldiamine hydrochloride
Thymol
Thymol (lozenge)
Thymol (mouthwash)
Turpentine oil

    (B) Approved as of August 23, 1995.

Bornyl acetate (topical)
Cedar leaf oil (topical)
Creosote, beechwood (topical)
Ephedrine (oral)
Ephedrine hydrochloride (oral)
Ephedrine sulfate (oral)
Racephedrine hydrochloride (oral/topical)

    (C) Approved as of April 11, 2007; October 11, 2007, for products 
with annual sales less than $25,000. Any ingredient(s) labeled with 
claims or directions for use for sinusitis or for relief of nasal 
congestion associated with sinusitis.
    (iii) Expectorant drug products.

Ammonium chloride
Antimony potassium tartrate
Beechwood creosote
Benzoin preparations (compound tincture of benzoin, tincture of benzoin)
Camphor
Chloroform
Eucalyptol/eucalyptus oil
Horehound
Iodides (calcium iodide anyhydrous, hydroidic acid syrup, iodized lime, 
potassium iodide)
Ipecac
Ipecac fluidextract
Ipecac syrup
Menthol/peppermint oil
Pine tar preparations (extract white pine compound, pine tar, syrup of 
pine tar, compound white pine syrup, white pine)
Potassium guaiacolsulfonate
Sodium citrate
Squill preparations (squill, squill extract)
Terpin hydrate preparations (terpin hydrate, terpin hydrate elixir)
Tolu preparations (tolu, tolu balsam, tolu balsam tincture)
Turpentine oil (spirits of turpentine)

    (iv) Bronchodilator drug products--(A) Approved as of October 2, 
1987.

Aminophylline
Belladonna alkaloids
Euphorbia pilulifera
Metaproterenol sulfate
Methoxyphenamine hydrochloride
Pseudoephedrine hydrochloride
Pseudoephedrine sulfate
Theophylline, anhydrous
Theophylline calcium salicylate
Theophylline sodium glycinate

    (B) Approved as of January 29, 1996. Any combination drug product 
containing theophylline (e.g., theophylline

[[Page 39]]

and ephedrine, or theophylline and ephedrine and phenobarbital).
    (C) Approved as of June 19, 1996. Any ingredient(s) in a pressurized 
metered-dose inhaler container.
    (D) Approved as of October 29, 2001. Any oral bronchodilator active 
ingredient (e.g., ephedrine, ephedrine hydrochloride, ephedrine sulfate, 
racephedrine hydrochloride, or any other ephedrine salt) in combination 
with any analgesic(s) or analgesic-antipyretic(s), anticholinergic, 
antihistamine, oral antitussive, or stimulant active ingredient.
    (7) Dandruff/seborrheic dermatitis/psoriasis drug products.

Alkyl isoquinolinium bromide
Allantoin
Benzalkonium chloride
Benzethonium chloride
Boric acid
Calcium undecylenate
Captan
Chloroxylenol
Colloidal oatmeal
Cresol, saponated
Ethohexadiol
Eucalyptol
Juniper tar
Lauryl isoquinolinium bromide
Menthol
Mercury oleate
Methylbenzethonium chloride
Methyl salicylate
Phenol
Phenolate sodium
Pine tar
Povidone-iodine
Resorcinol
Sodium borate
Sodium salicylate
Thymol
Undecylenic acid

    (8) Digestive aid drug products--(i) Approved as of May 7, 1991.

Bismuth sodium tartrate
Calcium carbonate
Cellulase
Dehydrocholic acid
Dihydroxyaluminum sodium carbonate
Duodenal substance
Garlic, dehydrated
Glutamic acid hydrochloride
Hemicellulase
Homatropine methylbromide
Magnesium hydroxide
Magnesium trisilicate
Ox bile extract
Pancreatin
Pancrelipase
Papain
Peppermint oil
Pepsin
Sodium bicarbonate
Sodium citrate
Sorbitol

    (ii) Approved as of November 10, 1993.

Alcohol
Aluminum hydroxide
Amylase
Anise seed
Aromatic powder
Asafetida
Aspergillus oryza enzymes (except lactase enzyme derived from 
Aspergillus oryzae)
Bacillus acidophilus
Bean
Belladonna alkaloids
Belladonna leaves, powdered extract
Betaine hydrochloride
Bismuth subcarbonate
Bismuth subgallate
Black radish powder
Blessed thistle (cnicus benedictus)
Buckthorn
Calcium gluconate
Capsicum
Capsicum, fluid extract of
Carbon
Cascara sagrada extract
Catechu, tincture
Catnip
Chamomile flowers
Charcoal, wood
Chloroform
Cinnamon oil
Cinnamon tincture
Citrus pectin
Diastase
Diastase malt
Dog grass
Elecampane
Ether
Fennel acid
Galega
Ginger
Glycine
Hydrastis canadensis (golden seal)
Hectorite
Horsetail
Huckleberry
Hydrastis fluid extract
Hydrochloric acid
Iodine
Iron ox bile
Johnswort
Juniper
Kaolin, colloidal
Knotgrass
Lactic acid
Lactose
Lavender compound, tincture of
Linden
Lipase
Lysine hydrochloride
Mannitol
Mycozyme
Myrrh, fluid extract of

[[Page 40]]

Nettle
Nickel-pectin
Nux vomica extract
Orthophosphoric acid
Papaya, natural
Pectin
Peppermint
Peppermint spirit
Phenacetin
Potassium bicarbonate
Potassium carbonate
Protease
Prolase
Rhubarb fluid extract
Senna
Sodium chloride
Sodium salicylate
Stem bromelain
Strawberry
Strychnine
Tannic acid
Trillium
Woodruff

    (iii) Charcoal, activated
    (9) [Reserved]
    (10) External analgesic drug products--(i) Analgesic and anesthetic 
drug products.

Aspirin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eugenol
Hexylresorcinol
Methapyrilene hydrochloride
Salicylamide
Thymol

    (ii) Counterirritant drug products.

Chloral hydrate
Eucalyptus oil

    (iii) Male genital desensitizer drug products.

Benzyl alcohol
Camphorated metacresol
Ephedrine hydrochloride

    (iv) Diaper rash drug products. Any ingredient(s) labeled with 
claims or directions for use in the treatment and/or prevention of 
diaper rash.
    (v) Fever blister and cold sore treatment drug products.

Allyl isothiocyanate
Aspirin
Bismuth sodium tartrate
Camphor (exceeding 3 percent)
Capsaicin
Capsicum
Capsicum oleoresin
Chloral hydrate
Chlorobutanol
Cyclomethycaine sulfate
Eucalyptus oil
Eugenol
Glycol salicylate
Hexylresorcinol
Histamine dihydrochloride
Menthol (exceeding 1 percent)
Methapyrilene hydrochloride
Methyl nicotinate
Methyl salicylate
Pectin
Salicylamide
Strong ammonia solution
Tannic acid
Thymol
Tripelennamine hydrochloride
Trolamine salicylate
Turpentine oil
Zinc sulfate

    (vi) Insect bite and sting drug products.

Alcohol
Alcohol, ethoxylated alkyl
Benzalkonium chloride
Calamine
Ergot fluidextract
Ferric chloride
Panthenol
Peppermint oil
Pyrilamine maleate
Sodium borate
Trolamine salicylate
Turpentine oil
Zinc oxide
Zirconium oxide

    (vii) Poison ivy, poison oak, and poison sumac drug products.

Alcohol
Aspirin
Benzethonium chloride
Benzocaine (0.5 to 1.25 percent)
Bithionol
Calamine
Cetalkonium chloride
Chloral hydrate
Chlorobutanol
Chlorpheniramine maleate
Creosote, beechwood
Cyclomethycaine sulfate
Dexpanthenol
Diperodon hydrochloride
Eucalyptus oil
Eugenol
Glycerin
Glycol salicylate
Hectorite
Hexylresorcinol
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Merbromin
Mercuric chloride
Methapyrilene hydrochloride

[[Page 41]]

Panthenol
Parethoxycaine hydrochloride
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Pyrilamine maleate
Salicylamide
Salicylic acid
Simethicone
Sulfur
Tannic acid
Thymol
Trolamine salicylate
Turpentine oil
Zirconium oxide
Zyloxin

    (11) [Reserved]
    (12) Laxative drug products--(i)(A) Bulk laxatives.

Agar
Carrageenan (degraded)
Carrageenan (native)
Guar gun

    (i)(B) Bulk laxatives--Approved as of March 29, 2007.

Granular dosage forms containing psyllium (hemicellulose), psyllium 
hydrophilic mucilloid, psyllium seed, psyllium seed (blond), psyllium 
seed husks, plantago husks, or plantago seed including, but not limited 
to, any granules that are:
(1) Swallowed dry prior to drinking liquid,
(2) Dispersed, suspended, or partially dissolved in liquid prior to 
swallowing,
(3) Chewed, partially chewed, or unchewed, and then washed down (or 
swallowed) with liquid, or
(4) Sprinkled over food.

    (ii) Saline laxative.

Tartaric acid

    (iii) Stool softener.

Poloxamer 188

    (iv)(A) Stimulant laxatives--Approved as of May 7, 1991.

Aloin
Bile salts/acids
Calcium pantothenate
Calomel
Colocynth
Elaterin resin
Frangula
Gamboge
Ipomea
Jalap
Ox bile
Podophyllum resin
Prune concentrate dehydrate
Prune powder
Rhubarb, Chinese
Sodium Oleate

    (iv)(B) Stimulant laxatives--Approved as of January 29, 1999.

Danthron
Phenolphthalein

    (C) Stimulant laxatives--Approved as of November 5, 2002.

Aloe ingredients (aloe, aloe extract, aloe flower extract)
Cascara sagrada ingredients (casanthranol, cascara fluidextract 
aromatic, cascara sagrada bark, cascara sagrada extract, cascara sagrada 
fluidextract).

    (13) [Reserved]
    (14) Oral health care drug products (nonantimicrobial).

Antipyrine
Camphor
Cresol
Dibucaine
Dibucaine hydrochloride
Eucalyptol
Lidocaine
Lidocaine hydrochloride
Methly salicylate
Myrrh tincture
Pyrilamine maleate
Sorbitol
Sugars
Tetracaine
Tetracaine hydrochloride
Thymol

    (15) Topical otic drug products--(i) For the prevention of swimmer's 
ear and for the drying of water-clogged ears, approved as of May 7, 
1991.

Acetic acid

    (ii) For the prevention of swimmer's ear, approved as of August 15, 
1995.

Glycerin and anhydrous glycerin
Isopropyl alcohol

    (16) Poison treatment drug products.

Ipecac fluidextract
Ipecac tincture
Zinc sulfate

    (17) Skin bleaching drug products.

Mercury, ammoniated

    (18) Skin protectant drug products--(i)(A) Ingredients--Approved as 
of May 7, 1991.

Allantoin (wound healing claims only)
Sulfur
Tannic acid
Zinc acetate (wound healing claims only)


[[Page 42]]


    (B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for 
products with annual sales less than $25,000.

Beeswax
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol

    (ii) Astringent drug products.

Acetone
Alcohol
Alum, ammonium
Alum, potassium
Aluminum chlorhydroxy complex
Aromatics
Benzalkonium chloride
Benzethonium chloride
Benzocaine
Benzoic acid
Boric acid
Calcium acetate (except calcium acetate monohydrate when combined with 
aluminum sulfate tetradecahydrate to provide an aluminum acetate 
solution as described in Sec. 347.20(b) of this chapter)
Camphor gum
Clove oil
Colloidal oatmeal
Cresol
Cupric sulfate
Eucalyptus oil
Eugenol
Ferric subsulfate (Monsel's Solution)
Honey
Isopropyl alcohol
Menthol
Methyl salicylate
Oxyquinoline sulfate
P-t-butyl-m-cresol
Peppermint oil
Phenol
Polyoxeythylene laurate
Potassium ferrocyanide
Sage oil
Silver nitrate
Sodium borate
Sodium diacetate
Talc
Tannic acid glycerite
Thymol
Topical starch
Zinc chloride
Zinc oxide
Zinc phenolsulfonate
Zinc stearate
Zinc sulfate

    (iii) Diaper rash drug products.

Aluminum hydroxide
Cocoa butter
Cysteine hydrochloride
Glycerin
Protein hydrolysate
Racemethionine
Sulfur
Tannic acid
Zinc acetate
Zinc carbonate

    (iv) Fever blister and cold sore treatment drug products.

Bismuth subnitrate
Boric acid
Pyridoxine hydrochloride
Sulfur
Tannic acid
Topical starch
Trolamine
Zinc sulfate

    (v) Insect bite and sting drug products--(A) Ingredients--Approved 
as of November 10, 1993.

Alcohol
Alcohol, ethoxylated alkyl
Ammonia solution, strong
Ammonium hydroxide
Benzalkonium chloride
Camphor
Ergot fluid extract
Ferric chloride
Menthol
Peppermint oil
Phenol
Pyrilamine maleate
Sodium borate
Trolamine
Turpentine oil
Zirconium oxide

    (B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for 
products with annual sales less than $25,000.

Beeswax
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol

    (vi) Poison ivy, poison oak, and poison sumac drug products--(A) 
Ingredients--Approved as of November 10, 1993.

Alcohol
Anion and cation exchange resins buffered
Benzethonium chloride
Benzocaine
Benzyl alcohol
Bismuth subnitrate
Bithionol
Boric acid
Camphor

[[Page 43]]

Cetalkonium chloride
Chloral hydrate
Chlorpheniramine maleate
Creosote
Diperodon hydrochloride
Diphenhydramine hydrochloride
Eucalyptus oil
Ferric chloride
Glycerin
Hectorite
Hydrogen peroxide
Impatiens biflora tincture
Iron oxide
Isopropyl alcohol
Lanolin
Lead acetate
Lidocaine
Menthol
Merbromin
Mercuric chloride
Panthenol
Parethoxycaine hydrochloride
Phenol
Phenyltoloxamine dihydrogen citrate
Povidone-vinylacetate copolymers
Salicylic acid
Simethicone
Tannic acid
Topical starch
Trolamine
Turpentine oil
Zirconium oxide
Zyloxin

    (B) Ingredients--Approved as of June 4, 2004; June 6, 2005, for 
products with annual sales less than $25,000.

Beeswax
Bismuth subnitrate
Boric acid
Cetyl alcohol
Glyceryl stearate
Isopropyl palmitate
Live yeast cell derivative
Shark liver oil
Stearyl alcohol

    (19) [Reserved]
    (20) Weight control drug products.

Alcohol
Alfalfa
Alginic acid
Anise oil
Arginine
Ascorbic acid
Bearberry
Biotin
Bone marrow, red
Buchu
Buchu, potassium extract
Caffeine
Caffeine citrate
Calcium
Calcium carbonate
Calcium caseinate
Calcium lactate
Calcium pantothenate
Carboxymethylcellulose sodium
Carrageenan
Cholecalcierol
Choline
Chondrus
Citric acid
Cnicus benedictus
Copper
Copper gluconate
Corn oil
Corn syrup
Corn silk, potassium extract
Cupric sulfate
Cyanocobalamin (vitamin B12)
Cystine
Dextrose
Docusate sodium
Ergocalciferol
Ferric ammonium citrate
Ferric pyrophosphate
Ferrous fumarate
Ferrous gluconate
Ferrous sulfate (iron)
Flax seed
Folic acid
Fructose
Guar gum
Histidine
Hydrastis canadensis
Inositol
Iodine
Isoleucine
Juniper, potassium extract
Karaya gum
Kelp
Lactose
Lecithin
Leucine
Liver concentrate
Lysine
Lysine hydrochloride
Magnesium
Magnesium oxide
Malt
Maltodextrin
Manganese citrate
Mannitol
Methionine
Methylcellulose
Mono- and di-glycerides
Niacinamide
Organic vegetables
Pancreatin
Pantothenic acid
Papain
Papaya enzymes
Pepsin
Phenacetin
Phenylalanine
Phosphorus
Phytolacca
Pineapple enzymes
Plantago seed
Potassium citrate
Pyridoxine hydrochloride (vitamin B6)
Riboflavin

[[Page 44]]

Rice polishings
Saccharin
Sea minerals
Sesame seed
Sodium
Sodium bicarbonate
Sodium caseinate
Sodium chloride (salt)
Soybean protein
Soy meal
Sucrose
Thiamine hydrochloride (vitamin B1)
Thiamine mononitrate (vitamin B1 mononitrate)
Threonine
Tricalcium phosphate
Tryptophan
Tyrosine
Uva ursi, potassium extract
Valine
Vegetable
Vitamin A
Vitamin A acetate
Vitamin A palmitate
Vitamin E
Wheat germ
Xanthan gum
Yeast

    (21) Ophthalmic drug products. (i) Ophthalmic anesthetic drug 
products.

Antipyrine
Piperocaine hydrochloride

    (ii) Ophthalmic anti-infective drug products.

Boric acid
Mild silver protein
Yellow mercuric oxide

    (iii) Ophthalmic astringent drug products.

Infusion of rose petals

    (iv) Ophthalmic demulcent drug products.

Polyethylene glycol 6000

    (v) Ophthalmic vasoconstrictor drug products.

Phenylephrine hydrochloride (less than 0.08 percent)

    (22) Topical antifungal drug products. (i) Diaper rash drug 
products. Any ingredient(s) labeled with claims or directions for use in 
the treatment and/or prevention of diaper rash.
    (ii) Ingredients.

Alcloxa
Alum, potassium
Aluminum sulfate
Amyltricresols, secondary
Basic fuchsin
Benzethonium chloride
Benzoic acid
Benzoxiquine
Boric acid
Camphor
Candicidin
Chlorothymol
Coal tar
Dichlorophen
Menthol
Methylparaben
Oxyquinoline
Oxyquinoline sulfate
Phenol
Phenolate sodium
Phenyl salicylate
Propionic acid
Propylparaben
Resorcinol
Salicylic acid
Sodium borate
Sodium caprylate
Sodium propionate
Sulfur
Tannic acid
Thymol
Tolindate
Triacetin
Zinc caprylate
Zinc propionate

    (iii) Any ingredient(s) labeled with claims or directions for use on 
the scalp or on the nails.
    (iv) Ingredients.

Camphorated metacresol
Chloroxylenol
m-cresol
Nystatin

    (23) Internal analgesic drug products--(i) Approved as of November 
10, 1993.

Aminobenzoic acid
Antipyrine
Aspirin, aluminum
Calcium salicylate
Codeine
Codeine phosphate
Codeine sulfate
Iodoantipyrine
Lysine aspirin
Methapyrilene fumarate
Phenacetin
Pheniramine maleate
Pyrilamine maleate
Quinine
Salsalate
Sodium aminobenzoate

    (ii) Approved as of February 22, 1999.

Any atropine ingredient
Any ephedrine ingredient

    (24) Orally administered menstrual drug products--(i) Approved as of 
November 10, 1993.


[[Page 45]]


Alcohol
Alfalfa leaves
Aloes
Asclepias tuberosa
Asparagus
Barosma
Bearberry (extract of uva ursi)
Bearberry fluidextract (extract of bearberry)
Blessed thistle (cnicus benedictus)
Buchu powdered extract (extract of buchu)
Calcium lactate
Calcium pantothenate
Capsicum oleoresin
Cascara fluidextract, aromatic (extract of cascara)
Chlorprophenpyridamine maleate
Cimicifuga racemosa
Codeine
Collinsonia (extract stone root)
Corn silk
Couch grass
Dog grass extract
Ethyl nitrite
Ferric chloride
Ferrous sulfate
Gentiana lutea (gentian)
Glycyrrhiza (licorice)
Homatropine methylbromide
Hydrangea, powdered extract (extract of hydrangea)
Hydrastis canadensis (golden seal)
Hyoscyamine sulfate
Juniper oil (oil of juniper)
Magnesium sulfate
Methapyrilene hydrochloride
Methenamine
Methylene blue
Natural estrogenic hormone
Niacinamide
Nutmeg oil (oil of nutmeg)
Oil of erigeron
Parsley
Peppermint spirit
Pepsin, essence
Phenacetin
Phenindamine tartrate
Phenyl salicylate
Piscidia erythrina
Pipsissewa
Potassium acetate
Potassium nitrate
Riboflavin
Saw palmetto
Senecio aureus
Sodium benzoate
Sodium nitrate
Sucrose
Sulferated oils of turpentine
Taraxacum officinale
Theobromine sodium salicylate
Theophylline
Thiamine hydrochloride
Triticum
Turpentine, venice (venice turpertine)
Urea

    (ii) Approved as of February 22, 1999.

Any atropine ingredient
Any ephedrine ingredient

    (25) Pediculicide drug products--(i) Approved as of November 10, 
1993.

Benzocaine
Benzyl alcohol
Benzyl benzoate
Chlorophenothane (dichlorodiphenyl trichloroethane)
Coconut oil soap, aqueous
Copper oleate
Docusate sodium
Formic acid
Isobornyl thiocyanoacetate
Picrotoxin
Propylene glycol
Sabadilla alkaloids
Sulfur, sublimed
Thiocyanoacetate

    (ii) Approved as of June 14, 1994. The combination of pyrethrum 
extract (formerly named pyrethrins) and piperonyl butoxide in an aerosol 
dosage formulation.
    (26) Anorectal drug products--(i) Anticholinergic drug products.

Atropine
Belladonna extract

    (ii) Antiseptic drug products.

Boric acid
Boroglycerin
Hydrastis
Phenol
Resorcinol
Sodium salicylic acid phenolate

    (iii) Astringent drug products.

Tannic acid

    (iv) Counterirritant drug products.

Camphor (greater than 3 to 11 percent)
Hydrastis
Menthol (1.25 to 16 percent)
Turpentine oil (rectified) (6 to 50 percent)

    (v) Keratolytic drug products.

Precipitated sulfur
Sublimed sulfur

    (vi) Local anesthetic drug products.

Diperodon
Phenacaine hydrochloride

    (vii) Other drug products.

Collinsonia extract
Escherichia coli vaccines
Lappa extract
Leptandra extract
Live yeast cell derivative
Mullein

    (viii) Protectant drug products.


[[Page 46]]


Bismuth oxide
Bismuth subcarbonate
Bismuth subgallate
Bismuth subnitrate
Lanolin alcohols

    (ix) Vasoconstrictor drug products.

Epinephrine undecylenate

    (x) Wound healinq drug products.

Cholecalciferol
Cod liver oil
Live yeast cell derivative
Peruvian balsam
Shark liver oil
Vitamin A

    (xi) Combination drug products. Any combination drug product 
containing hydrocortisone and pramoxine hydrochloride.
    (27) Topical antimicrobial drug products--(i) First aid antiseptic 
drug products.

Ammoniated mercury
Calomel (mercurous chloride)
Merbromin (mercurochrome)
Mercufenol chloride (ortho-chloromercuriphenol, ortho-
hydroxyphenylmercuric chloride)
Mercuric chloride (bichloride of mercury, mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin

    (ii) Diaper rash drug products.

Para-chloromercuriphenol
Any other ingredient containing mercury

    (28) Vaginal contraceptive drug products--(i) Approved as of October 
22, 1998.

Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)
Laureth 10S
Methoxypolyoxyethyleneglycol 550 laurate
Phenylmercuric acetate
Phenylmercuric nitrate
Any other ingredient containing mercury

    (ii) Approved as of November 5, 2002.
Octoxynol 9

    (29) Sunscreen drug products.

Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum

    (30) [Reserved]
    (b) Any OTC drug product that is labeled, represented, or promoted 
for the uses specified and containing any active ingredient(s) as 
specified in paragraph (a) of this section is regarded as a new drug 
within the meaning of section 210(p) of the Federal Food, Drug, and 
Cosmetic Act (the Act), for which an approved new drug application under 
section 505 of the Act and part 314 of this chapter is required for 
marketing. In the absence of an approved new drug application, such 
product is also misbranded under section 502 of the Act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for the OTC uses and 
containing any active ingredient(s) as specified in paragraph (a) of 
this section is safe and effective for the purpose intended must comply 
with the requirements and procedures governing the use of 
investigational new drugs set forth in part 312 of this chapter.
    (d) Any OTC drug product that is not in compliance with this section 
is subject to regulatory action if initially introduced or initially 
delivered for introduction into interstate commerce after the dates 
specified in paragraphs (d)(1) through (d)(39) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii) through 
(a)(12)(iv)(A), (a)(14) through (a)(15)(i), (a)(16) through 
(a)(18)(i)(A), (a)(18)(ii) (except as covered by paragraph (d)(22) of 
this section), (a)(18)(iii), (a)(18)(iv), (a)(18)(v)(A), and 
(a)(18)(vi)(A) of this section.
    (2) February 10, 1992, for products subject to paragraph (a)(20) of 
this section.
    (3) December 4, 1992, for products subject to paragraph (a)(7) of 
this section that contain menthol as an antipruritic in combination with 
the antidandruff ingredient coal tar identified

[[Page 47]]

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

[[Page 48]]

    (37) September 25, 2003, for products subject to paragraph 
(a)(26)(xi) of this section.
    (38) October 1, 2007, for products subject to paragraph 
(a)(12)(i)(B) of this section.
    (39) September 6, 2010, for products subject to paragraph 
(a)(18)(ii) of this section that contain calcium acetate monohydrate, 
except as provided in Sec. 347.20(b) of this chapter.

[55 FR 46919, Nov. 7, 1990]

    Editorial Note: For Federal Register citations affecting Sec. 
310.545, see the List of CFR Sections Affected, which appears in the 
Finding Aids section of the printed volume and at www.fdsys.gov.

    Effective Date Note: At 61 FR 9571, Mar. 8, 1996, in Sec. 310.545 
in paragraph (a)(6)(ii)(B), the entry for ``l-desoxyephedrine 
(topical)'' was stayed until further notice.

    Effective Date Note: At 76 FR 35665, June 17, 2011, Sec. 310.545 
was amended by revising paragraphs (a)(29) and (d)(31) and adding new 
paragraph (d)(40), effective June 18, 2012. For the convenience of the 
user, the added and revised text is set forth as follows:



Sec. 310.545  Drug products containing certain active ingredients 
          offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (29) Sunscreen drug products.
    (i) Ingredients.

Diethanolamine methoxycinnamate
Digalloyl trioleate
Ethyl 4-[bis(hydroxypropyl)] aminobenzoate
Glyceryl aminobenzoate
Lawsone with dihydroxyacetone
Red petrolatum

    (ii) Any ingredients labeled with any of the following or similar 
claims. Instant protection or protection immediately upon application.
    Claims for ``all-day'' protection or extended wear claims citing a 
specific number of hours of protection that is inconsistent with the 
directions for application in 21 CFR 201.327.

                                * * * * *

    (d) * * *
    (31) December 31, 2002, for products subject to paragraph (a)(29)(i) 
of this section.

                                * * * * *

    (40) June 18, 2012, for products subject to paragraph (a)(29)(ii) of 
this section. June 17, 2013, for products with annual sales less than 
$25,000.



Sec. 310.546  Drug products containing active ingredients offered 
over-the-counter (OTC) for the treatment and/or prevention of 

nocturnal leg muscle cramps.

    (a) Quinine sulfate alone or in combination with vitamin E has been 
present in over-the-counter (OTC) drug products for the treatment and/or 
prevention of nocturnal leg muscle cramps, i.e., a condition of 
localized pain in the lower extremities usually occurring in middle life 
and beyond with no regular pattern concerning time or severity. There is 
a lack of adequate data to establish general recognition of the safety 
and effectiveness of quinine sulfate, vitamin E, or any other 
ingredients for OTC use in the treatment and/or prevention of nocturnal 
leg muscle cramps. In the doses used to treat or prevent this condition, 
quinine sulfate has caused adverse events such as transient visual and 
auditory disturbances, dizziness, fever, nausea, vomiting, and diarrhea. 
Quinine sulfate may cause unpredictable serious and life-threatening 
hypersensitivity reactions requiring medical intervention and 
hospitalization; fatalities have been reported. The risk associated with 
use of quinine sulfate, in the absence of evidence of its effectiveness, 
outweighs any potential benefit in treating and/or preventing this 
benign, self-limiting condition. Based upon the adverse benefit-to-risk 
ratio, any drug product containing quinine or quinine sulfate cannot be 
considered generally recognized as safe for the treatment and/or 
prevention of nocturnal leg muscle cramps.
    (b) Any OTC drug product that is labeled, represented, or promoted 
for the treatment and/or prevention of nocturnal leg muscle cramps is 
regarded as a new drug within the meaning of section 201(p) of the 
Federal Food, Drug, and Cosmetic Act (the act), for which an approved 
application or abbreviated application under section 505 of the act and 
part 314 of this chapter is required for marketing. In the absence of an 
approved new drug application or abbreviated new drug application, such 
product is also misbranded under section 502 of the act.

[[Page 49]]

    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use for the 
treatment and/or prevention of nocturnal leg muscle cramps is safe and 
effective for the purpose intended must comply with the requirements and 
procedures governing the use of investigational new drugs set forth in 
part 312 of this chapter.
    (d) After February 22, 1995, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[59 FR 43252, Aug. 22, 1994]



Sec. 310.547  Drug products containing quinine offered 
over-the-counter (OTC) for the treatment and/or prevention 

of malaria.

    (a) Quinine and quinine salts have been used OTC for the treatment 
and/or prevention of malaria, a serious and potentially life-threatening 
disease. Quinine is no longer the drug of choice for the treatment and/
or prevention of most types of malaria. In addition, there are serious 
and complicating aspects of the disease itself and some potentially 
serious and life-threatening risks associated with the use of quinine at 
doses employed for the treatment of malaria. There is a lack of adequate 
data to establish general recognition of the safety of quinine drug 
products for OTC use in the treatment and/or prevention of malaria. 
Therefore, quinine or quinine salts cannot be safely and effectively 
used for the treatment and/or prevention of malaria except under the 
care and supervision of a doctor.
    (b) Any OTC drug product containing quinine or quinine salts that is 
labeled, represented, or promoted for the treatment and/or prevention of 
malaria is regarded as a new drug within the meaning of section 201(p) 
of the act, for which an approved application or abbreviated application 
under section 505 of the act and part 314 of this chapter is required 
for marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use for the 
treatment and/or prevention of malaria is safe and effective for the 
purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After April 20, 1998, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[63 FR 13528, Mar. 20, 1998]



Sec. 310.548  Drug products containing colloidal silver ingredients
or silver salts offered over-the-counter (OTC) for the treatment 

and/or prevention of disease.

    (a) Colloidal silver ingredients and silver salts have been marketed 
in over-the-counter (OTC) drug products for the treatment and prevention 
of numerous disease conditions. There are serious and complicating 
aspects to many of the diseases these silver ingredients purport to 
treat or prevent. Further, there is a lack of adequate data to establish 
general recognition of the safety and effectiveness of colloidal silver 
ingredients or silver salts for OTC use in the treatment or prevention 
of any disease. These ingredients and salts include, but are not limited 
to, silver proteins, mild silver protein, strong silver protein, silver, 
silver ion, silver chloride, silver cyanide, silver iodide, silver 
oxide, and silver phosphate.
    (b) Any OTC drug product containing colloidal silver ingredients or 
silver salts that is labeled, represented, or promoted for the treatment 
and/or prevention of any disease is regarded as a new drug within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
(the act) for which an approved application or abbreviated application 
under section 505 of the act and part 314 of this chapter is required 
for marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.

[[Page 50]]

    (c) Clinical investigations designed to obtain evidence that any 
drug product containing colloidal silver or silver salts labeled, 
represented, or promoted for any OTC drug use is safe and effective for 
the purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs as set forth in part 312 
of this chapter.
    (d) After September 16, 1999, any such OTC drug product containing 
colloidal silver or silver salts initially introduced or initially 
delivered for introduction into interstate commerce that is not in 
compliance with this section is subject to regulatory action.

[64 FR 44658, Aug. 17, 1999]



PART 312_INVESTIGATIONAL NEW DRUG APPLICATION--Table of Contents



                      Subpart A_General Provisions

Sec.
312.1 Scope.
312.2 Applicability.
312.3 Definitions and interpretations.
312.6 Labeling of an investigational new drug.
312.7 Promotion of investigational drugs.
312.8 Charging for investigational drugs under an IND.
312.10 Waivers.

          Subpart B_Investigational New Drug Application (IND)

312.20 Requirement for an IND.
312.21 Phases of an investigation.
312.22 General principles of the IND submission.
312.23 IND content and format.
312.30 Protocol amendments.
312.31 Information amendments.
312.32 IND safety reporting.
312.33 Annual reports.
312.38 Withdrawal of an IND.

                    Subpart C_Administrative Actions

312.40 General requirements for use of an investigational new drug in a 
          clinical investigation.
312.41 Comment and advice on an IND.
312.42 Clinical holds and requests for modification.
312.44 Termination.
312.45 Inactive status.
312.47 Meetings.
312.48 Dispute resolution.

        Subpart D_Responsibilities of Sponsors and Investigators

312.50 General responsibilities of sponsors.
312.52 Transfer of obligations to a contract research organization.
312.53 Selecting investigators and monitors.
312.54 Emergency research under Sec. 50.24 of this chapter.
312.55 Informing investigators.
312.56 Review of ongoing investigations.
312.57 Recordkeeping and record retention.
312.58 Inspection of sponsor's records and reports.
312.59 Disposition of unused supply of investigational drug.
312.60 General responsibilities of investigators.
312.61 Control of the investigational drug.
312.62 Investigator recordkeeping and record retention.
312.64 Investigator reports.
312.66 Assurance of IRB review.
312.68 Inspection of investigator's records and reports.
312.69 Handling of controlled substances.
312.70 Disqualification of a clinical investigator.

    Subpart E_Drugs Intended to Treat Life-threatening and Severely-
                         debilitating Illnesses

312.80 Purpose.
312.81 Scope.
312.82 Early consultation.
312.83 Treatment protocols.
312.84 Risk-benefit analysis in review of marketing applications for 
          drugs to treat life-threatening and severely-debilitating 
          illnesses.
312.85 Phase 4 studies.
312.86 Focused FDA regulatory research.
312.87 Active monitoring of conduct and evaluation of clinical trials.
312.88 Safeguards for patient safety.

                         Subpart F_Miscellaneous

312.110 Import and export requirements.
312.120 Foreign clinical studies not conducted under an IND.
312.130 Availability for public disclosure of data and information in an 
          IND.
312.140 Address for correspondence.
312.145 Guidance documents.

 Subpart G_Drugs for Investigational Use in Laboratory Research Animals 
                            or in Vitro Tests

312.160 Drugs for investigational use in laboratory research animals or 
          in vitro tests.

Subpart H [Reserved]

[[Page 51]]

  Subpart I_Expanded Access to Investigational Drugs for Treatment Use

312.300 General.
312.305 Requirements for all expanded access uses.
312.310 Individual patients, including for emergency use.
312.315 Intermediate-size patient populations.
312.320 Treatment IND or treatment protocol.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 42 
U.S.C. 262.

    Source: 52 FR 8831, Mar. 19, 1987, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 312 can be found at 69 
FR 13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 312.1  Scope.

    (a) This part contains procedures and requirements governing the use 
of investigational new drugs, including procedures and requirements for 
the submission to, and review by, the Food and Drug Administration of 
investigational new drug applications (IND's). An investigational new 
drug for which an IND is in effect in accordance with this part is 
exempt from the premarketing approval requirements that are otherwise 
applicable and may be shipped lawfully for the purpose of conducting 
clinical investigations of that drug.
    (b) References in this part to regulations in the Code of Federal 
Regulations are to chapter I of title 21, unless otherwise noted.



Sec. 312.2  Applicability.

    (a) Applicability. Except as provided in this section, this part 
applies to all clinical investigations of products that are subject to 
section 505 of the Federal Food, Drug, and Cosmetic Act or to the 
licensing provisions of the Public Health Service Act (58 Stat. 632, as 
amended (42 U.S.C. 201 et seq.)).
    (b) Exemptions. (1) The clinical investigation of a drug product 
that is lawfully marketed in the United States is exempt from the 
requirements of this part if all the following apply:
    (i) The investigation is not intended to be reported to FDA as a 
well-controlled study in support of a new indication for use nor 
intended to be used to support any other significant change in the 
labeling for the drug;
    (ii) If the drug that is undergoing investigation is lawfully 
marketed as a prescription drug product, the investigation is not 
intended to support a significant change in the advertising for the 
product;
    (iii) The investigation does not involve a route of administration 
or dosage level or use in a patient population or other factor that 
significantly increases the risks (or decreases the acceptability of the 
risks) associated with the use of the drug product;
    (iv) The investigation is conducted in compliance with the 
requirements for institutional review set forth in part 56 and with the 
requirements for informed consent set forth in part 50; and
    (v) The investigation is conducted in compliance with the 
requirements of Sec. 312.7.
    (2)(i) A clinical investigation involving an in vitro diagnostic 
biological product listed in paragraph (b)(2)(ii) of this section is 
exempt from the requirements of this part if (a) it is intended to be 
used in a diagnostic procedure that confirms the diagnosis made by 
another, medically established, diagnostic product or procedure and (b) 
it is shipped in compliance with Sec. 312.160.
    (ii) In accordance with paragraph (b)(2)(i) of this section, the 
following products are exempt from the requirements of this part: (a) 
blood grouping serum; (b) reagent red blood cells; and (c) anti-human 
globulin.
    (3) A drug intended solely for tests in vitro or in laboratory 
research animals is exempt from the requirements of this part if shipped 
in accordance with Sec. 312.160.
    (4) FDA will not accept an application for an investigation that is 
exempt under the provisions of paragraph (b)(1) of this section.
    (5) A clinical investigation involving use of a placebo is exempt 
from the requirements of this part if the investigation does not 
otherwise require submission of an IND.
    (6) A clinical investigation involving an exception from informed 
consent under Sec. 50.24 of this chapter is not exempt from the 
requirements of this part.

[[Page 52]]

    (c) Bioavailability studies. The applicability of this part to in 
vivo bioavailability studies in humans is subject to the provisions of 
Sec. 320.31.
    (d) Unlabeled indication. This part does not apply to the use in the 
practice of medicine for an unlabeled indication of a new drug product 
approved under part 314 or of a licensed biological product.
    (e) Guidance. FDA may, on its own initiative, issue guidance on the 
applicability of this part to particular investigational uses of drugs. 
On request, FDA will advise on the applicability of this part to a 
planned clinical investigation.

[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 64 
FR 401, Jan. 5, 1999]



Sec. 312.3  Definitions and interpretations.

    (a) The definitions and interpretations of terms contained in 
section 201 of the Act apply to those terms when used in this part:
    (b) The following definitions of terms also apply to this part:
    Act means the Federal Food, Drug, and Cosmetic Act (secs. 201-902, 
52 Stat. 1040 et seq., as amended (21 U.S.C. 301-392)).
    Clinical investigation means any experiment in which a drug is 
administered or dispensed to, or used involving, one or more human 
subjects. For the purposes of this part, an experiment is any use of a 
drug except for the use of a marketed drug in the course of medical 
practice.
    Contract research organization means a person that assumes, as an 
independent contractor with the sponsor, one or more of the obligations 
of a sponsor, e.g., design of a protocol, selection or monitoring of 
investigations, evaluation of reports, and preparation of materials to 
be submitted to the Food and Drug Administration.
    FDA means the Food and Drug Administration.
    IND means an investigational new drug application. For purposes of 
this part, ``IND'' is synonymous with ``Notice of Claimed 
Investigational Exemption for a New Drug.''
    Independent ethics committee (IEC) means a review panel that is 
responsible for ensuring the protection of the rights, safety, and well-
being of human subjects involved in a clinical investigation and is 
adequately constituted to provide assurance of that protection. An 
institutional review board (IRB), as defined in Sec. 56.102(g) of this 
chapter and subject to the requirements of part 56 of this chapter, is 
one type of IEC.
    Investigational new drug means a new drug or biological drug that is 
used in a clinical investigation. The term also includes a biological 
product that is used in vitro for diagnostic purposes. The terms 
``investigational drug'' and ``investigational new drug'' are deemed to 
be synonymous for purposes of this part.
    Investigator means an individual who actually conducts a clinical 
investigation (i.e., under whose immediate direction the drug is 
administered or dispensed to a subject). In the event an investigation 
is conducted by a team of individuals, the investigator is the 
responsible leader of the team. ``Subinvestigator'' includes any other 
individual member of that team.
    Marketing application means an application for a new drug submitted 
under section 505(b) of the act or a biologics license application for a 
biological product submitted under the Public Health Service Act.
    Sponsor means a person who takes responsibility for and initiates a 
clinical investigation. The sponsor may be an individual or 
pharmaceutical company, governmental agency, academic institution, 
private organization, or other organization. The sponsor does not 
actually conduct the investigation unless the sponsor is a sponsor-
investigator. A person other than an individual that uses one or more of 
its own employees to conduct an investigation that it has initiated is a 
sponsor, not a sponsor-investigator, and the employees are 
investigators.
    Sponsor-Investigator means an individual who both initiates and 
conducts an investigation, and under whose immediate direction the 
investigational drug is administered or dispensed. The term does not 
include any person other than an individual. The requirements applicable 
to a sponsor-investigator under this part include both those applicable 
to an investigator and a sponsor.

[[Page 53]]

    Subject means a human who participates in an investigation, either 
as a recipient of the investigational new drug or as a control. A 
subject may be a healthy human or a patient with a disease.

[52 FR 8831, Mar. 19, 1987, as amended at 64 FR 401, Jan. 5, 1999; 64 FR 
56449, Oct. 20, 1999; 73 FR 22815, Apr. 28, 2008]



Sec. 312.6  Labeling of an investigational new drug.

    (a) The immediate package of an investigational new drug intended 
for human use shall bear a label with the statement ``Caution: New 
Drug--Limited by Federal (or United States) law to investigational 
use.''
    (b) The label or labeling of an investigational new drug shall not 
bear any statement that is false or misleading in any particular and 
shall not represent that the investigational new drug is safe or 
effective for the purposes for which it is being investigated.
    (c) The appropriate FDA Center Director, according to the procedures 
set forth in Sec. Sec. 201.26 or 610.68 of this chapter, may grant an 
exception or alternative to the provision in paragraph (a) of this 
section, to the extent that this provision is not explicitly required by 
statute, for specified lots, batches, or other units of a human drug 
product that is or will be included in the Strategic National Stockpile.

[52 FR 8831, Mar. 19, 1987, as amended at 72 FR 73599, Dec. 28, 2007]



Sec. 312.7  Promotion of investigational drugs.

    (a) Promotion of an investigational new drug. A sponsor or 
investigator, or any person acting on behalf of a sponsor or 
investigator, shall not represent in a promotional context that an 
investigational new drug is safe or effective for the purposes for which 
it is under investigation or otherwise promote the drug. This provision 
is not intended to restrict the full exchange of scientific information 
concerning the drug, including dissemination of scientific findings in 
scientific or lay media. Rather, its intent is to restrict promotional 
claims of safety or effectiveness of the drug for a use for which it is 
under investigation and to preclude commercialization of the drug before 
it is approved for commercial distribution.
    (b) Commercial distribution of an investigational new drug. A 
sponsor or investigator shall not commercially distribute or test market 
an investigational new drug.
    (c) Prolonging an investigation. A sponsor shall not unduly prolong 
an investigation after finding that the results of the investigation 
appear to establish sufficient data to support a marketing application.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987; 67 
FR 9585, Mar. 4, 2002; 74 FR 40899, Aug. 13, 2009]



Sec. 312.8  Charging for investigational drugs under an IND.

    (a) General criteria for charging. (1) A sponsor must meet the 
applicable requirements in paragraph (b) of this section for charging in 
a clinical trial or paragraph (c) of this section for charging for 
expanded access to an investigational drug for treatment use under 
subpart I of this part, except that sponsors need not fulfill the 
requirements in this section to charge for an approved drug obtained 
from another entity not affiliated with the sponsor for use as part of 
the clinical trial evaluation (e.g., in a clinical trial of a new use of 
the approved drug, for use of the approved drug as an active control).
    (2) A sponsor must justify the amount to be charged in accordance 
with paragraph (d) of this section.
    (3) A sponsor must obtain prior written authorization from FDA to 
charge for an investigational drug.
    (4) FDA will withdraw authorization to charge if it determines that 
charging is interfering with the development of a drug for marketing 
approval or that the criteria for the authorization are no longer being 
met.
    (b) Charging in a clinical trial--(1) Charging for a sponsor's drug. 
A sponsor who wishes to charge for its investigational drug, including 
investigational use of its approved drug, must:
    (i) Provide evidence that the drug has a potential clinical benefit 
that, if demonstrated in the clinical investigations, would provide a 
significant advantage over available products in the diagnosis, 
treatment, mitigation, or prevention of a disease or condition;

[[Page 54]]

    (ii) Demonstrate that the data to be obtained from the clinical 
trial would be essential to establishing that the drug is effective or 
safe for the purpose of obtaining initial approval of a drug, or would 
support a significant change in the labeling of an approved drug (e.g., 
new indication, inclusion of comparative safety information); and
    (iii) Demonstrate that the clinical trial could not be conducted 
without charging because the cost of the drug is extraordinary to the 
sponsor. The cost may be extraordinary due to manufacturing complexity, 
scarcity of a natural resource, the large quantity of drug needed (e.g., 
due to the size or duration of the trial), or some combination of these 
or other extraordinary circumstances (e.g., resources available to a 
sponsor).
    (2) Duration of charging in a clinical trial. Unless FDA specifies a 
shorter period, charging may continue for the length of the clinical 
trial.
    (c) Charging for expanded access to investigational drug for 
treatment use. (1) A sponsor who wishes to charge for expanded access to 
an investigational drug for treatment use under subpart I of this part 
must provide reasonable assurance that charging will not interfere with 
developing the drug for marketing approval.
    (2) For expanded access under Sec. 312.320 (treatment IND or 
treatment protocol), such assurance must include:
    (i) Evidence of sufficient enrollment in any ongoing clinical 
trial(s) needed for marketing approval to reasonably assure FDA that the 
trial(s) will be successfully completed as planned;
    (ii) Evidence of adequate progress in the development of the drug 
for marketing approval; and
    (iii) Information submitted under the general investigational plan 
(Sec. 312.23(a)(3)(iv)) specifying the drug development milestones the 
sponsor plans to meet in the next year.
    (3) The authorization to charge is limited to the number of patients 
authorized to receive the drug under the treatment use, if there is a 
limitation.
    (4) Unless FDA specifies a shorter period, charging for expanded 
access to an investigational drug for treatment use under subpart I of 
this part may continue for 1 year from the time of FDA authorization. A 
sponsor may request that FDA reauthorize charging for additional 
periods.
    (d) Costs recoverable when charging for an investigational drug. (1) 
A sponsor may recover only the direct costs of making its 
investigational drug available.
    (i) Direct costs are costs incurred by a sponsor that can be 
specifically and exclusively attributed to providing the drug for the 
investigational use for which FDA has authorized cost recovery. Direct 
costs include costs per unit to manufacture the drug (e.g., raw 
materials, labor, and nonreusable supplies and equipment used to 
manufacture the quantity of drug needed for the use for which charging 
is authorized) or costs to acquire the drug from another manufacturing 
source, and direct costs to ship and handle (e.g., store) the drug.
    (ii) Indirect costs include costs incurred primarily to produce the 
drug for commercial sale (e.g., costs for facilities and equipment used 
to manufacture the supply of investigational drug, but that are 
primarily intended to produce large quantities of drug for eventual 
commercial sale) and research and development, administrative, labor, or 
other costs that would be incurred even if the clinical trial or 
treatment use for which charging is authorized did not occur.
    (2) For expanded access to an investigational drug for treatment use 
under Sec. Sec. 312.315 (intermediate-size patient populations) and 
312.320 (treatment IND or treatment protocol), in addition to the direct 
costs described in paragraph (d)(1)(i) of this section, a sponsor may 
recover the costs of monitoring the expanded access IND or protocol, 
complying with IND reporting requirements, and other administrative 
costs directly associated with the expanded access IND.
    (3) To support its calculation for cost recovery, a sponsor must 
provide supporting documentation to show that the calculation is 
consistent with the requirements of paragraphs (d)(1) and, if 
applicable, (d)(2) of this section. The documentation must be 
accompanied by a statement that an independent

[[Page 55]]

certified public accountant has reviewed and approved the calculations.

[74 FR 40899, Aug. 13, 2009]



Sec. 312.10  Waivers.

    (a) A sponsor may request FDA to waive applicable requirement under 
this part. A waiver request may be submitted either in an IND or in an 
information amendment to an IND. In an emergency, a request may be made 
by telephone or other rapid communication means. A waiver request is 
required to contain at least one of the following:
    (1) An explanation why the sponsor's compliance with the requirement 
is unnecessary or cannot be achieved;
    (2) A description of an alternative submission or course of action 
that satisfies the purpose of the requirement; or
    (3) Other information justifying a waiver.
    (b) FDA may grant a waiver if it finds that the sponsor's 
noncompliance would not pose a significant and unreasonable risk to 
human subjects of the investigation and that one of the following is 
met:
    (1) The sponsor's compliance with the requirement is unnecessary for 
the agency to evaluate the application, or compliance cannot be 
achieved;
    (2) The sponsor's proposed alternative satisfies the requirement; or
    (3) The applicant's submission otherwise justifies a waiver.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9585, Mar. 4, 2002]



          Subpart B_Investigational New Drug Application (IND)



Sec. 312.20  Requirement for an IND.

    (a) A sponsor shall submit an IND to FDA if the sponsor intends to 
conduct a clinical investigation with an investigational new drug that 
is subject to Sec. 312.2(a).
    (b) A sponsor shall not begin a clinical investigation subject to 
Sec. 312.2(a) until the investigation is subject to an IND which is in 
effect in accordance with Sec. 312.40.
    (c) A sponsor shall submit a separate IND for any clinical 
investigation involving an exception from informed consent under Sec. 
50.24 of this chapter. Such a clinical investigation is not permitted to 
proceed without the prior written authorization from FDA. FDA shall 
provide a written determination 30 days after FDA receives the IND or 
earlier.

[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 62 
FR 32479, June 16, 1997]



Sec. 312.21  Phases of an investigation.

    An IND may be submitted for one or more phases of an investigation. 
The clinical investigation of a previously untested drug is generally 
divided into three phases. Although in general the phases are conducted 
sequentially, they may overlap. These three phases of an investigation 
are a follows:
    (a) Phase 1. (1) Phase 1 includes the initial introduction of an 
investigational new drug into humans. Phase 1 studies are typically 
closely monitored and may be conducted in patients or normal volunteer 
subjects. These studies are designed to determine the metabolism and 
pharmacologic actions of the drug in humans, the side effects associated 
with increasing doses, and, if possible, to gain early evidence on 
effectiveness. During Phase 1, sufficient information about the drug's 
pharmacokinetics and pharmacological effects should be obtained to 
permit the design of well-controlled, scientifically valid, Phase 2 
studies. The total number of subjects and patients included in Phase 1 
studies varies with the drug, but is generally in the range of 20 to 80.
    (2) Phase 1 studies also include studies of drug metabolism, 
structure-activity relationships, and mechanism of action in humans, as 
well as studies in which investigational drugs are used as research 
tools to explore biological phenomena or disease processes.
    (b) Phase 2. Phase 2 includes the controlled clinical studies 
conducted to evaluate the effectiveness of the drug for a particular 
indication or indications in patients with the disease or condition 
under study and to determine the common short-term side effects and 
risks associated with the drug. Phase 2 studies are typically well 
controlled, closely monitored, and conducted in a relatively small 
number of

[[Page 56]]

patients, usually involving no more than several hundred subjects.
    (c) Phase 3. Phase 3 studies are expanded controlled and 
uncontrolled trials. They are performed after preliminary evidence 
suggesting effectiveness of the drug has been obtained, and are intended 
to gather the additional information about effectiveness and safety that 
is needed to evaluate the overall benefit-risk relationship of the drug 
and to provide an adequate basis for physician labeling. Phase 3 studies 
usually include from several hundred to several thousand subjects.



Sec. 312.22  General principles of the IND submission.

    (a) FDA's primary objectives in reviewing an IND are, in all phases 
of the investigation, to assure the safety and rights of subjects, and, 
in Phase 2 and 3, to help assure that the quality of the scientific 
evaluation of drugs is adequate to permit an evaluation of the drug's 
effectiveness and safety. Therefore, although FDA's review of Phase 1 
submissions will focus on assessing the safety of Phase 1 
investigations, FDA's review of Phases 2 and 3 submissions will also 
include an assessment of the scientific quality of the clinical 
investigations and the likelihood that the investigations will yield 
data capable of meeting statutory standards for marketing approval.
    (b) The amount of information on a particular drug that must be 
submitted in an IND to assure the accomplishment of the objectives 
described in paragraph (a) of this section depends upon such factors as 
the novelty of the drug, the extent to which it has been studied 
previously, the known or suspected risks, and the developmental phase of 
the drug.
    (c) The central focus of the initial IND submission should be on the 
general investigational plan and the protocols for specific human 
studies. Subsequent amendments to the IND that contain new or revised 
protocols should build logically on previous submissions and should be 
supported by additional information, including the results of animal 
toxicology studies or other human studies as appropriate. Annual reports 
to the IND should serve as the focus for reporting the status of studies 
being conducted under the IND and should update the general 
investigational plan for the coming year.
    (d) The IND format set forth in Sec. 312.23 should be followed 
routinely by sponsors in the interest of fostering an efficient review 
of applications. Sponsors are expected to exercise considerable 
discretion, however, regarding the content of information submitted in 
each section, depending upon the kind of drug being studied and the 
nature of the available information. Section 312.23 outlines the 
information needed for a commercially sponsored IND for a new molecular 
entity. A sponsor-investigator who uses, as a research tool, an 
investigational new drug that is already subject to a manufacturer's IND 
or marketing application should follow the same general format, but 
ordinarily may, if authorized by the manufacturer, refer to the 
manufacturer's IND or marketing application in providing the technical 
information supporting the proposed clinical investigation. A sponsor-
investigator who uses an investigational drug not subject to a 
manufacturer's IND or marketing application is ordinarily required to 
submit all technical information supporting the IND, unless such 
information may be referenced from the scientific literature.



Sec. 312.23  IND content and format.

    (a) A sponsor who intends to conduct a clinical investigation 
subject to this part shall submit an ``Investigational New Drug 
Application'' (IND) including, in the following order:
    (1) Cover sheet (Form FDA-1571). A cover sheet for the application 
containing the following:
    (i) The name, address, and telephone number of the sponsor, the date 
of the application, and the name of the investigational new drug.
    (ii) Identification of the phase or phases of the clinical 
investigation to be conducted.
    (iii) A commitment not to begin clinical investigations until an IND 
covering the investigations is in effect.
    (iv) A commitment that an Institutional Review Board (IRB) that 
complies with the requirements set forth in

[[Page 57]]

part 56 will be responsible for the initial and continuing review and 
approval of each of the studies in the proposed clinical investigation 
and that the investigator will report to the IRB proposed changes in the 
research activity in accordance with the requirements of part 56.
    (v) A commitment to conduct the investigation in accordance with all 
other applicable regulatory requirements.
    (vi) The name and title of the person responsible for monitoring the 
conduct and progress of the clinical investigations.
    (vii) The name(s) and title(s) of the person(s) responsible under 
Sec. 312.32 for review and evaluation of information relevant to the 
safety of the drug.
    (viii) If a sponsor has transferred any obligations for the conduct 
of any clinical study to a contract research organization, a statement 
containing the name and address of the contract research organization, 
identification of the clinical study, and a listing of the obligations 
transferred. If all obligations governing the conduct of the study have 
been transferred, a general statement of this transfer--in lieu of a 
listing of the specific obligations transferred--may be submitted.
    (ix) The signature of the sponsor or the sponsor's authorized 
representative. If the person signing the application does not reside or 
have a place of business within the United States, the IND is required 
to contain the name and address of, and be countersigned by, an 
attorney, agent, or other authorized official who resides or maintains a 
place of business within the United States.
    (2) A table of contents.
    (3) Introductory statement and general investigational plan. (i) A 
brief introductory statement giving the name of the drug and all active 
ingredients, the drug's pharmacological class, the structural formula of 
the drug (if known), the formulation of the dosage form(s) to be used, 
the route of administration, and the broad objectives and planned 
duration of the proposed clinical investigation(s).
    (ii) A brief summary of previous human experience with the drug, 
with reference to other IND's if pertinent, and to investigational or 
marketing experience in other countries that may be relevant to the 
safety of the proposed clinical investigation(s).
    (iii) If the drug has been withdrawn from investigation or marketing 
in any country for any reason related to safety or effectiveness, 
identification of the country(ies) where the drug was withdrawn and the 
reasons for the withdrawal.
    (iv) A brief description of the overall plan for investigating the 
drug product for the following year. The plan should include the 
following: (a) The rationale for the drug or the research study; (b) the 
indication(s) to be studied; (c) the general approach to be followed in 
evaluating the drug; (d) the kinds of clinical trials to be conducted in 
the first year following the submission (if plans are not developed for 
the entire year, the sponsor should so indicate); (e) the estimated 
number of patients to be given the drug in those studies; and (f) any 
risks of particular severity or seriousness anticipated on the basis of 
the toxicological data in animals or prior studies in humans with the 
drug or related drugs.
    (4) [Reserved]
    (5) Investigator's brochure. If required under Sec. 312.55, a copy 
of the investigator's brochure, containing the following information:
    (i) A brief description of the drug substance and the formulation, 
including the structural formula, if known.
    (ii) A summary of the pharmacological and toxicological effects of 
the drug in animals and, to the extent known, in humans.
    (iii) A summary of the pharmacokinetics and biological disposition 
of the drug in animals and, if known, in humans.
    (iv) A summary of information relating to safety and effectiveness 
in humans obtained from prior clinical studies. (Reprints of published 
articles on such studies may be appended when useful.)
    (v) A description of possible risks and side effects to be 
anticipated on the basis of prior experience with the drug under 
investigation or with related drugs, and of precautions or special 
monitoring to be done as part of the investigational use of the drug.

[[Page 58]]

    (6) Protocols. (i) A protocol for each planned study. (Protocols for 
studies not submitted initially in the IND should be submitted in 
accordance with Sec. 312.30(a).) In general, protocols for Phase 1 
studies may be less detailed and more flexible than protocols for Phase 
2 and 3 studies. Phase 1 protocols should be directed primarily at 
providing an outline of the investigation--an estimate of the number of 
patients to be involved, a description of safety exclusions, and a 
description of the dosing plan including duration, dose, or method to be 
used in determining dose--and should specify in detail only those 
elements of the study that are critical to safety, such as necessary 
monitoring of vital signs and blood chemistries. Modifications of the 
experimental design of Phase 1 studies that do not affect critical 
safety assessments are required to be reported to FDA only in the annual 
report.
    (ii) In Phases 2 and 3, detailed protocols describing all aspects of 
the study should be submitted. A protocol for a Phase 2 or 3 
investigation should be designed in such a way that, if the sponsor 
anticipates that some deviation from the study design may become 
necessary as the investigation progresses, alternatives or contingencies 
to provide for such deviation are built into the protocols at the 
outset. For example, a protocol for a controlled short-term study might 
include a plan for an early crossover of nonresponders to an alternative 
therapy.
    (iii) A protocol is required to contain the following, with the 
specific elements and detail of the protocol reflecting the above 
distinctions depending on the phase of study:
    (a) A statement of the objectives and purpose of the study.
    (b) The name and address and a statement of the qualifications 
(curriculum vitae or other statement of qualifications) of each 
investigator, and the name of each subinvestigator (e.g., research 
fellow, resident) working under the supervision of the investigator; the 
name and address of the research facilities to be used; and the name and 
address of each reviewing Institutional Review Board.
    (c) The criteria for patient selection and for exclusion of patients 
and an estimate of the number of patients to be studied.
    (d) A description of the design of the study, including the kind of 
control group to be used, if any, and a description of methods to be 
used to minimize bias on the part of subjects, investigators, and 
analysts.
    (e) The method for determining the dose(s) to be administered, the 
planned maximum dosage, and the duration of individual patient exposure 
to the drug.
    (f) A description of the observations and measurements to be made to 
fulfill the objectives of the study.
    (g) A description of clinical procedures, laboratory tests, or other 
measures to be taken to monitor the effects of the drug in human 
subjects and to minimize risk.
    (7) Chemistry, manufacturing, and control information. (i) As 
appropriate for the particular investigations covered by the IND, a 
section describing the composition, manufacture, and control of the drug 
substance and the drug product. Although in each phase of the 
investigation sufficient information is required to be submitted to 
assure the proper identification, quality, purity, and strength of the 
investigational drug, the amount of information needed to make that 
assurance will vary with the phase of the investigation, the proposed 
duration of the investigation, the dosage form, and the amount of 
information otherwise available. FDA recognizes that modifications to 
the method of preparation of the new drug substance and dosage form and 
changes in the dosage form itself are likely as the investigation 
progresses. Therefore, the emphasis in an initial Phase 1 submission 
should generally be placed on the identification and control of the raw 
materials and the new drug substance. Final specifications for the drug 
substance and drug product are not expected until the end of the 
investigational process.
    (ii) It should be emphasized that the amount of information to be 
submitted depends upon the scope of the proposed clinical investigation. 
For example, although stability data are required in all phases of the 
IND to demonstrate that the new drug substance and drug product are 
within acceptable chemical

[[Page 59]]

and physical limits for the planned duration of the proposed clinical 
investigation, if very short-term tests are proposed, the supporting 
stability data can be correspondingly limited.
    (iii) As drug development proceeds and as the scale or production is 
changed from the pilot-scale production appropriate for the limited 
initial clinical investigations to the larger-scale production needed 
for expanded clinical trials, the sponsor should submit information 
amendments to supplement the initial information submitted on the 
chemistry, manufacturing, and control processes with information 
appropriate to the expanded scope of the investigation.
    (iv) Reflecting the distinctions described in this paragraph (a)(7), 
and based on the phase(s) to be studied, the submission is required to 
contain the following:
    (a) Drug substance. A description of the drug substance, including 
its physical, chemical, or biological characteristics; the name and 
address of its manufacturer; the general method of preparation of the 
drug substance; the acceptable limits and analytical methods used to 
assure the identity, strength, quality, and purity of the drug 
substance; and information sufficient to support stability of the drug 
substance during the toxicological studies and the planned clinical 
studies. Reference to the current edition of the United States 
Pharmacopeia--National Formulary may satisfy relevant requirements in 
this paragraph.
    (b) Drug product. A list of all components, which may include 
reasonable alternatives for inactive compounds, used in the manufacture 
of the investigational drug product, including both those components 
intended to appear in the drug product and those which may not appear 
but which are used in the manufacturing process, and, where applicable, 
the quantitative composition of the investigational drug product, 
including any reasonable variations that may be expected during the 
investigational stage; the name and address of the drug product 
manufacturer; a brief general description of the manufacturing and 
packaging procedure as appropriate for the product; the acceptable 
limits and analytical methods used to assure the identity, strength, 
quality, and purity of the drug product; and information sufficient to 
assure the product's stability during the planned clinical studies. 
Reference to the current edition of the United States Pharmacopeia--
National Formulary may satisfy certain requirements in this paragraph.
    (c) A brief general description of the composition, manufacture, and 
control of any placebo used in a controlled clinical trial.
    (d) Labeling. A copy of all labels and labeling to be provided to 
each investigator.
    (e) Environmental analysis requirements. A claim for categorical 
exclusion under Sec. 25.30 or 25.31 or an environmental assessment 
under Sec. 25.40.
    (8) Pharmacology and toxicology information. Adequate information 
about pharmacological and toxicological studies of the drug involving 
laboratory animals or in vitro, on the basis of which the sponsor has 
concluded that it is reasonably safe to conduct the proposed clinical 
investigations. The kind, duration, and scope of animal and other tests 
required varies with the duration and nature of the proposed clinical 
investigations. Guidance documents are available from FDA that describe 
ways in which these requirements may be met. Such information is 
required to include the identification and qualifications of the 
individuals who evaluated the results of such studies and concluded that 
it is reasonably safe to begin the proposed investigations and a 
statement of where the investigations were conducted and where the 
records are available for inspection. As drug development proceeds, the 
sponsor is required to submit informational amendments, as appropriate, 
with additional information pertinent to safety.
    (i) Pharmacology and drug disposition. A section describing the 
pharmacological effects and mechanism(s) of action of the drug in 
animals, and information on the absorption, distribution, metabolism, 
and excretion of the drug, if known.
    (ii) Toxicology. (a) An integrated summary of the toxicological 
effects of the drug in animals and in vitro. Depending on the nature of 
the drug and the

[[Page 60]]

phase of the investigation, the description is to include the results of 
acute, subacute, and chronic toxicity tests; tests of the drug's effects 
on reproduction and the developing fetus; any special toxicity test 
related to the drug's particular mode of administration or conditions of 
use (e.g., inhalation, dermal, or ocular toxicology); and any in vitro 
studies intended to evaluate drug toxicity.
    (b) For each toxicology study that is intended primarily to support 
the safety of the proposed clinical investigation, a full tabulation of 
data suitable for detailed review.
    (iii) For each nonclinical laboratory study subject to the good 
laboratory practice regulations under part 58, a statement that the 
study was conducted in compliance with the good laboratory practice 
regulations in part 58, or, if the study was not conducted in compliance 
with those regulations, a brief statement of the reason for the 
noncompliance.
    (9) Previous human experience with the investigational drug. A 
summary of previous human experience known to the applicant, if any, 
with the investigational drug. The information is required to include 
the following:
    (i) If the investigational drug has been investigated or marketed 
previously, either in the United States or other countries, detailed 
information about such experience that is relevant to the safety of the 
proposed investigation or to the investigation's rationale. If the drug 
has been the subject of controlled trials, detailed information on such 
trials that is relevant to an assessment of the drug's effectiveness for 
the proposed investigational use(s) should also be provided. Any 
published material that is relevant to the safety of the proposed 
investigation or to an assessment of the drug's effectiveness for its 
proposed investigational use should be provided in full. Published 
material that is less directly relevant may be supplied by a 
bibliography.
    (ii) If the drug is a combination of drugs previously investigated 
or marketed, the information required under paragraph (a)(9)(i) of this 
section should be provided for each active drug component. However, if 
any component in such combination is subject to an approved marketing 
application or is otherwise lawfully marketed in the United States, the 
sponsor is not required to submit published material concerning that 
active drug component unless such material relates directly to the 
proposed investigational use (including publications relevant to 
component-component interaction).
    (iii) If the drug has been marketed outside the United States, a 
list of the countries in which the drug has been marketed and a list of 
the countries in which the drug has been withdrawn from marketing for 
reasons potentially related to safety or effectiveness.
    (10) Additional information. In certain applications, as described 
below, information on special topics may be needed. Such information 
shall be submitted in this section as follows:
    (i) Drug dependence and abuse potential. If the drug is a 
psychotropic substance or otherwise has abuse potential, a section 
describing relevant clinical studies and experience and studies in test 
animals.
    (ii) Radioactive drugs. If the drug is a radioactive drug, 
sufficient data from animal or human studies to allow a reasonable 
calculation of radiation-absorbed dose to the whole body and critical 
organs upon administration to a human subject. Phase 1 studies of 
radioactive drugs must include studies which will obtain sufficient data 
for dosimetry calculations.
    (iii) Pediatric studies. Plans for assessing pediatric safety and 
effectiveness.
    (iv) Other information. A brief statement of any other information 
that would aid evaluation of the proposed clinical investigations with 
respect to their safety or their design and potential as controlled 
clinical trials to support marketing of the drug.
    (11) Relevant information. If requested by FDA, any other relevant 
information needed for review of the application.
    (b) Information previously submitted. The sponsor ordinarily is not 
required to resubmit information previously submitted, but may 
incorporate the information by reference. A reference to information 
submitted previously must identify the file by name, reference number, 
volume, and page number where the information can be found. A

[[Page 61]]

reference to information submitted to the agency by a person other than 
the sponsor is required to contain a written statement that authorizes 
the reference and that is signed by the person who submitted the 
information.
    (c) Material in a foreign language. The sponsor shall submit an 
accurate and complete English translation of each part of the IND that 
is not in English. The sponsor shall also submit a copy of each original 
literature publication for which an English translation is submitted.
    (d) Number of copies. The sponsor shall submit an original and two 
copies of all submissions to the IND file, including the original 
submission and all amendments and reports.
    (e) Numbering of IND submissions. Each submission relating to an IND 
is required to be numbered serially using a single, three-digit serial 
number. The initial IND is required to be numbered 000; each subsequent 
submission (e.g., amendment, report, or correspondence) is required to 
be numbered chronologically in sequence.
    (f) Identification of exception from informed consent. If the 
investigation involves an exception from informed consent under Sec. 
50.24 of this chapter, the sponsor shall prominently identify on the 
cover sheet that the investigation is subject to the requirements in 
Sec. 50.24 of this chapter.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 
FR 1918, Jan. 25, 1988; 61 FR 51529, Oct. 2, 1996; 62 FR 40599, July 29, 
1997; 63 FR 66669, Dec. 2, 1998; 65 FR 56479, Sept. 19, 2000; 67 FR 
9585, Mar. 4, 2002]



Sec. 312.30  Protocol amendments.

    Once an IND is in effect, a sponsor shall amend it as needed to 
ensure that the clinical investigations are conducted according to 
protocols included in the application. This section sets forth the 
provisions under which new protocols may be submitted and changes in 
previously submitted protocols may be made. Whenever a sponsor intends 
to conduct a clinical investigation with an exception from informed 
consent for emergency research as set forth in Sec. 50.24 of this 
chapter, the sponsor shall submit a separate IND for such investigation.
    (a) New protocol. Whenever a sponsor intends to conduct a study that 
is not covered by a protocol already contained in the IND, the sponsor 
shall submit to FDA a protocol amendment containing the protocol for the 
study. Such study may begin provided two conditions are met: (1) The 
sponsor has submitted the protocol to FDA for its review; and (2) the 
protocol has been approved by the Institutional Review Board (IRB) with 
responsibility for review and approval of the study in accordance with 
the requirements of part 56. The sponsor may comply with these two 
conditions in either order.
    (b) Changes in a protocol. (1) A sponsor shall submit a protocol 
amendment describing any change in a Phase 1 protocol that significantly 
affects the safety of subjects or any change in a Phase 2 or 3 protocol 
that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Examples of 
changes requiring an amendment under this paragraph include:
    (i) Any increase in drug dosage or duration of exposure of 
individual subjects to the drug beyond that in the current protocol, or 
any significant increase in the number of subjects under study.
    (ii) Any significant change in the design of a protocol (such as the 
addition or dropping of a control group).
    (iii) The addition of a new test or procedure that is intended to 
improve monitoring for, or reduce the risk of, a side effect or adverse 
event; or the dropping of a test intended to monitor safety.
    (2)(i) A protocol change under paragraph (b)(1) of this section may 
be made provided two conditions are met:
    (a) The sponsor has submitted the change to FDA for its review; and
    (b) The change has been approved by the IRB with responsibility for 
review and approval of the study. The sponsor may comply with these two 
conditions in either order.
    (ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol 
change intended to eliminate an apparent immediate hazard to subjects 
may be implemented immediately provided FDA is subsequently notified by 
protocol amendment and the reviewing

[[Page 62]]

IRB is notified in accordance with Sec. 56.104(c).
    (c) New investigator. A sponsor shall submit a protocol amendment 
when a new investigator is added to carry out a previously submitted 
protocol, except that a protocol amendment is not required when a 
licensed practitioner is added in the case of a treatment protocol under 
Sec. 312.315 or Sec. 312.320. Once the investigator is added to the 
study, the investigational drug may be shipped to the investigator and 
the investigator may begin participating in the study. The sponsor shall 
notify FDA of the new investigator within 30 days of the investigator 
being added.
    (d) Content and format. A protocol amendment is required to be 
prominently identified as such (i.e., ``Protocol Amendment: New 
Protocol'', ``Protocol Amendment: Change in Protocol'', or ``Protocol 
Amendment: New Investigator''), and to contain the following:
    (1)(i) In the case of a new protocol, a copy of the new protocol and 
a brief description of the most clinically significant differences 
between it and previous protocols.
    (ii) In the case of a change in protocol, a brief description of the 
change and reference (date and number) to the submission that contained 
the protocol.
    (iii) In the case of a new investigator, the investigator's name, 
the qualifications to conduct the investigation, reference to the 
previously submitted protocol, and all additional information about the 
investigator's study as is required under Sec. 312.23(a)(6)(iii)(b).
    (2) Reference, if necessary, to specific technical information in 
the IND or in a concurrently submitted information amendment to the IND 
that the sponsor relies on to support any clinically significant change 
in the new or amended protocol. If the reference is made to supporting 
information already in the IND, the sponsor shall identify by name, 
reference number, volume, and page number the location of the 
information.
    (3) If the sponsor desires FDA to comment on the submission, a 
request for such comment and the specific questions FDA's response 
should address.
    (e) When submitted. A sponsor shall submit a protocol amendment for 
a new protocol or a change in protocol before its implementation. 
Protocol amendments to add a new investigator or to provide additional 
information about investigators may be grouped and submitted at 30-day 
intervals. When several submissions of new protocols or protocol changes 
are anticipated during a short period, the sponsor is encouraged, to the 
extent feasible, to include these all in a single submission.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 
FR 1918, Jan. 25, 1988; 61 FR 51530, Oct. 2, 1996; 67 FR 9585, Mar. 4, 
2002; 74 FR 40942, Aug. 13, 2009]



Sec. 312.31  Information amendments.

    (a) Requirement for information amendment. A sponsor shall report in 
an information amendment essential information on the IND that is not 
within the scope of a protocol amendment, IND safety reports, or annual 
report. Examples of information requiring an information amendment 
include:
    (1) New toxicology, chemistry, or other technical information; or
    (2) A report regarding the discontinuance of a clinical 
investigation.
    (b) Content and format of an information amendment. An information 
amendment is required to bear prominent identification of its contents 
(e.g., ``Information Amendment: Chemistry, Manufacturing, and Control'', 
``Information Amendment: Pharmacology-Toxicology'', ``Information 
Amendment: Clinical''), and to contain the following:
    (1) A statement of the nature and purpose of the amendment.
    (2) An organized submission of the data in a format appropriate for 
scientific review.
    (3) If the sponsor desires FDA to comment on an information 
amendment, a request for such comment.
    (c) When submitted. Information amendments to the IND should be 
submitted as necessary but, to the extent feasible, not more than every 
30 days.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53 
FR 1918, Jan. 25, 1988; 67 FR 9585, Mar. 4, 2002]

[[Page 63]]



Sec. 312.32  IND safety reporting.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Adverse event means any untoward medical occurrence associated with 
the use of a drug in humans, whether or not considered drug related.
    Life-threatening adverse event or life-threatening suspected adverse 
reaction. An adverse event or suspected adverse reaction is considered 
``life-threatening'' if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused 
death.
    Serious adverse event or serious suspected adverse reaction. An 
adverse event or suspected adverse reaction is considered ``serious'' 
if, in the view of either the investigator or sponsor, it results in any 
of the following outcomes: Death, a life-threatening adverse event, 
inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug 
dependency or drug abuse.
    Suspected adverse reaction means any adverse event for which there 
is a reasonable possibility that the drug caused the adverse event. For 
the purposes of IND safety reporting, ``reasonable possibility'' means 
there is evidence to suggest a causal relationship between the drug and 
the adverse event. Suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse 
event caused by a drug.
    Unexpected adverse event or unexpected suspected adverse reaction. 
An adverse event or suspected adverse reaction is considered 
``unexpected'' if it is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed; or, if 
an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. For example, under 
this definition, hepatic necrosis would be unexpected (by virtue of 
greater severity) if the investigator brochure referred only to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure listed only cerebral vascular 
accidents. ``Unexpected,'' as used in this definition, also refers to 
adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not 
specifically mentioned as occurring with the particular drug under 
investigation.
    (b) Review of safety information. The sponsor must promptly review 
all information relevant to the safety of the drug obtained or otherwise 
received by the sponsor from foreign or domestic sources, including 
information derived from any clinical or epidemiological investigations, 
animal or in vitro studies, reports in the scientific literature, and 
unpublished scientific papers, as well as reports from foreign 
regulatory authorities and reports of foreign commercial marketing 
experience for drugs that are not marketed in the United States.
    (c)(1) IND safety reports. The sponsor must notify FDA and all 
participating investigators (i.e., all investigators to whom the sponsor 
is providing drug under its INDs or under any investigator's IND) in an 
IND safety report of potential serious risks, from clinical trials or 
any other source, as soon as possible, but in no case later than 15 
calendar days after the sponsor determines that the information 
qualifies

[[Page 64]]

for reporting under paragraph (c)(1)(i), (c)(1)(ii), (c)(1)(iii), or 
(c)(1)(iv) of this section. In each IND safety report, the sponsor must 
identify all IND safety reports previously submitted to FDA concerning a 
similar suspected adverse reaction, and must analyze the significance of 
the suspected adverse reaction in light of previous, similar reports or 
any other relevant information.
    (i) Serious and unexpected suspected adverse reaction. The sponsor 
must report any suspected adverse reaction that is both serious and 
unexpected. The sponsor must report an adverse event as a suspected 
adverse reaction only if there is evidence to suggest a causal 
relationship between the drug and the adverse event, such as:
    (A) A single occurrence of an event that is uncommon and known to be 
strongly associated with drug exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome);
    (B) One or more occurrences of an event that is not commonly 
associated with drug exposure, but is otherwise uncommon in the 
population exposed to the drug (e.g., tendon rupture);
    (C) An aggregate analysis of specific events observed in a clinical 
trial (such as known consequences of the underlying disease or condition 
under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events 
occur more frequently in the drug treatment group than in a concurrent 
or historical control group.
    (ii) Findings from other studies. The sponsor must report any 
findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under paragraph 
(c)(1)(i) of this section), whether or not conducted under an IND, and 
whether or not conducted by the sponsor, that suggest a significant risk 
in humans exposed to the drug. Ordinarily, such a finding would result 
in a safety-related change in the protocol, informed consent, 
investigator brochure (excluding routine updates of these documents), or 
other aspects of the overall conduct of the clinical investigation.
    (iii) Findings from animal or in vitro testing. The sponsor must 
report any findings from animal or in vitro testing, whether or not 
conducted by the sponsor, that suggest a significant risk in humans 
exposed to the drug, such as reports of mutagenicity, teratogenicity, or 
carcinogenicity, or reports of significant organ toxicity at or near the 
expected human exposure. Ordinarily, any such findings would result in a 
safety-related change in the protocol, informed consent, investigator 
brochure (excluding routine updates of these documents), or other 
aspects of the overall conduct of the clinical investigation.
    (iv) Increased rate of occurrence of serious suspected adverse 
reactions. The sponsor must report any clinically important increase in 
the rate of a serious suspected adverse reaction over that listed in the 
protocol or investigator brochure.
    (v) Submission of IND safety reports. The sponsor must submit each 
IND safety report in a narrative format or on FDA Form 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files). The sponsor may submit foreign suspected adverse 
reactions on a Council for International Organizations of Medical 
Sciences (CIOMS) I Form instead of a FDA Form 3500A. Reports of overall 
findings or pooled analyses from published and unpublished in vitro, 
animal, epidemiological, or clinical studies must be submitted in a 
narrative format. Each notification to FDA must bear prominent 
identification of its contents, i.e., ``IND Safety Report,'' and must be 
transmitted to the review division in the Center for Drug Evaluation and 
Research or in the Center for Biologics Evaluation and Research that has 
responsibility for review of the IND. Upon request from FDA, the sponsor 
must submit to FDA any additional data or information that the agency 
deems necessary, as soon as possible, but in no case later than 15 
calendar days after receiving the request.
    (2) Unexpected fatal or life-threatening suspected adverse reaction 
reports. The sponsor must also notify FDA of any

[[Page 65]]

unexpected fatal or life-threatening suspected adverse reaction as soon 
as possible but in no case later than 7 calendar days after the 
sponsor's initial receipt of the information.
    (3) Reporting format or frequency. FDA may require a sponsor to 
submit IND safety reports in a format or at a frequency different than 
that required under this paragraph. The sponsor may also propose and 
adopt a different reporting format or frequency if the change is agreed 
to in advance by the director of the FDA review division that has 
responsibility for review of the IND.
    (4) Investigations of marketed drugs. A sponsor of a clinical study 
of a drug marketed or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected 
adverse reactions that are observed in the clinical study, at domestic 
or foreign study sites. The sponsor must also submit safety information 
from the clinical study as prescribed by the postmarketing safety 
reporting requirements (e.g., Sec. Sec. 310.305, 314.80, and 600.80 of 
this chapter).
    (5) Reporting study endpoints. Study endpoints (e.g., mortality or 
major morbidity) must be reported to FDA by the sponsor as described in 
the protocol and ordinarily would not be reported under paragraph (c) of 
this section. However, if a serious and unexpected adverse event occurs 
for which there is evidence suggesting a causal relationship between the 
drug and the event (e.g., death from anaphylaxis), the event must be 
reported under Sec. 312.32(c)(1)(i) as a serious and unexpected 
suspected adverse reaction even if it is a component of the study 
endpoint (e.g., all-cause mortality).
    (d) Followup. (1) The sponsor must promptly investigate all safety 
information it receives.
    (2) Relevant followup information to an IND safety report must be 
submitted as soon as the information is available and must be identified 
as such, i.e., ``Followup IND Safety Report.''
    (3) If the results of a sponsor's investigation show that an adverse 
event not initially determined to be reportable under paragraph (c) of 
this section is so reportable, the sponsor must report such suspected 
adverse reaction in an IND safety report as soon as possible, but in no 
case later than 15 calendar days after the determination is made.
    (e) Disclaimer. A safety report or other information submitted by a 
sponsor under this part (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the sponsor or 
FDA that the report or information constitutes an admission that the 
drug caused or contributed to an adverse event. A sponsor need not 
admit, and may deny, that the report or information submitted by the 
sponsor constitutes an admission that the drug caused or contributed to 
an adverse event.

[75 FR 59961, Sept. 29, 2010]



Sec. 312.33  Annual reports.

    A sponsor shall within 60 days of the anniversary date that the IND 
went into effect, submit a brief report of the progress of the 
investigation that includes:
    (a) Individual study information. A brief summary of the status of 
each study in progress and each study completed during the previous 
year. The summary is required to include the following information for 
each study:
    (1) The title of the study (with any appropriate study identifiers 
such as protocol number), its purpose, a brief statement identifying the 
patient population, and a statement as to whether the study is 
completed.
    (2) The total number of subjects initially planned for inclusion in 
the study; the number entered into the study to date, tabulated by age 
group, gender, and race; the number whose participation in the study was 
completed as planned; and the number who dropped out of the study for 
any reason.
    (3) If the study has been completed, or if interim results are 
known, a brief description of any available study results.
    (b) Summary information. Information obtained during the previous 
year's clinical and nonclinical investigations, including:
    (1) A narrative or tabular summary showing the most frequent and 
most

[[Page 66]]

serious adverse experiences by body system.
    (2) A summary of all IND safety reports submitted during the past 
year.
    (3) A list of subjects who died during participation in the 
investigation, with the cause of death for each subject.
    (4) A list of subjects who dropped out during the course of the 
investigation in association with any adverse experience, whether or not 
thought to be drug related.
    (5) A brief description of what, if anything, was obtained that is 
pertinent to an understanding of the drug's actions, including, for 
example, information about dose response, information from controlled 
trials, and information about bioavailability.
    (6) A list of the preclinical studies (including animal studies) 
completed or in progress during the past year and a summary of the major 
preclinical findings.
    (7) A summary of any significant manufacturing or microbiological 
changes made during the past year.
    (c) A description of the general investigational plan for the coming 
year to replace that submitted 1 year earlier. The general 
investigational plan shall contain the information required under Sec. 
312.23(a)(3)(iv).
    (d) If the investigator brochure has been revised, a description of 
the revision and a copy of the new brochure.
    (e) A description of any significant Phase 1 protocol modifications 
made during the previous year and not previously reported to the IND in 
a protocol amendment.
    (f) A brief summary of significant foreign marketing developments 
with the drug during the past year, such as approval of marketing in any 
country or withdrawal or suspension from marketing in any country.
    (g) If desired by the sponsor, a log of any outstanding business 
with respect to the IND for which the sponsor requests or expects a 
reply, comment, or meeting.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63 
FR 6862, Feb. 11, 1998; 67 FR 9585, Mar. 4, 2002]



Sec. 312.38  Withdrawal of an IND.

    (a) At any time a sponsor may withdraw an effective IND without 
prejudice.
    (b) If an IND is withdrawn, FDA shall be so notified, all clinical 
investigations conducted under the IND shall be ended, all current 
investigators notified, and all stocks of the drug returned to the 
sponsor or otherwise disposed of at the request of the sponsor in 
accordance with Sec. 312.59.
    (c) If an IND is withdrawn because of a safety reason, the sponsor 
shall promptly so inform FDA, all participating investigators, and all 
reviewing Institutional Review Boards, together with the reasons for 
such withdrawal.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



                    Subpart C_Administrative Actions



Sec. 312.40  General requirements for use of an investigational new 
drug in a clinical investigation.

    (a) An investigational new drug may be used in a clinical 
investigation if the following conditions are met:
    (1) The sponsor of the investigation submits an IND for the drug to 
FDA; the IND is in effect under paragraph (b) of this section; and the 
sponsor complies with all applicable requirements in this part and parts 
50 and 56 with respect to the conduct of the clinical investigations; 
and
    (2) Each participating investigator conducts his or her 
investigation in compliance with the requirements of this part and parts 
50 and 56.
    (b) An IND goes into effect:
    (1) Thirty days after FDA receives the IND, unless FDA notifies the 
sponsor that the investigations described in the IND are subject to a 
clinical hold under Sec. 312.42; or
    (2) On earlier notification by FDA that the clinical investigations 
in the IND may begin. FDA will notify the sponsor in writing of the date 
it receives the IND.
    (c) A sponsor may ship an investigational new drug to investigators 
named in the IND:
    (1) Thirty days after FDA receives the IND; or

[[Page 67]]

    (2) On earlier FDA authorization to ship the drug.
    (d) An investigator may not administer an investigational new drug 
to human subjects until the IND goes into effect under paragraph (b) of 
this section.



Sec. 312.41  Comment and advice on an IND.

    (a) FDA may at any time during the course of the investigation 
communicate with the sponsor orally or in writing about deficiencies in 
the IND or about FDA's need for more data or information.
    (b) On the sponsor's request, FDA will provide advice on specific 
matters relating to an IND. Examples of such advice may include advice 
on the adequacy of technical data to support an investigational plan, on 
the design of a clinical trial, and on whether proposed investigations 
are likely to produce the data and information that is needed to meet 
requirements for a marketing application.
    (c) Unless the communication is accompanied by a clinical hold order 
under Sec. 312.42, FDA communications with a sponsor under this section 
are solely advisory and do not require any modification in the planned 
or ongoing clinical investigations or response to the agency.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.42  Clinical holds and requests for modification.

    (a) General. A clinical hold is an order issued by FDA to the 
sponsor to delay a proposed clinical investigation or to suspend an 
ongoing investigation. The clinical hold order may apply to one or more 
of the investigations covered by an IND. When a proposed study is placed 
on clinical hold, subjects may not be given the investigational drug. 
When an ongoing study is placed on clinical hold, no new subjects may be 
recruited to the study and placed on the investigational drug; patients 
already in the study should be taken off therapy involving the 
investigational drug unless specifically permitted by FDA in the 
interest of patient safety.
    (b) Grounds for imposition of clinical hold--(1) Clinical hold of a 
Phase 1 study under an IND. FDA may place a proposed or ongoing Phase 1 
investigation on clinical hold if it finds that:
    (i) Human subjects are or would be exposed to an unreasonable and 
significant risk of illness or injury;
    (ii) The clinical investigators named in the IND are not qualified 
by reason of their scientific training and experience to conduct the 
investigation described in the IND;
    (iii) The investigator brochure is misleading, erroneous, or 
materially incomplete; or
    (iv) The IND does not contain sufficient information required under 
Sec. 312.23 to assess the risks to subjects of the proposed studies.
    (v) The IND is for the study of an investigational drug intended to 
treat a life-threatening disease or condition that affects both genders, 
and men or women with reproductive potential who have the disease or 
condition being studied are excluded from eligibility because of a risk 
or potential risk from use of the investigational drug of reproductive 
toxicity (i.e., affecting reproductive organs) or developmental toxicity 
(i.e., affecting potential offspring). The phrase ``women with 
reproductive potential'' does not include pregnant women. For purposes 
of this paragraph, ``life-threatening illnesses or diseases'' are 
defined as ``diseases or conditions where the likelihood of death is 
high unless the course of the disease is interrupted.'' The clinical 
hold would not apply under this paragraph to clinical studies conducted:
    (A) Under special circumstances, such as studies pertinent only to 
one gender (e.g., studies evaluating the excretion of a drug in semen or 
the effects on menstrual function);
    (B) Only in men or women, as long as a study that does not exclude 
members of the other gender with reproductive potential is being 
conducted concurrently, has been conducted, or will take place within a 
reasonable time agreed upon by the agency; or
    (C) Only in subjects who do not suffer from the disease or condition 
for which the drug is being studied.

[[Page 68]]

    (2) Clinical hold of a Phase 2 or 3 study under an IND. FDA may 
place a proposed or ongoing Phase 2 or 3 investigation on clinical hold 
if it finds that:
    (i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(v) 
of this section apply; or
    (ii) The plan or protocol for the investigation is clearly deficient 
in design to meet its stated objectives.
    (3) Clinical hold of an expanded access IND or expanded access 
protocol. FDA may place an expanded access IND or expanded access 
protocol on clinical hold under the following conditions:
    (i) Final use. FDA may place a proposed expanded access IND or 
treatment use protocol on clinical hold if it is determined that:
    (A) The pertinent criteria in subpart I of this part for permitting 
the expanded access use to begin are not satisfied; or
    (B) The expanded access IND or expanded access protocol does not 
comply with the requirements for expanded access submissions in subpart 
I of this part.
    (ii) Ongoing use. FDA may place an ongoing expanded access IND or 
expanded access protocol on clinical hold if it is determined that the 
pertinent criteria in subpart I of this part for permitting the expanded 
access are no longer satisfied.
    (4) Clinical hold of any study that is not designed to be adequate 
and well-controlled. FDA may place a proposed or ongoing investigation 
that is not designed to be adequate and well-controlled on clinical hold 
if it finds that:
    (i) Any of the conditions in paragraph (b)(1) or (b)(2) of this 
section apply; or
    (ii) There is reasonable evidence the investigation that is not 
designed to be adequate and well-controlled is impeding enrollment in, 
or otherwise interfering with the conduct or completion of, a study that 
is designed to be an adequate and well-controlled investigation of the 
same or another investigational drug; or
    (iii) Insufficient quantities of the investigational drug exist to 
adequately conduct both the investigation that is not designed to be 
adequate and well-controlled and the investigations that are designed to 
be adequate and well-controlled; or
    (iv) The drug has been studied in one or more adequate and well-
controlled investigations that strongly suggest lack of effectiveness; 
or
    (v) Another drug under investigation or approved for the same 
indication and available to the same patient population has demonstrated 
a better potential benefit/risk balance; or
    (vi) The drug has received marketing approval for the same 
indication in the same patient population; or
    (vii) The sponsor of the study that is designed to be an adequate 
and well-controlled investigation is not actively pursuing marketing 
approval of the investigational drug with due diligence; or
    (viii) The Commissioner determines that it would not be in the 
public interest for the study to be conducted or continued. FDA 
ordinarily intends that clinical holds under paragraphs (b)(4)(ii), 
(b)(4)(iii) and (b)(4)(v) of this section would only apply to additional 
enrollment in nonconcurrently controlled trials rather than eliminating 
continued access to individuals already receiving the investigational 
drug.
    (5) Clinical hold of any investigation involving an exception from 
informed consent under Sec. 50.24 of this chapter. FDA may place a 
proposed or ongoing investigation involving an exception from informed 
consent under Sec. 50.24 of this chapter on clinical hold if it is 
determined that:
    (i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this 
section apply; or
    (ii) The pertinent criteria in Sec. 50.24 of this chapter for such 
an investigation to begin or continue are not submitted or not 
satisfied.
    (6) Clinical hold of any investigation involving an exception from 
informed consent under Sec. 50.23(d) of this chapter. FDA may place a 
proposed or ongoing investigation involving an exception from informed 
consent under Sec. 50.23(d) of this chapter on clinical hold if it is 
determined that:
    (i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this 
section apply; or
    (ii) A determination by the President to waive the prior consent 
requirement

[[Page 69]]

for the administration of an investigational new drug has not been made.
    (c) Discussion of deficiency. Whenever FDA concludes that a 
deficiency exists in a clinical investigation that may be grounds for 
the imposition of clinical hold FDA will, unless patients are exposed to 
immediate and serious risk, attempt to discuss and satisfactorily 
resolve the matter with the sponsor before issuing the clinical hold 
order.
    (d) Imposition of clinical hold. The clinical hold order may be made 
by telephone or other means of rapid communication or in writing. The 
clinical hold order will identify the studies under the IND to which the 
hold applies, and will briefly explain the basis for the action. The 
clinical hold order will be made by or on behalf of the Division 
Director with responsibility for review of the IND. As soon as possible, 
and no more than 30 days after imposition of the clinical hold, the 
Division Director will provide the sponsor a written explanation of the 
basis for the hold.
    (e) Resumption of clinical investigations. An investigation may only 
resume after FDA (usually the Division Director, or the Director's 
designee, with responsibility for review of the IND) has notified the 
sponsor that the investigation may proceed. Resumption of the affected 
investigation(s) will be authorized when the sponsor corrects the 
deficiency(ies) previously cited or otherwise satisfies the agency that 
the investigation(s) can proceed. FDA may notify a sponsor of its 
determination regarding the clinical hold by telephone or other means of 
rapid communication. If a sponsor of an IND that has been placed on 
clinical hold requests in writing that the clinical hold be removed and 
submits a complete response to the issue(s) identified in the clinical 
hold order, FDA shall respond in writing to the sponsor within 30-
calendar days of receipt of the request and the complete response. FDA's 
response will either remove or maintain the clinical hold, and will 
state the reasons for such determination. Notwithstanding the 30-
calendar day response time, a sponsor may not proceed with a clinical 
trial on which a clinical hold has been imposed until the sponsor has 
been notified by FDA that the hold has been lifted.
    (f) Appeal. If the sponsor disagrees with the reasons cited for the 
clinical hold, the sponsor may request reconsideration of the decision 
in accordance with Sec. 312.48.
    (g) Conversion of IND on clinical hold to inactive status. If all 
investigations covered by an IND remain on clinical hold for 1 year or 
more, the IND may be placed on inactive status by FDA under Sec. 
312.45.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19477, May 22, 1987; 57 
FR 13249, Apr. 15, 1992; 61 FR 51530, Oct. 2, 1996; 63 FR 68678, Dec. 
14, 1998; 64 FR 54189, Oct. 5, 1999; 65 FR 34971, June 1, 2000; 74 FR 
40942, Aug. 13, 2009]



Sec. 312.44  Termination.

    (a) General. This section describes the procedures under which FDA 
may terminate an IND. If an IND is terminated, the sponsor shall end all 
clinical investigations conducted under the IND and recall or otherwise 
provide for the disposition of all unused supplies of the drug. A 
termination action may be based on deficiencies in the IND or in the 
conduct of an investigation under an IND. Except as provided in 
paragraph (d) of this section, a termination shall be preceded by a 
proposal to terminate by FDA and an opportunity for the sponsor to 
respond. FDA will, in general, only initiate an action under this 
section after first attempting to resolve differences informally or, 
when appropriate, through the clinical hold procedures described in 
Sec. 312.42.
    (b) Grounds for termination--(1) Phase 1. FDA may propose to 
terminate an IND during Phase 1 if it finds that:
    (i) Human subjects would be exposed to an unreasonable and 
significant risk of illness or unjury.
    (ii) The IND does not contain sufficient information required under 
Sec. 312.23 to assess the safety to subjects of the clinical 
investigations.
    (iii) The methods, facilities, and controls used for the 
manufacturing, processing, and packing of the investigational drug are 
inadequate to establish and maintain appropriate standards of identity, 
strength, quality, and purity as needed for subject safety.

[[Page 70]]

    (iv) The clinical investigations are being conducted in a manner 
substantially different than that described in the protocols submitted 
in the IND.
    (v) The drug is being promoted or distributed for commercial 
purposes not justified by the requirements of the investigation or 
permitted by Sec. 312.7.
    (vi) The IND, or any amendment or report to the IND, contains an 
untrue statement of a material fact or omits material information 
required by this part.
    (vii) The sponsor fails promptly to investigate and inform the Food 
and Drug Administration and all investigators of serious and unexpected 
adverse experiences in accordance with Sec. 312.32 or fails to make any 
other report required under this part.
    (viii) The sponsor fails to submit an accurate annual report of the 
investigations in accordance with Sec. 312.33.
    (ix) The sponsor fails to comply with any other applicable 
requirement of this part, part 50, or part 56.
    (x) The IND has remained on inactive status for 5 years or more.
    (xi) The sponsor fails to delay a proposed investigation under the 
IND or to suspend an ongoing investigation that has been placed on 
clinical hold under Sec. 312.42(b)(4).
    (2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2 
or Phase 3 if FDA finds that:
    (i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi) 
of this section apply; or
    (ii) The investigational plan or protocol(s) is not reasonable as a 
bona fide scientific plan to determine whether or not the drug is safe 
and effective for use; or
    (iii) There is convincing evidence that the drug is not effective 
for the purpose for which it is being investigated.
    (3) FDA may propose to terminate a treatment IND if it finds that:
    (i) Any of the conditions in paragraphs (b)(1)(i) through (x) of 
this section apply; or
    (ii) Any of the conditions in Sec. 312.42(b)(3) apply.
    (c) Opportunity for sponsor response. (1) If FDA proposes to 
terminate an IND, FDA will notify the sponsor in writing, and invite 
correction or explanation within a period of 30 days.
    (2) On such notification, the sponsor may provide a written 
explanation or correction or may request a conference with FDA to 
provide the requested explanation or correction. If the sponsor does not 
respond to the notification within the allocated time, the IND shall be 
terminated.
    (3) If the sponsor responds but FDA does not accept the explanation 
or correction submitted, FDA shall inform the sponsor in writing of the 
reason for the nonacceptance and provide the sponsor with an opportunity 
for a regulatory hearing before FDA under part 16 on the question of 
whether the IND should be terminated. The sponsor's request for a 
regulatory hearing must be made within 10 days of the sponsor's receipt 
of FDA's notification of nonacceptance.
    (d) Immediate termination of IND. Notwithstanding paragraphs (a) 
through (c) of this section, if at any time FDA concludes that 
continuation of the investigation presents an immediate and substantial 
danger to the health of individuals, the agency shall immediately, by 
written notice to the sponsor from the Director of the Center for Drug 
Evaluation and Research or the Director of the Center for Biologics 
Evaluation and Research, terminate the IND. An IND so terminated is 
subject to reinstatement by the Director on the basis of additional 
submissions that eliminate such danger. If an IND is terminated under 
this paragraph, the agency will afford the sponsor an opportunity for a 
regulatory hearing under part 16 on the question of whether the IND 
should be reinstated.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 
FR 11579, Mar. 29, 1990; 57 FR 13249, Apr. 15, 1992; 67 FR 9586, Mar. 4, 
2002]



Sec. 312.45  Inactive status.

    (a) If no subjects are entered into clinical studies for a period of 
2 years or more under an IND, or if all investigations under an IND 
remain on clinical hold for 1 year or more, the IND may be placed by FDA 
on inactive status. This action may be taken by FDA either on request of 
the sponsor or on FDA's own initiative. If FDA seeks to

[[Page 71]]

act on its own initiative under this section, it shall first notify the 
sponsor in writing of the proposed inactive status. Upon receipt of such 
notification, the sponsor shall have 30 days to respond as to why the 
IND should continue to remain active.
    (b) If an IND is placed on inactive status, all investigators shall 
be so notified and all stocks of the drug shall be returned or otherwise 
disposed of in accordance with Sec. 312.59.
    (c) A sponsor is not required to submit annual reports to an IND on 
inactive status. An inactive IND is, however, still in effect for 
purposes of the public disclosure of data and information under Sec. 
312.130.
    (d) A sponsor who intends to resume clinical investigation under an 
IND placed on inactive status shall submit a protocol amendment under 
Sec. 312.30 containing the proposed general investigational plan for 
the coming year and appropriate protocols. If the protocol amendment 
relies on information previously submitted, the plan shall reference 
such information. Additional information supporting the proposed 
investigation, if any, shall be submitted in an information amendment. 
Notwithstanding the provisions of Sec. 312.30, clinical investigations 
under an IND on inactive status may only resume (1) 30 days after FDA 
receives the protocol amendment, unless FDA notifies the sponsor that 
the investigations described in the amendment are subject to a clinical 
hold under Sec. 312.42, or (2) on earlier notification by FDA that the 
clinical investigations described in the protocol amendment may begin.
    (e) An IND that remains on inactive status for 5 years or more may 
be terminated under Sec. 312.44.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.47  Meetings.

    (a) General. Meetings between a sponsor and the agency are 
frequently useful in resolving questions and issues raised during the 
course of a clinical investigation. FDA encourages such meetings to the 
extent that they aid in the evaluation of the drug and in the solution 
of scientific problems concerning the drug, to the extent that FDA's 
resources permit. The general principle underlying the conduct of such 
meetings is that there should be free, full, and open communication 
about any scientific or medical question that may arise during the 
clinical investigation. These meetings shall be conducted and documented 
in accordance with part 10.
    (b) ``End-of-Phase 2'' meetings and meetings held before submission 
of a marketing application. At specific times during the drug 
investigation process, meetings between FDA and a sponsor can be 
especially helpful in minimizing wasteful expenditures of time and money 
and thus in speeding the drug development and evaluation process. In 
particular, FDA has found that meetings at the end of Phase 2 of an 
investigation (end-of-Phase 2 meetings) are of considerable assistance 
in planning later studies and that meetings held near completion of 
Phase 3 and before submission of a marketing application (``pre-NDA'' 
meetings) are helpful in developing methods of presentation and 
submission of data in the marketing application that facilitate review 
and allow timely FDA response.
    (1) End-of-Phase 2 meetings--(i) Purpose. The purpose of an end-of-
phase 2 meeting is to determine the safety of proceeding to Phase 3, to 
evaluate the Phase 3 plan and protocols and the adequacy of current 
studies and plans to assess pediatric safety and effectiveness, and to 
identify any additional information necessary to support a marketing 
application for the uses under investigation.
    (ii) Eligibility for meeting. While the end-of-Phase 2 meeting is 
designed primarily for IND's involving new molecular entities or major 
new uses of marketed drugs, a sponsor of any IND may request and obtain 
an end-of-Phase 2 meeting.
    (iii) Timing. To be most useful to the sponsor, end-of-Phase 2 
meetings should be held before major commitments of effort and resources 
to specific Phase 3 tests are made. The scheduling of an end-of-Phase 2 
meeting is not, however, intended to delay the transition of an 
investigation from Phase 2 to Phase 3.
    (iv) Advance information. At least 1 month in advance of an end-of-
Phase 2

[[Page 72]]

meeting, the sponsor should submit background information on the 
sponsor's plan for Phase 3, including summaries of the Phase 1 and 2 
investigations, the specific protocols for Phase 3 clinical studies, 
plans for any additional nonclinical studies, plans for pediatric 
studies, including a time line for protocol finalization, enrollment, 
completion, and data analysis, or information to support any planned 
request for waiver or deferral of pediatric studies, and, if available, 
tentative labeling for the drug. The recommended contents of such a 
submission are described more fully in FDA Staff Manual Guide 4850.7 
that is publicly available under FDA's public information regulations in 
part 20.
    (v) Conduct of meeting. Arrangements for an end-of-Phase 2 meeting 
are to be made with the division in FDA's Center for Drug Evaluation and 
Research or the Center for Biologics Evaluation and Research which is 
responsible for review of the IND. The meeting will be scheduled by FDA 
at a time convenient to both FDA and the sponsor. Both the sponsor and 
FDA may bring consultants to the meeting. The meeting should be directed 
primarily at establishing agreement between FDA and the sponsor of the 
overall plan for Phase 3 and the objectives and design of particular 
studies. The adequacy of the technical information to support Phase 3 
studies and/or a marketing application may also be discussed. FDA will 
also provide its best judgment, at that time, of the pediatric studies 
that will be required for the drug product and whether their submission 
will be deferred until after approval. Agreements reached at the meeting 
on these matters will be recorded in minutes of the conference that will 
be taken by FDA in accordance with Sec. 10.65 and provided to the 
sponsor. The minutes along with any other written material provided to 
the sponsor will serve as a permanent record of any agreements reached. 
Barring a significant scientific development that requires otherwise, 
studies conducted in accordance with the agreement shall be presumed to 
be sufficient in objective and design for the purpose of obtaining 
marketing approval for the drug.
    (2) ``Pre-NDA'' and ``pre-BLA'' meetings. FDA has found that delays 
associated with the initial review of a marketing application may be 
reduced by exchanges of information about a proposed marketing 
application. The primary purpose of this kind of exchange is to uncover 
any major unresolved problems, to identify those studies that the 
sponsor is relying on as adequate and well-controlled to establish the 
drug's effectiveness, to identify the status of ongoing or needed 
studies adequate to assess pediatric safety and effectiveness, to 
acquaint FDA reviewers with the general information to be submitted in 
the marketing application (including technical information), to discuss 
appropriate methods for statistical analysis of the data, and to discuss 
the best approach to the presentation and formatting of data in the 
marketing application. Arrangements for such a meeting are to be 
initiated by the sponsor with the division responsible for review of the 
IND. To permit FDA to provide the sponsor with the most useful advice on 
preparing a marketing application, the sponsor should submit to FDA's 
reviewing division at least 1 month in advance of the meeting the 
following information:
    (i) A brief summary of the clinical studies to be submitted in the 
application.
    (ii) A proposed format for organizing the submission, including 
methods for presenting the data.
    (iii) Information on the status of needed or ongoing pediatric 
studies.
    (iv) Any other information for discussion at the meeting.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 
FR 11580, Mar. 29, 1990; 63 FR 66669, Dec. 2, 1998; 67 FR 9586, Mar. 4, 
2002]



Sec. 312.48  Dispute resolution.

    (a) General. The Food and Drug Administration is committed to 
resolving differences between sponsors and FDA reviewing divisions with 
respect to requirements for IND's as quickly and amicably as possible 
through the cooperative exchange of information and views.
    (b) Administrative and procedural issues. When administrative or 
procedural disputes arise, the sponsor should

[[Page 73]]

first attempt to resolve the matter with the division in FDA's Center 
for Drug Evaluation and Research or Center for Biologics Evaluation and 
Research which is responsible for review of the IND, beginning with the 
consumer safety officer assigned to the application. If the dispute is 
not resolved, the sponsor may raise the matter with the person 
designated as ombudsman, whose function shall be to investigate what has 
happened and to facilitate a timely and equitable resolution. 
Appropriate issues to raise with the ombudsman include resolving 
difficulties in scheduling meetings and obtaining timely replies to 
inquiries. Further details on this procedure are contained in FDA Staff 
Manual Guide 4820.7 that is publicly available under FDA's public 
information regulations in part 20.
    (c) Scientific and medical disputes. (1) When scientific or medical 
disputes arise during the drug investigation process, sponsors should 
discuss the matter directly with the responsible reviewing officials. If 
necessary, sponsors may request a meeting with the appropriate reviewing 
officials and management representatives in order to seek a resolution. 
Requests for such meetings shall be directed to the director of the 
division in FDA's Center for Drug Evaluation and Research or Center for 
Biologics Evaluation and Research which is responsible for review of the 
IND. FDA will make every attempt to grant requests for meetings that 
involve important issues and that can be scheduled at mutually 
convenient times.
    (2) The ``end-of-Phase 2'' and ``pre-NDA'' meetings described in 
Sec. 312.47(b) will also provide a timely forum for discussing and 
resolving scientific and medical issues on which the sponsor disagrees 
with the agency.
    (3) In requesting a meeting designed to resolve a scientific or 
medical dispute, applicants may suggest that FDA seek the advice of 
outside experts, in which case FDA may, in its discretion, invite to the 
meeting one or more of its advisory committee members or other 
consultants, as designated by the agency. Applicants may rely on, and 
may bring to any meeting, their own consultants. For major scientific 
and medical policy issues not resolved by informal meetings, FDA may 
refer the matter to one of its standing advisory committees for its 
consideration and recommendations.

[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990]



        Subpart D_Responsibilities of Sponsors and Investigators



Sec. 312.50  General responsibilities of sponsors.

    Sponsors are responsibile for selecting qualified investigators, 
providing them with the information they need to conduct an 
investigation properly, ensuring proper monitoring of the 
investigation(s), ensuring that the investigation(s) is conducted in 
accordance with the general investigational plan and protocols contained 
in the IND, maintaining an effective IND with respect to the 
investigations, and ensuring that FDA and all participating 
investigators are promptly informed of significant new adverse effects 
or risks with respect to the drug. Additional specific responsibilities 
of sponsors are described elsewhere in this part.



Sec. 312.52  Transfer of obligations to a contract research organization.

    (a) A sponsor may transfer responsibility for any or all of the 
obligations set forth in this part to a contract research organization. 
Any such transfer shall be described in writing. If not all obligations 
are transferred, the writing is required to describe each of the 
obligations being assumed by the contract research organization. If all 
obligations are transferred, a general statement that all obligations 
have been transferred is acceptable. Any obligation not covered by the 
written description shall be deemed not to have been transferred.
    (b) A contract research organization that assumes any obligation of 
a sponsor shall comply with the specific regulations in this chapter 
applicable to this obligation and shall be subject to the same 
regulatory action as a sponsor for failure to comply with any obligation 
assumed under these regulations. Thus, all references to ``sponsor'' in 
this part apply to a contract research organization to the extent that

[[Page 74]]

it assumes one or more obligations of the sponsor.



Sec. 312.53  Selecting investigators and monitors.

    (a) Selecting investigators. A sponsor shall select only 
investigators qualified by training and experience as appropriate 
experts to investigate the drug.
    (b) Control of drug. A sponsor shall ship investigational new drugs 
only to investigators participating in the investigation.
    (c) Obtaining information from the investigator. Before permitting 
an investigator to begin participation in an investigation, the sponsor 
shall obtain the following:
    (1) A signed investigator statement (Form FDA-1572) containing:
    (i) The name and address of the investigator;
    (ii) The name and code number, if any, of the protocol(s) in the IND 
identifying the study(ies) to be conducted by the investigator;
    (iii) The name and address of any medical school, hospital, or other 
research facility where the clinical investigation(s) will be conducted;
    (iv) The name and address of any clinical laboratory facilities to 
be used in the study;
    (v) The name and address of the IRB that is responsible for review 
and approval of the study(ies);
    (vi) A commitment by the investigator that he or she:
    (a) Will conduct the study(ies) in accordance with the relevant, 
current protocol(s) and will only make changes in a protocol after 
notifying the sponsor, except when necessary to protect the safety, the 
rights, or welfare of subjects;
    (b) Will comply with all requirements regarding the obligations of 
clinical investigators and all other pertinent requirements in this 
part;
    (c) Will personally conduct or supervise the described 
investigation(s);
    (d) Will inform any potential subjects that the drugs are being used 
for investigational purposes and will ensure that the requirements 
relating to obtaining informed consent (21 CFR part 50) and 
institutional review board review and approval (21 CFR part 56) are met;
    (e) Will report to the sponsor adverse experiences that occur in the 
course of the investigation(s) in accordance with Sec. 312.64;
    (f) Has read and understands the information in the investigator's 
brochure, including the potential risks and side effects of the drug; 
and
    (g) Will ensure that all associates, colleagues, and employees 
assisting in the conduct of the study(ies) are informed about their 
obligations in meeting the above commitments.
    (vii) A commitment by the investigator that, for an investigation 
subject to an institutional review requirement under part 56, an IRB 
that complies with the requirements of that part will be responsible for 
the initial and continuing review and approval of the clinical 
investigation and that the investigator will promptly report to the IRB 
all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others, and will not make any 
changes in the research without IRB approval, except where necessary to 
eliminate apparent immediate hazards to the human subjects.
    (viii) A list of the names of the subinvestigators (e.g., research 
fellows, residents) who will be assisting the investigator in the 
conduct of the investigation(s).
    (2) Curriculum vitae. A curriculum vitae or other statement of 
qualifications of the investigator showing the education, training, and 
experience that qualifies the investigator as an expert in the clinical 
investigation of the drug for the use under investigation.
    (3) Clinical protocol. (i) For Phase 1 investigations, a general 
outline of the planned investigation including the estimated duration of 
the study and the maximum number of subjects that will be involved.
    (ii) For Phase 2 or 3 investigations, an outline of the study 
protocol including an approximation of the number of subjects to be 
treated with the drug and the number to be employed as controls, if any; 
the clinical uses to be investigated; characteristics of subjects by 
age, sex, and condition; the kind of clinical observations and 
laboratory tests to be conducted; the estimated duration of the study; 
and copies or a

[[Page 75]]

description of case report forms to be used.
    (4) Financial disclosure information. Sufficient accurate financial 
information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under part 54 of this 
chapter. The sponsor shall obtain a commitment from the clinical 
investigator to promptly update this information if any relevant changes 
occur during the course of the investigation and for 1 year following 
the completion of the study.
    (d) Selecting monitors. A sponsor shall select a monitor qualified 
by training and experience to monitor the progress of the investigation.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 61 
FR 57280, Nov. 5, 1996; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4, 
2002]



Sec. 312.54  Emergency research under Sec. 50.24 of this chapter.

    (a) The sponsor shall monitor the progress of all investigations 
involving an exception from informed consent under Sec. 50.24 of this 
chapter. When the sponsor receives from the IRB information concerning 
the public disclosures required by Sec. 50.24(a)(7)(ii) and (a)(7)(iii) 
of this chapter, the sponsor promptly shall submit to the IND file and 
to Docket Number 95S-0158 in the Division of Dockets Management (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852, copies of the information that was disclosed, 
identified by the IND number.
    (b) The sponsor also shall monitor such investigations to identify 
when an IRB determines that it cannot approve the research because it 
does not meet the criteria in the exception in Sec. 50.24(a) of this 
chapter or because of other relevant ethical concerns. The sponsor 
promptly shall provide this information in writing to FDA, investigators 
who are asked to participate in this or a substantially equivalent 
clinical investigation, and other IRB's that are asked to review this or 
a substantially equivalent investigation.

[61 FR 51530, Oct. 2, 1996, as amended at 68 FR 24879, May 9, 2003]



Sec. 312.55  Informing investigators.

    (a) Before the investigation begins, a sponsor (other than a 
sponsor-investigator) shall give each participating clinical 
investigator an investigator brochure containing the information 
described in Sec. 312.23(a)(5).
    (b) The sponsor shall, as the overall investigation proceeds, keep 
each participating investigator informed of new observations discovered 
by or reported to the sponsor on the drug, particularly with respect to 
adverse effects and safe use. Such information may be distributed to 
investigators by means of periodically revised investigator brochures, 
reprints or published studies, reports or letters to clinical 
investigators, or other appropriate means. Important safety information 
is required to be relayed to investigators in accordance with Sec. 
312.32.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.56  Review of ongoing investigations.

    (a) The sponsor shall monitor the progress of all clinical 
investigations being conducted under its IND.
    (b) A sponsor who discovers that an investigator is not complying 
with the signed agreement (Form FDA-1572), the general investigational 
plan, or the requirements of this part or other applicable parts shall 
promptly either secure compliance or discontinue shipments of the 
investigational new drug to the investigator and end the investigator's 
participation in the investigation. If the investigator's participation 
in the investigation is ended, the sponsor shall require that the 
investigator dispose of or return the investigational drug in accordance 
with the requirements of Sec. 312.59 and shall notify FDA.
    (c) The sponsor shall review and evaluate the evidence relating to 
the safety and effectiveness of the drug as it is obtained from the 
investigator. The sponsors shall make such reports to FDA regarding 
information relevant to the safety of the drug as are required under 
Sec. 312.32. The sponsor shall make annual reports on the progress of 
the investigation in accordance with Sec. 312.33.

[[Page 76]]

    (d) A sponsor who determines that its investigational drug presents 
an unreasonable and significant risk to subjects shall discontinue those 
investigations that present the risk, notify FDA, all institutional 
review boards, and all investigators who have at any time participated 
in the investigation of the discontinuance, assure the disposition of 
all stocks of the drug outstanding as required by Sec. 312.59, and 
furnish FDA with a full report of the sponsor's actions. The sponsor 
shall discontinue the investigation as soon as possible, and in no event 
later than 5 working days after making the determination that the 
investigation should be discontinued. Upon request, FDA will confer with 
a sponsor on the need to discontinue an investigation.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.57  Recordkeeping and record retention.

    (a) A sponsor shall maintain adequate records showing the receipt, 
shipment, or other disposition of the investigational drug. These 
records are required to include, as appropriate, the name of the 
investigator to whom the drug is shipped, and the date, quantity, and 
batch or code mark of each such shipment.
    (b) A sponsor shall maintain complete and accurate records showing 
any financial interest in Sec. 54.4(a)(3)(i), (a)(3)(ii), (a)(3)(iii), 
and (a)(3)(iv) of this chapter paid to clinical investigators by the 
sponsor of the covered study. A sponsor shall also maintain complete and 
accurate records concerning all other financial interests of 
investigators subject to part 54 of this chapter.
    (c) A sponsor shall retain the records and reports required by this 
part for 2 years after a marketing application is approved for the drug; 
or, if an application is not approved for the drug, until 2 years after 
shipment and delivery of the drug for investigational use is 
discontinued and FDA has been so notified.
    (d) A sponsor shall retain reserve samples of any test article and 
reference standard identified in, and used in any of the bioequivalence 
or bioavailability studies described in, Sec. 320.38 or Sec. 320.63 of 
this chapter, and release the reserve samples to FDA upon request, in 
accordance with, and for the period specified in Sec. 320.38.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 58 
FR 25926, Apr. 28, 1993; 63 FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4, 
2002]



Sec. 312.58  Inspection of sponsor's records and reports.

    (a) FDA inspection. A sponsor shall upon request from any properly 
authorized officer or employee of the Food and Drug Administration, at 
reasonable times, permit such officer or employee to have access to and 
copy and verify any records and reports relating to a clinical 
investigation conducted under this part. Upon written request by FDA, 
the sponsor shall submit the records or reports (or copies of them) to 
FDA. The sponsor shall discontinue shipments of the drug to any 
investigator who has failed to maintain or make available records or 
reports of the investigation as required by this part.
    (b) Controlled substances. If an investigational new drug is a 
substance listed in any schedule of the Controlled Substances Act (21 
U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery, 
receipt, and disposition of the drug, which are required to be kept 
under this part or other applicable parts of this chapter shall, upon 
the request of a properly authorized employee of the Drug Enforcement 
Administration of the U.S. Department of Justice, be made available by 
the investigator or sponsor to whom the request is made, for inspection 
and copying. In addition, the sponsor shall assure that adequate 
precautions are taken, including storage of the investigational drug in 
a securely locked, substantially constructed cabinet, or other securely 
locked, substantially constructed enclosure, access to which is limited, 
to prevent theft or diversion of the substance into illegal channels of 
distribution.

[[Page 77]]



Sec. 312.59  Disposition of unused supply of investigational drug.

    The sponsor shall assure the return of all unused supplies of the 
investigational drug from each individual investigator whose 
participation in the investigation is discontinued or terminated. The 
sponsor may authorize alternative disposition of unused supplies of the 
investigational drug provided this alternative disposition does not 
expose humans to risks from the drug. The sponsor shall maintain written 
records of any disposition of the drug in accordance with Sec. 312.57.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.60  General responsibilities of investigators.

    An investigator is responsible for ensuring that an investigation is 
conducted according to the signed investigator statement, the 
investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the investigator's care; 
and for the control of drugs under investigation. An investigator shall, 
in accordance with the provisions of part 50 of this chapter, obtain the 
informed consent of each human subject to whom the drug is administered, 
except as provided in Sec. Sec. 50.23 or 50.24 of this chapter. 
Additional specific responsibilities of clinical investigators are set 
forth in this part and in parts 50 and 56 of this chapter.

[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51530, Oct. 2, 1996]



Sec. 312.61  Control of the investigational drug.

    An investigator shall administer the drug only to subjects under the 
investigator's personal supervision or under the supervision of a 
subinvestigator responsible to the investigator. The investigator shall 
not supply the investigational drug to any person not authorized under 
this part to receive it.



Sec. 312.62  Investigator recordkeeping and record retention.

    (a) Disposition of drug. An investigator is required to maintain 
adequate records of the disposition of the drug, including dates, 
quantity, and use by subjects. If the investigation is terminated, 
suspended, discontinued, or completed, the investigator shall return the 
unused supplies of the drug to the sponsor, or otherwise provide for 
disposition of the unused supplies of the drug under Sec. 312.59.
    (b) Case histories. An investigator is required to prepare and 
maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a 
control in the investigation. Case histories include the case report 
forms and supporting data including, for example, signed and dated 
consent forms and medical records including, for example, progress notes 
of the physician, the individual's hospital chart(s), and the nurses' 
notes. The case history for each individual shall document that informed 
consent was obtained prior to participation in the study.
    (c) Record retention. An investigator shall retain records required 
to be maintained under this part for a period of 2 years following the 
date a marketing application is approved for the drug for the indication 
for which it is being investigated; or, if no application is to be filed 
or if the application is not approved for such indication, until 2 years 
after the investigation is discontinued and FDA is notified.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 61 
FR 57280, Nov. 5, 1996; 67 FR 9586, Mar. 4, 2002]



Sec. 312.64  Investigator reports.

    (a) Progress reports. The investigator shall furnish all reports to 
the sponsor of the drug who is responsible for collecting and evaluating 
the results obtained. The sponsor is required under Sec. 312.33 to 
submit annual reports to FDA on the progress of the clinical 
investigations.
    (b) Safety reports. An investigator must immediately report to the 
sponsor any serious adverse event, whether or not considered drug 
related, including those listed in the protocol or investigator brochure 
and must include an assessment of whether there is a reasonable 
possibility that the drug caused the event. Study endpoints that

[[Page 78]]

are serious adverse events (e.g., all-cause mortality) must be reported 
in accordance with the protocol unless there is evidence suggesting a 
causal relationship between the drug and the event (e.g., death from 
anaphylaxis). In that case, the investigator must immediately report the 
event to the sponsor. The investigator must record nonserious adverse 
events and report them to the sponsor according to the timetable for 
reporting specified in the protocol.
    (c) Final report. An investigator shall provide the sponsor with an 
adequate report shortly after completion of the investigator's 
participation in the investigation.
    (d) Financial disclosure reports. The clinical investigator shall 
provide the sponsor with sufficient accurate financial information to 
allow an applicant to submit complete and accurate certification or 
disclosure statements as required under part 54 of this chapter. The 
clinical investigator shall promptly update this information if any 
relevant changes occur during the course of the investigation and for 1 
year following the completion of the study.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63 
FR 5252, Feb. 2, 1998; 67 FR 9586, Mar. 4, 2002; 75 FR 59963, Sept. 29, 
2010]



Sec. 312.66  Assurance of IRB review.

    An investigator shall assure that an IRB that complies with the 
requirements set forth in part 56 will be responsible for the initial 
and continuing review and approval of the proposed clinical study. The 
investigator shall also assure that he or she will promptly report to 
the IRB all changes in the research activity and all unanticipated 
problems involving risk to human subjects or others, and that he or she 
will not make any changes in the research without IRB approval, except 
where necessary to eliminate apparent immediate hazards to human 
subjects.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 67 
FR 9586, Mar. 4, 2002]



Sec. 312.68  Inspection of investigator's records and reports.

    An investigator shall upon request from any properly authorized 
officer or employee of FDA, at reasonable times, permit such officer or 
employee to have access to, and copy and verify any records or reports 
made by the investigator pursuant to Sec. 312.62. The investigator is 
not required to divulge subject names unless the records of particular 
individuals require a more detailed study of the cases, or unless there 
is reason to believe that the records do not represent actual case 
studies, or do not represent actual results obtained.



Sec. 312.69  Handling of controlled substances.

    If the investigational drug is subject to the Controlled Substances 
Act, the investigator shall take adequate precautions, including storage 
of the investigational drug in a securely locked, substantially 
constructed cabinet, or other securely locked, substantially constructed 
enclosure, access to which is limited, to prevent theft or diversion of 
the substance into illegal channels of distribution.



Sec. 312.70  Disqualification of a clinical investigator.

    (a) If FDA has information indicating that an investigator 
(including a sponsor-investigator) has repeatedly or deliberately failed 
to comply with the requirements of this part, part 50, or part 56 of 
this chapter, or has submitted to FDA or to the sponsor false 
information in any required report, the Center for Drug Evaluation and 
Research or the Center for Biologics Evaluation and Research will 
furnish the investigator written notice of the matter complained of and 
offer the investigator an opportunity to explain the matter in writing, 
or, at the option of the investigator, in an informal conference. If an 
explanation is offered but not accepted by the Center for Drug 
Evaluation and Research or the Center for Biologics Evaluation and 
Research, the investigator will be given an opportunity for a regulatory 
hearing under part 16 on the question of whether the investigator is 
entitled to receive investigational new drugs.
    (b) After evaluating all available information, including any 
explanation presented by the investigator, if the

[[Page 79]]

Commissioner determines that the investigator has repeatedly or 
deliberately failed to comply with the requirements of this part, part 
50, or part 56 of this chapter, or has deliberately or repeatedly 
submitted false information to FDA or to the sponsor in any required 
report, the Commissioner will notify the investigator and the sponsor of 
any investigation in which the investigator has been named as a 
participant that the investigator is not entitled to receive 
investigational drugs. The notification will provide a statement of 
basis for such determination.
    (c) Each IND and each approved application submitted under part 314 
containing data reported by an investigator who has been determined to 
be ineligible to receive investigational drugs will be examined to 
determine whether the investigator has submitted unreliable data that 
are essential to the continuation of the investigation or essential to 
the approval of any marketing application.
    (d) If the Commissioner determines, after the unreliable data 
submitted by the investigator are eliminated from consideration, that 
the data remaining are inadequate to support a conclusion that it is 
reasonably safe to continue the investigation, the Commissioner will 
notify the sponsor who shall have an opportunity for a regulatory 
hearing under part 16. If a danger to the public health exists, however, 
the Commissioner shall terminate the IND immediately and notify the 
sponsor of the determination. In such case, the sponsor shall have an 
opportunity for a regulatory hearing before FDA under part 16 on the 
question of whether the IND should be reinstated.
    (e) If the Commissioner determines, after the unreliable data 
submitted by the investigator are eliminated from consideration, that 
the continued approval of the drug product for which the data were 
submitted cannot be justified, the Commissioner will proceed to withdraw 
approval of the drug product in accordance with the applicable 
provisions of the act.
    (f) An investigator who has been determined to be ineligible to 
receive investigational drugs may be reinstated as eligible when the 
Commissioner determines that the investigator has presented adequate 
assurances that the investigator will employ investigational drugs 
solely in compliance with the provisions of this part and of parts 50 
and 56.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 
FR 11580, Mar. 29, 1990; 62 FR 46876, Sept. 5, 1997; 67 FR 9586, Mar. 4, 
2002]



    Subpart E_Drugs Intended to Treat Life-threatening and Severely-
                         debilitating Illnesses

    Authority: 21 U.S.C. 351, 352, 353, 355, 371; 42 U.S.C. 262.

    Source: 53 FR 41523, Oct. 21, 1988, unless otherwise noted.



Sec. 312.80  Purpose.

    The purpose of this section is to establish procedures designed to 
expedite the development, evaluation, and marketing of new therapies 
intended to treat persons with life-threatening and severely-
debilitating illnesses, especially where no satisfactory alternative 
therapy exists. As stated Sec. 314.105(c) of this chapter, while the 
statutory standards of safety and effectiveness apply to all drugs, the 
many kinds of drugs that are subject to them, and the wide range of uses 
for those drugs, demand flexibility in applying the standards. The Food 
and Drug Administration (FDA) has determined that it is appropriate to 
exercise the broadest flexibility in applying the statutory standards, 
while preserving appropriate guarantees for safety and effectiveness. 
These procedures reflect the recognition that physicians and patients 
are generally willing to accept greater risks or side effects from 
products that treat life-threatening and severely-debilitating 
illnesses, than they would accept from products that treat less serious 
illnesses. These procedures also reflect the recognition that the 
benefits of the drug need to be evaluated in light of the severity of 
the disease being treated. The procedure outlined in this section should 
be interpreted consistent with that purpose.

[[Page 80]]



Sec. 312.81  Scope.

    This section applies to new drug and biological products that are 
being studied for their safety and effectiveness in treating life-
threatening or severely-debilitating diseases.
    (a) For purposes of this section, the term ``life-threatening'' 
means:
    (1) Diseases or conditions where the likelihood of death is high 
unless the course of the disease is interrupted; and
    (2) Diseases or conditions with potentially fatal outcomes, where 
the end point of clinical trial analysis is survival.
    (b) For purposes of this section, the term ``severely debilitating'' 
means diseases or conditions that cause major irreversible morbidity.
    (c) Sponsors are encouraged to consult with FDA on the applicability 
of these procedures to specific products.

[53 FR 41523, Oct. 21, 1988, as amended at 64 FR 401, Jan. 5, 1999]



Sec. 312.82  Early consultation.

    For products intended to treat life-threatening or severely-
debilitating illnesses, sponsors may request to meet with FDA-reviewing 
officials early in the drug development process to review and reach 
agreement on the design of necessary preclinical and clinical studies. 
Where appropriate, FDA will invite to such meetings one or more outside 
expert scientific consultants or advisory committee members. To the 
extent FDA resources permit, agency reviewing officials will honor 
requests for such meetings
    (a) Pre-investigational new drug (IND) meetings. Prior to the 
submission of the initial IND, the sponsor may request a meeting with 
FDA-reviewing officials. The primary purpose of this meeting is to 
review and reach agreement on the design of animal studies needed to 
initiate human testing. The meeting may also provide an opportunity for 
discussing the scope and design of phase 1 testing, plans for studying 
the drug product in pediatric populations, and the best approach for 
presentation and formatting of data in the IND.
    (b) End-of-phase 1 meetings. When data from phase 1 clinical testing 
are available, the sponsor may again request a meeting with FDA-
reviewing officials. The primary purpose of this meeting is to review 
and reach agreement on the design of phase 2 controlled clinical trials, 
with the goal that such testing will be adequate to provide sufficient 
data on the drug's safety and effectiveness to support a decision on its 
approvability for marketing, and to discuss the need for, as well as the 
design and timing of, studies of the drug in pediatric patients. For 
drugs for life-threatening diseases, FDA will provide its best judgment, 
at that time, whether pediatric studies will be required and whether 
their submission will be deferred until after approval. The procedures 
outlined in Sec. 312.47(b)(1) with respect to end-of-phase 2 
conferences, including documentation of agreements reached, would also 
be used for end-of-phase 1 meetings.

[53 FR 41523, Oct. 21, 1988, as amended at 63 FR 66669, Dec. 2, 1998]



Sec. 312.83  Treatment protocols.

    If the preliminary analysis of phase 2 test results appears 
promising, FDA may ask the sponsor to submit a treatment protocol to be 
reviewed under the procedures and criteria listed in Sec. Sec. 312.305 
and 312.320. Such a treatment protocol, if requested and granted, would 
normally remain in effect while the complete data necessary for a 
marketing application are being assembled by the sponsor and reviewed by 
FDA (unless grounds exist for clinical hold of ongoing protocols, as 
provided in Sec. 312.42(b)(3)(ii)).

[53 FR 41523, Oct. 21, 1988, as amended at 76 FR 13880, Mar. 15, 2011]



Sec. 312.84  Risk-benefit analysis in review of marketing applications
for drugs to treat life-threatening and severely-debilitating 

illnesses.

    (a) FDA's application of the statutory standards for marketing 
approval shall recognize the need for a medical risk-benefit judgment in 
making the final decision on approvability. As part of this evaluation, 
consistent with the statement of purpose in Sec. 312.80, FDA will 
consider whether the benefits of the drug outweigh the known and 
potential risks of the drug and the need to answer remaining questions 
about risks and benefits of the drug, taking

[[Page 81]]

into consideration the severity of the disease and the absence of 
satisfactory alternative therapy.
    (b) In making decisions on whether to grant marketing approval for 
products that have been the subject of an end-of-phase 1 meeting under 
Sec. 312.82, FDA will usually seek the advice of outside expert 
scientific consultants or advisory committees. Upon the filing of such a 
marketing application under Sec. 314.101 or part 601 of this chapter, 
FDA will notify the members of the relevant standing advisory committee 
of the application's filing and its availability for review.
    (c) If FDA concludes that the data presented are not sufficient for 
marketing approval, FDA will issue a complete response letter under 
Sec. 314.110 of this chapter or the biological product licensing 
procedures. Such letter, in describing the deficiencies in the 
application, will address why the results of the research design agreed 
to under Sec. 312.82, or in subsequent meetings, have not provided 
sufficient evidence for marketing approval. Such letter will also 
describe any recommendations made by the advisory committee regarding 
the application.
    (d) Marketing applications submitted under the procedures contained 
in this section will be subject to the requirements and procedures 
contained in part 314 or part 600 of this chapter, as well as those in 
this subpart.

[53 FR 41523, Oct. 21, 1988, as amended at 73 FR 39607, July 10, 2008]



Sec. 312.85  Phase 4 studies.

    Concurrent with marketing approval, FDA may seek agreement from the 
sponsor to conduct certain postmarketing (phase 4) studies to delineate 
additional information about the drug's risks, benefits, and optimal 
use. These studies could include, but would not be limited to, studying 
different doses or schedules of administration than were used in phase 2 
studies, use of the drug in other patient populations or other stages of 
the disease, or use of the drug over a longer period of time.



Sec. 312.86  Focused FDA regulatory research.

    At the discretion of the agency, FDA may undertake focused 
regulatory research on critical rate-limiting aspects of the 
preclinical, chemical/manufacturing, and clinical phases of drug 
development and evaluation. When initiated, FDA will undertake such 
research efforts as a means for meeting a public health need in 
facilitating the development of therapies to treat life-threatening or 
severely debilitating illnesses.



Sec. 312.87  Active monitoring of conduct and evaluation of clinical trials.

    For drugs covered under this section, the Commissioner and other 
agency officials will monitor the progress of the conduct and evaluation 
of clinical trials and be involved in facilitating their appropriate 
progress.



Sec. 312.88  Safeguards for patient safety.

    All of the safeguards incorporated within parts 50, 56, 312, 314, 
and 600 of this chapter designed to ensure the safety of clinical 
testing and the safety of products following marketing approval apply to 
drugs covered by this section. This includes the requirements for 
informed consent (part 50 of this chapter) and institutional review 
boards (part 56 of this chapter). These safeguards further include the 
review of animal studies prior to initial human testing (Sec. 312.23), 
and the monitoring of adverse drug experiences through the requirements 
of IND safety reports (Sec. 312.32), safety update reports during 
agency review of a marketing application (Sec. 314.50 of this chapter), 
and postmarketing adverse reaction reporting (Sec. 314.80 of this 
chapter).



                         Subpart F_Miscellaneous



Sec. 312.110  Import and export requirements.

    (a) Imports. An investigational new drug offered for import into the 
United States complies with the requirements of this part if it is 
subject to an IND that is in effect for it under Sec. 312.40 and: (1) 
The consignee in the United States is the sponsor of the IND; (2) the 
consignee is a qualified investigator named in the IND; or (3) the 
consignee

[[Page 82]]

is the domestic agent of a foreign sponsor, is responsible for the 
control and distribution of the investigational drug, and the IND 
identifies the consignee and describes what, if any, actions the 
consignee will take with respect to the investigational drug.
    (b) Exports. An investigational new drug may be exported from the 
United States for use in a clinical investigation under any of the 
following conditions:
    (1) An IND is in effect for the drug under Sec. 312.40, the drug 
complies with the laws of the country to which it is being exported, and 
each person who receives the drug is an investigator in a study 
submitted to and allowed to proceed under the IND; or
    (2) The drug has valid marketing authorization in Australia, Canada, 
Israel, Japan, New Zealand, Switzerland, South Africa, or in any country 
in the European Union or the European Economic Area, and complies with 
the laws of the country to which it is being exported, section 
802(b)(1)(A), (f), and (g) of the act, and Sec. 1.101 of this chapter; 
or
    (3) The drug is being exported to Australia, Canada, Israel, Japan, 
New Zealand, Switzerland, South Africa, or to any country in the 
European Union or the European Economic Area, and complies with the laws 
of the country to which it is being exported, the applicable provisions 
of section 802(c), (f), and (g) of the act, and Sec. 1.101 of this 
chapter. Drugs exported under this paragraph that are not the subject of 
an IND are exempt from the label requirement in Sec. 312.6(a); or
    (4) Except as provided in paragraph (b)(5) of this section, the 
person exporting the drug sends a written certification to the Office of 
International Programs (HFG-1), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, at the time the drug is first 
exported and maintains records documenting compliance with this 
paragraph. The certification shall describe the drug that is to be 
exported (i.e., trade name (if any), generic name, and dosage form), 
identify the country or countries to which the drug is to be exported, 
and affirm that:
    (i) The drug is intended for export;
    (ii) The drug is intended for investigational use in a foreign 
country;
    (iii) The drug meets the foreign purchaser's or consignee's 
specifications;
    (iv) The drug is not in conflict with the importing country's laws;
    (v) The outer shipping package is labeled to show that the package 
is intended for export from the United States;
    (vi) The drug is not sold or offered for sale in the United States;
    (vii) The clinical investigation will be conducted in accordance 
with Sec. 312.120;
    (viii) The drug is manufactured, processed, packaged, and held in 
substantial conformity with current good manufacturing practices;
    (ix) The drug is not adulterated within the meaning of section 
501(a)(1), (a)(2)(A), (a)(3), (c), or (d) of the act;
    (x) The drug does not present an imminent hazard to public health, 
either in the United States, if the drug were to be reimported, or in 
the foreign country; and
    (xi) The drug is labeled in accordance with the foreign country's 
laws.
    (5) In the event of a national emergency in a foreign country, where 
the national emergency necessitates exportation of an investigational 
new drug, the requirements in paragraph (b)(4) of this section apply as 
follows:
    (i) Situations where the investigational new drug is to be 
stockpiled in anticipation of a national emergency. There may be 
instances where exportation of an investigational new drug is needed so 
that the drug may be stockpiled and made available for use by the 
importing country if and when a national emergency arises. In such 
cases:
    (A) A person may export an investigational new drug under paragraph 
(b)(4) of this section without making an affirmation with respect to any 
one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(vi), 
(b)(4)(vii), (b)(4)(viii), and/or (b)(4)(ix) of this section, provided 
that he or she:
    (1) Provides a written statement explaining why compliance with each 
such paragraph is not feasible or is contrary to the best interests of 
the individuals who may receive the investigational new drug;

[[Page 83]]

    (2) Provides a written statement from an authorized official of the 
importing country's government. The statement must attest that the 
official agrees with the exporter's statement made under paragraph 
(b)(5)(i)(A)(1) of this section; explain that the drug is to be 
stockpiled solely for use of the importing country in a national 
emergency; and describe the potential national emergency that warrants 
exportation of the investigational new drug under this provision; and
    (3) Provides a written statement showing that the Secretary of 
Health and Human Services (the Secretary), or his or her designee, 
agrees with the findings of the authorized official of the importing 
country's government. Persons who wish to obtain a written statement 
from the Secretary should direct their requests to Secretary's 
Operations Center, Office of Emergency Operations and Security Programs, 
Office of Public Health Emergency Preparedness, Office of the Secretary, 
Department of Health and Human Services, 200 Independence Ave. SW., 
Washington, DC 20201. Requests may be also be sent by FAX: 202-619-7870 
or by e-mail: HHS.SOC@hhs.gov.
    (B) Exportation may not proceed until FDA has authorized exportation 
of the investigational new drug. FDA may deny authorization if the 
statements provided under paragraphs (b)(5)(i)(A)(1) or (b)(5)(i)(A)(2) 
of this section are inadequate or if exportation is contrary to public 
health.
    (ii) Situations where the investigational new drug is to be used for 
a sudden and immediate national emergency. There may be instances where 
exportation of an investigational new drug is needed so that the drug 
may be used in a sudden and immediate national emergency that has 
developed or is developing. In such cases:
    (A) A person may export an investigational new drug under paragraph 
(b)(4) of this section without making an affirmation with respect to any 
one or more of paragraphs (b)(4)(i), (b)(4)(iv), (b)(4)(v), (b)(4)(vi), 
(b)(4)(vii), (b)(4)(viii), (b)(4)(ix), and/or (b)(4)(xi), provided that 
he or she:
    (1) Provides a written statement explaining why compliance with each 
such paragraph is not feasible or is contrary to the best interests of 
the individuals who are expected to receive the investigational new drug 
and
    (2) Provides sufficient information from an authorized official of 
the importing country's government to enable the Secretary, or his or 
her designee, to decide whether a national emergency has developed or is 
developing in the importing country, whether the investigational new 
drug will be used solely for that national emergency, and whether prompt 
exportation of the investigational new drug is necessary. Persons who 
wish to obtain a determination from the Secretary should direct their 
requests to Secretary's Operations Center, Office of Emergency 
Operations and Security Programs, Office of Public Health Emergency 
Preparedness, Office of the Secretary, Department of Health and Human 
Services, 200 Independence Ave. SW., Washington, DC 20201. Requests may 
be also be sent by FAX: 202-619-7870 or by e-mail: HHS.SOC@hhs.gov.
    (B) Exportation may proceed without prior FDA authorization.
    (c) Limitations. Exportation under paragraph (b) of this section may 
not occur if:
    (1) For drugs exported under paragraph (b)(1) of this section, the 
IND pertaining to the clinical investigation is no longer in effect;
    (2) For drugs exported under paragraph (b)(2) of this section, the 
requirements in section 802(b)(1), (f), or (g) of the act are no longer 
met;
    (3) For drugs exported under paragraph (b)(3) of this section, the 
requirements in section 802(c), (f), or (g) of the act are no longer 
met;
    (4) For drugs exported under paragraph (b)(4) of this section, the 
conditions underlying the certification or the statements submitted 
under paragraph (b)(5) of this section are no longer met; or
    (5) For any investigational new drugs under this section, the drug 
no longer complies with the laws of the importing country.
    (d) Insulin and antibiotics. New insulin and antibiotic drug 
products may be exported for investigational use in accordance with 
section 801(e)(1) of the

[[Page 84]]

act without complying with this section.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 64 
FR 401, Jan. 5, 1999; 67 FR 9586, Mar. 4, 2002; 70 FR 70729, Nov. 23, 
2005]



Sec. 312.120  Foreign clinical studies not conducted under an IND.

    (a) Acceptance of studies. (1) FDA will accept as support for an IND 
or application for marketing approval (an application under section 505 
of the act or section 351 of the Public Health Service Act (the PHS Act) 
(42 U.S.C. 262)) a well-designed and well-conducted foreign clinical 
study not conducted under an IND, if the following conditions are met:
    (i) The study was conducted in accordance with good clinical 
practice (GCP). For the purposes of this section, GCP is defined as a 
standard for the design, conduct, performance, monitoring, auditing, 
recording, analysis, and reporting of clinical trials in a way that 
provides assurance that the data and reported results are credible and 
accurate and that the rights, safety, and well-being of trial subjects 
are protected. GCP includes review and approval (or provision of a 
favorable opinion) by an independent ethics committee (IEC) before 
initiating a study, continuing review of an ongoing study by an IEC, and 
obtaining and documenting the freely given informed consent of the 
subject (or a subject's legally authorized representative, if the 
subject is unable to provide informed consent) before initiating a 
study. GCP does not require informed consent in life-threatening 
situations when the IEC reviewing the study finds, before initiation of 
the study, that informed consent is not feasible and either that the 
conditions present are consistent with those described in Sec. 50.23 or 
Sec. 50.24(a) of this chapter, or that the measures described in the 
study protocol or elsewhere will protect the rights, safety, and well-
being of subjects; and
    (ii) FDA is able to validate the data from the study through an 
onsite inspection if the agency deems it necessary.
    (2) Although FDA will not accept as support for an IND or 
application for marketing approval a study that does not meet the 
conditions of paragraph (a)(1) of this section, FDA will examine data 
from such a study.
    (3) Marketing approval of a new drug based solely on foreign 
clinical data is governed by Sec. 314.106 of this chapter.
    (b) Supporting information. A sponsor or applicant who submits data 
from a foreign clinical study not conducted under an IND as support for 
an IND or application for marketing approval must submit to FDA, in 
addition to information required elsewhere in parts 312, 314, or 601 of 
this chapter, a description of the actions the sponsor or applicant took 
to ensure that the research conformed to GCP as described in paragraph 
(a)(1)(i) of this section. The description is not required to duplicate 
information already submitted in the IND or application for marketing 
approval. Instead, the description must provide either the following 
information or a cross-reference to another section of the submission 
where the information is located:
    (1) The investigator's qualifications;
    (2) A description of the research facilities;
    (3) A detailed summary of the protocol and results of the study and, 
should FDA request, case records maintained by the investigator or 
additional background data such as hospital or other institutional 
records;
    (4) A description of the drug substance and drug product used in the 
study, including a description of the components, formulation, 
specifications, and, if available, bioavailability of the specific drug 
product used in the clinical study;
    (5) If the study is intended to support the effectiveness of a drug 
product, information showing that the study is adequate and well 
controlled under Sec. 314.126 of this chapter;
    (6) The name and address of the IEC that reviewed the study and a 
statement that the IEC meets the definition in Sec. 312.3 of this 
chapter. The sponsor or applicant must maintain records supporting such 
statement, including records of the names and qualifications of IEC 
members, and make these records available for agency review upon 
request;

[[Page 85]]

    (7) A summary of the IEC's decision to approve or modify and approve 
the study, or to provide a favorable opinion;
    (8) A description of how informed consent was obtained;
    (9) A description of what incentives, if any, were provided to 
subjects to participate in the study;
    (10) A description of how the sponsor(s) monitored the study and 
ensured that the study was carried out consistently with the study 
protocol; and
    (11) A description of how investigators were trained to comply with 
GCP (as described in paragraph (a)(1)(i) of this section) and to conduct 
the study in accordance with the study protocol, and a statement on 
whether written commitments by investigators to comply with GCP and the 
protocol were obtained. Any signed written commitments by investigators 
must be maintained by the sponsor or applicant and made available for 
agency review upon request.
    (c) Waivers. (1) A sponsor or applicant may ask FDA to waive any 
applicable requirements under paragraphs (a)(1) and (b) of this section. 
A waiver request may be submitted in an IND or in an information 
amendment to an IND, or in an application or in an amendment or 
supplement to an application submitted under part 314 or 601 of this 
chapter. A waiver request is required to contain at least one of the 
following:
    (i) An explanation why the sponsor's or applicant's compliance with 
the requirement is unnecessary or cannot be achieved;
    (ii) A description of an alternative submission or course of action 
that satisfies the purpose of the requirement; or
    (iii) Other information justifying a waiver.
    (2) FDA may grant a waiver if it finds that doing so would be in the 
interest of the public health.
    (d) Records. A sponsor or applicant must retain the records required 
by this section for a foreign clinical study not conducted under an IND 
as follows:
    (1) If the study is submitted in support of an application for 
marketing approval, for 2 years after an agency decision on that 
application;
    (2) If the study is submitted in support of an IND but not an 
application for marketing approval, for 2 years after the submission of 
the IND.

[73 FR 22815, Apr. 28, 2008]



Sec. 312.130  Availability for public disclosure of data and information
in an IND.

    (a) The existence of an investigational new drug application will 
not be disclosed by FDA unless it has previously been publicly disclosed 
or acknowledged.
    (b) The availability for public disclosure of all data and 
information in an investigational new drug application for a new drug 
will be handled in accordance with the provisions established in Sec. 
314.430 for the confidentiality of data and information in applications 
submitted in part 314. The availability for public disclosure of all 
data and information in an investigational new drug application for a 
biological product will be governed by the provisions of Sec. Sec. 
601.50 and 601.51.
    (c) Notwithstanding the provisions of Sec. 314.430, FDA shall 
disclose upon request to an individual to whom an investigational new 
drug has been given a copy of any IND safety report relating to the use 
in the individual.
    (d) The availability of information required to be publicly 
disclosed for investigations involving an exception from informed 
consent under Sec. 50.24 of this chapter will be handled as follows: 
Persons wishing to request the publicly disclosable information in the 
IND that was required to be filed in Docket Number 95S-0158 in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, shall submit a request 
under the Freedom of Information Act.

[52 FR 8831, Mar. 19, 1987. Redesignated at 53 FR 41523, Oct. 21, 1988, 
as amended at 61 FR 51530, Oct. 2, 1996; 64 FR 401, Jan. 5, 1999; 68 FR 
24879, May 9, 2003]



Sec. 312.140  Address for correspondence.

    (a) A sponsor must send an initial IND submission to the Center for 
Drug Evaluation and Research (CDER) or to the Center for Biologics 
Evaluation and Research (CBER), depending on the

[[Page 86]]

Center responsible for regulating the product as follows:
    (1) For drug products regulated by CDER. Send the IND submission to 
the Central Document Room, Center for Drug Evaluation and Research, Food 
and Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-
1266; except send an IND submission for an in vivo bioavailability or 
bioequivalence study in humans to support an abbreviated new drug 
application to the Office of Generic Drugs (HFD-600), Center for Drug 
Evaluation and Research, Food and Drug Administration, Metro Park North 
VII, 7620 Standish Pl., Rockville, MD 20855.
    (2) For biological products regulated by CDER. Send the IND 
submission to the CDER Therapeutic Biological Products Document Room, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
12229 Wilkins Ave., Rockville, MD 20852.
    (3) For biological products regulated by CBER. Send the IND 
submission to the Document Control Center (HFM-99), Center for Biologics 
Evaluation and Research, Food and Drug Administration, 1401 Rockville 
Pike, suite 200N, Rockville, MD 20852-1448.
    (b) On receiving the IND, the responsible Center will inform the 
sponsor which one of the divisions in CDER or CBER is responsible for 
the IND. Amendments, reports, and other correspondence relating to 
matters covered by the IND should be sent to the appropriate center at 
the address indicated in this section and marked to the attention of the 
responsible division. The outside wrapper of each submission shall state 
what is contained in the submission, for example, ``IND Application'', 
``Protocol Amendment'', etc.
    (c) All correspondence relating to export of an investigational drug 
under Sec. 312.110(b)(2) shall be submitted to the International 
Affairs Staff (HFY-50), Office of Health Affairs, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.

[70 FR 14981, Mar. 24, 2005, as amended at 74 FR 13113, Mar. 26, 2009; 
74 FR 55771, Oct. 29, 2009; 75 FR 37295, June 29, 2010]



Sec. 312.145  Guidance documents.

    (a) FDA has made available guidance documents under Sec. 10.115 of 
this chapter to help you to comply with certain requirements of this 
part.
    (b) The Center for Drug Evaluation and Research (CDER) and the 
Center for Biologics Evaluation and Research (CBER) maintain lists of 
guidance documents that apply to the centers' regulations. The lists are 
maintained on the Internet and are published annually in the Federal 
Register. A request for a copy of the CDER list should be directed to 
the Office of Training and Communications, Division of Drug Information, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Silver Spring, MD 20993-0002. A request for a 
copy of the CBER list should be directed to the Office of Communication, 
Training, and Manufacturers Assistance (HFM-40), Center for Biologics 
Evaluation and Research, Food and Drug Administration, 1401 Rockville 
Pike, Rockville, MD 20852-1448.

[65 FR 56479, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009]



 Subpart G_Drugs for Investigational Use in Laboratory Research Animals 
                            or In Vitro Tests



Sec. 312.160  Drugs for investigational use in laboratory research
animals or in vitro tests.

    (a) Authorization to ship. (1)(i) A person may ship a drug intended 
solely for tests in vitro or in animals used only for laboratory 
research purposes if it is labeled as follows:

    CAUTION: Contains a new drug for investigational use only in 
laboratory research animals, or for tests in vitro. Not for use in 
humans.

    (ii) A person may ship a biological product for investigational in 
vitro diagnostic use that is listed in Sec. 312.2(b)(2)(ii) if it is 
labeled as follows:

    CAUTION: Contains a biological product for investigational in vitro 
diagnostic tests only.

    (2) A person shipping a drug under paragraph (a) of this section 
shall use

[[Page 87]]

due diligence to assure that the consignee is regularly engaged in 
conducting such tests and that the shipment of the new drug will 
actually be used for tests in vitro or in animals used only for 
laboratory research.
    (3) A person who ships a drug under paragraph (a) of this section 
shall maintain adequate records showing the name and post office address 
of the expert to whom the drug is shipped and the date, quantity, and 
batch or code mark of each shipment and delivery. Records of shipments 
under paragraph (a)(1)(i) of this section are to be maintained for a 
period of 2 years after the shipment. Records and reports of data and 
shipments under paragraph (a)(1)(ii) of this section are to be 
maintained in accordance with Sec. 312.57(b). The person who ships the 
drug shall upon request from any properly authorized officer or employee 
of the Food and Drug Administration, at reasonable times, permit such 
officer or employee to have access to and copy and verify records 
required to be maintained under this section.
    (b) Termination of authorization to ship. FDA may terminate 
authorization to ship a drug under this section if it finds that:
    (1) The sponsor of the investigation has failed to comply with any 
of the conditions for shipment established under this section; or
    (2) The continuance of the investigation is unsafe or otherwise 
contrary to the public interest or the drug is used for purposes other 
than bona fide scientific investigation. FDA will notify the person 
shipping the drug of its finding and invite immediate correction. If 
correction is not immediately made, the person shall have an opportunity 
for a regulatory hearing before FDA pursuant to part 16.
    (c) Disposition of unused drug. The person who ships the drug under 
paragraph (a) of this section shall assure the return of all unused 
supplies of the drug from individual investigators whenever the 
investigation discontinues or the investigation is terminated. The 
person who ships the drug may authorize in writing alternative 
disposition of unused supplies of the drug provided this alternative 
disposition does not expose humans to risks from the drug, either 
directly or indirectly (e.g., through food-producing animals). The 
shipper shall maintain records of any alternative disposition.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987. 
Redesignated at 53 FR 41523, Oct. 21, 1988; 67 FR 9586, Mar. 4, 2002]

Subpart H [Reserved]



  Subpart I_Expanded Access to Investigational Drugs for Treatment Use

    Source: 74 FR 40942, Aug. 13, 2009, unless otherwise noted.



Sec. 312.300  General.

    (a) Scope. This subpart contains the requirements for the use of 
investigational new drugs and approved drugs where availability is 
limited by a risk evaluation and mitigation strategy (REMS) when the 
primary purpose is to diagnose, monitor, or treat a patient's disease or 
condition. The aim of this subpart is to facilitate the availability of 
such drugs to patients with serious diseases or conditions when there is 
no comparable or satisfactory alternative therapy to diagnose, monitor, 
or treat the patient's disease or condition.
    (b) Definitions. The following definitions of terms apply to this 
subpart:
    Immediately life-threatening disease or condition means a stage of 
disease in which there is reasonable likelihood that death will occur 
within a matter of months or in which premature death is likely without 
early treatment.
    Serious disease or condition means a disease or condition associated 
with morbidity that has substantial impact on day-to-day functioning. 
Short-lived and self-limiting morbidity will usually not be sufficient, 
but the morbidity need not be irreversible, provided it is persistent or 
recurrent. Whether a disease or condition is serious is a matter of 
clinical judgment, based on its impact on such factors as survival, day-
to-day functioning, or the likelihood that the disease, if left 
untreated, will progress from a less severe condition to a more serious 
one.

[[Page 88]]



Sec. 312.305  Requirements for all expanded access uses.

    The criteria, submission requirements, safeguards, and beginning 
treatment information set out in this section apply to all expanded 
access uses described in this subpart. Additional criteria, submission 
requirements, and safeguards that apply to specific types of expanded 
access are described in Sec. Sec. 312.310 through 312.320.
    (a) Criteria. FDA must determine that:
    (1) The patient or patients to be treated have a serious or 
immediately life-threatening disease or condition, and there is no 
comparable or satisfactory alternative therapy to diagnose, monitor, or 
treat the disease or condition;
    (2) The potential patient benefit justifies the potential risks of 
the treatment use and those potential risks are not unreasonable in the 
context of the disease or condition to be treated; and
    (3) Providing the investigational drug for the requested use will 
not interfere with the initiation, conduct, or completion of clinical 
investigations that could support marketing approval of the expanded 
access use or otherwise compromise the potential development of the 
expanded access use.
    (b) Submission. (1) An expanded access submission is required for 
each type of expanded access described in this subpart. The submission 
may be a new IND or a protocol amendment to an existing IND. Information 
required for a submission may be supplied by referring to pertinent 
information contained in an existing IND if the sponsor of the existing 
IND grants a right of reference to the IND.
    (2) The expanded access submission must include:
    (i) A cover sheet (Form FDA 1571) meeting the requirements of Sec. 
312.23(a);
    (ii) The rationale for the intended use of the drug, including a 
list of available therapeutic options that would ordinarily be tried 
before resorting to the investigational drug or an explanation of why 
the use of the investigational drug is preferable to the use of 
available therapeutic options;
    (iii) The criteria for patient selection or, for an individual 
patient, a description of the patient's disease or condition, including 
recent medical history and previous treatments of the disease or 
condition;
    (iv) The method of administration of the drug, dose, and duration of 
therapy;
    (v) A description of the facility where the drug will be 
manufactured;
    (vi) Chemistry, manufacturing, and controls information adequate to 
ensure the proper identification, quality, purity, and strength of the 
investigational drug;
    (vii) Pharmacology and toxicology information adequate to conclude 
that the drug is reasonably safe at the dose and duration proposed for 
expanded access use (ordinarily, information that would be adequate to 
permit clinical testing of the drug in a population of the size expected 
to be treated); and
    (viii) A description of clinical procedures, laboratory tests, or 
other monitoring necessary to evaluate the effects of the drug and 
minimize its risks.
    (3) The expanded access submission and its mailing cover must be 
plainly marked ``EXPANDED ACCESS SUBMISSION.'' If the expanded access 
submission is for a treatment IND or treatment protocol, the applicable 
box on Form FDA 1571 must be checked.
    (c) Safeguards. The responsibilities of sponsors and investigators 
set forth in subpart D of this part are applicable to expanded access 
use under this subpart as described in this paragraph.
    (1) A licensed physician under whose immediate direction an 
investigational drug is administered or dispensed for an expanded access 
use under this subpart is considered an investigator, for purposes of 
this part, and must comply with the responsibilities for investigators 
set forth in subpart D of this part to the extent they are applicable to 
the expanded access use.
    (2) An individual or entity that submits an expanded access IND or 
protocol under this subpart is considered a sponsor, for purposes of 
this part, and must comply with the responsibilities for sponsors set 
forth in subpart D of this part to the extent they are applicable to the 
expanded access use.
    (3) A licensed physician under whose immediate direction an 
investigational drug is administered or dispensed, and

[[Page 89]]

who submits an IND for expanded access use under this subpart is 
considered a sponsor-investigator, for purposes of this part, and must 
comply with the responsibilities for sponsors and investigators set 
forth in subpart D of this part to the extent they are applicable to the 
expanded access use.
    (4) Investigators. In all cases of expanded access, investigators 
are responsible for reporting adverse drug events to the sponsor, 
ensuring that the informed consent requirements of part 50 of this 
chapter are met, ensuring that IRB review of the expanded access use is 
obtained in a manner consistent with the requirements of part 56 of this 
chapter, and maintaining accurate case histories and drug disposition 
records and retaining records in a manner consistent with the 
requirements of Sec. 312.62. Depending on the type of expanded access, 
other investigator responsibilities under subpart D may also apply.
    (5) Sponsors. In all cases of expanded access, sponsors are 
responsible for submitting IND safety reports and annual reports (when 
the IND or protocol continues for 1 year or longer) to FDA as required 
by Sec. Sec. 312.32 and 312.33, ensuring that licensed physicians are 
qualified to administer the investigational drug for the expanded access 
use, providing licensed physicians with the information needed to 
minimize the risk and maximize the potential benefits of the 
investigational drug (the investigator's brochure must be provided if 
one exists for the drug), maintaining an effective IND for the expanded 
access use, and maintaining adequate drug disposition records and 
retaining records in a manner consistent with the requirements of Sec. 
312.57. Depending on the type of expanded access, other sponsor 
responsibilities under subpart D may also apply.
    (d) Beginning treatment--(1) INDs. An expanded access IND goes into 
effect 30 days after FDA receives the IND or on earlier notification by 
FDA that the expanded access use may begin.
    (2) Protocols. With the following exceptions, expanded access use 
under a protocol submitted under an existing IND may begin as described 
in Sec. 312.30(a).
    (i) Expanded access use under the emergency procedures described in 
Sec. 312.310(d) may begin when the use is authorized by the FDA 
reviewing official.
    (ii) Expanded access use under Sec. 312.320 may begin 30 days after 
FDA receives the protocol or upon earlier notification by FDA that use 
may begin.
    (3) Clinical holds. FDA may place any expanded access IND or 
protocol on clinical hold as described in Sec. 312.42.



Sec. 312.310  Individual patients, including for emergency use.

    Under this section, FDA may permit an investigational drug to be 
used for the treatment of an individual patient by a licensed physician.
    (a) Criteria. The criteria in Sec. 312.305(a) must be met; and the 
following determinations must be made:
    (1) The physician must determine that the probable risk to the 
person from the investigational drug is not greater than the probable 
risk from the disease or condition; and
    (2) FDA must determine that the patient cannot obtain the drug under 
another IND or protocol.
    (b) Submission. The expanded access submission must include 
information adequate to demonstrate that the criteria in Sec. 
312.305(a) and paragraph (a) of this section have been met. The expanded 
access submission must meet the requirements of Sec. 312.305(b).
    (1) If the drug is the subject of an existing IND, the expanded 
access submission may be made by the sponsor or by a licensed physician.
    (2) A sponsor may satisfy the submission requirements by amending 
its existing IND to include a protocol for individual patient expanded 
access.
    (3) A licensed physician may satisfy the submission requirements by 
obtaining from the sponsor permission for FDA to refer to any 
information in the IND that would be needed to support the expanded 
access request (right of reference) and by providing any other required 
information not contained in the IND (usually only the information 
specific to the individual patient).
    (c) Safeguards. (1) Treatment is generally limited to a single 
course of

[[Page 90]]

therapy for a specified duration unless FDA expressly authorizes 
multiple courses or chronic therapy.
    (2) At the conclusion of treatment, the licensed physician or 
sponsor must provide FDA with a written summary of the results of the 
expanded access use, including adverse effects.
    (3) FDA may require sponsors to monitor an individual patient 
expanded access use if the use is for an extended duration.
    (4) When a significant number of similar individual patient expanded 
access requests have been submitted, FDA may ask the sponsor to submit 
an IND or protocol for the use under Sec. 312.315 or Sec. 312.320.
    (d) Emergency procedures. If there is an emergency that requires the 
patient to be treated before a written submission can be made, FDA may 
authorize the expanded access use to begin without a written submission. 
The FDA reviewing official may authorize the emergency use by telephone.
    (1) Emergency expanded access use may be requested by telephone, 
facsimile, or other means of electronic communications. For 
investigational biological drug products regulated by the Center for 
Biologics Evaluation and Research, the request should be directed to the 
Office of Communication, Outreach and Development, Center for Biologics 
Evaluation and Research, 301-827-1800 or 1-800-835-4709, e-mail: 
ocod@fda.hhs.gov. For all other investigational drugs, the request for 
authorization should be directed to the Division of Drug Information, 
Center for Drug Evaluation and Research, 301-796-3400, e-mail: 
druginfo@fda.hhs.gov. After normal working hours (8 a.m. to 4:30 p.m.), 
the request should be directed to the FDA Emergency Call Center, 866-
300-4374, e-mail: emergency.operations@fda.hhs.gov.
    (2) The licensed physician or sponsor must explain how the expanded 
access use will meet the requirements of Sec. Sec. 312.305 and 312.310 
and must agree to submit an expanded access submission within 15 working 
days of FDA's authorization of the use.

[74 FR 40942, Aug. 13, 2009, as amended at 75 FR 32659, June 9, 2010]



Sec. 312.315  Intermediate-size patient populations.

    Under this section, FDA may permit an investigational drug to be 
used for the treatment of a patient population smaller than that typical 
of a treatment IND or treatment protocol. FDA may ask a sponsor to 
consolidate expanded access under this section when the agency has 
received a significant number of requests for individual patient 
expanded access to an investigational drug for the same use.
    (a) Need for expanded access. Expanded access under this section may 
be needed in the following situations:
    (1) Drug not being developed. The drug is not being developed, for 
example, because the disease or condition is so rare that the sponsor is 
unable to recruit patients for a clinical trial.
    (2) Drug being developed. The drug is being studied in a clinical 
trial, but patients requesting the drug for expanded access use are 
unable to participate in the trial. For example, patients may not be 
able to participate in the trial because they have a different disease 
or stage of disease than the one being studied or otherwise do not meet 
the enrollment criteria, because enrollment in the trial is closed, or 
because the trial site is not geographically accessible.
    (3) Approved or related drug. (i) The drug is an approved drug 
product that is no longer marketed for safety reasons or is unavailable 
through marketing due to failure to meet the conditions of the approved 
application, or
    (ii) The drug contains the same active moiety as an approved drug 
product that is unavailable through marketing due to failure to meet the 
conditions of the approved application or a drug shortage.
    (b) Criteria. The criteria in Sec. 312.305(a) must be met; and FDA 
must determine that:
    (1) There is enough evidence that the drug is safe at the dose and 
duration proposed for expanded access use to justify a clinical trial of 
the drug in the approximate number of patients expected to receive the 
drug under expanded access; and
    (2) There is at least preliminary clinical evidence of effectiveness 
of the drug, or of a plausible pharmacologic

[[Page 91]]

effect of the drug to make expanded access use a reasonable therapeutic 
option in the anticipated patient population.
    (c) Submission. The expanded access submission must include 
information adequate to satisfy FDA that the criteria in Sec. 
312.305(a) and paragraph (b) of this section have been met. The expanded 
access submission must meet the requirements of Sec. 312.305(b). In 
addition:
    (1) The expanded access submission must state whether the drug is 
being developed or is not being developed and describe the patient 
population to be treated.
    (2) If the drug is not being actively developed, the sponsor must 
explain why the drug cannot currently be developed for the expanded 
access use and under what circumstances the drug could be developed.
    (3) If the drug is being studied in a clinical trial, the sponsor 
must explain why the patients to be treated cannot be enrolled in the 
clinical trial and under what circumstances the sponsor would conduct a 
clinical trial in these patients.
    (d) Safeguards. (1) Upon review of the IND annual report, FDA will 
determine whether it is appropriate for the expanded access to continue 
under this section.
    (i) If the drug is not being actively developed or if the expanded 
access use is not being developed (but another use is being developed), 
FDA will consider whether it is possible to conduct a clinical study of 
the expanded access use.
    (ii) If the drug is being actively developed, FDA will consider 
whether providing the investigational drug for expanded access use is 
interfering with the clinical development of the drug.
    (iii) As the number of patients enrolled increases, FDA may ask the 
sponsor to submit an IND or protocol for the use under Sec. 312.320.
    (2) The sponsor is responsible for monitoring the expanded access 
protocol to ensure that licensed physicians comply with the protocol and 
the regulations applicable to investigators.



Sec. 312.320  Treatment IND or treatment protocol.

    Under this section, FDA may permit an investigational drug to be 
used for widespread treatment use.
    (a) Criteria. The criteria in Sec. 312.305(a) must be met, and FDA 
must determine that:
    (1) Trial status. (i) The drug is being investigated in a controlled 
clinical trial under an IND designed to support a marketing application 
for the expanded access use, or
    (ii) All clinical trials of the drug have been completed; and
    (2) Marketing status. The sponsor is actively pursuing marketing 
approval of the drug for the expanded access use with due diligence; and
    (3) Evidence. (i) When the expanded access use is for a serious 
disease or condition, there is sufficient clinical evidence of safety 
and effectiveness to support the expanded access use. Such evidence 
would ordinarily consist of data from phase 3 trials, but could consist 
of compelling data from completed phase 2 trials; or
    (ii) When the expanded access use is for an immediately life-
threatening disease or condition, the available scientific evidence, 
taken as a whole, provides a reasonable basis to conclude that the 
investigational drug may be effective for the expanded access use and 
would not expose patients to an unreasonable and significant risk of 
illness or injury. This evidence would ordinarily consist of clinical 
data from phase 3 or phase 2 trials, but could be based on more 
preliminary clinical evidence.
    (b) Submission. The expanded access submission must include 
information adequate to satisfy FDA that the criteria in Sec. 
312.305(a) and paragraph (a) of this section have been met. The expanded 
access submission must meet the requirements of Sec. 312.305(b).
    (c) Safeguard. The sponsor is responsible for monitoring the 
treatment protocol to ensure that licensed physicians comply with the 
protocol and the regulations applicable to investigators.

[[Page 92]]



PART 314_APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG--Table of
Contents



                      Subpart A_General Provisions

Sec.
314.1 Scope of this part.
314.2 Purpose.
314.3 Definitions.

                         Subpart B_Applications

314.50 Content and format of an application.
314.52 Notice of certification of invalidity or noninfringement of a 
          patent.
314.53 Submission of patent information.
314.54 Procedure for submission of an application requiring 
          investigations for approval of a new indication for, or other 
          change from, a listed drug.
314.55 Pediatric use information.
314.60 Amendments to an unapproved application, supplement, or 
          resubmission.
314.65 Withdrawal by the applicant of an unapproved application.
314.70 Supplements and other changes to an approved application.
314.71 Procedures for submission of a supplement to an approved 
          application.
314.72 Change in ownership of an application.
314.80 Postmarketing reporting of adverse drug experiences.
314.81 Other postmarketing reports.
314.90 Waivers.

                   Subpart C_Abbreviated Applications

314.91 Obtaining a reduction in the discontinuance notification period.
314.92 Drug products for which abbreviated applications may be 
          submitted.
314.93 Petition to request a change from a listed drug.
314.94 Content and format of an abbreviated application.
314.95 Notice of certification of invalidity or noninfringement of a 
          patent.
314.96 Amendments to an unapproved abbreviated application.
314.97 Supplements and other changes to an approved abbreviated 
          application.
314.98 Postmarketing reports.
314.99 Other responsibilities of an applicant of an abbreviated 
          application.

    Subpart D_FDA Action on Applications and Abbreviated Applications

314.100 Timeframes for reviewing applications and abbreviated 
          applications.
314.101 Filing an application and receiving an abbreviated new drug 
          application.
314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an application and an abbreviated application.
314.106 Foreign data.
314.107 Effective date of approval of a 505(b)(2) application or 
          abbreviated new drug application under section 505(j) of the 
          act.
314.108 New drug product exclusivity.
314.110 Complete response letter to the applicant.
314.120 [Reserved]
314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) 
          petition that relies on, a listed drug that is no longer 
          marketed.
314.125 Refusal to approve an application.
314.126 Adequate and well-controlled studies.
314.127 Refusal to approve an abbreviated new drug application.
314.150 Withdrawal of approval of an application or abbreviated 
          application.
314.151 Withdrawal of approval of an abbreviated new drug application 
          under section 505(j)(5) of the act.
314.152 Notice of withdrawal of approval of an application or 
          abbreviated application for a new drug.
314.153 Suspension of approval of an abbreviated new drug application.
314.160 Approval of an application or abbreviated application for which 
          approval was previously refused, suspended, or withdrawn.
314.161 Determination of reasons for voluntary withdrawal of a listed 
          drug.
314.162 Removal of a drug product from the list.
314.170 Adulteration and misbranding of an approved drug.

               Subpart E_Hearing Procedures for New Drugs

314.200 Notice of opportunity for hearing; notice of participation and 
          request for hearing; grant or denial of hearing.
314.201 Procedure for hearings.
314.235 Judicial review.

Subpart F [Reserved]

                   Subpart G_Miscellaneous Provisions

314.410 Imports and exports of new drugs.
314.420 Drug master files.
314.430 Availability for public disclosure of data and information in an 
          application or abbreviated application.
314.440 Addresses for applications and abbreviated applications.

[[Page 93]]

314.445 Guidance documents.

    Subpart H_Accelerated Approval of New Drugs for Serious or Life-
                          Threatening Illnesses

314.500 Scope.
314.510 Approval based on a surrogate endpoint or on an effect on a 
          clinical endpoint other than survival or irreversible 
          morbidity.
314.520 Approval with restrictions to assure safe use.
314.530 Withdrawal procedures.
314.540 Postmarketing safety reporting.
314.550 Promotional materials.
314.560 Termination of requirements.

  Subpart I_Approval of New Drugs When Human Efficacy Studies Are Not 
                           Ethical or Feasible

314.600 Scope.
314.610 Approval based on evidence of effectiveness from studies in 
          animals.
314.620 Withdrawal procedures.
314.630 Postmarketing safety reporting.
314.640 Promotional materials.
314.650 Termination of requirements.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 356a, 356b, 
356c, 371, 374, 379e.

    Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 314 can be found at 69 
FR 13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 314.1  Scope of this part.

    (a) This part sets forth procedures and requirements for the 
submission to, and the review by, the Food and Drug Administration of 
applications and abbreviated applications to market a new drug under 
section 505 of the Federal Food, Drug, and Cosmetic Act, as well as 
amendments, supplements, and postmarketing reports to them.
    (b) This part does not apply to drug products subject to licensing 
by FDA under the Public Health Service Act (58 Stat. 632 as amended (42 
U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the 
Code of Federal Regulations.
    (c) References in this part to regulations in the Code of Federal 
Regulations are to chapter I of title 21, unless otherwise noted.

[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 64 
FR 401, Jan. 5, 1999]



Sec. 314.2  Purpose.

    The purpose of this part is to establish an efficient and thorough 
drug review process in order to: (a) Facilitate the approval of drugs 
shown to be safe and effective; and (b) ensure the disapproval of drugs 
not shown to be safe and effective. These regulations are also intended 
to establish an effective system for FDA's surveillance of marketed 
drugs. These regulations shall be construed in light of these 
objectives.



Sec. 314.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the act apply to those terms when used in this part.
    (b) The following definitions of terms apply to this part:
    Abbreviated application means the application described under Sec. 
314.94, including all amendments and supplements to the application. 
``Abbreviated application'' applies to both an abbreviated new drug 
application and an abbreviated antibiotic application.
    Act means the Federal Food, Drug, and Cosmetic Act (sections 201-901 
(21 U.S.C. 301-392)).
    Applicant means any person who submits an application or abbreviated 
application or an amendment or supplement to them under this part to 
obtain FDA approval of a new drug or an antibiotic drug and any person 
who owns an approved application or abbreviated application.
    Application means the application described under Sec. 314.50, 
including all amendements and supplements to the application.
    505(b)(2) Application means an application submitted under section 
505(b)(1) of the act for a drug for which the investigations described 
in section 505(b)(1)(A) of the act and relied upon by the applicant for 
approval of the application were not conducted by or for the applicant 
and for which the applicant has not obtained a right of reference or use 
from the person by or for whom the investigations were conducted.

[[Page 94]]

    Approval letter means a written communication to an applicant from 
FDA approving an application or an abbreviated application.
    Assess the effects of the change means to evaluate the effects of a 
manufacturing change on the identity, strength, quality, purity, and 
potency of a drug product as these factors may relate to the safety or 
effectiveness of the drug product.
    Authorized generic drug means a listed drug, as defined in this 
section, that has been approved under section 505(c) of the act and is 
marketed, sold, or distributed directly or indirectly to retail class of 
trade with labeling, packaging (other than repackaging as the listed 
drug in blister packs, unit doses, or similar packaging for use in 
institutions), product code, labeler code, trade name, or trademark that 
differs from that of the listed drug.
    Class 1 resubmission means the resubmission of an application or 
efficacy supplement, following receipt of a complete response letter, 
that contains one or more of the following: Final printed labeling, 
draft labeling, certain safety updates, stability updates to support 
provisional or final dating periods, commitments to perform 
postmarketing studies (including proposals for such studies), assay 
validation data, final release testing on the last lots used to support 
approval, minor reanalyses of previously submitted data, and other 
comparatively minor information.
    Class 2 resubmission means the resubmission of an application or 
efficacy supplement, following receipt of a complete response letter, 
that includes any item not specified in the definition of ``Class 1 
resubmission,'' including any item that would require presentation to an 
advisory committee.
    Complete response letter means a written communication to an 
applicant from FDA usually describing all of the deficiencies that the 
agency has identified in an application or abbreviated application that 
must be satisfactorily addressed before it can be approved.
    Drug product means a finished dosage form, for example, tablet, 
capsule, or solution, that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients.
    Drug substance means an active ingredient that is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease or to 
affect the structure or any function of the human body, but does not 
include intermediates use in the synthesis of such ingredient.
    Efficacy supplement means a supplement to an approved application 
proposing to make one or more related changes from among the following 
changes to product labeling:
    (1) Add or modify an indication or claim;
    (2) Revise the dose or dose regimen;
    (3) Provide for a new route of administration;
    (4) Make a comparative efficacy claim naming another drug product;
    (5) Significantly alter the intended patient population;
    (6) Change the marketing status from prescription to over-the-
counter use;
    (7) Provide for, or provide evidence of effectiveness necessary for, 
the traditional approval of a product originally approved under subpart 
H of part 314; or
    (8) Incorporate other information based on at least one adequate and 
well-controlled clinical study.
    FDA means the Food and Drug Administration.
    Listed drug means a new drug product that has an effective approval 
under section 505(c) of the act for safety and effectiveness or under 
section 505(j) of the act, which has not been withdrawn or suspended 
under section 505(e)(1) through (e)(5) or (j)(5) of the act, and which 
has not been withdrawn from sale for what FDA has determined are reasons 
of safety or effectiveness. Listed drug status is evidenced by the drug 
product's identification as a drug with an effective approval in the 
current edition of FDA's ``Approved Drug Products with Therapeutic 
Equivalence Evaluations'' (the list) or any current supplement thereto, 
as a drug with an effective approval. A drug product is deemed to be a 
listed drug on the date of effective approval of the application or 
abbreviated application for that drug product.

[[Page 95]]

    Newly acquired information means data, analyses, or other 
information not previously submitted to the agency, which may include 
(but are not limited to) data derived from new clinical studies, reports 
of adverse events, or new analyses of previously submitted data (e.g., 
meta-analyses) if the studies, events or analyses reveal risks of a 
different type or greater severity or frequency than previously included 
in submissions to FDA.
    Original application means a pending application for which FDA has 
never issued a complete response letter or approval letter, or an 
application that was submitted again after FDA had refused to file it or 
after it was withdrawn without being approved.
    Reference listed drug means the listed drug identified by FDA as the 
drug product upon which an applicant relies in seeking approval of its 
abbreviated application.
    Resubmission means submission by the applicant of all materials 
needed to fully address all deficiencies identified in the complete 
response letter. An application or abbreviated application for which FDA 
issued a complete response letter, but which was withdrawn before 
approval and later submitted again, is not a resubmission.
    Right of reference or use means the authority to rely upon, and 
otherwise use, an investigation for the purpose of obtaining approval of 
an application, including the ability to make available the underlying 
raw data from the investigation for FDA audit, if necessary.
    Specification means the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved application 
to confirm the quality of drug substances, drug products, intermediates, 
raw materials, reagents, components, in-process materials, container 
closure systems, and other materials used in the production of a drug 
substance or drug product. For the purpose of this definition, 
acceptance criteriameans numerical limits, ranges, or other criteria for 
the tests described.
    The list means the list of drug products with effective approvals 
published in the current edition of FDA's publication ``Approved Drug 
Products with Therapeutic Equivalence Evaluations'' and any current 
supplement to the publication.

[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992; 69 
FR 18763, Apr. 8, 2004; 73 FR 39607, July 10, 2008; 73 FR 49609, Aug. 
22, 2008; 74 FR 37167, July 28, 2009]



                         Subpart B_Applications



Sec. 314.50  Content and format of an application.

    Applications and supplements to approved applications are required 
to be submitted in the form and contain the information, as appropriate 
for the particular submission, required under this section. Three copies 
of the application are required: An archival copy, a review copy, and a 
field copy. An application for a new chemical entity will generally 
contain an application form, an index, a summary, five or six technical 
sections, case report tabulations of patient data, case report forms, 
drug samples, and labeling, including, if applicable, any Medication 
Guide required under part 208 of this chapter. Other applications will 
generally contain only some of those items, and information will be 
limited to that needed to support the particular submission. These 
include an application of the type described in section 505(b)(2) of the 
act, an amendment, and a supplement. The application is required to 
contain reports of all investigations of the drug product sponsored by 
the applicant, and all other information about the drug pertinent to an 
evaluation of the application that is received or otherwise obtained by 
the applicant from any source. FDA will maintain guidance documents on 
the format and content of applications to assist applicants in their 
preparation.
    (a) Application form. The applicant shall submit a completed and 
signed application form that contains the following:
    (1) The name and address of the applicant; the date of the 
application; the application number if previously issued (for example, 
if the application is a resubmission, an amendment, or a supplement); 
the name of the drug product, including its established, proprietary, 
code, and chemical names; the dosage form and strength; the route of 
administration; the identification

[[Page 96]]

numbers of all investigational new drug applications that are referenced 
in the application; the identification numbers of all drug master files 
and other applications under this part that are referenced in the 
application; and the drug product's proposed indications for use.
    (2) A statement whether the submission is an original submission, a 
505(b)(2) application, a resubmission, or a supplement to an application 
under Sec. 314.70.
    (3) A statement whether the applicant proposes to market the drug 
product as a prescription or an over-the-counter product.
    (4) A check-list identifying what enclosures required under this 
section the applicant is submitting.
    (5) The applicant, or the applicant's attorney, agent, or other 
authorized official shall sign the application. If the person signing 
the application does not reside or have a place of business within the 
United States, the application is required to contain the name and 
address of, and be countersigned by, an attorney, agent, or other 
authorized official who resides or maintains a place of business within 
the United States.
    (b) Index. The archival copy of the application is required to 
contain a comprehensive index by volume number and page number to the 
summary under paragraph (c) of this section, the technical sections 
under paragraph (d) of this section, and the supporting information 
under paragraph (f) of this section.
    (c) Summary. (1) An application is required to contain a summary of 
the application in enough detail that the reader may gain a good general 
understanding of the data and information in the application, including 
an understanding of the quantitative aspects of the data. The summary is 
not required for supplements under Sec. 314.70. Resubmissions of an 
application should contain an updated summary, as appropriate. The 
summary should discuss all aspects of the application, and synthesize 
the information into a well-structured and unified document. The summary 
should be written at approximately the level of detail required for 
publication in, and meet the editorial standards generally applied by, 
refereed scientific and medical journals. In addition to the agency 
personnel reviewing the summary in the context of their review of the 
application, FDA may furnish the summary to FDA advisory committee 
members and agency officials whose duties require an understanding of 
the application. To the extent possible, data in the summary should be 
presented in tabular and graphic forms. FDA has prepared a guideline 
under Sec. 10.90(b) that provides information about how to prepare a 
summary. The summary required under this paragraph may be used by FDA or 
the applicant to prepare the Summary Basis of Approval document for 
public disclosure (under Sec. 314.430(e)(2)(ii)) when the application 
is approved.
    (2) The summary is required to contain the following information:
    (i) The proposed text of the labeling, including, if applicable, any 
Medication Guide required under part 208 of this chapter, for the drug, 
with annotations to the information in the summary and technical 
sections of the application that support the inclusion of each statement 
in the labeling, and, if the application is for a prescription drug, 
statements describing the reasons for omitting a section or subsection 
of the labeling format in Sec. 201.57 of this chapter.
    (ii) A statement identifying the pharmacologic class of the drug and 
a discussion of the scientific rationale for the drug, its intended use, 
and the potential clinical benefits of the drug product.
    (iii) A brief description of the marketing history, if any, of the 
drug outside the United States, including a list of the countries in 
which the drug has been marketed, a list of any countries in which the 
drug has been withdrawn from marketing for any reason related to safety 
or effectiveness, and a list of countries in which applications for 
marketing are pending. The description is required to describe both 
marketing by the applicant and, if known, the marketing history of other 
persons.
    (iv) A summary of the chemistry, manufacturing, and controls section 
of the application.

[[Page 97]]

    (v) A summary of the nonclinical pharmacology and toxicology section 
of the application.
    (vi) A summary of the human pharmacokinetics and bioavailability 
section of the application.
    (vii) A summary of the microbiology section of the application (for 
anti-infective drugs only).
    (viii) A summary of the clinical data section of the application, 
including the results of statistical analyses of the clinical trials.
    (ix) A concluding discussion that presents the benefit and risk 
considerations related to the drug, including a discussion of any 
proposed additional studies or surveillance the applicant intends to 
conduct postmarketing.
    (d) Technical sections. The application is required to contain the 
technical sections described below. Each technical section is required 
to contain data and information in sufficient detail to permit the 
agency to make a knowledgeable judgment about whether to approve the 
application or whether grounds exist under section 505(d) of the act to 
refuse to approve the application. The required technical sections are 
as follows:
    (1) Chemistry, manufacturing, and controls section. A section 
describing the composition, manufacture, and specification of the drug 
substance and the drug product, including the following:
    (i) Drug substance. A full description of the drug substance 
including its physical and chemical characteristics and stability; the 
name and address of its manufacturer; the method of synthesis (or 
isolation) and purification of the drug substance; the process controls 
used during manufacture and packaging; and the specifications necessary 
to ensure the identity, strength, quality, and purity of the drug 
substance and the bioavailability of the drug products made from the 
substance, including, for example, tests, analytical procedures, and 
acceptance criteria relating to stability, sterility, particle size, and 
crystalline form. The application may provide additionally for the use 
of alternatives to meet any of these requirements, including alternative 
sources, process controls, and analytical procedures. Reference to the 
current edition of the U.S. Pharmacopeia and the National Formulary may 
satisfy relevant requirements in this paragraph.
    (ii)(a) Drug product. A list of all components used in the 
manufacture of the drug product (regardless of whether they appear in 
the drug product) and a statement of the composition of the drug 
product; the specifications for each component; the name and address of 
each manufacturer of the drug product; a description of the 
manufacturing and packaging procedures and in-process controls for the 
drug product; the specifications necessary to ensure the identity, 
strength, quality, purity, potency, and bioavailability of the drug 
product, including, for example, tests, analytical procedures, and 
acceptance criteria relating to sterility, dissolution rate, container 
closure systems; and stability data with proposed expiration dating. The 
application may provide additionally for the use of alternatives to meet 
any of these requirements, including alternative components, 
manufacturing and packaging procedures, in-process controls, and 
analytical procedures. Reference to the current edition of the U.S. 
Pharmacopeia and the National Formulary may satisfy relevant 
requirements in this paragraph.
    (b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for 
each batch of the drug product used to conduct a bioavailability or 
bioequivalence study described in Sec. 320.38 or Sec. 320.63 of this 
chapter or used to conduct a primary stability study: The batch 
production record; the specification for each component and for the drug 
product; the names and addresses of the sources of the active and 
noncompendial inactive components and of the container and closure 
system for the drug product; the name and address of each contract 
facility involved in the manufacture, processing, packaging, or testing 
of the drug product and identification of the operation performed by 
each contract facility; and the results of any test performed on the 
components used in the manufacture of the drug product as required by 
Sec. 211.84(d) of this chapter and on the drug product as required by 
Sec. 211.165 of this chapter.

[[Page 98]]

    (c) The proposed or actual master production record, including a 
description of the equipment, to be used for the manufacture of a 
commercial lot of the drug product or a comparably detailed description 
of the production process for a representative batch of the drug 
product.
    (iii) Environmental impact. The application is required to contain 
either a claim for categorical exclusion under Sec. 25.30 or 25.31 of 
this chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
    (iv) The applicant may, at its option, submit a complete chemistry, 
manufacturing, and controls section 90 to 120 days before the 
anticipated submission of the remainder of the application. FDA will 
review such early submissions as resources permit.
    (v) The applicant shall include a statement certifying that the 
field copy of the application has been provided to the applicant's home 
FDA district office.
    (2) Nonclinical pharmacology and toxicology section. A section 
describing, with the aid of graphs and tables, animal and in vitro 
studies with drug, including the following:
    (i) Studies of the pharmacological actions of the drug in relation 
to its proposed therapeutic indication and studies that otherwise define 
the pharmacologic properties of the drug or are pertinent to possible 
adverse effects.
    (ii) Studies of the toxicological effects of the drug as they relate 
to the drug's intended clinical uses, including, as appropriate, studies 
assessing the drug's acute, subacute, and chronic toxicity; 
carcinogenicity; and studies of toxicities related to the drug's 
particular mode of administration or conditions of use.
    (iii) Studies, as appropriate, of the effects of the drug on 
reproduction and on the developing fetus.
    (iv) Any studies of the absorption, distribution, metabolism, and 
excretion of the drug in animals.
    (v) For each nonclinical laboratory study subject to the good 
laboratory practice regulations under part 58 a statement that it was 
conducted in compliance with the good laboratory practice regulations in 
part 58, or, if the study was not conducted in compliance with those 
regulations, a brief statement of the reason for the noncompliance.
    (3) Human pharmacokinetics and bioavailability section. A section 
describing the human pharmacokinetic data and human bioavailability 
data, or information supporting a waiver of the submission of in vivo 
bioavailability data under subpart B of part 320, including the 
following:
    (i) A description of each of the bioavailability and pharmacokinetic 
studies of the drug in humans performed by or on behalf of the applicant 
that includes a description of the analytical procedures and statistical 
methods used in each study and a statement with respect to each study 
that it either was conducted in compliance with the institutional review 
board regulations in part 56, or was not subject to the regulations 
under Sec. 56.104 or Sec. 56.105, and that it was conducted in 
compliance with the informed consent regulations in part 50.
    (ii) If the application describes in the chemistry, manufacturing, 
and controls section tests, analytical procedures, and acceptance 
criteria needed to assure the bioavailability of the drug product or 
drug substance, or both, a statement in this section of the rationale 
for establishing the tests, analytical procedures, and acceptance 
criteria, including data and information supporting the rationale.
    (iii) A summarizing discussion and analysis of the pharmacokinetics 
and metabolism of the active ingredients and the bioavailability or 
bioequivalence, or both, of the drug product.
    (4) Microbiology section. If the drug is an anti-infective drug, a 
section describing the microbiology data, including the following:
    (i) A description of the biochemical basis of the drug's action on 
microbial physiology.
    (ii) A description of the antimicrobial spectra of the drug, 
including results of in vitro preclinical studies to demonstrate 
concentrations of the drug required for effective use.
    (iii) A description of any known mechanisms of resistance to the 
drug, including results of any known epidemiologic studies to 
demonstrate prevalence of resistance factors.

[[Page 99]]

    (iv) A description of clinical microbiology laboratory procedures 
(for example, in vitro sensitivity discs) needed for effective use of 
the drug.
    (5) Clinical data section. A section describing the clinical 
investigations of the drug, including the following:
    (i) A description and analysis of each clinical pharmacology study 
of the drug, including a brief comparison of the results of the human 
studies with the animal pharmacology and toxicology data.
    (ii) A description and analysis of each controlled clinical study 
pertinent to a proposed use of the drug, including the protocol and a 
description of the statistical analyses used to evaluate the study. If 
the study report is an interim analysis, this is to be noted and a 
projected completion date provided. Controlled clinical studies that 
have not been analyzed in detail for any reason (e.g., because they have 
been discontinued or are incomplete) are to be included in this section, 
including a copy of the protocol and a brief description of the results 
and status of the study.
    (iii) A description of each uncontrolled clinical study, a summary 
of the results, and a brief statement explaining why the study is 
classified as uncontrolled.
    (iv) A description and analysis of any other data or information 
relevant to an evaluation of the safety and effectiveness of the drug 
product obtained or otherwise received by the applicant from any source, 
foreign or domestic, including information derived from clinical 
investigations, including controlled and uncontrolled studies of uses of 
the drug other than those proposed in the application, commercial 
marketing experience, reports in the scientific literature, and 
unpublished scientific papers.
    (v) An integrated summary of the data demonstrating substantial 
evidence of effectiveness for the claimed indications. Evidence is also 
required to support the dosage and administration section of the 
labeling, including support for the dosage and dose interval 
recommended. The effectiveness data shall be presented by gender, age, 
and racial subgroups and shall identify any modifications of dose or 
dose interval needed for specific subgroups. Effectiveness data from 
other subgroups of the population of patients treated, when appropriate, 
such as patients with renal failure or patients with different levels of 
severity of the disease, also shall be presented.
    (vi) A summary and updates of safety information, as follows:
    (a) The applicant shall submit an integrated summary of all 
available information about the safety of the drug product, including 
pertinent animal data, demonstrated or potential adverse effects of the 
drug, clinically significant drug/drug interactions, and other safety 
considerations, such as data from epidemiological studies of related 
drugs. The safety data shall be presented by gender, age, and racial 
subgroups. When appropriate, safety data from other subgroups of the 
population of patients treated also shall be presented, such as for 
patients with renal failure or patients with different levels of 
severity of the disease. A description of any statistical analyses 
performed in analyzing safety data should also be included, unless 
already included under paragraph (d)(5)(ii) of this section.
    (b) The applicant shall, under section 505(i) of the act, update 
periodically its pending application with new safety information learned 
about the drug that may reasonably affect the statement of 
contraindications, warnings, precautions, and adverse reactions in the 
draft labeling and, if applicable, any Medication Guide required under 
part 208 of this chapter. These ``safety update reports'' are required 
to include the same kinds of information (from clinical studies, animal 
studies, and other sources) and are required to be submitted in the same 
format as the integrated summary in paragraph (d)(5)(vi)(a) of this 
section. In addition, the reports are required to include the case 
report forms for each patient who died during a clinical study or who 
did not complete the study because of an adverse event (unless this 
requirement is waived). The applicant shall submit these reports (1) 4 
months after the initial submission; (2) in a resubmission following 
receipt of a complete response letter; and (3) at other times as 
requested by FDA. Prior to the submission of the first such report, 
applicants

[[Page 100]]

are encouraged to consult with FDA regarding further details on its form 
and content.
    (vii) If the drug has a potential for abuse, a description and 
analysis of studies or information related to abuse of the drug, 
including a proposal for scheduling under the Controlled Substances Act. 
A description of any studies related to overdosage is also required, 
including information on dialysis, antidotes, or other treatments, if 
known.
    (viii) An integrated summary of the benefits and risks of the drug, 
including a discussion of why the benefits exceed the risks under the 
conditions stated in the labeling.
    (ix) A statement with respect to each clinical study involving human 
subjects that it either was conducted in compliance with the 
institutional review board regulations in part 56, or was not subject to 
the regulations under Sec. 56.104 or Sec. 56.105, and that it was 
conducted in compliance with the informed consent regulations in part 
50.
    (x) If a sponsor has transferred any obligations for the conduct of 
any clinical study to a contract research organization, a statement 
containing the name and address of the contract research organization, 
identification of the clinical study, and a listing of the obligations 
transferred. If all obligations governing the conduct of the study have 
been transferred, a general statement of this transfer--in lieu of a 
listing of the specific obligations transferred--may be submitted.
    (xi) If original subject records were audited or reviewed by the 
sponsor in the course of monitoring any clinical study to verify the 
accuracy of the case reports submitted to the sponsor, a list 
identifying each clinical study so audited or reviewed.
    (6) Statistical section. A section describing the statistical 
evaluation of clinical data, including the following:
    (i) A copy of the information submitted under paragraph (d)(5)(ii) 
of this section concerning the description and analysis of each 
controlled clinical study, and the documentation and supporting 
statistical analyses used in evaluating the controlled clinical studies.
    (ii) A copy of the information submitted under paragraph 
(d)(5)(vi)(a) of this section concerning a summary of information about 
the safety of the drug product, and the documentation and supporting 
statistical analyses used in evaluating the safety information.
    (7) Pediatric use section. A section describing the investigation of 
the drug for use in pediatric populations, including an integrated 
summary of the information (the clinical pharmacology studies, 
controlled clinical studies, or uncontrolled clinical studies, or other 
data or information) that is relevant to the safety and effectiveness 
and benefits and risks of the drug in pediatric populations for the 
claimed indications, a reference to the full descriptions of such 
studies provided under paragraphs (d)(3) and (d)(5) of this section, and 
information required to be submitted under Sec. 314.55.
    (e) Samples and labeling. (1) Upon request from FDA, the applicant 
shall submit the samples described below to the places identified in the 
agency's request. FDA will generally ask applicants to submit samples 
directly to two or more agency laboratories that will perform all 
necessary tests on the samples and validate the applicant's analytical 
procedures.
    (i) Four representative samples of the following, each sample in 
sufficient quantity to permit FDA to perform three times each test 
described in the application to determine whether the drug substance and 
the drug product meet the specifications given in the application:
    (a) The drug product proposed for marketing;
    (b) The drug substance used in the drug product from which the 
samples of the drug product were taken; and
    (c) Reference standards and blanks (except that reference standards 
recognized in an official compendium need not be submitted).
    (ii) Samples of the finished market package, if requested by FDA.
    (2) The applicant shall submit the following in the archival copy of 
the application:
    (i) Three copies of the analytical procedures and related 
descriptive information contained in the chemistry,

[[Page 101]]

manufacturing, and controls section under paragraph (d)(1) of this 
section for the drug substance and the drug product that are necessary 
for FDA's laboratories to perform all necessary tests on the samples and 
to validate the applicant's analytical procedures. The related 
descriptive information includes a description of each sample; the 
proposed regulatory specifications for the drug; a detailed description 
of the methods of analysis; supporting data for accuracy, specificity, 
precision and ruggedness; and complete results of the applicant's tests 
on each sample.
    (ii) Copies of the label and all labeling for the drug product 
(including, if applicable, any Medication Guide required under part 208 
of this chapter) for the drug product (4 copies of draft labeling or 12 
copies of final printed labeling).
    (f) Case report forms and tabulations. The archival copy of the 
application is required to contain the following case report tabulations 
and case report forms:
    (1) Case report tabulations. The application is required to contain 
tabulations of the data from each adequate and well-controlled study 
under Sec. 314.126 (Phase 2 and Phase 3 studies as described in 
Sec. Sec. 312.21 (b) and (c) of this chapter), tabulations of the data 
from the earliest clinical pharmacology studies (Phase 1 studies as 
described in Sec. 312.21(a) of this chapter), and tabulations of the 
safety data from other clinical studies. Routine submission of other 
patient data from uncontrolled studies is not required. The tabulations 
are required to include the data on each patient in each study, except 
that the applicant may delete those tabulations which the agency agrees, 
in advance, are not pertinent to a review of the drug's safety or 
effectiveness. Upon request, FDA will discuss with the applicant in a 
``pre-NDA'' conference those tabulations that may be appropriate for 
such deletion. Barring unforeseen circumstances, tabulations agreed to 
be deleted at such a conference will not be requested during the conduct 
of FDA's review of the application. If such unforeseen circumstances do 
occur, any request for deleted tabulations will be made by the director 
of the FDA division responsible for reviewing the application, in 
accordance with paragraph (f)(3) of this section.
    (2) Case report forms. The application is required to contain copies 
of individual case report forms for each patient who died during a 
clinical study or who did not complete the study because of an adverse 
event, whether believed to be drug related or not, including patients 
receiving reference drugs or placebo. This requirement may be waived by 
FDA for specific studies if the case report forms are unnecessary for a 
proper review of the study.
    (3) Additional data. The applicant shall submit to FDA additional 
case report forms and tabulations needed to conduct a proper review of 
the application, as requested by the director of the FDA division 
responsible for reviewing the application. The applicant's failure to 
submit information requested by FDA within 30 days after receipt of the 
request may result in the agency viewing any eventual submission as a 
major amendment under Sec. 314.60 and extending the review period as 
necessary. If desired by the applicant, the FDA division director will 
verify in writing any request for additional data that was made orally.
    (4) Applicants are invited to meet with FDA before submitting an 
application to discuss the presentation and format of supporting 
information. If the applicant and FDA agree, the applicant may submit 
tabulations of patient data and case report forms in a form other than 
hard copy, for example, on microfiche or computer tapes.
    (g) Other. The following general requirements apply to the 
submission of information within the summary under paragraph (c) of this 
section and within the technical sections under paragraph (d) of this 
section.
    (1) The applicant ordinarily is not required to resubmit information 
previously submitted, but may incorporate the information by reference. 
A reference to information submitted previously is required to identify 
the file by name, reference number, volume, and page number in the 
agency's records where the information can be found. A reference to 
information submitted to the agency by a person other

[[Page 102]]

than the applicant is required to contain a written statement that 
authorizes the reference and that is signed by the person who submitted 
the information.
    (2) The applicant shall submit an accurate and complete English 
translation of each part of the application that is not in English. The 
applicant shall submit a copy of each original literature publication 
for which an English translation is submitted.
    (3) If an applicant who submits a new drug application under section 
505(b) of the act obtains a ``right of reference or use,'' as defined 
under Sec. 314.3(b), to an investigation described in clause (A) of 
section 505(b)(1) of the act, the applicant shall include in its 
application a written statement signed by the owner of the data from 
each such investigation that the applicant may rely on in support of the 
approval of its application, and provide FDA access to, the underlying 
raw data that provide the basis for the report of the investigation 
submitted in its application.
    (h) Patent information. The application is required to contain the 
patent information described under Sec. 314.53.
    (i) Patent certification--(1) Contents. A 505(b)(2) application is 
required to contain the following:
    (i) Patents claiming drug, drug product, or method of use. (A) 
Except as provided in paragraph (i)(2) of this section, a certification 
with respect to each patent issued by the United States Patent and 
Trademark Office that, in the opinion of the applicant and to the best 
of its knowledge, claims a drug (the drug product or drug substance that 
is a component of the drug product) on which investigations that are 
relied upon by the applicant for approval of its application were 
conducted or that claims an approved use for such drug and for which 
information is required to be filed under section 505(b) and (c) of the 
act and Sec. 314.53. For each such patent, the applicant shall provide 
the patent number and certify, in its opinion and to the best of its 
knowledge, one of the following circumstances:
    (1) That the patent information has not been submitted to FDA. The 
applicant shall entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant shall entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant shall 
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the application is submitted. The applicant shall entitle such a 
certification ``Paragraph IV Certification''. This certification shall 
be submitted in the following form:

I, (name of applicant), certify that Patent No. ------------ (is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this 
application is submitted.


The certification shall be accompanied by a statement that the applicant 
will comply with the requirements under Sec. 314.52(a) with respect to 
providing a notice to each owner of the patent or their representatives 
and to the holder of the approved application for the drug product which 
is claimed by the patent or a use of which is claimed by the patent and 
with the requirements under Sec. 314.52(c) with respect to the content 
of the notice.
    (B) If the drug on which investigations that are relied upon by the 
applicant were conducted is itself a licensed generic drug of a patented 
drug first approved under section 505(b) of the act, the appropriate 
patent certification under this section with respect to each patent that 
claims the first-approved patented drug or that claims an approved use 
for such a drug.
    (ii) No relevant patents. If, in the opinion of the applicant and to 
the best of its knowledge, there are no patents described in paragraph 
(i)(1)(i) of this section, a certification in the following form:

In the opinion and to the best knowledge of (name of applicant), there 
are no patents that claim the drug or drugs on which investigations that 
are relied upon in this application were conducted or that claim a use 
of such drug or drugs.

    (iii) Method of use patent. (A) If information that is submitted 
under section 505(b) or (c) of the act and Sec. 314.53 is for

[[Page 103]]

a method of use patent, and the labeling for the drug product for which 
the applicant is seeking approval does not include any indications that 
are covered by the use patent, a statement explaining that the method of 
use patent does not claim any of the proposed indications.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication that, according to the patent 
information submitted under section 505(b) or (c) of the act and Sec. 
314.53 or in the opinion of the applicant, is claimed by a use patent, 
the applicant shall submit an applicable certification under paragraph 
(i)(1)(i) of this section.
    (2) Method of manufacturing patent. An applicant is not required to 
make a certification with respect to any patent that claims only a 
method of manufacturing the drug product for which the applicant is 
seeking approval.
    (3) Licensing agreements. If a 505(b)(2) application is for a drug 
or method of using a drug claimed by a patent and the applicant has a 
licensing agreement with the patent owner, the applicant shall submit a 
certification under paragraph (i)(1)(i)(A)(4) of this section 
(``Paragraph IV Certification'') as to that patent and a statement that 
it has been granted a patent license. If the patent owner consents to an 
immediate effective date upon approval of the 505(b)(2) application, the 
application shall contain a written statement from the patent owner that 
it has a licensing agreement with the applicant and that it consents to 
an immediate effective date.
    (4) Late submission of patent information. If a patent described in 
paragraph (i)(1)(i)(A) of this section is issued and the holder of the 
approved application for the patented drug does not submit the required 
information on the patent within 30 days of issuance of the patent, an 
applicant who submitted a 505(b)(2) application that, before the 
submission of the patent information, contained an appropriate patent 
certification is not required to submit an amended certification. An 
applicant whose 505(b)(2) application is filed after a late submission 
of patent information or whose 505(b)(2) application was previously 
filed but did not contain an appropriate patent certification at the 
time of the patent submission shall submit a certification under 
paragraph (i)(1)(i) or (i)(1)(ii) of this section or a statement under 
paragraph (i)(1)(iii) of this section as to that patent.
    (5) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec. 314.53(f). 
Unless the patent information is withdrawn or changed, the applicant 
must submit an appropriate certification for each relevant patent.
    (6) Amended certifications. A certification submitted under 
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended 
at any time before the effective date of the approval of the 
application. An applicant shall submit an amended certification as an 
amendment to a pending application or by letter to an approved 
application. If an applicant with a pending application voluntarily 
makes a patent certification for an untimely filed patent, the applicant 
may withdraw the patent certification for the untimely filed patent. 
Once an amendment or letter for the change in certification has been 
submitted, the application will no longer be considered to be one 
containing the prior certification.
    (i) After finding of infringement. An applicant who has submitted a 
certification under paragraph (i)(1)(i)(A)(4) of this section and is 
sued for patent infringement within 45 days of the receipt of notice 
sent under Sec. 314.52 shall amend the certification if a final 
judgment in the action is entered finding the patent to be infringed 
unless the final judgment also finds the patent to be invalid. In the 
amended certification, the applicant shall certify under paragraph 
(i)(1)(i)(A)(3) of this section that the patent will expire on a 
specific date.
    (ii) After removal of a patent from the list. If a patent is removed 
from the list, any applicant with a pending application (including a 
tentatively approved application with a delayed effective date) who has 
made a certification with respect to such patent

[[Page 104]]

shall amend its certification. The applicant shall certify under 
paragraph (i)(1)(ii) of this section that no patents described in 
paragraph (i)(1)(i) of this section claim the drug or, if other relevant 
patents claim the drug, shall amend the certification to refer only to 
those relevant patents. In the amendment, the applicant shall state the 
reason for the change in certification (that the patent is or has been 
removed from the list). A patent that is the subject of a lawsuit under 
Sec. 314.107(c) shall not be removed from the list until FDA determines 
either that no delay in effective dates of approval is required under 
that section as a result of the lawsuit, that the patent has expired, or 
that any such period of delay in effective dates of approval is ended. 
An applicant shall submit an amended certification as an amendment to a 
pending application. Once an amendment for the change has been 
submitted, the application will no longer be considered to be one 
containing a certification under paragraph (i)(1)(i)(A)(4) of this 
section.
    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4) 
and (i)(6)(iii)(B) of this section, an applicant shall amend a submitted 
certification if, at any time before the effective date of the approval 
of the application, the applicant learns that the submitted 
certification is no longer accurate.
    (B) An applicant is not required to amend a submitted certification 
when information on an otherwise applicable patent is submitted after 
the effective date of approval for the 505(b)(2) application.
    (j) Claimed exclusivity. A new drug product, upon approval, may be 
entitled to a period of marketing exclusivity under the provisions of 
Sec. 314.108. If an applicant believes its drug product is entitled to 
a period of exclusivity, it shall submit with the new drug application 
prior to approval the following information:
    (1) A statement that the applicant is claiming exclusivity.
    (2) A reference to the appropriate paragraph under Sec. 314.108 
that supports its claim.
    (3) If the applicant claims exclusivity under Sec. 314.108(b)(2), 
information to show that, to the best of its knowledge or belief, a drug 
has not previously been approved under section 505(b) of the act 
containing any active moiety in the drug for which the applicant is 
seeking approval.
    (4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or 
(b)(5), the following information to show that the application contains 
``new clinical investigations'' that are ``essential to approval of the 
application or supplement'' and were ``conducted or sponsored by the 
applicant:''
    (i) ``New clinical investigations.'' A certification that to the 
best of the applicant's knowledge each of the clinical investigations 
included in the application meets the definition of ``new clinical 
investigation'' set forth in Sec. 314.108(a).
    (ii) ``Essential to approval.'' A list of all published studies or 
publicly available reports of clinical investigations known to the 
applicant through a literature search that are relevant to the 
conditions for which the applicant is seeking approval, a certification 
that the applicant has thoroughly searched the scientific literature 
and, to the best of the applicant's knowledge, the list is complete and 
accurate and, in the applicant's opinion, such published studies or 
publicly available reports do not provide a sufficient basis for the 
approval of the conditions for which the applicant is seeking approval 
without reference to the new clinical investigation(s) in the 
application, and an explanation as to why the studies or reports are 
insufficient.
    (iii) ``Conducted or sponsored by.'' If the applicant was the 
sponsor named in the Form FDA-1571 for an investigational new drug 
application (IND) under which the new clinical investigation(s) that is 
essential to the approval of its application was conducted, 
identification of the IND by number. If the applicant was not the 
sponsor of the IND under which the clinical investigation(s) was 
conducted, a certification that the applicant or its predecessor in 
interest provided substantial support for the clinical investigation(s) 
that is essential to the approval of its application, and information 
supporting the certification. To demonstrate ``substantial support,'' an 
applicant must

[[Page 105]]

either provide a certified statement from a certified public accountant 
that the applicant provided 50 percent or more of the cost of conducting 
the study or provide an explanation of why FDA should consider the 
applicant to have conducted or sponsored the study if the applicant's 
financial contribution to the study is less than 50 percent or the 
applicant did not sponsor the investigational new drug. A predecessor in 
interest is an entity, e.g., a corporation, that the applicant has taken 
over, merged with, or purchased, or from which the applicant has 
purchased all rights to the drug. Purchase of nonexclusive rights to a 
clinical investigation after it is completed is not sufficient to 
satisfy this definition.
    (k) Financial certification or disclosure statement. The application 
shall contain a financial certification or disclosure statement or both 
as required by part 54 of this chapter.
    (l) Format of an original application--(1) Archival copy. The 
applicant must submit a complete archival copy of the application that 
contains the information required under paragraphs (a) through (f) of 
this section. FDA will maintain the archival copy during the review of 
the application to permit individual reviewers to refer to information 
that is not contained in their particular technical sections of the 
application, to give other agency personnel access to the application 
for official business, and to maintain in one place a complete copy of 
the application. Except as required by paragraph (l)(1)(i) of this 
section, applicants may submit the archival copy on paper or in 
electronic format provided that electronic submissions are made in 
accordance with part 11 of this chapter.
    (i) Labeling. The content of labeling required under Sec. 
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (l)(5) of this section. This requirement is in 
addition to the requirements of paragraph (e)(2)(ii) of this section 
that copies of the formatted label and all labeling be submitted. 
Submissions under this paragraph must be made in accordance with part 11 
of this chapter, except for the requirements of Sec. 11.10(a), (c) 
through (h), and (k), and the corresponding requirements of Sec. 11.30.
    (ii) [Reserved]
    (2) Review copy. The applicant must submit a review copy of the 
application. Each of the technical sections, described in paragraphs 
(d)(1) through (d)(6) of this section, in the review copy is required to 
be separately bound with a copy of the application form required under 
paragraph (a) of this section and a copy of the summary required under 
paragraph (c) of this section.
    (3) Field copy. The applicant must submit a field copy of the 
application that contains the technical section described in paragraph 
(d)(1) of this section, a copy of the application form required under 
paragraph (a) of this section, a copy of the summary required under 
paragraph (c) of this section, and a certification that the field copy 
is a true copy of the technical section described in paragraph (d)(1) of 
this section contained in the archival and review copies of the 
application.
    (4) Binding folders. The applicant may obtain from FDA sufficient 
folders to bind the archival, the review, and the field copies of the 
application.
    (5) Electronic format submissions. Electronic format submissions 
must be in a form that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files).

[50 FR 7493, Feb. 22, 1985]

    Editorial Note: For Federal Register citations affecting Sec. 
314.50, see the List of CFR Sections Affected, which appears in the 
Finding Aids section of the printed volume and at www.fdsys.gov.



Sec. 314.52  Notice of certification of invalidity or noninfringement
of a patent.

    (a) Notice of certification. For each patent which claims the drug 
or drugs on which investigations that are relied upon by the applicant 
for approval of its application were conducted or which claims a use for 
such drug or drugs and which the applicant certifies under Sec. 
314.50(i)(1)(i)(A)(4) that a patent is invalid, unenforceable, or will 
not be

[[Page 106]]

infringed, the applicant shall send notice of such certification by 
registered or certified mail, return receipt requested to each of the 
following persons:
    (1) Each owner of the patent that is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the United States Patent and 
Trademark Office; and
    (2) The holder of the approved application under section 505(b) of 
the act for each drug product which is claimed by the patent or a use of 
which is claimed by the patent and for which the applicant is seeking 
approval, or, if the application holder does not reside or maintain a 
place of business within the United States, the application holder's 
attorney, agent, or other authorized official. The name and address of 
the application holder or its attorney, agent, or authorized official 
may be obtained from the Orange Book Staff, Office of Generic Drugs, 
7500 Standish Pl., Rockville, MD 20855.
    (3) This paragraph does not apply to a use patent that claims no 
uses for which the applicant is seeking approval.
    (b) Sending the notice. The applicant shall send the notice required 
by paragraph (a) of this section when it receives from FDA an 
acknowledgment letter stating that its application has been filed. At 
the same time, the applicant shall amend its application to include a 
statement certifying that the notice has been provided to each person 
identified under paragraph (a) of this section and that the notice met 
the content requirement under paragraph (c) of this section.
    (c) Content of a notice. In the notice, the applicant shall cite 
section 505(b)(3)(B) of the act and shall include, but not be limited 
to, the following information:
    (1) A statement that a 505(b)(2) application submitted by the 
applicant has been filed by FDA.
    (2) The application number.
    (3) The established name, if any, as defined in section 502(e)(3) of 
the act, of the proposed drug product.
    (4) The active ingredient, strength, and dosage form of the proposed 
drug product.
    (5) The patent number and expiration date, as submitted to the 
agency or as known to the applicant, of each patent alleged to be 
invalid, unenforceable, or not infringed.
    (6) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or will 
not be infringed. The applicant shall include in the detailed statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds supporting 
the allegation.
    (7) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United States 
authorized to accept service of process for the applicant.
    (d) Amendment to an application. If an application is amended to 
include the certification described in Sec. 314.50(i), the applicant 
shall send the notice required by paragraph (a) of this section at the 
same time that the amendment to the application is submitted to FDA.
    (e) Documentation of receipt of notice. The applicant shall amend 
its application to document receipt of the notice required under 
paragraph (a) of this section by each person provided the notice. The 
applicant shall include a copy of the return receipt or other similar 
evidence of the date the notification was received. FDA will accept as 
adequate documentation of the date of receipt a return receipt or a 
letter acknowledging receipt by the person provided the notice. An 
applicant may rely on another form of documentation only if FDA has 
agreed to such documentation in advance. A copy of the notice itself 
need not be submitted to the agency.
    (f) Approval. If the requirements of this section are met, the 
agency will presume the notice to be complete and sufficient, and it 
will count the day following the date of receipt of the notice

[[Page 107]]

by the patent owner or its representative and by the approved 
application holder as the first day of the 45-day period provided for in 
section 505(c)(3)(C) of the act. FDA may, if the applicant amends its 
application with a written statement that a later date should be used, 
count from such later date.

[59 FR 50362, Oct. 3, 1994, as amended at 68 FR 36703, June 18, 2003; 69 
FR 11310, Mar. 10, 2004; 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, 
2009]



Sec. 314.53  Submission of patent information.

    (a) Who must submit patent information. This section applies to any 
applicant who submits to FDA a new drug application or an amendment to 
it under section 505(b) of the act and Sec. 314.50 or a supplement to 
an approved application under Sec. 314.70, except as provided in 
paragraph (d)(2) of this section.
    (b) Patents for which information must be submitted and patents for 
which information must not be submitted--(1) General requirements. An 
applicant described in paragraph (a) of this section shall submit the 
required information on the declaration form set forth in paragraph (c) 
of this section for each patent that claims the drug or a method of 
using the drug that is the subject of the new drug application or 
amendment or supplement to it and with respect to which a claim of 
patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product. For purposes of this part, such patents 
consist of drug substance (active ingredient) patents, drug product 
(formulation and composition) patents, and method-of-use patents. For 
patents that claim the drug substance, the applicant shall submit 
information only on those patents that claim the drug substance that is 
the subject of the pending or approved application or that claim a drug 
substance that is the same as the active ingredient that is the subject 
of the approved or pending application. For patents that claim a 
polymorph that is the same as the active ingredient described in the 
approved or pending application, the applicant shall certify in the 
declaration forms that the applicant has test data, as set forth in 
paragraph (b)(2) of this section, demonstrating that a drug product 
containing the polymorph will perform the same as the drug product 
described in the new drug application. For patents that claim a drug 
product, the applicant shall submit information only on those patents 
that claim a drug product, as is defined in Sec. 314.3, that is 
described in the pending or approved application. For patents that claim 
a method of use, the applicant shall submit information only on those 
patents that claim indications or other conditions of use that are 
described in the pending or approved application. The applicant shall 
separately identify each pending or approved method of use and related 
patent claim. For approved applications, the applicant submitting the 
method-of-use patent shall identify with specificity the section of the 
approved labeling that corresponds to the method of use claimed by the 
patent submitted. Process patents, patents claiming packaging, patents 
claiming metabolites, and patents claiming intermediates are not covered 
by this section, and information on these patents must not be submitted 
to FDA.
    (2) Test Data for Submission of Patent Information for Patents That 
Claim a Polymorph. The test data, referenced in paragraph (b)(1) of this 
section, must include the following:
    (i) A full description of the polymorphic form of the drug 
substance, including its physical and chemical characteristics and 
stability; the method of synthesis (or isolation) and purification of 
the drug substance; the process controls used during manufacture and 
packaging; and such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, and purity of the 
polymorphic form of the drug substance;
    (ii) The executed batch record for a drug product containing the 
polymorphic form of the drug substance and documentation that the batch 
was manufactured under current good manufacturing practice requirements;
    (iii) Demonstration of bioequivalence between the executed batch of 
the drug product that contains the polymorphic

[[Page 108]]

form of the drug substance and the drug product as described in the NDA;
    (iv) A list of all components used in the manufacture of the drug 
product containing the polymorphic form and a statement of the 
composition of the drug product; a statement of the specifications and 
analytical methods for each component; a description of the 
manufacturing and packaging procedures and in-process controls for the 
drug product; such specifications and analytical methods as are 
necessary to assure the identity, strength, quality, purity, and 
bioavailability of the drug product, including release and stability 
data complying with the approved product specifications to demonstrate 
pharmaceutical equivalence and comparable product stability; and
    (v) Comparative in vitro dissolution testing on 12 dosage units each 
of the executed test batch and the new drug application product.
    (c) Reporting requirements--(1) General requirements. An applicant 
described in paragraph (a) of this section shall submit the required 
patent information described in paragraph (c)(2) of this section for 
each patent that meets the requirements described in paragraph (b) of 
this section. We will not accept the patent information unless it is 
complete and submitted on the appropriate forms, FDA Forms 3542 or 
3542a. These forms may be obtained on the Internet at http://www.fda.gov 
by searching for ``forms''.
    (2) Drug substance (active ingredient), drug product (formulation or 
composition), and method-of-use patents--(i) Original Declaration. For 
each patent that claims a drug substance (active ingredient), drug 
product (formulation and composition), or method of use, the applicant 
shall submit FDA Form 3542a. The following information and verification 
is required:
    (A) New drug application number;
    (B) Name of new drug application sponsor;
    (C) Trade name (or proposed trade name) of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form of new drug;
    (G) United States patent number, issue date, and expiration date of 
patent submitted;
    (H) The patent owner's name, full address, phone number and, if 
available, fax number and e-mail address;
    (I) The name, full address, phone number and, if available, fax 
number and e-mail address of an agent or representative who resides or 
maintains a place of business within the United States authorized to 
receive notice of patent certification under sections 505(b)(3) and 
505(j)(2)(B) of the act and Sec. Sec. 314.52 and 314.95 (if patent 
owner or new drug application applicant or holder does not reside or 
have a place of business within the United States);
    (J) Information on whether the patent has been submitted previously 
for the new drug application;
    (K) Information on whether the expiration date is a new expiration 
date if the patent had been submitted previously for listing;
    (L) Information on whether the patent is a product-by-process patent 
in which the product claimed is novel;
    (M) Information on the drug substance (active ingredient) patent 
including the following:
    (1) Whether the patent claims the drug substance that is the active 
ingredient in the drug product described in the new drug application or 
supplement;
    (2) Whether the patent claims a polymorph that is the same active 
ingredient that is described in the pending application or supplement;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing the 
polymorph will perform the same as the drug product described in the new 
drug application or supplement, and a description of the polymorphic 
form(s) claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (N) Information on the drug product (composition/formulation) patent 
including the following:
    (1) Whether the patent claims the drug product for which approval is 
being sought, as defined in Sec. 314.3; and
    (2) Whether the patent claims only an intermediate;

[[Page 109]]

    (O) Information on each method-of-use patent including the 
following:
    (1) Whether the patent claims one or more methods of using the drug 
product for which use approval is being sought and a description of each 
pending method of use or related indication and related patent claim of 
the patent being submitted; and
    (2) Identification of the specific section of the proposed labeling 
for the drug product that corresponds to the method of use claimed by 
the patent submitted;
    (P) Whether there are no relevant patents that claim the drug 
substance (active ingredient), drug product (formulation or composition) 
or method(s) of use, for which the applicant is seeking approval and 
with respect to which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product;
    (Q) A signed verification which states:

    ``The undersigned declares that this is an accurate and complete 
submission of patent information for the NDA, amendment or supplement 
pending under section 505 of the Federal Food, Drug, and Cosmetic Act. 
This time-sensitive patent information is submitted pursuant to 21 CFR 
314.53. I attest that I am familiar with 21 CFR 314.53 and this 
submission complies with the requirements of the regulation. I verify 
under penalty of perjury that the foregoing is true and correct.''; and

    (R) Information on whether the applicant, patent owner or attorney, 
agent, representative or other authorized official signed the form; the 
name of the person; and the full address, phone number and, if 
available, the fax number and e-mail address.
    (ii) Submission of patent information upon and after approval. 
Within 30 days after the date of approval of its application or 
supplement, the applicant shall submit FDA Form 3542 for each patent 
that claims the drug substance (active ingredient), drug product 
(formulation and composition), or approved method of use. FDA will rely 
only on the information submitted on this form and will not list or 
publish patent information if the patent declaration is incomplete or 
indicates the patent is not eligible for listing. Patent information 
must also be submitted for patents issued after the date of approval of 
the new drug application as required in paragraph (c)(2)(ii) of this 
section. As described in paragraph (d)(4) of this section, patent 
information must be submitted to FDA within 30 days of the date of 
issuance of the patent. If the applicant submits the required patent 
information within the 30 days, but we notify an applicant that a 
declaration form is incomplete or shows that the patent is not eligible 
for listing, the applicant must submit an acceptable declaration form 
within 15 days of FDA notification to be considered timely filed. The 
following information and verification statement is required:
    (A) New drug application number;
    (B) Name of new drug application sponsor;
    (C) Trade name of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form of new drug;
    (G) Approval date of new drug application or supplement;
    (H) United States patent number, issue date, and expiration date of 
patent submitted;
    (I) The patent owner's name, full address, phone number and, if 
available, fax number and e-mail address;
    (J) The name, full address, phone number and, if available, fax 
number and e-mail address of an agent or representative who resides or 
maintains a place of business within the United States authorized to 
receive notice of patent certification under sections 505(b)(3) and 
505(j)(2)(B) of the act and Sec. Sec. 314.52 and 314.95 (if patent 
owner or new drug application applicant or holder does not reside or 
have a place of business within the United States);
    (K) Information on whether the patent has been submitted previously 
for the new drug application;
    (L) Information on whether the expiration date is a new expiration 
date if the patent had been submitted previously for listing;
    (M) Information on whether the patent is a product-by-process patent 
in which the product claimed is novel;
    (N) Information on the drug substance (active ingredient) patent 
including the following:

[[Page 110]]

    (1) Whether the patent claims the drug substance that is the active 
ingredient in the drug product described in the approved application;
    (2) Whether the patent claims a polymorph that is the same as the 
active ingredient that is described in the approved application;
    (3) Whether the applicant has test data, described at paragraph 
(b)(2) of this section, demonstrating that a drug product containing the 
polymorph will perform the same as the drug product described in the 
approved application and a description of the polymorphic form(s) 
claimed by the patent for which such test data exist;
    (4) Whether the patent claims only a metabolite of the active 
ingredient; and
    (5) Whether the patent claims only an intermediate;
    (O) Information on the drug product (composition/formulation) patent 
including the following:
    (1) Whether the patent claims the approved drug product as defined 
in Sec. 314.3; and
    (2) Whether the patent claims only an intermediate;
    (P) Information on each method-of-use patent including the 
following:
    (1) Whether the patent claims one or more approved methods of using 
the approved drug product and a description of each approved method of 
use or indication and related patent claim of the patent being 
submitted;
    (2) Identification of the specific section of the approved labeling 
for the drug product that corresponds to the method of use claimed by 
the patent submitted; and
    (3) The description of the patented method of use as required for 
publication;
    (Q) Whether there are no relevant patents that claim the approved 
drug substance (active ingredient), the approved drug product 
(formulation or composition) or approved method(s) of use and with 
respect to which a claim of patent infringement could reasonably be 
asserted if a person not licensed by the owner of the patent engaged in 
the manufacture, use, or sale of the drug product;
    (R) A signed verification which states: ``The undersigned declares 
that this is an accurate and complete submission of patent information 
for the NDA, amendment or supplement approved under section 505 of the 
Federal Food, Drug, and Cosmetic Act. This time-sensitive patent 
information is submitted pursuant to 21 CFR 314.53. I attest that I am 
familiar with 21 CFR 314.53 and this submission complies with the 
requirements of the regulation. I verify under penalty of perjury that 
the foregoing is true and correct.''; and
    (S) Information on whether the applicant, patent owner or attorney, 
agent, representative or other authorized official signed the form; the 
name of the person; and the full address, phone number and, if 
available, the fax number and e-mail address.
    (3) No relevant patents. If the applicant believes that there are no 
relevant patents that claim the drug substance (active ingredient), drug 
product (formulation or composition), or the method(s) of use for which 
the applicant has received approval, and with respect to which a claim 
of patent infringement could reasonably be asserted if a person not 
licensed by the owner of the patent engaged in the manufacture, use, or 
sale of the drug product, the applicant will verify this information in 
the appropriate forms, FDA Forms 3542 or 3542a.
    (4) Authorized signature. The declarations required by this section 
shall be signed by the applicant or patent owner, or the applicant's or 
patent owner's attorney, agent (representative), or other authorized 
official.
    (d) When and where to submit patent information--(1) Original 
application. An applicant shall submit with its original application 
submitted under this part, including an application described in section 
505(b)(2) of the act, the information described in paragraph (c) of this 
section on each drug (ingredient), drug product (formulation and 
composition), and method of use patent issued before the application is 
filed with FDA and for which patent information is required to be 
submitted under this section. If a patent is issued after the 
application is filed with FDA but before the application is approved, 
the applicant shall, within 30 days of

[[Page 111]]

the date of issuance of the patent, submit the required patent 
information in an amendment to the application under Sec. 314.60.
    (2) Supplements. (i) An applicant shall submit patent information 
required under paragraph (c) of this section for a patent that claims 
the drug, drug product, or method of use for which approval is sought in 
any of the following supplements:
    (A) To change the formulation;
    (B) To add a new indication or other condition of use, including a 
change in route of administration;
    (C) To change the strength;
    (D) To make any other patented change regarding the drug, drug 
product, or any method of use.
    (ii) If the applicant submits a supplement for one of the changes 
listed under paragraph (d)(2)(i) of this section and existing patents 
for which information has already been submitted to FDA claim the 
changed product, the applicant shall submit a certification with the 
supplement identifying the patents that claim the changed product.
    (iii) If the applicant submits a supplement for one of the changes 
listed under paragraph (d)(2)(i) of this section and no patents, 
including previously submitted patents, claim the changed product, it 
shall so certify.
    (iv) The applicant shall comply with the requirements for amendment 
of formulation or composition and method of use patent information under 
paragraphs (c)(2)(ii) and (d)(3) of this section.
    (3) Patent information deadline. If a patent is issued for a drug, 
drug product, or method of use after an application is approved, the 
applicant shall submit to FDA the required patent information within 30 
days of the date of issuance of the patent.
    (4) Copies. The applicant shall submit two copies of each submission 
of patent information, an archival copy and a copy for the chemistry, 
manufacturing, and controls section of the review copy, to the Central 
Document Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266. The 
applicant shall submit the patent information by letter separate from, 
but at the same time as, submission of the supplement.
    (5) Submission date. Patent information shall be considered to be 
submitted to FDA as of the date the information is received by the 
Central Document Room.
    (6) Identification. Each submission of patent information, except 
information submitted with an original application, and its mailing 
cover shall bear prominent identification as to its contents, i.e., 
``Patent Information,'' or, if submitted after approval of an 
application, ``Time Sensitive Patent Information.''
    (e) Public disclosure of patent information. FDA will publish in the 
list the patent number and expiration date of each patent that is 
required to be, and is, submitted to FDA by an applicant, and for each 
use patent, the approved indications or other conditions of use covered 
by a patent. FDA will publish such patent information upon approval of 
the application, or, if the patent information is submitted by the 
applicant after approval of an application as provided under paragraph 
(d)(2) of this section, as soon as possible after the submission to the 
agency of the patent information. Patent information submitted by the 
last working day of a month will be published in that month's supplement 
to the list. Patent information received by the Agency between monthly 
publication of supplements to the list will be placed on public display 
in FDA's Division of Freedom of Information. A request for copies of the 
file shall be sent in writing to the Division of Freedom of Information 
(ELEM-1029), Food and Drug Administration, 12420 Parklawn Dr., Element 
Bldg., Rockville, MD 20857.
    (f) Correction of patent information errors. If any person disputes 
the accuracy or relevance of patent information submitted to the agency 
under this section and published by FDA in the list, or believes that an 
applicant has failed to submit required patent information, that person 
must first notify the agency in writing stating the grounds for 
disagreement. Such notification should be directed to the Office of 
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7500 
Standish Pl., Rockville, MD 20855. The agency

[[Page 112]]

will then request of the applicable new drug application holder that the 
correctness of the patent information or omission of patent information 
be confirmed. Unless the application holder withdraws or amends its 
patent information in response to FDA's request, the agency will not 
change the patent information in the list. If the new drug application 
holder does not change the patent information submitted to FDA, a 
505(b)(2) application or an abbreviated new drug application under 
section 505(j) of the act submitted for a drug that is claimed by a 
patent for which information has been submitted must, despite any 
disagreement as to the correctness of the patent information, contain an 
appropriate certification for each listed patent.

[59 FR 50363, Oct. 3, 1994, as amended at 68 FR 36703, June 18, 2003; 69 
FR 13473, Mar. 23, 2004; 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, 
2009; 76 FR 31470, June 1, 2011]



Sec. 314.54  Procedure for submission of an application requiring
investigations for approval of a new indication for, or other change

from, a listed drug.

    (a) The act does not permit approval of an abbreviated new drug 
application for a new indication, nor does it permit approval of other 
changes in a listed drug if investigations, other than bioavailability 
or bioequivalence studies, are essential to the approval of the change. 
Any person seeking approval of a drug product that represents a 
modification of a listed drug (e.g., a new indication or new dosage 
form) and for which investigations, other than bioavailability or 
bioequivalence studies, are essential to the approval of the changes 
may, except as provided in paragraph (b) of this section, submit a 
505(b)(2) application. This application need contain only that 
information needed to support the modification(s) of the listed drug.
    (1) The applicant shall submit a complete archival copy of the 
application that contains the following:
    (i) The information required under Sec. 314.50(a), (b), (c), 
(d)(1), (d)(3), (e), and (g), except that Sec. 314.50(d)(1)(ii)(c) 
shall contain the proposed or actual master production record, including 
a description of the equipment, to be used for the manufacture of a 
commercial lot of the drug product.
    (ii) The information required under Sec. 314.50 (d)(2), (d)(4) (if 
an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support 
the safety and effectiveness of the drug product.
    (iii) Identification of the listed drug for which FDA has made a 
finding of safety and effectiveness and on which finding the applicant 
relies in seeking approval of its proposed drug product by established 
name, if any, proprietary name, dosage form, strength, route of 
administration, name of listed drug's application holder, and listed 
drug's approved application number.
    (iv) If the applicant is seeking approval only for a new indication 
and not for the indications approved for the listed drug on which the 
applicant relies, a certification so stating.
    (v) Any patent information required under section 505(b)(1) of the 
act with respect to any patent which claims the drug for which approval 
is sought or a method of using such drug and to which a claim of patent 
infringement could reasonably be asserted if a person not licensed by 
the owner of the patent engaged in the manufacture, use, or sale of the 
drug product.
    (vi) Any patent certification or statement required under section 
505(b)(2) of the act with respect to any relevant patents that claim the 
listed drug or that claim any other drugs on which investigations relied 
on by the applicant for approval of the application were conducted, or 
that claim a use for the listed or other drug.
    (vii) If the applicant believes the change for which it is seeking 
approval is entitled to a period of exclusivity, the information 
required under Sec. 314.50(j).
    (2) The applicant shall submit a review copy that contains the 
technical sections described in Sec. 314.50(d)(1), except that Sec. 
314.50(d)(1)(ii)(c) shall contain the proposed or actual master 
production record, including a description of the equipment, to be used 
for the manufacture of a commercial lot of the drug product, and 
paragraph (d)(3), and the technical sections described in paragraphs 
(d)(2), (d)(4), (d)(5), (d)(6), and (f) when needed to support the 
modification. Each of the technical

[[Page 113]]

sections in the review copy is required to be separately bound with a 
copy of the information required under Sec. 314.50 (a), (b), and (c) 
and a copy of the proposed labeling.
    (3) The information required by Sec. 314.50 (d)(2), (d)(4) (if an 
anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on 
which the applicant relies shall be satisfied by reference to the listed 
drug under paragraph (a)(1)(iii) of this section.
    (4) The applicant shall submit a field copy of the application that 
contains the technical section described in Sec. 314.50(d)(1), a copy 
of the information required under Sec. 314.50(a) and (c), and 
certification that the field copy is a true copy of the technical 
section described in Sec. 314.50(d)(1) contained in the archival and 
review copies of the application.
    (b) An application may not be submitted under this section for a 
drug product whose only difference from the reference listed drug is 
that:
    (1) The extent to which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is less than that of the 
reference listed drug; or
    (2) The rate at which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is unintentionally less 
than that of the reference listed drug.

[57 FR 17982, Apr. 28, 1992; 57 FR 61612, Dec. 28, 1992, as amended at 
58 FR 47351, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994]



Sec. 314.55  Pediatric use information.

    (a) Required assessment. Except as provided in paragraphs (b), (c), 
and (d) of this section, each application for a new active ingredient, 
new indication, new dosage form, new dosing regimen, or new route of 
administration shall contain data that are adequate to assess the safety 
and effectiveness of the drug product for the claimed indications in all 
relevant pediatric subpopulations, and to support dosing and 
administration for each pediatric subpopulation for which the drug is 
safe and effective. Where the course of the disease and the effects of 
the drug are sufficiently similar in adults and pediatric patients, FDA 
may conclude that pediatric effectiveness can be extrapolated from 
adequate and well-controlled studies in adults usually supplemented with 
other information obtained in pediatric patients, such as 
pharmacokinetic studies. Studies may not be needed in each pediatric age 
group, if data from one age group can be extrapolated to another. 
Assessments of safety and effectiveness required under this section for 
a drug product that represents a meaningful therapeutic benefit over 
existing treatments for pediatric patients must be carried out using 
appropriate formulations for each age group(s) for which the assessment 
is required.
    (b) Deferred submission. (1) FDA may, on its own initiative or at 
the request of an applicant, defer submission of some or all assessments 
of safety and effectiveness described in paragraph (a) of this section 
until after approval of the drug product for use in adults. Deferral may 
be granted if, among other reasons, the drug is ready for approval in 
adults before studies in pediatric patients are complete, or pediatric 
studies should be delayed until additional safety or effectiveness data 
have been collected. If an applicant requests deferred submission, the 
request must provide a certification from the applicant of the grounds 
for delaying pediatric studies, a description of the planned or ongoing 
studies, and evidence that the studies are being or will be conducted 
with due diligence and at the earliest possible time.
    (2) If FDA determines that there is an adequate justification for 
temporarily delaying the submission of assessments of pediatric safety 
and effectiveness, the drug product may be approved for use in adults 
subject to the requirement that the applicant submit the required 
assessments within a specified time.
    (c) Waivers--(1) General. FDA may grant a full or partial waiver of 
the requirements of paragraph (a) of this section on its own initiative 
or at the request of an applicant. A request for a waiver must provide 
an adequate justification.
    (2) Full waiver. An applicant may request a waiver of the 
requirements of paragraph (a) of this section if the applicant certifies 
that:

[[Page 114]]

    (i) The drug product does not represent a meaningful therapeutic 
benefit over existing treatments for pediatric patients and is not 
likely to be used in a substantial number of pediatric patients;
    (ii) Necessary studies are impossible or highly impractical because, 
e.g., the number of such patients is so small or geographically 
dispersed; or
    (iii) There is evidence strongly suggesting that the drug product 
would be ineffective or unsafe in all pediatric age groups.
    (3) Partial waiver. An applicant may request a waiver of the 
requirements of paragraph (a) of this section with respect to a 
specified pediatric age group, if the applicant certifies that:
    (i) The drug product does not represent a meaningful therapeutic 
benefit over existing treatments for pediatric patients in that age 
group, and is not likely to be used in a substantial number of patients 
in that age group;
    (ii) Necessary studies are impossible or highly impractical because, 
e.g., the number of patients in that age group is so small or 
geographically dispersed;
    (iii) There is evidence strongly suggesting that the drug product 
would be ineffective or unsafe in that age group; or
    (iv) The applicant can demonstrate that reasonable attempts to 
produce a pediatric formulation necessary for that age group have 
failed.
    (4) FDA action on waiver. FDA shall grant a full or partial waiver, 
as appropriate, if the agency finds that there is a reasonable basis on 
which to conclude that one or more of the grounds for waiver specified 
in paragraphs (c)(2) or (c)(3) of this section have been met. If a 
waiver is granted on the ground that it is not possible to develop a 
pediatric formulation, the waiver will cover only those pediatric age 
groups requiring that formulation. If a waiver is granted because there 
is evidence that the product would be ineffective or unsafe in pediatric 
populations, this information will be included in the product's 
labeling.
    (5) Definition of ``meaningful therapeutic benefit''. For purposes 
of this section and Sec. 201.23 of this chapter, a drug will be 
considered to offer a meaningful therapeutic benefit over existing 
therapies if FDA estimates that:
    (i) If approved, the drug would represent a significant improvement 
in the treatment, diagnosis, or prevention of a disease, compared to 
marketed products adequately labeled for that use in the relevant 
pediatric population. Examples of how improvement might be demonstrated 
include, for example, evidence of increased effectiveness in treatment, 
prevention, or diagnosis of disease, elimination or substantial 
reduction of a treatment-limiting drug reaction, documented enhancement 
of compliance, or evidence of safety and effectiveness in a new 
subpopulation; or
    (ii) The drug is in a class of drugs or for an indication for which 
there is a need for additional therapeutic options.
    (d) Exemption for orphan drugs. This section does not apply to any 
drug for an indication or indications for which orphan designation has 
been granted under part 316, subpart C, of this chapter.

[63 FR 66670, Dec. 2, 1998]



Sec. 314.60  Amendments to an unapproved application, supplement, or
resubmission.

    (a) FDA generally assumes that when an original application, 
supplement to an approved application, or resubmission of an application 
or supplement is submitted to the agency for review, the applicant 
believes that the agency can approve the application, supplement, or 
resubmission as submitted. However, the applicant may submit an 
amendment to an application that has been filed under Sec. 314.101 but 
is not yet approved.
    (b)(1) Submission of a major amendment to an original application, 
efficacy supplement, or resubmission of an application or efficacy 
supplement within 3 months of the end of the initial review cycle 
constitutes an agreement by the applicant under section 505(c) of the 
act to extend the initial review cycle by 3 months. (For references to a 
resubmission of an application or efficacy supplement in paragraph (b) 
of this section, the timeframe for reviewing the resubmission is the 
``review cycle'' rather than the ``initial

[[Page 115]]

review cycle.'') FDA may instead defer review of the amendment until the 
subsequent review cycle. If the agency extends the initial review cycle 
for an original application, efficacy supplement, or resubmission under 
this paragraph, the division responsible for reviewing the application, 
supplement, or resubmission will notify the applicant of the extension. 
The initial review cycle for an original application, efficacy 
supplement, or resubmission of an application or efficacy supplement may 
be extended only once due to submission of a major amendment. FDA may, 
at its discretion, review any subsequent major amendment during the 
initial review cycle (as extended) or defer review until the subsequent 
review cycle.
    (2) Submission of a major amendment to an original application, 
efficacy supplement, or resubmission of an application or efficacy 
supplement more than 3 months before the end of the initial review cycle 
will not extend the cycle. FDA may, at its discretion, review such an 
amendment during the initial review cycle or defer review until the 
subsequent review cycle.
    (3) Submission of an amendment to an original application, efficacy 
supplement, or resubmission of an application or efficacy supplement 
that is not a major amendment will not extend the initial review cycle. 
FDA may, at its discretion, review such an amendment during the initial 
review cycle or defer review until the subsequent review cycle.
    (4) Submission of a major amendment to a manufacturing supplement 
within 2 months of the end of the initial review cycle constitutes an 
agreement by the applicant under section 505(c) of the act to extend the 
initial review cycle by 2 months. FDA may instead defer review of the 
amendment until the subsequent review cycle. If the agency extends the 
initial review cycle for a manufacturing supplement under this 
paragraph, the division responsible for reviewing the supplement will 
notify the applicant of the extension. The initial review cycle for a 
manufacturing supplement may be extended only once due to submission of 
a major amendment. FDA may, at its discretion, review any subsequent 
major amendment during the initial review cycle (as extended) or defer 
review until the subsequent review cycle.
    (5) Submission of an amendment to a supplement other than an 
efficacy or manufacturing supplement will not extend the initial review 
cycle. FDA may, at its discretion, review such an amendment during the 
initial review cycle or defer review until the subsequent review cycle.
    (6) A major amendment may not include data to support an indication 
or claim that was not included in the original application, supplement, 
or resubmission, but it may include data to support a minor modification 
of an indication or claim that was included in the original application, 
supplement, or resubmission.
    (7) When FDA defers review of an amendment until the subsequent 
review cycle, the agency will notify the applicant of the deferral in 
the complete response letter sent to the applicant under Sec. 314.110 
of this part.
    (c)(1) An unapproved application may not be amended if all of the 
following conditions apply:
    (i) The unapproved application is for a drug for which a previous 
application has been approved and granted a period of exclusivity in 
accordance with section 505(c)(3)(D)(ii) of the act that has not 
expired;
    (ii) The applicant seeks to amend the unapproved application to 
include a published report of an investigation that was conducted or 
sponsored by the applicant entitled to exclusivity for the drug;
    (iii) The applicant has not obtained a right of reference to the 
investigation described in paragraph (c)(1)(ii) of this section; and
    (iv) The report of the investigation described in paragraph 
(c)(1)(ii) of this section would be essential to the approval of the 
unapproved application.
    (2) The submission of an amendment described in paragraph (c)(1) of 
this section will cause the unapproved application to be deemed to be 
withdrawn by the applicant under Sec. 314.65 on the date of receipt by 
FDA of the amendment. The amendment will be considered a resubmission of 
the application, which may not be accepted except as

[[Page 116]]

provided in accordance with section 505(c)(3)(D)(ii) of the act.
    (d) The applicant shall submit a field copy of each amendment to 
Sec. 314.50(d)(1). The applicant shall include in its submission of 
each such amendment to FDA a statement certifying that a field copy of 
the amendment has been sent to the applicant's home FDA district office.

[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17983, Apr. 28, 1992; 58 
FR 47352, Sept. 8, 1993; 63 FR 5252, Feb. 2, 1998; 69 FR 18764, Apr. 8, 
2004; 73 FR 39608, July 10, 2008]



Sec. 314.65  Withdrawal by the applicant of an unapproved application.

    An applicant may at any time withdraw an application that is not yet 
approved by notifying the Food and Drug Administration in writing. If, 
by the time it receives such notice, the agency has identified any 
deficiencies in the application, we will list such deficiencies in the 
letter we send the applicant acknowledging the withdrawal. A decision to 
withdraw the application is without prejudice to refiling. The agency 
will retain the application and will provide a copy to the applicant on 
request under the fee schedule in Sec. 20.45 of FDA's public 
information regulations.

[50 FR 7493, Feb. 22, 1985, as amended at 68 FR 25287, May 12, 2003; 73 
FR 39609, July 10, 2008]



Sec. 314.70  Supplements and other changes to an approved application.

    (a) Changes to an approved application.
    (1)(i) Except as provided in paragraph (a)(1)(ii) of this section, 
the applicant must notify FDA about each change in each condition 
established in an approved application beyond the variations already 
provided for in the application. The notice is required to describe the 
change fully. Depending on the type of change, the applicant must notify 
FDA about the change in a supplement under paragraph (b) or (c) of this 
section or by inclusion of the information in the annual report to the 
application under paragraph (d) of this section.
    (ii) The submission and grant of a written request for an exception 
or alternative under Sec. 201.26 of this chapter satisfies the 
applicable requirements in paragraphs (a) through (c) of this section. 
However, any grant of a request for an exception or alternative under 
Sec. 201.26 of this chapter must be reported as part of the annual 
report to the application under paragraph (d) of this section.
    (2) The holder of an approved application under section 505 of the 
act must assess the effects of the change before distributing a drug 
product made with a manufacturing change.
    (3) Notwithstanding the requirements of paragraphs (b) and (c) of 
this section, an applicant must make a change provided for in those 
paragraphs in accordance with a regulation or guidance that provides for 
a less burdensome notification of the change (for example, by submission 
of a supplement that does not require approval prior to distribution of 
the product or in an annual report).
    (4) The applicant must promptly revise all promotional labeling and 
advertising to make it consistent with any labeling change implemented 
in accordance with paragraphs (b) and (c) of this section.
    (5) Except for a supplement providing for a change in the labeling, 
the applicant must include in each supplement and amendment to a 
supplement providing for a change under paragraph (b) or (c) of this 
section a statement certifying that a field copy has been provided in 
accordance with Sec. 314.440(a)(4).
    (6) A supplement or annual report must include a list of all changes 
contained in the supplement or annual report. For supplements, this list 
must be provided in the cover letter.
    (b) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (1) A 
supplement must be submitted for any change in the drug substance, drug 
product, production process, quality controls, equipment, or facilities 
that has a substantial potential to have an adverse effect on the 
identity, strength, quality, purity, or potency of the drug product as 
these factors may relate to the safety or effectiveness of the drug 
product.
    (2) These changes include, but are not limited to:
    (i) Except those described in paragraphs (c) and (d) of this 
section,

[[Page 117]]

changes in the qualitative or quantitative formulation of the drug 
product, including inactive ingredients, or in the specifications 
provided in the approved application;
    (ii) Changes requiring completion of studies in accordance with part 
320 of this chapter to demonstrate the equivalence of the drug product 
to the drug product as manufactured without the change or to the 
reference listed drug;
    (iii) Changes that may affect drug substance or drug product 
sterility assurance, such as changes in drug substance, drug product, or 
component sterilization method(s) or an addition, deletion, or 
substitution of steps in an aseptic processing operation;
    (iv) Changes in the synthesis or manufacture of the drug substance 
that may affect the impurity profile and/or the physical, chemical, or 
biological properties of the drug substance;
    (v) The following labeling changes:
    (A) Changes in labeling, except those described in paragraphs 
(c)(6)(iii), (d)(2)(ix), or (d)(2)(x) of this section;
    (B) If applicable, any change to a Medication Guide required under 
part 208 of this chapter, except for changes in the information 
specified in Sec. 208.20(b)(8)(iii) and (b)(8)(iv) of this chapter; and
    (C) Any change to the information required by Sec. 201.57(a) of 
this chapter, with the following exceptions that may be reported in an 
annual report under paragraph (d)(2)(x) of this section:
    (1) Removal of a listed section(s) specified in Sec. 201.57(a)(5) 
of this chapter; and
    (2) Changes to the most recent revision date of the labeling as 
specified in Sec. 201.57(a)(15) of this chapter.
    (vi) Changes in a drug product container closure system that 
controls the drug product delivered to a patient or changes in the type 
(e.g., glass to high density polyethylene (HDPE), HDPE to polyvinyl 
chloride, vial to syringe) or composition (e.g., one HDPE resin to 
another HDPE resin) of a packaging component that may affect the 
impurity profile of the drug product.
    (vii) Changes solely affecting a natural product, a recombinant DNA-
derived protein/polypeptide, or a complex or conjugate of a drug 
substance with a monoclonal antibody for the following:
    (A) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (B) Changes in the source material or cell line; and
    (C) Establishment of a new master cell bank or seed.
    (viii) Changes to a drug product under an application that is 
subject to a validity assessment because of significant questions 
regarding the integrity of the data supporting that application.
    (3) The applicant must obtain approval of a supplement from FDA 
prior to distribution of a drug product made using a change under 
paragraph (b) of this section. Except for submissions under paragraph 
(e) of this section, the following information must be contained in the 
supplement:
    (i) A detailed description of the proposed change;
    (ii) The drug product(s) involved;
    (iii) The manufacturing site(s) or area(s) affected;
    (iv) A description of the methods used and studies performed to 
assess the effects of the change;
    (v) The data derived from such studies;
    (vi) For a natural product, a recombinant DNA-derived protein/
polypeptide, or a complex or conjugate of a drug substance with a 
monoclonal antibody, relevant validation protocols and a list of 
relevant standard operating procedures must be provided in addition to 
the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of this section; 
and
    (vii) For sterilization process and test methodologies related to 
sterilization process validation, relevant validation protocols and a 
list of relevant standard operating procedures must be provided in 
addition to the requirements in paragraphs (b)(3)(iv) and (b)(3)(v) of 
this section.
    (4) An applicant may ask FDA to expedite its review of a supplement 
for public health reasons or if a delay in making the change described 
in it would impose an extraordinary hardship on the applicant. Such a 
supplement and its mailing cover should be

[[Page 118]]

plainly marked: ``Prior Approval Supplement-Expedited Review 
Requested.''
    (c) Changes requiring supplement submission at least 30 days prior 
to distribution of the drug product made using the change (moderate 
changes). (1) A supplement must be submitted for any change in the drug 
substance, drug product, production process, quality controls, 
equipment, or facilities that has a moderate potential to have an 
adverse effect on the identity, strength, quality, purity, or potency of 
the drug product as these factors may relate to the safety or 
effectiveness of the drug product. If the supplement provides for a 
labeling change under paragraph (c)(6)(iii) of this section, 12 copies 
of the final printed labeling must be included.
    (2) These changes include, but are not limited to:
    (i) A change in the container closure system that does not affect 
the quality of the drug product, except those described in paragraphs 
(b) and (d) of this section; and
    (ii) Changes solely affecting a natural protein, a recombinant DNA-
derived protein/polypeptide or a complex or conjugate of a drug 
substance with a monoclonal antibody, including:
    (A) An increase or decrease in production scale during finishing 
steps that involves different equipment; and
    (B) Replacement of equipment with that of a different design that 
does not affect the process methodology or process operating parameters.
    (iii) Relaxation of an acceptance criterion or deletion of a test to 
comply with an official compendium that is consistent with FDA statutory 
and regulatory requirements.
    (3) A supplement submitted under paragraph (c)(1) of this section is 
required to give a full explanation of the basis for the change and 
identify the date on which the change is to be made. The supplement must 
be labeled ``Supplement--Changes Being Effected in 30 Days'' or, if 
applicable under paragraph (c)(6) of this section, ``Supplement--Changes 
Being Effected.''
    (4) Pending approval of the supplement by FDA, except as provided in 
paragraph (c)(6) of this section, distribution of the drug product made 
using the change may begin not less than 30 days after receipt of the 
supplement by FDA. The information listed in paragraphs (b)(3)(i) 
through (b)(3)(vii) of this section must be contained in the supplement.
    (5) The applicant must not distribute the drug product made using 
the change if within 30 days following FDA's receipt of the supplement, 
FDA informs the applicant that either:
    (i) The change requires approval prior to distribution of the drug 
product in accordance with paragraph (b) of this section; or
    (ii) Any of the information required under paragraph (c)(4) of this 
section is missing; the applicant must not distribute the drug product 
made using the change until the supplement has been amended to provide 
the missing information.
    (6) The agency may designate a category of changes for the purpose 
of providing that, in the case of a change in such category, the holder 
of an approved application may commence distribution of the drug product 
involved upon receipt by the agency of a supplement for the change. 
These changes include, but are not limited to:
    (i) Addition to a specification or changes in the methods or 
controls to provide increased assurance that the drug substance or drug 
product will have the characteristics of identity, strength, quality, 
purity, or potency that it purports or is represented to possess;
    (ii) A change in the size and/or shape of a container for a 
nonsterile drug product, except for solid dosage forms, without a change 
in the labeled amount of drug product or from one container closure 
system to another;
    (iii) Changes in the labeling to reflect newly acquired information, 
except for changes to the information required in Sec. 201.57(a) of 
this chapter (which must be made under paragraph (b)(2)(v)(C) of this 
section), to accomplish any of the following:
    (A) To add or strengthen a contraindication, warning, precaution, or 
adverse reaction for which the evidence of a causal association 
satisfies the standard for inclusion in the labeling under Sec. 
201.57(c) of this chapter;

[[Page 119]]

    (B) To add or strengthen a statement about drug abuse, dependence, 
psychological effect, or overdosage;
    (C) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the drug 
product;
    (D) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness; or
    (E) Any labeling change normally requiring a supplement submission 
and approval prior to distribution of the drug product that FDA 
specifically requests be submitted under this provision.
    (7) If the agency disapproves the supplemental application, it may 
order the manufacturer to cease distribution of the drug product(s) made 
with the manufacturing change.
    (d) Changes to be described in an annual report (minor changes). (1) 
Changes in the drug substance, drug product, production process, quality 
controls, equipment, or facilities that have a minimal potential to have 
an adverse effect on the identity, strength, quality, purity, or potency 
of the drug product as these factors may relate to the safety or 
effectiveness of the drug product must be documented by the applicant in 
the next annual report in accordance with Sec. 314.81(b)(2).
    (2) These changes include, but are not limited to:
    (i) Any change made to comply with a change to an official 
compendium, except a change described in paragraph (c)(2)(iii) of this 
section, that is consistent with FDA statutory and regulatory 
requirements.
    (ii) The deletion or reduction of an ingredient intended to affect 
only the color of the drug product;
    (iii) Replacement of equipment with that of the same design and 
operating principles except those equipment changes described in 
paragraph (c) of this section;
    (iv) A change in the size and/or shape of a container containing the 
same number of dosage units for a nonsterile solid dosage form drug 
product, without a change from one container closure system to another;
    (v) A change within the container closure system for a nonsterile 
drug product, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (vi) An extension of an expiration dating period based upon full 
shelf life data on production batches obtained from a protocol approved 
in the application;
    (vii) The addition or revision of an alternative analytical 
procedure that provides the same or increased assurance of the identity, 
strength, quality, purity, or potency of the material being tested as 
the analytical procedure described in the approved application, or 
deletion of an alternative analytical procedure;
    (viii) The addition by embossing, debossing, or engraving of a code 
imprint to a solid oral dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint;
    (ix) A change in the labeling concerning the description of the drug 
product or in the information about how the drug product is supplied, 
that does not involve a change in the dosage strength or dosage form; 
and
    (x) An editorial or similar minor change in labeling, including a 
change to the information allowed by paragraphs (b)(2)(v)(C)(1) and (2) 
of this section.
    (3) For changes under this category, the applicant is required to 
submit in the annual report:
    (i) A statement by the holder of the approved application that the 
effects of the change have been assessed;
    (ii) A full description of the manufacturing and controls changes, 
including the manufacturing site(s) or area(s) involved;
    (iii) The date each change was implemented;
    (iv) Data from studies and tests performed to assess the effects of 
the change; and,
    (v) For a natural product, recombinant DNA-derived protein/
polypeptide, complex or conjugate of a drug substance with a monoclonal 
antibody, sterilization process or test methodology related to 
sterilization process validation, a cross-reference to relevant 
validation protocols and/or standard operating procedures.

[[Page 120]]

    (e) Protocols. An applicant may submit one or more protocols 
describing the specific tests and studies and acceptance criteria to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, and 
potency of the drug product as these factors may relate to the safety or 
effectiveness of the drug product. Any such protocols, if not included 
in the approved application, or changes to an approved protocol, must be 
submitted as a supplement requiring approval from FDA prior to 
distribution of a drug product produced with the manufacturing change. 
The supplement, if approved, may subsequently justify a reduced 
reporting category for the particular change because the use of the 
protocol for that type of change reduces the potential risk of an 
adverse effect.
    (f) Patent information. The applicant must comply with the patent 
information requirements under section 505(c)(2) of the act.
    (g) Claimed exclusivity. If an applicant claims exclusivity under 
Sec. 314.108 upon approval of a supplement for change to its previously 
approved drug product, the applicant must include with its supplement 
the information required under Sec. 314.50(j).

[69 FR 18764, Apr. 8, 2004, as amended at 71 FR 3997, Jan. 24, 2006; 72 
FR 73600, Dec. 28, 2007; 73 FR 49609, Aug. 22, 2008]



Sec. 314.71  Procedures for submission of a supplement to an approved
application.

    (a) Only the applicant may submit a supplement to an application.
    (b) All procedures and actions that apply to an application under 
Sec. 314.50 also apply to supplements, except that the information 
required in the supplement is limited to that needed to support the 
change. A supplement is required to contain an archival copy and a 
review copy that include an application form and appropriate technical 
sections, samples, and labeling; except that a supplement for a change 
other than a change in labeling is required also to contain a field 
copy.
    (c) All procedures and actions that apply to applications under this 
part, including actions by applicants and the Food and Drug 
Administration, also apply to supplements except as specified otherwise 
in this part.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 58 
FR 47352, Sept. 8, 1993; 67 FR 9586, Mar. 4, 2002; 73 FR 39609, July 10, 
2008]



Sec. 314.72  Change in ownership of an application.

    (a) An applicant may transfer ownership of its application. At the 
time of transfer the new and former owners are required to submit 
information to the Food and Drug Administration as follows:
    (1) The former owner shall submit a letter or other document that 
states that all rights to the application have been transferred to the 
new owner.
    (2) The new owner shall submit an application form signed by the new 
owner and a letter or other document containing the following:
    (i) The new owner's commitment to agreements, promises, and 
conditions made by the former owner and contained in the application;
    (ii) The date that the change in ownership is effective; and
    (iii) Either a statement that the new owner has a complete copy of 
the approved application, including supplements and records that are 
required to be kept under Sec. 314.81, or a request for a copy of the 
application from FDA's files. FDA will provide a copy of the application 
to the new owner under the fee schedule in Sec. 20.45 of FDA's public 
information regulations.
    (b) The new owner shall advise FDA about any change in the 
conditions in the approved application under Sec. 314.70, except the 
new owner may advise FDA in the next annual report about a change in the 
drug product's label or labeling to change the product's brand or the 
name of its manufacturer, packer, or distributor.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 67 FR 9586, Mar. 4, 2002; 68 FR 25287, May 12, 
2003]



Sec. 314.80  Postmarketing reporting of adverse drug experiences.

    (a) Definitions. The following definitions of terms apply to this 
section:

[[Page 121]]

    Adverse drug experience. Any adverse event associated with the use 
of a drug in humans, whether or not considered drug related, including 
the following: An adverse event occurring in the course of the use of a 
drug product in professional practice; an adverse event occurring from 
drug overdose whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial reporter, 
at immediate risk of death from the adverse drug experience as it 
occurred, i.e., it does not include an adverse drug experience that, had 
it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
    Unexpected adverse drug experience. Any adverse drug experience that 
is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event 
because of greater severity or specificity. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the labeling only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the labeling 
only listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) Review of adverse drug experiences. Each applicant having an 
approved application under Sec. 314.50 or, in the case of a 505(b)(2) 
application, an effective approved application, shall promptly review 
all adverse drug experience information obtained or otherwise received 
by the applicant from any source, foreign or domestic, including 
information derived from commercial marketing experience, postmarketing 
clinical investigations, postmarketing epidemiological/surveillance 
studies, reports in the scientific literature, and unpublished 
scientific papers. Applicants are not required to resubmit to FDA 
adverse drug experience reports forwarded to the applicant by FDA; 
however, applicants must submit all followup information on such reports 
to FDA. Any person subject to the reporting requirements under paragraph 
(c) of this section shall also develop written procedures for the 
surveillance, receipt, evaluation, and reporting of postmarketing 
adverse drug experiences to FDA.
    (c) Reporting requirements. The applicant shall report to FDA 
adverse drug experience information, as described in this section. The 
applicant shall submit two copies of each report described in this 
section to the Central Document Room, 5901-B Ammendale Rd., Beltsville, 
MD 20705-1266. FDA may waive the requirement for the second copy in 
appropriate instances.
    (1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall 
report each adverse drug experience that is both serious and unexpected, 
whether foreign

[[Page 122]]

or domestic, as soon as possible but in no case later than 15 calendar 
days of initial receipt of the information by the applicant.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The applicant 
shall promptly investigate all adverse drug experiences that are the 
subject of these postmarketing 15-day Alert reports and shall submit 
followup reports within 15 calendar days of receipt of new information 
or as requested by FDA. If additional information is not obtainable, 
records should be maintained of the unsuccessful steps taken to seek 
additional information. Postmarketing 15-day Alert reports and followups 
to them shall be submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person other 
than the applicant (nonapplicant) whose name appears on the label of an 
approved drug product as a manufacturer, packer, or distributor. To 
avoid unnecessary duplication in the submission to FDA of reports 
required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, 
obligations of a nonapplicant may be met by submission of all reports of 
serious adverse drug experiences to the applicant. If a nonapplicant 
elects to submit adverse drug experience reports to the applicant rather 
than to FDA, the nonapplicant shall submit each report to the applicant 
within 5 calendar days of receipt of the report by the nonapplicant, and 
the applicant shall then comply with the requirements of this section. 
Under this circumstance, the nonapplicant shall maintain a record of 
this action which shall include:
    (A) A copy of each adverse drug experience report;
    (B) The date the report was received by the nonapplicant;
    (C) The date the report was submitted to the applicant; and
    (D) The name and address of the applicant.
    (iv) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' or ``15-day Alert report-followup.''
    (2) Periodic adverse drug experience reports. (i) The applicant 
shall report each adverse drug experience not reported under paragraph 
(c)(1)(i) of this section at quarterly intervals, for 3 years from the 
date of approval of the application, and then at annual intervals. The 
applicant shall submit each quarterly report within 30 days of the close 
of the quarter (the first quarter beginning on the date of approval of 
the application) and each annual report within 60 days of the 
anniversary date of approval of the application. Upon written notice, 
FDA may extend or reestablish the requirement that an applicant submit 
quarterly reports, or require that the applicant submit reports under 
this section at different times than those stated. For example, the 
agency may reestablish a quarterly reporting requirement following the 
approval of a major supplement. Followup information to adverse drug 
experiences submitted in a periodic report may be submitted in the next 
periodic report.
    (ii) Each periodic report is required to contain: (a) a narrative 
summary and analysis of the information in the report and an analysis of 
the 15-day Alert reports submitted during the reporting interval (all 
15-day Alert reports being appropriately referenced by the applicant's 
patient identification number, adverse reaction term(s), and date of 
submission to FDA); (b) a FDA Form 3500A (Adverse Reaction Report) for 
each adverse drug experience not reported under paragraph (c)(1)(i) of 
this section (with an index consisting of a line listing of the 
applicant's patient identification number and adverse reaction term(s)); 
and (c) a history of actions taken since the last report because of 
adverse drug experiences (for example, labeling changes or studies 
initiated).
    (iii) Periodic reporting, except for information regarding 15-day 
Alert reports, does not apply to adverse drug experience information 
obtained from postmarketing studies (whether or not conducted under an 
investigational new drug application), from reports in the scientific 
literature, and from foreign marketing experience.
    (d) Scientific literature. (1) A 15-day Alert report based on 
information from

[[Page 123]]

the scientific literature is required to be accompanied by a copy of the 
published article. The 15-day reporting requirements in paragraph 
(c)(1)(i) of this section (i.e., serious, unexpected adverse drug 
experiences) apply only to reports found in scientific and medical 
journals either as case reports or as the result of a formal clinical 
trial.
    (2) As with all reports submitted under paragraph (c)(1)(i) of this 
section, reports based on the scientific literature shall be submitted 
on FDA Form 3500A or comparable format as prescribed by paragraph (f) of 
this section. In cases where the applicant believes that preparing the 
FDA Form 3500A constitutes an undue hardship, the applicant may arrange 
with the Office of Surveillance and Epidemiology for an acceptable 
alternative reporting format.
    (e) Postmarketing studies. (1) An applicant is not required to 
submit a 15-day Alert report under paragraph (c) of this section for an 
adverse drug experience obtained from a postmarketing study (whether or 
not conducted under an investigational new drug application) unless the 
applicant concludes that there is a reasonable possibility that the drug 
caused the adverse experience.
    (2) The applicant shall separate and clearly mark reports of adverse 
drug experiences that occur during a postmarketing study as being 
distinct from those experiences that are being reported spontaneously to 
the applicant.
    (f) Reporting FDA Form 3500A. (1) Except as provided in paragraph 
(f)(3) of this section, the applicant shall complete FDA Form 3500A for 
each report of an adverse drug experience (foreign events may be 
submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I 
form).
    (2) Each completed FDA Form 3500A should refer only to an individual 
patient or a single attached publication.
    (3) Instead of using FDA Form 3500A, an applicant may use a 
computer-generated FDA Form 3500A or other alternative format (e.g., a 
computer-generated tape or tabular listing) provided that:
    (i) The content of the alternative format is equivalent in all 
elements of information to those specified in FDA Form 3500A; and
    (ii) The format is agreed to in advance by the Office of 
Surveillance and Epidemiology.
    (4) FDA Form 3500A and instructions for completing the form are 
available on the Internet at http://www.fda.gov/medwatch/index.html.
    (g) Multiple reports. An applicant should not include in reports 
under this section any adverse drug experiences that occurred in 
clinical trials if they were previously submitted as part of the 
approved application. If a report applies to a drug for which an 
applicant holds more than one approved application, the applicant should 
submit the report to the application that was first approved. If a 
report refers to more than one drug marketed by an applicant, the 
applicant should submit the report to the application for the drug 
listed first in the report.
    (h) Patient privacy. An applicant should not include in reports 
under this section the names and addresses of individual patients; 
instead, the applicant should assign a unique code number to each 
report, preferably not more than eight characters in length. The 
applicant should include the name of the reporter from whom the 
information was received. Names of patients, health care professionals, 
hospitals, and geographical identifiers in adverse drug experience 
reports are not releasable to the public under FDA's public information 
regulations in part 20.
    (i) Recordkeeping. The applicant shall maintain for a period of 10 
years records of all adverse drug experiences known to the applicant, 
including raw data and any correspondence relating to adverse drug 
experiences.
    (j) Withdrawal of approval. If an applicant fails to establish and 
maintain records and make reports required under this section, FDA may 
withdraw approval of the application and, thus, prohibit continued 
marketing of the drug product that is the subject of the application.
    (k) Disclaimer. A report or information submitted by an applicant 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the applicant 
or FDA that the report or information constitutes an admission that the 
drug caused or contributed to

[[Page 124]]

an adverse effect. An applicant need not admit, and may deny, that the 
report or information submitted under this section constitutes an 
admission that the drug caused or contributed to an adverse effect. For 
purposes of this provision, the term ``applicant'' also includes any 
person reporting under paragraph (c)(1)(iii) of this section.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 51 FR 24481, July 3, 1986; 52 FR 37936, Oct. 13, 
1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 28, 1992; 62 FR 
34168, June 25, 1997; 62 FR 52251, Oct. 7, 1997; 63 FR 14611, Mar. 26, 
1998; 67 FR 9586, Mar. 4, 2002; 69 FR 13473, Mar. 23, 2004; 74 FR 13113, 
Mar. 26, 2009]



Sec. 314.81  Other postmarketing reports.

    (a) Applicability. Each applicant shall make the reports for each of 
its approved applications and abbreviated applications required under 
this section and section 505(k) of the act.
    (b) Reporting requirements. The applicant shall submit to the Food 
and Drug Administration at the specified times two copies of the 
following reports:
    (1) NDA--Field alert report. The applicant shall submit information 
of the following kinds about distributed drug products and articles to 
the FDA district office that is responsible for the facility involved 
within 3 working days of receipt by the applicant. The information may 
be provided by telephone or other rapid communication means, with prompt 
written followup. The report and its mailing cover should be plainly 
marked: ``NDA--Field Alert Report.''
    (i) Information concerning any incident that causes the drug product 
or its labeling to be mistaken for, or applied to, another article.
    (ii) Information concerning any bacteriological contamination, or 
any significant chemical, physical, or other change or deterioration in 
the distributed drug product, or any failure of one or more distributed 
batches of the drug product to meet the specification established for it 
in the application.
    (2) Annual report. The applicant shall submit each year within 60 
days of the anniversary date of U.S. approval of the application, two 
copies of the report to the FDA division responsible for reviewing the 
application. Each annual report is required to be accompanied by a 
completed transmittal Form FDA 2252 (Transmittal of Periodic Reports for 
Drugs for Human Use), and must include all the information required 
under this section that the applicant received or otherwise obtained 
during the annual reporting interval that ends on the U.S. anniversary 
date. The report is required to contain in the order listed:
    (i) Summary. A brief summary of significant new information from the 
previous year that might affect the safety, effectiveness, or labeling 
of the drug product. The report is also required to contain a brief 
description of actions the applicant has taken or intends to take as a 
result of this new information, for example, submit a labeling 
supplement, add a warning to the labeling, or initiate a new study. The 
summary shall briefly state whether labeling supplements for pediatric 
use have been submitted and whether new studies in the pediatric 
population to support appropriate labeling for the pediatric population 
have been initiated. Where possible, an estimate of patient exposure to 
the drug product, with special reference to the pediatric population 
(neonates, infants, children, and adolescents) shall be provided, 
including dosage form.
    (ii)(a) Distribution data. Information about the quantity of the 
drug product distributed under the approved application, including that 
distributed to distributors. The information is required to include the 
National Drug Code (NDC) number, the total number of dosage units of 
each strength or potency distributed (e.g., 100,000/5 milligram tablets, 
50,000/10 milliliter vials), and the quantities distributed for domestic 
use and the quantities distributed for foreign use. Disclosure of 
financial or pricing data is not required.
    (b) Authorized generic drugs. If applicable, the date each 
authorized generic drug (as defined in Sec. 314.3) entered the market, 
the date each authorized generic drug ceased being distributed, and the 
corresponding trade or brand name. Each dosage form and/or strength is a 
different authorized generic drug and should be listed separately. The 
first annual report submitted on or after January 25, 2010

[[Page 125]]

must include the information listed in this paragraph for any authorized 
generic drug that was marketed during the time period covered by an 
annual report submitted after January 1, 1999. If information is 
included in the annual report with respect to any authorized generic 
drug, a copy of that portion of the annual report must be sent to the 
Food and Drug Administration, Center for Drug Evaluation and Research, 
Office of New Drug Quality Assessment, Bldg. 21, rm. 2562, 10903 New 
Hampshire Ave., Silver Spring, MD 20993-0002, and marked ``Authorized 
Generic Submission'' or, by e-mail, to the Authorized Generics 
electronic mailbox at AuthorizedGenerics@fda.hhs.gov with ``Authorized 
Generic Submission'' indicated in the subject line. However, at such 
time that FDA has required that annual reports be submitted in an 
electronic format, the information required by this paragraph must be 
submitted as part of the annual report, in the electronic format 
specified for submission of annual reports at that time, and not as a 
separate submission under the preceding sentence in this paragraph.
    (iii) Labeling. (a) Currently used professional labeling, patient 
brochures or package inserts (if any), and a representative sample of 
the package labels.
    (b) The content of labeling required under Sec. 201.100(d)(3) of 
this chapter (i.e., the package insert or professional labeling), 
including all text, tables, and figures, must be submitted in electronic 
format. Electronic format submissions must be in a form that FDA can 
process, review, and archive. FDA will periodically issue guidance on 
how to provide the electronic submission (e.g., method of transmission, 
media, file formats, preparation and organization of files). Submissions 
under this paragraph must be made in accordance with part 11 of this 
chapter, except for the requirements of Sec. 11.10(a), (c) through (h), 
and (k), and the corresponding requirements of Sec. 11.30.
    (c) A summary of any changes in labeling that have been made since 
the last report listed by date in the order in which they were 
implemented, or if no changes, a statement of that fact.
    (iv) Chemistry, manufacturing, and controls changes. (a) Reports of 
experiences, investigations, studies, or tests involving chemical or 
physical properties, or any other properties of the drug (such as the 
drug's behavior or properties in relation to microorganisms, including 
both the effects of the drug on microorganisms and the effects of 
microorganisms on the drug). These reports are only required for new 
information that may affect FDA's previous conclusions about the safety 
or effectiveness of the drug product.
    (b) A full description of the manufacturing and controls changes not 
requiring a supplemental application under Sec. 314.70 (b) and (c), 
listed by date in the order in which they were implemented.
    (v) Nonclinical laboratory studies. Copies of unpublished reports 
and summaries of published reports of new toxicological findings in 
animal studies and in vitro studies (e.g., mutagenicity) conducted by, 
or otherwise obtained by, the applicant concerning the ingredients in 
the drug product. The applicant shall submit a copy of a published 
report if requested by FDA.
    (vi) Clinical data. (a) Published clinical trials of the drug (or 
abstracts of them), including clinical trials on safety and 
effectiveness; clinical trials on new uses; biopharmaceutic, 
pharmacokinetic, and clinical pharmacology studies; and reports of 
clinical experience pertinent to safety (for example, epidemiologic 
studies or analyses of experience in a monitored series of patients) 
conducted by or otherwise obtained by the applicant. Review articles, 
papers describing the use of the drug product in medical practice, 
papers and abstracts in which the drug is used as a research tool, 
promotional articles, press clippings, and papers that do not contain 
tabulations or summaries of original data should not be reported.
    (b) Summaries of completed unpublished clinical trials, or 
prepublication manuscripts if available, conducted by, or otherwise 
obtained by, the applicant. Supporting information should not be 
reported. (A study is considered completed 1 year after it is 
concluded.)

[[Page 126]]

    (c) Analysis of available safety and efficacy data in the pediatric 
population and changes proposed in the labeling based on this 
information. An assessment of data needed to ensure appropriate labeling 
for the pediatric population shall be included.
    (vii) Status reports of postmarketing study commitments. A status 
report of each postmarketing study of the drug product concerning 
clinical safety, clinical efficacy, clinical pharmacology, and 
nonclinical toxicology that is required by FDA (e.g., accelerated 
approval clinical benefit studies, pediatric studies) or that the 
applicant has committed, in writing, to conduct either at the time of 
approval of an application for the drug product or a supplement to an 
application, or after approval of the application or a supplement. For 
pediatric studies, the status report shall include a statement 
indicating whether postmarketing clinical studies in pediatric 
populations were required by FDA under Sec. 201.23 of this chapter. The 
status of these postmarketing studies shall be reported annually until 
FDA notifies the applicant, in writing, that the agency concurs with the 
applicant's determination that the study commitment has been fulfilled 
or that the study is either no longer feasible or would no longer 
provide useful information.
    (a) Content of status report. The following information must be 
provided for each postmarketing study reported under this paragraph:
    (1) Applicant's name.
    (2) Product name. Include the approved drug product's established 
name and proprietary name, if any.
    (3) NDA, ANDA, and supplement number.
    (4) Date of U.S. approval of NDA or ANDA.
    (5) Date of postmarketing study commitment.
    (6) Description of postmarketing study commitment. The description 
must include sufficient information to uniquely describe the study. This 
information may include the purpose of the study, the type of study, the 
patient population addressed by the study and the indication(s) and 
dosage(s) that are to be studied.
    (7) Schedule for completion and reporting of the postmarketing study 
commitment. The schedule should include the actual or projected dates 
for submission of the study protocol to FDA, completion of patient 
accrual or initiation of an animal study, completion of the study, 
submission of the final study report to FDA, and any additional 
milestones or submissions for which projected dates were specified as 
part of the commitment. In addition, it should include a revised 
schedule, as appropriate. If the schedule has been previously revised, 
provide both the original schedule and the most recent, previously 
submitted revision.
    (8) Current status of the postmarketing study commitment. The status 
of each postmarketing study should be categorized using one of the 
following terms that describes the study's status on the anniversary 
date of U.S. approval of the application or other agreed upon date:
    (i) Pending. The study has not been initiated, but does not meet the 
criterion for delayed.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(2)(vii)(a)(7) of this 
section.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(2)(vii)(a)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(2)(vii)(a)(8) of this 
section. If the study has been completed, include the date the study was 
completed and the date the final study report was submitted to FDA, as 
applicable. Provide a revised schedule, as well as the reason(s) for the 
revision, if the schedule under paragraph (b)(2)(vii)(a)(7) of this

[[Page 127]]

section has changed since the last report.
    (b) Public disclosure of information. Except for the information 
described in this paragraph, FDA may publicly disclose any information 
described in paragraph (b)(2)(vii) of this section, concerning a 
postmarketing study, if the agency determines that the information is 
necessary to identify the applicant or to establish the status of the 
study, including the reasons, if any, for failure to conduct, complete, 
and report the study. Under this section, FDA will not publicly disclose 
trade secrets, as defined in Sec. 20.61 of this chapter, or 
information, described in Sec. 20.63 of this chapter, the disclosure of 
which would constitute an unwarranted invasion of personal privacy.
    (viii) Status of other postmarketing studies. A status report of any 
postmarketing study not included under paragraph (b)(2)(vii) of this 
section that is being performed by, or on behalf of, the applicant. A 
status report is to be included for any chemistry, manufacturing, and 
controls studies that the applicant has agreed to perform and for all 
product stability studies.
    (ix) Log of outstanding regulatory business. To facilitate 
communications between FDA and the applicant, the report may, at the 
applicant's discretion, also contain a list of any open regulatory 
business with FDA concerning the drug product subject to the application 
(e.g., a list of the applicant's unanswered correspondence with the 
agency, a list of the agency's unanswered correspondence with the 
applicant).
    (3) Other reporting--(i) Advertisements and promotional labeling. 
The applicant shall submit specimens of mailing pieces and any other 
labeling or advertising devised for promotion of the drug product at the 
time of initial dissemination of the labeling and at the time of initial 
publication of the advertisement for a prescription drug product. 
Mailing pieces and labeling that are designed to contain samples of a 
drug product are required to be complete, except the sample of the drug 
product may be omitted. Each submission is required to be accompanied by 
a completed transmittal Form FDA-2253 (Transmittal of Advertisements and 
Promotional Labeling for Drugs for Human Use) and is required to include 
a copy of the product's current professional labeling. Form FDA-2253 is 
available on the Internet at http://www.fda.gov/opacom/morechoices/
fdaforms/cder.html.
    (ii) Special reports. Upon written request the agency may require 
that the applicant submit the reports under this section at different 
times than those stated.
    (iii) Notification of discontinuance. (a) An applicant who is the 
sole manufacturer of an approved drug product must notify FDA in writing 
at least 6 months prior to discontinuance of manufacture of the drug 
product if:
    (1) The drug product is life supporting, life sustaining, or 
intended for use in the prevention of a serious disease or condition; 
and
    (2) The drug product was not originally derived from human tissue 
and replaced by a recombinant product.
    (b) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must be submitted to FDA either electronically or by phone 
according to instructions on FDA's Drug Shortages Web site at: http://
www.fda.gov/Drugs/DrugSafety/DrugShortages.
    (c) FDA will publicly disclose a list of all drug products to be 
discontinued under paragraph (b)(3)(iii)(a) of this section. If the 
notification period is reduced under Sec. 314.91, the list will state 
the reason(s) for such reduction and the anticipated date that 
manufacturing will cease.
    (d) For purposes of this section and Sec. 314.91, the terms 
``discontinuance'' and ``sole manufacturer'' are defined as follows:
    Discontinuance means any interruption in manufacturing of a drug 
product described in paragraph (b)(3)(iii)(a) of this section for sale 
in the United States that could lead to a potential disruption in supply 
of the drug product, whether the interruption is intended to be 
temporary or permanent.
    Sole manufacturer means an applicant that is the only entity 
currently manufacturing a drug product of a specific strength, dosage 
form, or route of administration for sale in the United

[[Page 128]]

States, whether the product is manufactured by the applicant or for the 
applicant under contract with one or more different entities.
    (iv) Withdrawal of approved drug product from sale. (a) The 
applicant shall submit on Form FDA 2657 (Drug Product Listing), within 
15 working days of the withdrawal from sale of a drug product, the 
following information:
    (1) The National Drug Code (NDC) number.
    (2) The identity of the drug product by established name and by 
proprietary name.
    (3) The new drug application or abbreviated application number.
    (4) The date of withdrawal from sale. It is requested but not 
required that the reason for withdrawal of the drug product from sale be 
included with the information.
    (b) The applicant shall submit each Form FDA-2657 to the Records 
Repository Team (HFD-143), Center for Drug Evaluation and Research, Food 
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (c) Reporting under paragraph (b)(3)(iv) of this section constitutes 
compliance with the requirements under Sec. 207.30(a) of this chapter 
to report ``at the discretion of the registrant when the change 
occurs.''
    (c) General requirements--(1) Multiple applications. For all reports 
required by this section, the applicant shall submit the information 
common to more than one application only to the application first 
approved, and shall not report separately on each application. The 
submission is required to identify all the applications to which the 
report applies.
    (2) Patient identification. Applicants should not include in reports 
under this section the names and addresses of individual patients; 
instead, the applicant should code the patient names whenever possible 
and retain the code in the applicant's files. The applicant shall 
maintain sufficient patient identification information to permit FDA, by 
using that information alone or along with records maintained by the 
investigator of a study, to identify the name and address of individual 
patients; this will ordinarily occur only when the agency needs to 
investigate the reports further or when there is reason to believe that 
the reports do not represent actual results obtained.
    (d) Withdrawal of approval. If an applicant fails to make reports 
required under this section, FDA may withdraw approval of the 
application and, thus, prohibit continued marketing of the drug product 
that is the subject of the application.

(Collection of information requirements approved by the Office of 
Management and Budget under control number 0910-0001)

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 
28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 
64617, Oct. 30, 2000; 66 FR 10815, Feb. 20, 2001; 68 FR 69019, Dec. 11, 
2003; 69 FR 18766, Apr. 8, 2004; 69 FR 48775, Aug. 11, 2004; 72 FR 
58999, Oct. 18, 2007; 74 FR 13113, Mar. 26, 2009; 74 FR 37167, July 28, 
2009; 76 FR 78539, Dec. 19, 2011]



Sec. 314.90  Waivers.

    (a) An applicant may ask the Food and Drug Administration to waive 
under this section any requirement that applies to the applicant under 
Sec. Sec. 314.50 through 314.81. An applicant may ask FDA to waive 
under Sec. 314.126(c) any criteria of an adequate and well-controlled 
study described in Sec. 314.126(b). A waiver request under this section 
is required to be submitted with supporting documentation in an 
application, or in an amendment or supplement to an application. The 
waiver request is required to contain one of the following:
    (1) An explanation why the applicant's compliance with the 
requirement is unnecessary or cannot be achieved;
    (2) A description of an alternative submission that satisfies the 
purpose of the requirement; or
    (3) Other information justifying a waiver.
    (b) FDA may grant a waiver if it finds one of the following:
    (1) The applicant's compliance with the requirement is unnecessary 
for the agency to evaluate the application or compliance cannot be 
achieved;
    (2) The applicant's alternative submission satisfies the 
requirement; or

[[Page 129]]

    (3) The applicant's submission otherwise justifies a waiver.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 67 
FR 9586, Mar. 4, 2002]



Sec. 314.91  Obtaining a reduction in the discontinuance notification
period.

    (a) What is the discontinuance notification period? The 
discontinuance notification period is the 6-month period required under 
Sec. 314.81(b)(3)(iii)(a). The discontinuance notification period 
begins when an applicant who is the sole manufacturer of certain 
products notifies FDA that it will discontinue manufacturing the 
product. The discontinuance notification period ends when manufacturing 
ceases.
    (b) When can FDA reduce the discontinuance notification period? FDA 
can reduce the 6-month discontinuance notification period when it finds 
good cause exists for the reduction. FDA may find good cause exists 
based on information certified by an applicant in a request for a 
reduction of the discontinuance notification period. In limited 
circumstances, FDA may find good cause exists based on information 
already known to the agency. These circumstances can include the 
withdrawal of the drug from the market based upon formal FDA regulatory 
action (e.g., under the procedures described in Sec. 314.150 for the 
publication of a notice of opportunity for a hearing describing the 
basis for the proposed withdrawal of a drug from the market) or 
resulting from the applicant's consultations with the agency.
    (c) How can an applicant request a reduction in the discontinuance 
notification period? (1) The applicant must certify in a written request 
that, in its opinion and to the best of its knowledge, good cause exists 
for the reduction. The applicant must submit the following 
certification:
    The undersigned certifies that good cause exists for a reduction in 
the 6-month notification period required in Sec. 314.81(b)(3)(iii)(a) 
for discontinuing the manufacture of (name of the drug product). The 
following circumstances establish good cause (one or more of the 
circumstances in paragraph (d) of this section).
    (2) The certification must be signed by the applicant or the 
applicant's attorney, agent (representative), or other authorized 
official. If the person signing the certification does not reside or 
have a place of business within the United States, the certification 
must contain the name and address of, and must also be signed by, an 
attorney, agent, or other authorized official who resides or maintains a 
place of business within the United States.
    (3) For drugs regulated by the Center for Drug Evaluation and 
Research (CDER) or the Center for Biologics Evaluation and Research 
(CBER), one copy of the certification must be submitted to the Drug 
Shortage Coordinator at the address of the Director of CDER, one copy to 
the CDER Drug Registration and Listing Team, Division of Compliance Risk 
Management and Surveillance in CDER, and one copy to either the director 
of the review division in CDER responsible for reviewing the 
application, or the director of the office in CBER responsible for 
reviewing the application.
    (d) What circumstances and information can establish good cause for 
a reduction in the discontinuance notification period? (1) A public 
health problem may result from continuation of manufacturing for the 6-
month period. This certification must include a detailed description of 
the potential threat to the public health.
    (2) A biomaterials shortage prevents the continuation of the 
manufacturing for the 6-month period. This certification must include a 
detailed description of the steps taken by the applicant in an attempt 
to secure an adequate supply of biomaterials to enable manufacturing to 
continue for the 6-month period and an explanation of why the 
biomaterials could not be secured.
    (3) A liability problem may exist for the manufacturer if the 
manufacturing is continued for the 6-month period. This certification 
must include a detailed description of the potential liability problem.
    (4) Continuation of the manufacturing for the 6-month period may 
cause substantial economic hardship for the manufacturer. This 
certification must include a detailed description of the financial 
impact of continuing to manufacture the drug product over the 6-month 
period.

[[Page 130]]

    (5) The manufacturer has filed for bankruptcy under chapter 7 or 11 
of title 11, United States Code (11 U.S.C. 701 et seq. and 1101 et 
seq.). This certification must be accompanied by documentation of the 
filing or proof that the filing occurred.
    (6) The manufacturer can continue distribution of the drug product 
to satisfy existing market need for 6 months. This certification must 
include a detailed description of the manufacturer's processes to ensure 
such distribution for the 6-month period.
    (7) Other good cause exists for the reduction. This certification 
must include a detailed description of the need for a reduction.

[72 FR 58999, Oct. 18, 2007]



                   Subpart C_Abbreviated Applications

    Source: 57 FR 17983, Apr. 28, 1992, unless otherwise noted.



Sec. 314.92  Drug products for which abbreviated applications may be 
submitted.

    (a) Abbreviated applications are suitable for the following drug 
products within the limits set forth under Sec. 314.93:
    (1) Drug products that are the same as a listed drug. A ``listed 
drug'' is defined in Sec. 314.3. For determining the suitability of an 
abbreviated new drug application, the term ``same as'' means identical 
in active ingredient(s), dosage form, strength, route of administration, 
and conditions of use, except that conditions of use for which approval 
cannot be granted because of exclusivity or an existing patent may be 
omitted. If a listed drug has been voluntarily withdrawn from or not 
offered for sale by its manufacturer, a person who wishes to submit an 
abbreviated new drug application for the drug shall comply with Sec. 
314.122.
    (2) [Reserved]
    (3) Drug products that have been declared suitable for an 
abbreviated new drug application submission by FDA through the petition 
procedures set forth under Sec. 10.30 of this chapter and Sec. 314.93.
    (b) FDA will publish in the list listed drugs for which abbreviated 
applications may be submitted. The list is available from the 
Superintendent of Documents, U.S. Government Printing Office, 
Washington, DC 20402, 202-783-3238.

[57 FR 17983, Apr. 28, 1992, as amended at 64 FR 401, Jan. 5, 1999]



Sec. 314.93  Petition to request a change from a listed drug.

    (a) The only changes from a listed drug for which the agency will 
accept a petition under this section are those changes described in 
paragraph (b) of this section. Petitions to submit abbreviated new drug 
applications for other changes from a listed drug will not be approved.
    (b) A person who wants to submit an abbreviated new drug application 
for a drug product which is not identical to a listed drug in route of 
administration, dosage form, and strength, or in which one active 
ingredient is substituted for one of the active ingredients in a listed 
combination drug, must first obtain permission from FDA to submit such 
an abbreviated application.
    (c) To obtain permission to submit an abbreviated new drug 
application for a change described in paragraph (b) of this section, a 
person must submit and obtain approval of a petition requesting the 
change. A person seeking permission to request such a change from a 
reference listed drug shall submit a petition in accordance with Sec. 
10.20 of this chapter and in the format specified in Sec. 10.30 of this 
chapter. The petition shall contain the information specified in Sec. 
10.30 of this chapter and any additional information required by this 
section. If any provision of Sec. 10.20 or Sec. 10.30 of this chapter 
is inconsistent with any provision of this section, the provisions of 
this section apply.
    (d) The petitioner shall identify a listed drug and include a copy 
of the proposed labeling for the drug product that is the subject of the 
petition and a copy of the approved labeling for the listed drug. The 
petitioner may, under limited circumstances, identify more than one 
listed drug, for example, when the proposed drug product is a 
combination product that differs from the

[[Page 131]]

combination reference listed drug with regard to an active ingredient, 
and the different active ingredient is an active ingredient of a listed 
drug. The petitioner shall also include information to show that:
    (1) The active ingredients of the proposed drug product are of the 
same pharmacological or therapeutic class as those of the reference 
listed drug.
    (2) The drug product can be expected to have the same therapeutic 
effect as the reference listed drug when administered to patients for 
each condition of use in the reference listed drug's labeling for which 
the applicant seeks approval.
    (3) If the proposed drug product is a combination product with one 
different active ingredient, including a different ester or salt, from 
the reference listed drug, that the different active ingredient has 
previously been approved in a listed drug or is a drug that does not 
meet the definition of ``new drug'' in section 201(b) of the act.
    (e) No later than 90 days after the date a petition that is 
permitted under paragraph (a) of this section is submitted, FDA will 
approve or disapprove the petition.
    (1) FDA will approve a petition properly submited under this section 
unless it finds that:
    (i) Investigations must be conducted to show the safety and 
effectiveness of the drug product or of any of its active ingredients, 
its route of administration, dosage form, or strength which differs from 
the reference listed drug; or
    (ii) For a petition that seeks to change an active ingredient, the 
drug product that is the subject of the petition is not a combination 
drug; or
    (iii) For a combination drug product that is the subject of the 
petition and has an active ingredient different from the reference 
listed drug:
    (A) The drug product may not be adequately evaluated for approval as 
safe and effective on the basis of the information required to be 
submitted under Sec. 314.94; or
    (B) The petition does not contain information to show that the 
different active ingredient of the drug product is of the same 
pharmacological or therapeutic class as the ingredient of the reference 
listed drug that is to be changed and that the drug product can be 
expected to have the same therapeutic effect as the reference listed 
drug when administered to patients for each condition of use in the 
listed drug's labeling for which the applicant seeks approval; or
    (C) The different active ingredient is not an active ingredient in a 
listed drug or a drug that meets the requirements of section 201(p) of 
the act; or
    (D) The remaining active ingredients are not identical to those of 
the listed combination drug; or
    (iv) Any of the proposed changes from the listed drug would 
jeopardize the safe or effective use of the product so as to necessitate 
significant labeling changes to address the newly introduced safety or 
effectiveness problem; or
    (v) FDA has determined that the reference listed drug has been 
withdrawn from sale for safety or effectiveness reasons under Sec. 
314.161, or the reference listed drug has been voluntarily withdrawn 
from sale and the agency has not determined whether the withdrawal is 
for safety or effectiveness reasons.
    (2) For purposes of this paragraph, ``investigations must be 
conducted'' means that information derived from animal or clinical 
studies is necessary to show that the drug product is safe or effective. 
Such information may be contained in published or unpublished reports.
    (3) If FDA approves a petition submitted under this section, the 
agency's response may describe what additional information, if any, will 
be required to support an abbreviated new drug application for the drug 
product. FDA may, at any time during the course of its review of an 
abbreviated new drug application, request additional information 
required to evaluate the change approved under the petition.
    (f) FDA may withdraw approval of a petition if the agency receives 
any information demonstrating that the petition no longer satisfies the 
conditions under paragraph (e) of this section.

[[Page 132]]



Sec. 314.94  Content and format of an abbreviated application.

    Abbreviated applications are required to be submitted in the form 
and contain the information required under this section. Three copies of 
the application are required, an archival copy, a review copy, and a 
field copy. FDA will maintain guidance documents on the format and 
content of applications to assist applicants in their preparation.
    (a) Abbreviated new drug applications. Except as provided in 
paragraph (b) of this section, the applicant shall submit a complete 
archival copy of the abbreviated new drug application that includes the 
following:
    (1) Application form. The applicant shall submit a completed and 
signed application form that contains the information described under 
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant shall 
state whether the submission is an abbreviated application under this 
section or a supplement to an abbreviated application under Sec. 
314.97.
    (2) Table of contents. the archival copy of the abbreviated new drug 
application is required to contain a table of contents that shows the 
volume number and page number of the contents of the submission.
    (3) Basis for abbreviated new drug application submission. An 
abbreviated new drug application must refer to a listed drug. 
Ordinarily, that listed drug will be the drug product selected by the 
agency as the reference standard for conducting bioequivalence testing. 
The application shall contain:
    (i) The name of the reference listed drug, including its dosage form 
and strength. For an abbreviated new drug application based on an 
approverd petition under Sec. 10.30 of this chapter or Sec. 314.93, 
the reference listed drug must be the same as the listed drug approved 
in the petition.
    (ii) A statement as to whether, according to the information 
published in the list, the reference listed drug is entitled to a period 
of marketing exclusivity under section 505(j)(4)(D) of the act.
    (iii) For an abbreviated new drug application based on an approved 
petition under Sec. 10.30 of this chapter or Sec. 314.93, a reference 
to FDA-assigned docket number for the petition and a copy of FDA's 
correspondence approving the petition.
    (4) Conditions of use. (i) A statement that the conditions of use 
prescribed, recommended, or suggested in the labeling proposed for the 
drug product have been previously approved for the reference listed 
drug.
    (ii) A reference to the applicant's annotated proposed labeling and 
to the currently approved labeling for the reference listed drug 
provided under paragraph (a)(8) of this section.
    (5) Active ingredients. (i) For a single-active-ingredient drug 
product, information to show that the active ingredient is the same as 
that of the reference single-active-ingredient listed drug, as follows:
    (A) A statement that the active ingredient of the proposed drug 
product is the same as that of the reference listed drug.
    (B) A reference to the applicant's annotated proposed labeling and 
to the currently approved labeling for the reference listed drug 
provided under paragraph (a)(8) of this section.
    (ii) For a combination drug product, information to show that the 
active ingredients are the same as those of the reference listed drug 
except for any different active ingredient that has been the subject of 
an approved petition, as follows:
    (A) A statement that the active ingredients of the proposed drug 
product are the same as those of the reference listed drug, or if one of 
the active ingredients differs from one of the active ingredients of the 
reference listed drug and the abbreviated application is submitted under 
the approval of a petition under Sec. 314.93 to vary such active 
ingredient, information to show that the other active ingredients of the 
drug product are the same as the other active ingredients of the 
reference listed drug, information to show that the different active 
ingredient is an active ingredient of another listed drug or of a drug 
that does not meet the definition of ``new drug'' in section 201(p) of 
the act, and such other information about the different active 
ingredient that FDA may require.
    (B) A reference to the applicant's annotated proposed labeling and 
to the

[[Page 133]]

currently approved labeling for the reference listed drug provided under 
paragraph (a)(8) of this section.
    (6) Route of administration, dosage form, and strength. (i) 
Information to show that the route of administration, dosage form, and 
strength of the drug product are the same as those of the reference 
listed drug except for any differences that have been the subject of an 
approved petition, as follows:
    (A) A statement that the route of administration, dosage form, and 
strength of the proposed drug product are the same as those of the 
reference listed drug.
    (B) A reference to the applicant's annotated proposed labeling and 
to the currently approved labeling for the reference listed drug 
provided under paragraph (a)(8) of this section.
    (ii) If the route of administration, dosage form, or strength of the 
drug product differs from the reference listed drug and the abbreviated 
application is submitted under an approved petition under Sec. 314.93, 
such information about the different route of administration, dosage 
form, or strength that FDA may require.
    (7) Bioequivalence. (i) Information that shows that the drug product 
is bioequivalent to the reference listed drug upon which the applicant 
relies. A complete study report must be submitted for the bioequivalence 
study upon which the applicant relies for approval. For all other 
bioequivalence studies conducted on the same drug product formulation as 
defined in Sec. 320.1(g) of this chapter, the applicant must submit 
either a complete or summary report. If a summary report of a 
bioequivalence study is submitted and FDA determines that there may be 
bioequivalence issues or concerns with the product, FDA may require that 
the applicant submit a complete report of the bioequivalence study to 
FDA; or
    (ii) If the abbreviated new drug application is submitted under a 
petition approved under Sec. 314.93, the results of any bioavailability 
of bioequivalence testing required by the agency, or any other 
information required by the agency to show that the active ingredients 
of the proposed drug product are of the same pharmacological or 
therapeutic class as those in the reference listed drug and that the 
proposed drug product can be expected to have the same therapeutic 
effect as the reference listed drug. If the proposed drug product 
contains a different active ingredient than the reference listed drug, 
FDA will consider the proposed drug product to have the same therapeutic 
effect as the reference listed drug if the applicant provides 
information demonstrating that:
    (A) There is an adequate scientific basis for determining that 
substitution of the specific proposed dose of the different active 
ingredient for the dose of the member of the same pharmacological or 
therapeutic class in the reference listed drug will yield a resulting 
drug product whose safety and effectiveness have not been adversely 
affected.
    (B) The unchanged active ingredients in the proposed drug product 
are bioequivalent to those in the reference listed drug.
    (C) The different active ingredient in the proposed drug product is 
bioequivalent to an approved dosage form containing that ingredient and 
approved for the same indication as the proposed drug product or is 
bioequivalent to a drug product offered for that indication which does 
not meet the definition of ``new drug'' under section 201(p) of the act.
    (iii) For each in vivo bioequivalence study contained in the 
abbreviated new drug application, a description of the analytical and 
statistical methods used in each study and a statement with respect to 
each study that it either was conducted in compliance with the 
institutional review board regulations in part 56 of this chapter, or 
was not subject to the regulations under Sec. 56.104 or Sec. 56.105 of 
this chapter and that each study was conducted in compliance with the 
informed consent regulations in part 50 of this chapter.
    (8) Labeling--(i) Listed drug labeling. A copy of the currently 
approved labeling (including, if applicable, any Medication Guide 
required under part 208 of this chapter) for the listed drug referred to 
in the abbreviated new drug application, if the abbreviated new drug 
application relies on a reference listed drug.

[[Page 134]]

    (ii) Copies of proposed labeling. Copies of the label and all 
labeling for the drug product including, if applicable, any Medication 
Guide required under part 208 of this chapter (4 copies of draft 
labeling or 12 copies of final printed labeling).
    (iii) Statement on proposed labeling. A statement that the 
applicant's proposed labeling including, if applicable, any Medication 
Guide required under part 208 of this chapter is the same as the 
labeling of the reference listed drug except for differences annotated 
and explained under paragraph (a)(8)(iv) of this section.
    (iv) Comparison of approved and proposed labeling. A side-by-side 
comparison of the applicant's proposed labeling including, if 
applicable, any Medication Guide required under part 208 of this chapter 
with the approved labeling for the reference listed drug with all 
differences annotated and explained. Labeling (including the container 
label, package insert, and, if applicable, Medication Guide) proposed 
for the drug product must be the same as the labeling approved for the 
reference listed drug, except for changes required because of 
differences approved under a petition filed under Sec. 314.93 or 
because the drug product and the reference listed drug are produced or 
distributed by different manufacturers. Such differences between the 
applicant's proposed labeling and labeling approved for the reference 
listed drug may include differences in expiration date, formulation, 
bioavailability, or pharmacokinetics, labeling revisions made to comply 
with current FDA labeling guidelines or other guidance, or omission of 
an indication or other aspect of labeling protected by patent or 
accorded exclusivity under section 505(j)(5)(F) of the act.
    (9) Chemistry, manufacturing, and controls. (i) The information 
required under Sec. 314.50(d)(1), except that Sec. 314.50(d)(1)(ii)(c) 
shall contain the proposed or actual master production record, including 
a description of the equipment, to be used for the manufacture of a 
commercial lot of the drug product.
    (ii) Inactive ingredients. Unless otherwise stated in paragraphs 
(a)(9)(iii) through (a)(9)(v) of this section, an applicant shall 
identify and characterize the inactive ingredients in the proposed drug 
product and provide information demonstrating that such inactive 
ingredients do not affect the safety or efficacy of the proposed drug 
product.
    (iii) Inactive ingredient changes permitted in drug products 
intended for parenteral use. Generally, a drug product intended for 
parenteral use shall contain the same inactive ingredients and in the 
same concentration as the reference listed drug identified by the 
applicant under paragraph (a)(3) of this section. However, an applicant 
may seek approval of a drug product that differs from the reference 
listed drug in preservative, buffer, or antioxidant provided that the 
applicant identifies and characterizes the differences and provides 
information demonstrating that the differences do not affect the safety 
or efficacy of the proposed drug product.
    (iv) Inactive ingredient changes permitted in drug products intended 
for ophthalmic or otic use. Generally, a drug product intended for 
ophthalmic or otic use shall contain the same inactive ingredients and 
in the same concentration as the reference listed drug identified by the 
applicant under paragraph (a)(3) of this section. However, an applicant 
may seek approval of a drug product that differs from the reference 
listed drug in preservative, buffer, substance to adjust tonicity, or 
thickening agent provided that the applicant identifies and 
characterizes the differences and provides information demonstrating 
that the differences do not affect the safety or efficacy of the 
proposed drug product, except that, in a product intended for ophthalmic 
use, an applicant may not change a buffer or substance to adjust 
tonicity for the purpose of claiming a therapeutic advantage over or 
difference from the listed drug, e.g., by using a balanced salt solution 
as a diluent as opposed to an isotonic saline solution, or by making a 
significant change in the pH or other change that may raise questions of 
irritability.
    (v) Inactive ingredient changes permitted in drug products intended 
for topical use. Generally, a drug product intended for topical use, 
solutions for

[[Page 135]]

aerosolization or nebulization, and nasal solutions shall contain the 
same inactive ingredients as the reference listed drug identified by the 
applicant under paragraph (a)(3) of this section. However, an 
abbreviated application may include different inactive ingredients 
provided that the applicant identifies and characterizes the differences 
and provides information demonstrating that the differences do not 
affect the safety or efficacy of the proposed drug product.
    (10) Samples. The information required under Sec. 314.50(e)(1) and 
(e)(2)(i). Samples need not be submitted until requested by FDA.
    (11) Other. The information required under Sec. 314.50(g).
    (12) Patent certification--(i) Patents claiming drug, drug product, 
or method of use. (A) Except as provided in paragraph (a)(12)(iv) of 
this section, a certification with respect to each patent issued by the 
United States Patent and Trademark Office that, in the opinion of the 
applicant and to the best of its knowledge, claims the reference listed 
drug or that claims a use of such listed drug for which the applicant is 
seeking approval under section 505(j) of the act and for which 
information is required to be filed under section 505(b) and (c) of the 
act and Sec. 314.53. For each such patent, the applicant shall provide 
the patent number and certify, in its opinion and to the best of its 
knowledge, one of the following circumstances:
    (1) That the patent information has not been submitted to FDA. The 
applicant shall entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant shall entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant shall 
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the abbreviated application is submitted. The applicant shall entitle 
such a certification ``Paragraph IV Certification''. This certification 
shall be submitted in the following form:

    I, (name of applicant), certify that Patent No. ------------ (is 
invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of) (name of proposed drug product) for which this 
application is submitted.


The certification shall be accompanied by a statement that the applicant 
will comply with the requirements under Sec. 314.95(a) with respect to 
providing a notice to each owner of the patent or their representatives 
and to the holder of the approved application for the listed drug, and 
with the requirements under Sec. 314.95(c) with respect to the content 
of the notice.
    (B) If the abbreviated new drug application refers to a listed drug 
that is itself a licensed generic product of a patented drug first 
approved under section 505(b) of the act, the appropriate patent 
certification under paragraph (a)(12)(i) of this section with respect to 
each patent that claims the first-approved patented drug or that claims 
a use for such drug.
    (ii) No relevant patents. If, in the opinion of the applicant and to 
the best of its knowledge, there are no patents described in paragraph 
(a)(12)(i) of this section, a certification in the following form:

    In the opinion and to the best knowledge of (name of applicant), 
there are no patents that claim the listed drug referred to in this 
application or that claim a use of the listed drug.

    (iii) Method of use patent. (A) If patent information is submitted 
under section 505(b) or (c) of the act and Sec. 314.53 for a patent 
claiming a method of using the listed drug, and the labeling for the 
drug product for which the applicant is seeking approval does not 
include any indications that are covered by the use patent, a statement 
explaining that the method of use patent does not claim any of the 
proposed indications.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication that, according to the patent 
information submitted under section 505(b) or (c) of the act and Sec. 
314.53 or in the opinion of the applicant, is claimed by a use patent, 
an applicable certification under paragraph (a)(12)(i) of this section.
    (iv) Method of manufacturing patent. An applicant is not required to 
make a

[[Page 136]]

certification with respect to any patent that claims only a method of 
manufacturing the listed drug.
    (v) Licensing agreements. If the abbreviated new drug application is 
for a drug or method of using a drug claimed by a patent and the 
applicant has a licensing agreement with the patent owner, a 
certification under paragraph (a)(12)(i)(A)(4) of this section 
(``Paragraph IV Certification'') as to that patent and a statement that 
it has been granted a patent license.
    (vi) Late submission of patent information. If a patent on the 
listed drug is issued and the holder of the approved application for the 
listed drug does not submit the required information on the patent 
within 30 days of issuance of the patent, an applicant who submitted an 
abbreviated new drug application for that drug that contained an 
appropriate patent certification before the submission of the patent 
information is not required to submit an amended certification. An 
applicant whose abbreviated new drug application is submitted after a 
late submission of patent information, or whose pending abbreviated 
application was previously submitted but did not contain an appropriate 
patent certification at the time of the patent submission, shall submit 
a certification under paragraph (a)(12)(i) of this section or a 
statement under paragraph (a)(12)(iii) of this section as to that 
patent.
    (vii) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec. 314.53(f). 
Unless the patent information is withdrawn or changed, the applicant 
shall submit an appropriate certification for each relevant patent.
    (viii) Amended certifications. A certification submitted under 
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be 
amended at any time before the effective date of the approval of the 
application. However, an applicant who has submitted a paragraph IV 
patent certification may not change it to a paragraph III certification 
if a patent infringement suit has been filed against another paragraph 
IV applicant unless the agency has determined that no applicant is 
entitled to 180-day exclusivity or the patent expires before the lawsuit 
is resolved or expires after the suit is resolved but before the end of 
the 180-day exclusivity period. If an applicant with a pending 
application voluntarily makes a patent certification for an untimely 
filed patent, the applicant may withdraw the patent certification for 
the untimely filed patent. An applicant shall submit an amended 
certification by letter or as an amendment to a pending application or 
by letter to an approved application. Once an amendment or letter is 
submitted, the application will no longer be considered to contain the 
prior certification.
    (A) After finding of infringement. An applicant who has submitted a 
certification under paragraph (a)(12)(i)(A)(4) of this section and is 
sued for patent infringement within 45 days of the receipt of notice 
sent under Sec. 314.95 shall amend the certification if a final 
judgment in the action against the applicant is entered finding the 
patent to be infringed. In the amended certification, the applicant 
shall certify under paragraph (a)(12)(i)(A)(3) of this section that the 
patent will expire on a specific date. Once an amendment or letter for 
the change has been submitted, the application will no longer be 
considered to be one containing a certification under paragraph 
(a)(12)(i)(A)(4) of this section. If a final judgment finds the patent 
to be invalid and infringed, an amended certification is not required.
    (B) After removal of a patent from the list. If a patent is removed 
from the list, any applicant with a pending application (including a 
tentatively approved application with a delayed effective date) who has 
made a certification with respect to such patent shall amend its 
certification. The applicant shall certify under paragraph (a)(12)(ii) 
of this section that no patents described in paragraph (a)(12)(i) of 
this section claim the drug or, if other relevant patents claim the 
drug, shall amend the certification to refer only to those relevant 
patents. In the amendment, the applicant shall state the reason for the 
change in certification (that the patent is or has been removed

[[Page 137]]

from the list). A patent that is the subject of a lawsuit under Sec. 
314.107(c) shall not be removed from the list until FDA determines 
either that no delay in effective dates of approval is required under 
that section as a result of the lawsuit, that the patent has expired, or 
that any such period of delay in effective dates of approval is ended. 
An applicant shall submit an amended certification. Once an amendment or 
letter for the change has been submitted, the application will no longer 
be considered to be one containing a certification under paragraph 
(a)(12)(i)(A)(4) of this section.
    (C) Other amendments. (1) Except as provided in paragraphs 
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section, an applicant shall 
amend a submitted certification if, at any time before the effective 
date of the approval of the application, the applicant learns that the 
submitted certification is no longer accurate.
    (2) An applicant is not required to amend a submitted certification 
when information on a patent on the listed drug is submitted after the 
effective date of approval of the abbreviated application.
    (13) Financial certification or disclosure statement. An abbreviated 
application shall contain a financial certification or disclosure 
statement as required by part 54 of this chapter.
    (b) Drug products subject to the Drug Efficacy Study Implementation 
(DESI) review. If the abbreviated new drug application is for a 
duplicate of a drug product that is subject to FDA's DESI review (a 
review of drug products approved as safe between 1938 and 1962) or other 
DESI-like review and the drug product evaluated in the review is a 
listed drug, the applicant shall comply with the provisions of paragraph 
(a) of this section.
    (c) [Reserved]
    (d) Format of an abbreviated application. (1) The applicant must 
submit a complete archival copy of the abbreviated application as 
required under paragraphs (a) and (c) of this section. FDA will maintain 
the archival copy during the review of the application to permit 
individual reviewers to refer to information that is not contained in 
their particular technical sections of the application, to give other 
agency personnel access to the application for official business, and to 
maintain in one place a complete copy of the application.
    (i) Format of submission. An applicant may submit portions of the 
archival copy of the abbreviated application in any form that the 
applicant and FDA agree is acceptable, except as provided in paragraph 
(d)(1)(ii) of this section.
    (ii) Labeling. The content of labeling required under Sec. 
201.100(d)(3) of this chapter (commonly referred to as the package 
insert or professional labeling), including all text, tables, and 
figures, must be submitted to the agency in electronic format as 
described in paragraph (d)(1)(iii) of this section. This requirement 
applies to the content of labeling for the proposed drug product only 
and is in addition to the requirements of paragraph (a)(8)(ii) of this 
section that copies of the formatted label and all proposed labeling be 
submitted. Submissions under this paragraph must be made in accordance 
with part 11 of this chapter, except for the requirements of Sec. 
11.10(a), (c) through (h), and (k), and the corresponding requirements 
of Sec. 11.30.
    (iii) Electronic format submissions. Electronic format submissions 
must be in a form that FDA can process, review, and archive. FDA will 
periodically issue guidance on how to provide the electronic submission 
(e.g., method of transmission, media, file formats, preparation and 
organization of files).
    (2) For abbreviated new drug applications, the applicant shall 
submit a review copy of the abbreviated application that contains two 
separate sections. One section shall contain the information described 
under paragraphs (a)(2) through (a)(6), (a)(8), and (a)(9) of this 
section 505(j)(2)(A)(vii) of the act and one copy of the analytical 
procedures and descriptive information needed by FDA's laboratories to 
perform tests on samples of the proposed drug product and to validate 
the applicant's analytical procedures. The other section shall contain 
the information described under paragraphs (a)(3), (a)(7), and (a)(8) of 
this section. Each of the sections in the review copy is required to 
contain a copy of the application form described under Sec. 314.50(a).

[[Page 138]]

    (3) [Reserved]
    (4) The applicant may obtain from FDA sufficient folders to bind the 
archival, the review, and the field copies of the abbreviated 
application.
    (5) The applicant shall submit a field copy of the abbreviated 
application that contains the technical section described in paragraph 
(a)(9) of this section, a copy of the application form required under 
paragraph (a)(1) of this section, and a certification that the field 
copy is a true copy of the technical section described in paragraph 
(a)(9) of this section contained in the archival and review copies of 
the abbreviated application.

[57 FR 17983, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 
FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2, 
1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 56479, 
Sept. 19, 2000; 67 FR 77672, Dec. 19, 2002; 68 FR 69019, Dec. 11, 2003; 
69 FR 18766, Apr. 8, 2004; 74 FR 2861, Jan. 16, 2009; 76 FR 13880, Mar. 
15, 2011]



Sec. 314.95  Notice of certification of invalidity or noninfringement 
of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or that claims a use for such listed drug for which the applicant 
is seeking approval and that the applicant certifies under Sec. 
314.94(a)(12) is invalid, unenforceable, or will not be infringed, the 
applicant shall send notice of such certification by registered or 
certified mail, return receipt requested to each of the following 
persons:
    (1) Each owner of the patent which is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the United States Patent and 
Trademark Office; and
    (2) The holder of the approved application under section 505(b) of 
the act for the listed drug that is claimed by the patent and for which 
the applicant is seeking approval, or, if the application holder does 
not reside or maintain a place of business within the United States, the 
application holder's attorney, agent, or other authorized official. The 
name and address of the application holder or its attorney, agent, or 
authorized official may be obtained from the Orange Book Staff, Office 
of Generic Drugs, 7500 Standish Pl., Rockville, MD 20855.
    (3) This paragraph does not apply to a use patent that claims no 
uses for which the applicant is seeking approval.
    (b) Sending the notice. The applicant shall send the notice required 
by paragraph (a) of this section when it receives from FDA an 
acknowledgment letter stating that its abbreviated new drug application 
is sufficiently complete to permit a substantive review. At the same 
time, the applicant shall amend its abbreviated new drug application to 
include a statement certifying that the notice has been provided to each 
person identified under paragraph (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, the applicant shall cite 
section 505(j)(2)(B)(ii) of the act and shall include, but not be 
limited to, the following information:
    (1) A statement that FDA has received an abbreviated new drug 
application submitted by the applicant containing any required 
bioavailability or bioequivalence data or information.
    (2) The abbreviated application number.
    (3) The established name, if any, as defined in section 502(e)(3) of 
the act, of the proposed drug product.
    (4) The active ingredient, strength, and dosage form of the proposed 
drug product.
    (5) The patent number and expiration date, as submitted to the 
agency or as known to the applicant, of each patent alleged to be 
invalid, unenforceable, or not infringed.
    (6) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or will 
not be infringed. The applicant shall include in the detailed statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds supporting 
the allegation.

[[Page 139]]

    (7) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United States 
authorized to accept service of process for the applicant.
    (d) Amendment to an abbreviated application. If an abbreviated 
application is amended to include the certification described in Sec. 
314.94(a)(12)(i)(A)(4), the applicant shall send the notice required by 
paragraph (a) of this section at the same time that the amendment to the 
abbreviated application is submitted to FDA.
    (e) Documentation of receipt of notice. The applicant shall amend 
its abbreviated application to document receipt of the notice required 
under paragraph (a) of this section by each person provided the notice. 
The applicant shall include a copy of the return receipt or other 
similar evidence of the date the notification was received. FDA will 
accept as adequate documentation of the date of receipt a return receipt 
or a letter acknowledging receipt by the person provided the notice. An 
applicant may rely on another form of documentation only if FDA has 
agreed to such documentation in advance. A copy of the notice itself 
need not be submitted to the agency.
    (f) Approval. If the requirements of this section are met, FDA will 
presume the notice to be complete and sufficient, and it will count the 
day following the date of receipt of the notice by the patent owner or 
its representative and by the approved application holder as the first 
day of the 45-day period provided for in section 505(j)(4)(B)(iii) of 
the act. FDA may, if the applicant provides a written statement to FDA 
that a later date should be used, count from such later date.

[59 FR 50366, Oct. 3, 1994, as amended at 68 FR 36705, June 18, 2003; 69 
FR 11310, Mar. 10, 2004; 74 FR 9766, Mar. 6, 2009; 74 FR 36605, July 24, 
2009]



Sec. 314.96  Amendments to an unapproved abbreviated application.

    (a) Abbreviated new drug application. (1) An applicant may amend an 
abbreviated new drug application that is submitted under Sec. 314.94, 
but not yet approved, to revise existing information or provide 
additional information. Amendments containing bioequivalence studies 
must contain reports of all bioequivalence studies conducted by the 
applicant on the same drug product formulation, unless the information 
has previously been submitted to FDA in the abbreviated new drug 
application. A complete study report must be submitted for any 
bioequivalence study upon which the applicant relies for approval. For 
all other bioequivalence studies conducted on the same drug product 
formulation as defined in Sec. 320.1(g) of this chapter, the applicant 
must submit either a complete or summary report. If a summary report of 
a bioequivalence study is submitted and FDA determines that there may be 
bioequivalence issues or concerns with the product, FDA may require that 
the applicant submit a complete report of the bioequivalence study to 
FDA.
    (2) Submission of an amendment containing significant data or 
information before the end of the initial review cycle constitutes an 
agreement between FDA and the applicant to extend the initial review 
cycle only for the time necessary to review the significant data or 
information and for no more than 180 days.
    (b) The applicant shall submit a field copy of each amendment to 
Sec. 314.94(a)(9). The applicant, other than a foreign applicant, shall 
include in its submission of each such amendment to FDA a statement 
certifying that a field copy of the amendment has been sent to the 
applicant's home FDA district office.

[57 FR 17983, Apr. 28, 1992, as amended at 58 FR 47352, Sept. 8, 1993; 
64 FR 401, Jan. 5, 1999; 73 FR 39609, July 10, 2008; 74 FR 2861, Jan. 
16, 2009]



Sec. 314.97  Supplements and other changes to an approved abbreviated
application.

    The applicant shall comply with the requirements of Sec. Sec. 
314.70 and 314.71 regarding the submission of supplemental applications 
and other changes to an approved abbreviated application.



Sec. 314.98  Postmarketing reports.

    (a) Except as provided in paragraph (b) of this section, each 
applicant having an approved abbreviated new drug

[[Page 140]]

application under Sec. 314.94 that is effective shall comply with the 
requirements of Sec. 314.80 regarding the reporting and recordkeeping 
of adverse drug experiences.
    (b) Each applicant shall submit one copy of each report required 
under Sec. 314.80 to the Central Document Room, Center for Drug 
Evaluation and Research, Food and Drug Administration, 5901-B Ammendale 
Rd., Beltsville, MD 20705-1266.
    (c) Each applicant shall make the reports required under Sec. 
314.81 and section 505(k) of the act for each of its approved 
abbreviated applications.

[57 FR 17983, Apr. 28, 1992, as amended at 64 FR 401, Jan. 5, 1999; 74 
FR 13113, Mar. 26, 2009]



Sec. 314.99  Other responsibilities of an applicant of an abbreviated
application.

    (a) An applicant shall comply with the requirements of Sec. 314.65 
regarding withdrawal by the applicant of an unapproved abbreviated 
application and Sec. 314.72 regarding a change in ownership of an 
abbreviated application.
    (b) An applicant may ask FDA to waive under this section any 
requirement that applies to the applicant under Sec. Sec. 314.92 
through 314.99. The applicant shall comply with the requirements for a 
waiver under Sec. 314.90.



    Subpart D_FDA Action on Applications and Abbreviated Applications

    Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. 
Redesignated at 57 FR 17983, Apr. 28, 1992.



Sec. 314.100  Timeframes for reviewing applications and abbreviated 
applications.

    (a) Except as provided in paragraph (c) of this section, within 180 
days of receipt of an application for a new drug under section 505(b) of 
the act or an abbreviated application for a new drug under section 
505(j) of the act, FDA will review it and send the applicant either an 
approval letter under Sec. 314.105 or a complete response letter under 
Sec. 314.110. This 180-day period is called the ``initial review 
cycle.''
    (b) At any time before approval, an applicant may withdraw an 
application under Sec. 314.65 or an abbreviated application under Sec. 
314.99 and later submit it again for consideration.
    (c) The initial review cycle may be adjusted by mutual agreement 
between FDA and an applicant or as provided in Sec. Sec. 314.60 and 
314.96, as the result of a major amendment.

[73 FR 39609, July 10, 2008]



Sec. 314.101  Filing an application and receiving an abbreviated new
drug application.

    (a)(1) Within 60 days after FDA receives an application, the agency 
will determine whether the application may be filed. The filing of an 
application means that FDA has made a threshold determination that the 
application is sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for refusing to file the application apply, the agency 
will file the application and notify the applicant in writing. The date 
of filing will be the date 60 days after the date FDA received the 
application. The date of filing begins the 180-day period described in 
section 505(c) of the act. This 180-day period is called the ``filing 
clock.''
    (3) If FDA refuses to file the application, the agency will notify 
the applicant in writing and state the reason under paragraph (d) or (e) 
of this section for the refusal. If FDA refuses to file the application 
under paragraph (d) of this section, the applicant may request in 
writing within 30 days of the date of the agency's notification an 
informal conference with the agency about whether the agency should file 
the application. If, following the informal conference, the applicant 
requests that FDA file the application (with or without amendments to 
correct the deficiencies), the agency will file the application over 
protest under paragraph (a)(2) of this section, notify the applicant in 
writing, and review it as filed. If the application is filed over 
protest, the date of filing will be the date 60 days after the date the 
applicant requested the informal conference. The applicant need not 
resubmit a copy of

[[Page 141]]

an application that is filed over protest. If FDA refuses to file the 
application under paragraph (e) of this section, the applicant may amend 
the application and resubmit it, and the agency will make a 
determination under this section whether it may be filed.
    (b)(1) An abbreviated new drug application will be reviewed after it 
is submitted to determine whether the abbreviated application may be 
received. Receipt of an abbreviated new drug application means that FDA 
has made a threshold determination that the abbreviated application is 
sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for considering the abbreviated new drug application not 
to have been received applies, the agency will receive the abbreviated 
new drug application and notify the applicant in writing.
    (3) If FDA considers the abbreviated new drug application not to 
have been received under paragraph (d) or (e) of this section, FDA will 
notify the applicant, ordinarily by telephone. The applicant may then:
    (i) Withdraw the abbreviated new drug application under Sec. 
314.99; or
    (ii) Amend the abbreviated new drug application to correct the 
deficiencies; or
    (iii) Take no action, in which case FDA will refuse to receive the 
abbreviated new drug application.
    (c) [Reserved]
    (d) FDA may refuse to file an application or may not consider an 
abbreviated new drug application to be received if any of the following 
applies:
    (1) The application does not contain a completed application form.
    (2) The application is not submitted in the form required under 
Sec. 314.50 or Sec. 314.94.
    (3) The application or abbreviated application is incomplete because 
it does not on its face contain information required under section 
505(b), section 505(j), or section 507 of the act and Sec. 314.50 or 
Sec. 314.94.
    (4) The applicant fails to submit a complete environmental 
assessment, which addresses each of the items specified in the 
applicable format under Sec. 25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is subject 
to categorical exclusion under Sec. 25.30 or Sec. 25.31 of this 
chapter.
    (5) The application or abbreviated application does not contain an 
accurate and complete English translation of each part of the 
application that is not in English.
    (6) The application does not contain a statement for each 
nonclinical laboratory study that it was conducted in compliance with 
the requirements set forth in part 58 of this chapter, or, for each 
study not conducted in compliance with part 58 of this chapter, a brief 
statement of the reason for the noncompliance.
    (7) The application does not contain a statement for each clinical 
study that it was conducted in compliance with the institutional review 
board regulations in part 56 of this chapter, or was not subject to 
those regulations, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter, or, if the 
study was subject to but was not conducted in compliance with those 
regulations, the application does not contain a brief statement of the 
reason for the noncompliance.
    (8) The drug product that is the subject of the submission is 
already covered by an approved application or abbreviated application 
and the applicant of the submission:
    (i) Has an approved application or abbreviated application for the 
same drug product; or
    (ii) Is merely a distributor and/or repackager of the already 
approved drug product.
    (9) The application is submitted as a 505(b)(2) application for a 
drug that is a duplicate of a listed drug and is eligible for approval 
under section 505(j) of the act.
    (e) The agency will refuse to file an application or will consider 
an abbreviated new drug application not to have been received if any of 
the following applies:
    (1) The drug product is subject to licensing by FDA under the Public 
Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of this 
chapter.

[[Page 142]]

    (2) In the case of a 505(b)(2) application or an abbreviated new 
drug application, the drug product contains the same active moiety as a 
drug that:
    (i) Was approved after September 24, 1984, in an application under 
section 505(b) of the act, and
    (ii) Is entitled to a 5-year period of exclusivity under section 
505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act and Sec. 314.108(b)(2), 
unless the 5-year exclusivity period has elapsed or unless 4 years of 
the 5-year period have elapsed and the application or abbreviated 
application contains a certification of patent invalidity or 
noninfringement described in Sec. 314.50(i)(1)(i)(A)(4) or Sec. 
314.94(a)(12)(i)(A)(4).
    (f)(1) Within 180 days after the date of filing, plus the period of 
time the review period was extended (if any), FDA will either:
    (i) Approve the application; or
    (ii) Issue a notice of opportunity for a hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an application 
in response to a complete response letter.
    (2) Within 180 days after the date of receipt, plus the period of 
time the review clock was extended (if any), FDA will either approve or 
disapprove the abbreviated new drug application. If FDA disapproves the 
abbreviated new drug application, FDA will issue a notice of opportunity 
for hearing if the applicant asked FDA to provide it an opportunity for 
a hearing on an abbreviated new drug application in response to a 
complete response letter.
    (3) This paragraph does not apply to applications or abbreviated 
applications that have been withdrawn from FDA review by the applicant.

[57 FR 17987, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 59 
FR 50366, Oct. 3, 1994; 62 FR 40599, July 29, 1997; 64 FR 402, Jan. 5, 
1999; 73 FR 39609, July 10, 2008]



Sec. 314.102  Communications between FDA and applicants.

    (a) General principles. During the course of reviewing an 
application or an abbreviated application, FDA shall communicate with 
applicants about scientific, medical, and procedural issues that arise 
during the review process. Such communication may take the form of 
telephone conversations, letters, or meetings, whichever is most 
appropriate to discuss the particular issue at hand. Communications 
shall be appropriately documented in the application in accordance with 
Sec. 10.65 of this chapter. Further details on the procedures for 
communication between FDA and applicants are contained in a staff manual 
guide that is publicly available.
    (b) Notification of easily correctable deficiencies. FDA reviewers 
shall make every reasonable effort to communicate promptly to applicants 
easily correctable deficiencies found in an application or an 
abbreviated application when those deficiencies are discovered, 
particularly deficiencies concerning chemistry, manufacturing, and 
controls issues. The agency will also inform applicants promptly of its 
need for more data or information or for technical changes in the 
application or the abbreviated application needed to facilitate the 
agency's review. This early communication is intended to permit 
applicants to correct such readily identified deficiencies relatively 
early in the review process and to submit an amendment before the review 
period has elapsed. Such early communication would not ordinarily apply 
to major scientific issues, which require consideration of the entire 
pending application or abbreviated application by agency managers as 
well as reviewing staff. Instead, major scientific issues will 
ordinarily be addressed in a complete response letter.
    (c) Ninety-day conference. Approximately 90 days after the agency 
receives the application, FDA will provide applicants with an 
opportunity to meet with agency reviewing officials. The purpose of the 
meeting will be to inform applicants of the general progress and status 
of their applications, and to advise applicants of deficiencies that 
have been identified by that time and that have not already been 
communicated. This meeting will be available on applications for all new 
chemical entities and major new indications of marketed drugs. Such 
meetings will be held at the applicant's option, and may be held by 
telephone if mutually agreed upon. Such meetings

[[Page 143]]

would not ordinarily be held on abbreviated applications because they 
are not submitted for new chemical entities or new indications.
    (d) End-of-review conference. At the conclusion of FDA's review of 
an NDA as designated by the issuance of a complete response letter, FDA 
will provide the applicant with an opportunity to meet with agency 
reviewing officials. The purpose of the meeting will be to discuss what 
further steps need to be taken by the applicant before the application 
can be approved. Requests for such meetings must be directed to the 
director of the division responsible for reviewing the application.
    (e) Other meetings. Other meetings between FDA and applicants may be 
held, with advance notice, to discuss scientific, medical, and other 
issues that arise during the review process. Requests for meetings shall 
be directed to the director of the division responsible for reviewing 
the application or abbreviated application. FDA will make every attempt 
to grant requests for meetings that involve important issues and that 
can be scheduled at mutually convenient times. However, ``drop-in'' 
visits (i.e., an unannounced and unscheduled visit by a company 
representative) are discouraged except for urgent matters, such as to 
discuss an important new safety issue.

[57 FR 17988, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 73 
FR 39609, July 10, 2008]



Sec. 314.103  Dispute resolution.

    (a) General. FDA is committed to resolving differences between 
applicants and FDA reviewing divisions with respect to technical 
requirements for applications or abbreviated applications as quickly and 
amicably as possible through the cooperative exchange of information and 
views.
    (b) Administrative and procedural issues. When administrative or 
procedural disputes arise, the applicant should first attempt to resolve 
the matter with the division responsible for reviewing the application 
or abbreviated application, beginning with the consumer safety officer 
assigned to the application or abbreviated application. If resolution is 
not achieved, the applicant may raise the matter with the person 
designated as ombudsman, whose function shall be to investigate what has 
happened and to facilitate a timely and equitable resolution. 
Appropriate issues to raise with the ombudsman include resolving 
difficulties in scheduling meetings, obtaining timely replies to 
inquiries, and obtaining timely completion of pending reviews. Further 
details on this procedure are contained in a staff manual guide that is 
publicly available under FDA's public information regulations in part 
20.
    (c) Scientific and medical disputes. (1) Because major scientific 
issues are ordinarily communicated to applicants in a complete response 
letter pursuant to Sec. 314.110, the ``end-of-review conference'' 
described in Sec. 314.102(d) will provide a timely forum for discussing 
and resolving, if possible, scientific and medical issues on which the 
applicant disagrees with the agency. In addition, the ``ninety-day 
conference'' described in Sec. 314.102(c) will provide a timely forum 
for discussing and resolving, if possible, issues identified by that 
date.
    (2) When scientific or medical disputes arise at other times during 
the review process, applicants should discuss the matter directly with 
the responsible reviewing officials. If necessary, applicants may 
request a meeting with the appropriate reviewing officials and 
management representatives in order to seek a resolution. Ordinarily, 
such meetings would be held first with the Division Director, then with 
the Office Director, and finally with the Center Director if the matter 
is still unresolved. Requests for such meetings shall be directed to the 
director of the division responsible for reviewing the application or 
abrreviated application. FDA will make every attempt to grant requests 
for meetings that involve important issues and that can be scheduled at 
mutually convenient times.
    (3) In requesting a meeting designed to resolve a scientific or 
medical dispute, applicants may suggest that FDA seek the advice of 
outside experts, in which case FDA may, in its discretion, invite to the 
meeting one or more of its advisory committee members or other 
consultants, as designated by the agency. Applicants may also bring 
their own consultants. For major scientific

[[Page 144]]

and medical policy issues not resolved by informal meetings, FDA may 
refer the matter to one of its standing advisory committees for its 
consideration and recommendations.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 57 
FR 17989, Apr. 28, 1992; 73 FR 39609, July 10, 2008]



Sec. 314.104  Drugs with potential for abuse.

    The Food and Drug Administration will inform the Drug Enforcement 
Administration under section 201(f) of the Controlled Substances Act (21 
U.S.C. 801) when an application or abbreviated application is submitted 
for a drug that appears to have an abuse potential.

[57 FR 17989, Apr. 28, 1992]



Sec. 314.105  Approval of an application and an abbreviated application.

    (a) The Food and Drug Administration will approve an application and 
send the applicant an approval letter if none of the reasons in Sec. 
314.125 for refusing to approve the application applies. An approval 
becomes effective on the date of the issuance of the approval letter, 
except with regard to an approval under section 505(b)(2) of the act 
with a delayed effective date. An approval with a delayed effective date 
is tentative and does not become final until the effective date. A new 
drug product or antibiotic approved under this paragraph may not be 
marketed until an approval is effective.
    (b) FDA will approve an application and issue the applicant an 
approval letter on the basis of draft labeling if the only deficiencies 
in the application concern editorial or similar minor deficiencies in 
the draft labeling. Such approval will be conditioned upon the applicant 
incorporating the specified labeling changes exactly as directed, and 
upon the applicant submitting to FDA a copy of the final printed 
labeling prior to marketing.
    (c) FDA will approve an application after it determines that the 
drug meets the statutory standards for safety and effectiveness, 
manufacturing and controls, and labeling, and an abbreviated application 
after it determines that the drug meets the statutory standards for 
manufacturing and controls, labeling, and, where applicable, 
bioequivalence. While the statutory standards apply to all drugs, the 
many kinds of drugs that are subject to the statutory standards and the 
wide range of uses for those drugs demand flexibility in applying the 
standards. Thus FDA is required to exercise its scientific judgment to 
determine the kind and quantity of data and information an applicant is 
required to provide for a particular drug to meet the statutory 
standards. FDA makes its views on drug products and classes of drugs 
available through guidance documents, recommendations, and other 
statements of policy.
    (d) FDA will approve an abbreviated new drug application and send 
the applicant an approval letter if none of the reasons in Sec. 314.127 
for refusing to approve the abbreviated new drug application applies. 
The approval becomes effective on the date of the issuance of the 
agency's approval letter unless the approval letter provides for a 
delayed effective date. An approval with a delayed effective date is 
tentative and does not become final until the effective date. A new drug 
product approved under this paragraph may not be introduced or delivered 
for introduction into interstate commerce until approval of the 
abbreviated new drug application is effective. Ordinarily, the effective 
date of approval will be stated in the approval letter.

[57 FR 17989, Apr. 28, 1992, as amended at 64 FR 402, Jan. 5, 1999; 65 
FR 56479, Sept. 19, 2000; 73 FR 39609, July 10, 2008]



Sec. 314.106  Foreign data.

    (a) General. The acceptance of foreign data in an application 
generally is governed by Sec. 312.120 of this chapter.
    (b) As sole basis for marketing approval. An application based 
solely on foreign clinical data meeting U.S. criteria for marketing 
approval may be approved if: (1) The foreign data are applicable to the 
U.S. population and U.S. medical practice; (2) the studies have been 
performed by clinical investigators of recognized competence; and (3) 
the data may be considered valid without the need for an on-site 
inspection by FDA or, if FDA considers such an inspection to be 
necessary, FDA is able to validate the data through an on-site 
inspection or other appropriate means.

[[Page 145]]

Failure of an application to meet any of these criteria will result in 
the application not being approvable based on the foreign data alone. 
FDA will apply this policy in a flexible manner according to the nature 
of the drug and the data being considered.
    (c) Consultation between FDA and applicants. Applicants are 
encouraged to meet with agency officials in a ``presubmission'' meeting 
when approval based solely on foreign data will be sought.

[50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11580, Mar. 29, 1990]



Sec. 314.107  Effective date of approval of a 505(b)(2) application or
abbreviated new drug application under section 505(j) of the act.

    (a) General. A drug product may be introduced or delivered for 
introduction into interstate commerce when approval of the application 
or abbreviated application for the drug product becomes effective. 
Except as provided in this section, approval of an application or 
abbreviated application for a drug product becomes effective on the date 
FDA issues an approval letter under Sec. 314.105 for the application or 
abbreviated application.
    (b) Effect of patent on the listed drug. If approval of an 
abbreviated new drug application submitted under section 505(j) of the 
act or of a 505(b)(2) application is granted, that approval will become 
effective in accordance with the following:
    (1) Date of approval letter. Except as provided in paragraphs 
(b)(3), (b)(4), and (c) of this section, approval will become effective 
on the date FDA issues an approval letter under Sec. 314.105 if the 
applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that:
    (i) There are no relevant patents; or
    (ii) The applicant is aware of a relevant patent but the patent 
information required under section 505 (b) or (c) of the act has not 
been submitted to FDA; or
    (iii) The relevant patent has expired; or
    (iv) The relevant patent is invalid, unenforceable, or will not be 
infringed.
    (2) Patent expiration. If the applicant certifies under Sec. 
314.50(i) or Sec. 314.94(a)(12) that the relevant patent will expire on 
a specified date, approval will become effective on the specified date.
    (3) Disposition of patent litigation. (i)(A) Except as provided in 
paragraphs (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this section, if 
the applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) 
that the relevant patent is invalid, unenforceable, or will not be 
infringed, and the patent owner or its representative or the exclusive 
patent licensee brings suit for patent infringement within 45 days of 
receipt by the patent owner of the notice of certification from the 
applicant under Sec. 314.52 or Sec. 314.95, approval may be made 
effective 30 months after the date of the receipt of the notice of 
certification by the patent owner or by the exclusive licensee (or their 
representatives) unless the court has extended or reduced the period 
because of a failure of either the plaintiff or defendant to cooperate 
reasonably in expediting the action; or
    (B) If the patented drug product qualifies for 5 years of exclusive 
marketing under Sec. 314.108(b)(2) and the patent owner or its 
representative or the exclusive patent licensee brings suit for patent 
infringement during the 1-year period beginning 4 years after the date 
the patented drug was approved and within 45 days of receipt by the 
patent owner of the notice of certification, the approval may be made 
effective at the expiration of the 7\1/2\ years from the date of 
approval of the application for the patented drug product.
    (ii) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court issues a final order that the patent 
is invalid, unenforceable, or not infringed, approval may be made 
effective on the date the court enters judgment;
    (iii) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court issues a final order or judgment that 
the patent has been infringed, approval may be made effective on the 
date the court determines that the patent will expire or otherwise 
orders; or
    (iv) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court grants a preliminary injunction 
prohibiting the applicant

[[Page 146]]

from engaging in the commercial manufacture or sale of the drug product 
until the court decides the issues of patent validity and infringement, 
and if the court later decides that the patent is invalid, 
unenforceable, or not infringed, approval may be made effective on the 
date the court enters a final order or judgment that the patent is 
invalid, unenforceable, or not infringed.
    (v) FDA will issue a tentative approval letter when tentative 
approval is appropriate in accordance with paragraph (b)(3) of this 
section. In order for an approval to be made effective under paragraph 
(b)(3) of this section, the applicant must receive an approval letter 
from the agency indicating that the application has received final 
approval. Tentative approval of an application does not constitute 
``approval'' of an application and cannot, absent a final approval 
letter from the agency, result in an effective approval under paragraph 
(b)(3) of this section.
    (4) Multiple certifications. If the applicant has submitted 
certifications under Sec. 314.50(i) or Sec. 314.94(a)(12) for more 
than one patent, the date of approval will be calculated for each 
certification, and the approval will become effective on the last 
applicable date.
    (c) Subsequent abbreviated new drug application submission. (1) If 
an abbreviated new drug application contains a certification that a 
relevant patent is invalid, unenforceable, or will not be infringed and 
the application is for a generic copy of the same listed drug for which 
one or more substantially complete abbreviated new drug applications 
were previously submitted containing a certification that the same 
patent was invalid, unenforceable, or would not be infringed, approval 
of the subsequent abbreviated new drug application will be made 
effective no sooner than 180 days from whichever of the following dates 
is earlier:
    (i) The date the applicant submitting the first application first 
commences commercial marketing of its drug product; or
    (ii) The date of a decision of the court holding the relevant patent 
invalid, unenforceable, or not infringed.
    (2) For purposes of paragraph (c)(1) of this section, the 
``applicant submitting the first application'' is the applicant that 
submits an application that is both substantially complete and contains 
a certification that the patent was invalid, unenforceable, or not 
infringed prior to the submission of any other application for the same 
listed drug that is both substantially complete and contains the same 
certification. A ``substantially complete'' application must contain the 
results of any required bioequivalence studies, or, if applicable, a 
request for a waiver of such studies.
    (3) For purposes of paragraph (c)(1) of this section, if FDA 
concludes that the applicant submitting the first application is not 
actively pursuing approval of its abbreviated application, FDA will make 
the approval of subsequent abbreviated applications immediately 
effective if they are otherwise eligible for an immediately effective 
approval.
    (4) For purposes of paragraph (c)(1)(i) of this section, the 
applicant submitting the first application shall notify FDA of the date 
that it commences commercial marketing of its drug product. Commercial 
marketing commences with the first date of introduction or delivery for 
introduction into interstate commerce outside the control of the 
manufacturer of a drug product, except for investigational use under 
part 312 of this chapter, but does not include transfer of the drug 
product for reasons other than sale within the control of the 
manufacturer or application holder. If an applicant does not promptly 
notify FDA of such date, the effective date of approval shall be deemed 
to be the date of the commencement of first commercial marketing.
    (d) Delay due to exclusivity. The agency will also delay the 
effective date of the approval of an abbreviated new drug application 
under section 505(j) of the act or a 505(b)(2) application if delay is 
required by the exclusivity provisions in Sec. 314.108. When the 
effective date of an application is delayed under both this section and 
Sec. 314.108, the effective date will be the later of the 2 days 
specified under this section and Sec. 314.108.
    (e) Notification of court actions. The applicant shall submit a copy 
of the entry of the order or judgment to the

[[Page 147]]

Office of Generic Drugs (HFD-600), or to the appropriate division in the 
Office of New Drugs within 10 working days of a final judgment.
    (f) Computation of 45-day time clock. (1) The 45-day clock described 
in paragraph (b)(3) of this section begins on the day after the date of 
receipt of the applicant's notice of certification by the patent owner 
or its representative, and by the approved application holder. When the 
45th day falls on Saturday, Sunday, or a Federal holiday, the 45th day 
will be the next day that is not a Saturday, Sunday, or a Federal 
holiday.
    (2) The abbreviated new drug applicant or the 505(b)(2) applicant 
shall notify FDA immediately of the filing of any legal action filed 
within 45 days of receipt of the notice of certification. If the 
applicant submitting the abbreviated new drug application or the 
505(b)(2) application or patent owner or its representative does not 
notify FDA in writing before the expiration of the 45-day time period or 
the completion of the agency's review of the application, whichever 
occurs later, that a legal action for patent infringement was filed 
within 45 days of receipt of the notice of certification, approval of 
the abbreviated new drug application or the 505(b)(2) application will 
be made effective immediately upon expiration of the 45 days or upon 
completion of the agency's review and approval of the application, 
whichever is later. The notification to FDA of the legal action shall 
include:
    (i) The abbreviated new drug application or 505(b)(2) application 
number.
    (ii) The name of the abbreviated new drug or 505(b)(2) application 
applicant.
    (iii) The established name of the drug product or, if no established 
name exists, the name(s) of the active ingredient(s), the drug product's 
strength, and dosage form.
    (iv) A certification that an action for patent infringement 
identified by number, has been filed in an appropriate court on a 
specified date.
    The applicant of an abbreviated new drug application shall send the 
notification to FDA's Office of Generic Drugs (HFD-600). A 505(b)(2) 
applicant shall send the notification to the appropriate division in the 
Office of New Drugs reviewing the application. A patent owner or its 
representative may also notify FDA of the filing of any legal action for 
patent infringement. The notice should contain the information and be 
sent to the offices or divisions described in this paragraph.
    (3) If the patent owner or approved application holder who is an 
exclusive patent licensee waives its opportunity to file a legal action 
for patent infringement within 45 days of a receipt of the notice of 
certification and the patent owner or approved application holder who is 
an exclusive patent licensee submits to FDA a valid waiver before the 45 
days elapse, approval of the abbreviated new drug application or the 
505(b)(2) application will be made effective upon completion of the 
agency's review and approval of the application. FDA will only accept a 
waiver in the following form:

    (Name of patent owner or exclusive patent licensee) has received 
notice from (name of applicant) under (section 505(b)(3) or 505(j)(2)(B) 
of the act) and does not intend to file an action for patent 
infringement against (name of applicant) concerning the drug (name of 
drug) before (date on which 45 days elapses. (Name of patent owner or 
exclusive patent licensee) waives the opportunity provided by (section 
505(c)(3)(C) or 505(j)(B)(iii) of the act) and does not object to FDA's 
approval of (name of applicant)'s (505(b)(2) or abbreviated new drug 
application) for (name of drug) with an immediate effective date on or 
after the date of this letter.

[59 FR 50367, Oct. 3, 1994, as amended at 63 FR 59712, Nov. 5, 1998; 65 
FR 43235, July 13, 2000; 73 FR 39609, July 10, 2008; 74 FR 9766, Mar. 6, 
2009]



Sec. 314.108  New drug product exclusivity.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Active moiety means the molecule or ion, excluding those appended 
portions of the molecule that cause the drug to be an ester, salt 
(including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological action of 
the drug substance.
    Approved under section 505(b) means an application submitted under 
section 505(b) and approved on or after October

[[Page 148]]

10, 1962, or an application that was ``deemed approved'' under section 
107(c)(2) of Pub. L. 87-781.
    Clinical investigation means any experiment other than a 
bioavailability study in which a drug is administered or dispensed to, 
or used on, human subjects.
    Conducted or sponsored by the applicant with regard to an 
investigation means that before or during the investigation, the 
applicant was named in Form FDA-1571 filed with FDA as the sponsor of 
the investigational new drug application under which the investigation 
was conducted, or the applicant or the applicant's predecessor in 
interest, provided substantial support for the investigation. To 
demonstrate ``substantial support,'' an applicant must either provide a 
certified statement from a certified public accountant that the 
applicant provided 50 percent or more of the cost of conducting the 
study or provide an explanation why FDA should consider the applicant to 
have conducted or sponsored the study if the applicant's financial 
contribution to the study is less than 50 percent or the applicant did 
not sponsor the investigational new drug. A predecessor in interest is 
an entity, e.g., a corporation, that the applicant has taken over, 
merged with, or purchased, or from which the applicant has purchased all 
rights to the drug. Purchase of nonexclusive rights to a clinical 
investigation after it is completed is not sufficient to satisfy this 
definition.
    Date of approval means the date on the letter from FDA stating that 
the new drug application is approved, whether or not final printed 
labeling or other materials must yet be submitted as long as approval of 
such labeling or materials is not expressly required. ``Date of 
approval'' refers only to a final approval and not to a tentative 
approval that may become effective at a later date.
    Essential to approval means, with regard to an investigation, that 
there are no other data available that could support approval of the 
application.
    FDA means the Food and Drug Administration.
    New chemical entity means a drug that contains no active moiety that 
has been approved by FDA in any other application submitted under 
section 505(b) of the act.
    New clinical investigation means an investigation in humans the 
results of which have not been relied on by FDA to demonstrate 
substantial evidence of effectiveness of a previously approved drug 
product for any indication or of safety for a new patient population and 
do not duplicate the results of another investigation that was relied on 
by the agency to demonstrate the effectiveness or safety in a new 
patient population of a previously approved drug product. For purposes 
of this section, data from a clinical investigation previously submitted 
for use in the comprehensive evaluation of the safety of a drug product 
but not to support the effectiveness of the drug product would be 
considered new.
    (b) Submission of and effective date of approval of an abbreviated 
new drug application submitted under section 505(j) of the act or a 
505(b)(2) application. (1) [Reserved]
    (2) If a drug product that contains a new chemical entity was 
approved after September 24, 1984, in an application submitted under 
section 505(b) of the act, no person may submit a 505(b)(2) application 
or abbreviated new drug application under section 505(j) of the act for 
a drug product that contains the same active moiety as in the new 
chemical entity for a period of 5 years from the date of approval of the 
first approved new drug application, except that the 505(b)(2) 
application or abbreviated application may be submitted after 4 years if 
it contains a certification of patent invalidity or noninfringement 
described in Sec. 314.50(i)(1)(i)(A)(4) or Sec. 
314.94(a)(12)(i)(A)(4).
    (3) The approval of a 505(b)(2) application or abbreviated 
application described in paragraph (b)(2) of this section will become 
effective as provided in Sec. 314.107(b)(1) or (b)(2), unless the owner 
of a patent that claims the drug, the patent owner's representative, or 
exclusive licensee brings suit for patent infringement against the 
applicant during the 1-year period beginning 48 months after the date of 
approval of the new drug application for the new chemical entity and 
within 45 days after receipt of the notice described at

[[Page 149]]

Sec. 314.52 or Sec. 314.95, in which case, approval of the 505(b)(2) 
application or abbreviated application will be made effective as 
provided in Sec. 314.107(b)(3).
    (4) If an application:
    (i) Was submitted under section 505(b) of the act;
    (ii) Was approved after September 24, 1984;
    (iii) Was for a drug product that contains an active moiety that has 
been previously approved in another application under section 505(b) of 
the act; and
    (iv) Contained reports of new clinical investigations (other than 
bioavailability studies) conducted or sponsored by the applicant that 
were essential to approval of the application, the agency will not make 
effective for a period of 3 years after the date of approval of the 
application the approval of a 505(b)(2) application or an abbreviated 
new drug application for the conditions of approval of the original 
application, or an abbreviated new drug application submitted pursuant 
to an approved petition under section 505(j)(2)(C) of the act that 
relies on the information supporting the conditions of approval of an 
original new drug application.
    (5) If a supplemental application:
    (i) Was approved after September 24, 1984; and
    (ii) Contained reports of new clinical investigations (other than 
bioavailability studies) that were conducted or sponsored by the 
applicant that were essential to approval of the supplemental 
application, the agency will not make effective for a period of 3 years 
after the date of approval of the supplemental application the approval 
of a 505(b)(2) application or an abbreviated new drug application for a 
change, or an abbreviated new drug application submitted pursuant to an 
approved petition under section 505(j)(2)(C) of the act that relies on 
the information supporting a change approved in the supplemental new 
drug application.

[59 FR 50368, Oct. 3, 1994]



Sec. 314.110  Complete response letter to the applicant.

    (a) Complete response letter. FDA will send the applicant a complete 
response letter if the agency determines that we will not approve the 
application or abbreviated application in its present form for one or 
more of the reasons given in Sec. 314.125 or Sec. 314.127, 
respectively.
    (1) Description of specific deficiencies. A complete response letter 
will describe all of the specific deficiencies that the agency has 
identified in an application or abbreviated application, except as 
stated in paragraph (a)(3) of this section.
    (2) Complete review of data. A complete response letter reflects 
FDA's complete review of the data submitted in an original application 
or abbreviated application (or, where appropriate, a resubmission) and 
any amendments that the agency has reviewed. The complete response 
letter will identify any amendments that the agency has not yet 
reviewed.
    (3) Inadequate data. If FDA determines, after an application is 
filed or an abbreviated application is received, that the data submitted 
are inadequate to support approval, the agency might issue a complete 
response letter without first conducting required inspections and/or 
reviewing proposed product labeling.
    (4) Recommendation of actions for approval. When possible, a 
complete response letter will recommend actions that the applicant might 
take to place the application or abbreviated application in condition 
for approval.
    (b) Applicant actions. After receiving a complete response letter, 
the applicant must take one of following actions:
    (1) Resubmission. Resubmit the application or abbreviated 
application, addressing all deficiencies identified in the complete 
response letter.
    (i) A resubmission of an application or efficacy supplement that FDA 
classifies as a Class 1 resubmission constitutes an agreement by the 
applicant to start a new 2-month review cycle beginning on the date FDA 
receives the resubmission.
    (ii) A resubmission of an application or efficacy supplement that 
FDA classifies as a Class 2 resubmission constitutes an agreement by the 
applicant

[[Page 150]]

to start a new 6-month review cycle beginning on the date FDA receives 
the resubmission.
    (iii) A resubmission of an NDA supplement other than an efficacy 
supplement constitutes an agreement by the applicant to start a new 
review cycle the same length as the initial review cycle for the 
supplement (excluding any extension due to a major amendment of the 
initial supplement), beginning on the date FDA receives the 
resubmission.
    (iv) A major resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new 6-month review cycle 
beginning on the date FDA receives the resubmission.
    (v) A minor resubmission of an abbreviated application constitutes 
an agreement by the applicant to start a new review cycle beginning on 
the date FDA receives the resubmission.
    (2) Withdrawal. Withdraw the application or abbreviated application. 
A decision to withdraw an application or abbreviated application is 
without prejudice to a subsequent submission.
    (3) Request opportunity for hearing. Ask the agency to provide the 
applicant an opportunity for a hearing on the question of whether there 
are grounds for denying approval of the application or abbreviated 
application under section 505(d) or (j)(4) of the act, respectively. The 
applicant must submit the request to the Associate Director for Policy, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Silver Spring, MD 20993. Within 60 days of the 
date of the request for an opportunity for a hearing, or within a 
different time period to which FDA and the applicant agree, the agency 
will either approve the application or abbreviated application under 
Sec. 314.105, or refuse to approve the application under Sec. 314.125 
or abbreviated application under Sec. 314.127 and give the applicant 
written notice of an opportunity for a hearing under Sec. 314.200 and 
section 505(c)(1)(B) or (j)(5)(c) of the act on the question of whether 
there are grounds for denying approval of the application or abbreviated 
application under section 505(d) or (j)(4) of the act, respectively.
    (c) Failure to take action. (1) An applicant agrees to extend the 
review period under section 505(c)(1) or (j)(5)(A) of the act until it 
takes any of the actions listed in paragraph (b) of this section. For an 
application or abbreviated application, FDA may consider an applicant's 
failure to take any of such actions within 1 year after issuance of a 
complete response letter to be a request by the applicant to withdraw 
the application, unless the applicant has requested an extension of time 
in which to resubmit the application. FDA will grant any reasonable 
request for such an extension. FDA may consider an applicant's failure 
to resubmit the application within the extended time period or to 
request an additional extension to be a request by the applicant to 
withdraw the application.
    (2) If FDA considers an applicant's failure to take action in 
accordance with paragraph (c)(1) of this section to be a request to 
withdraw the application, the agency will notify the applicant in 
writing. The applicant will have 30 days from the date of the 
notification to explain why the application should not be withdrawn and 
to request an extension of time in which to resubmit the application. 
FDA will grant any reasonable request for an extension. If the applicant 
does not respond to the notification within 30 days, the application 
will be deemed to be withdrawn.

[73 FR 39609, July 10, 2008]



Sec. 314.120  [Reserved]



Sec. 314.122  Submitting an abbreviated application for, or a
505(j)(2)(C) petition that relies on, a listed drug that is no 

longer marketed.

    (a) An abbreviated new drug application that refers to, or a 
petition under section 505(j)(2)(C) of the act and Sec. 314.93 that 
relies on, a listed drug that has been voluntarily withdrawn from sale 
in the United States must be accompanied by a petition seeking a 
determination whether the listed drug was withdrawn for safety or 
effectiveness reasons. The petition must be submitted under Sec. Sec. 
10.25(a) and 10.30 of this chapter and must contain all evidence 
available to the petitioner concerning

[[Page 151]]

the reasons for the withdrawal from sale.
    (b) When a petition described in paragraph (a) of this section is 
submitted, the agency will consider the evidence in the petition and any 
other evidence before the agency, and determine whether the listed drug 
is withdrawn from sale for safety or effectiveness reasons, in 
accordance with the procedures in Sec. 314.161.
    (c) An abbreviated new drug application described in paragraph (a) 
of this section will be disapproved, under Sec. 314.127(a)(11), and a 
505(j)(2)(C) petition described in paragraph (a) of this section will be 
disapproved, under Sec. 314.93(e)(1)(iv), unless the agency determines 
that the withdrawal of the listed drug was not for safety or 
effectiveness reasons.
    (d) Certain drug products approved for safety and effectiveness that 
were no longer marketed on September 24, 1984, are not included in the 
list. Any person who wishes to obtain marketing approval for such a drug 
product under an abbreviated new drug application must petition FDA for 
a determination whether the drug product was withdrawn from the market 
for safety or effectiveness reasons and request that the list be amended 
to include the drug product. A person seeking such a determination shall 
use the petition procedures established in Sec. 10.30 of this chapter. 
The petitioner shall include in the petition information to show that 
the drug product was approved for safety and effectiveness and all 
evidence available to the petitioner concerning the reason that 
marketing of the drug product ceased.

[57 FR 17990, Apr. 28, 1992; 57 FR 29353, July 1, 1992]



Sec. 314.125  Refusal to approve an application.

    (a) The Food and Drug Administration will refuse to approve the 
application and for a new drug give the applicant written notice of an 
opportunity for a hearing under Sec. 314.200 on the question of whether 
there are grounds for denying approval of the application under section 
505(d) of the act, if:
    (1) FDA sends the applicant a complete response letter under Sec. 
314.110;
    (2) The applicant requests an opportunity for hearing for a new drug 
on the question of whether the application is approvable; and
    (3) FDA finds that any of the reasons given in paragraph (b) of this 
section apply.
    (b) FDA may refuse to approve an application for any of the 
following reasons:
    (1) The methods to be used in, and the facilities and controls used 
for, the manufacture, processing, packing, or holding of the drug 
substance or the drug product are inadequate to preserve its identity, 
strength, quality, purity, stability, and bioavailability.
    (2) The investigations required under section 505(b) of the act do 
not include adequate tests by all methods reasonably applicable to show 
whether or not the drug is safe for use under the conditions prescribed, 
recommended, or suggested in its proposed labeling.
    (3) The results of the tests show that the drug is unsafe for use 
under the conditions prescribed, recommended, or suggested in its 
proposed labeling or the results do not show that the drug product is 
safe for use under those conditions.
    (4) There is insufficient information about the drug to determine 
whether the product is safe for use under the conditions prescribed, 
recommended, or suggested in its proposed labeling.
    (5) There is a lack of substantial evidence consisting of adequate 
and well-controlled investigations, as defined in Sec. 314.126, that 
the drug product will have the effect it purports or is represented to 
have under the conditions of use prescribed, recommended, or suggested 
in its proposed labeling.
    (6) The proposed labeling is false or misleading in any particular.
    (7) The application contains an untrue statement of a material fact.
    (8) The drug product's proposed labeling does not comply with the 
requirements for labels and labeling in part 201.
    (9) The application does not contain bioavailability or 
bioequivalence data required under part 320 of this chapter.
    (10) A reason given in a letter refusing to file the application 
under Sec. 314.101(d), if the deficiency is not corrected.

[[Page 152]]

    (11) The drug will be manufactured or processed in whole or in part 
in an establishment that is not registered and not exempt from 
registration under section 510 of the act and part 207.
    (12) The applicant does not permit a properly authorized officer or 
employee of the Department of Health and Human Services an adequate 
opportunity to inspect the facilities, controls, and any records 
relevant to the application.
    (13) The methods to be used in, and the facilities and controls used 
for, the manufacture, processing, packing, or holding of the drug 
substance or the drug product do not comply with the current good 
manufacturing practice regulations in parts 210 and 211.
    (14) The application does not contain an explanation of the omission 
of a report of any investigation of the drug product sponsored by the 
applicant, or an explanation of the omission of other information about 
the drug pertinent to an evaluation of the application that is received 
or otherwise obtained by the applicant from any source.
    (15) A nonclinical laboratory study that is described in the 
application and that is essential to show that the drug is safe for use 
under the conditions prescribed, recommended, or suggested in its 
proposed labeling was not conducted in compliance with the good 
laboratory practice regulations in part 58 of this chapter and no reason 
for the noncompliance is provided or, if it is, the differences between 
the practices used in conducting the study and the good laboratory 
practice regulations do not support the validity of the study.
    (16) Any clinical investigation involving human subjects described 
in the application, subject to the institutional review board 
regulations in part 56 of this chapter or informed consent regulations 
in part 50 of this chapter, was not conducted in compliance with those 
regulations such that the rights or safety of human subjects were not 
adequately protected.
    (17) The applicant or contract research organization that conducted 
a bioavailability or bioequivalence study described in Sec. 320.38 or 
Sec. 320.63 of this chapter that is contained in the application 
refuses to permit an inspection of facilities or records relevant to the 
study by a properly authorized officer or employee of the Department of 
Health and Human Services or refuses to submit reserve samples of the 
drug products used in the study when requested by FDA.
    (18) For a new drug, the application failed to contain the patent 
information required by section 505(b)(1) of the act.
    (c) For drugs intended to treat life-threatening or severely-
debilitating illnesses that are developed in accordance with Sec. Sec. 
312.80 through 312.88 of this chapter, the criteria contained in 
paragraphs (b) (3), (4), and (5) of this section shall be applied 
according to the considerations contained in Sec. 312.84 of this 
chapter.

[50 FR 7493, Feb. 22, 1985, as amended at 53 FR 41524, Oct. 21, 1988; 57 
FR 17991, Apr. 28, 1992; 58 FR 25926, Apr. 28, 1993; 64 FR 402, Jan. 5, 
1999; 73 FR 39610, July 10, 2008; 74 FR 9766, Mar. 6, 2009]



Sec. 314.126  Adequate and well-controlled studies.

    (a) The purpose of conducting clinical investigations of a drug is 
to distinguish the effect of a drug from other influences, such as 
spontaneous change in the course of the disease, placebo effect, or 
biased observation. The characteristics described in paragraph (b) of 
this section have been developed over a period of years and are 
recognized by the scientific community as the essentials of an adequate 
and well-controlled clinical investigation. The Food and Drug 
Administration considers these characteristics in determining whether an 
investigation is adequate and well-controlled for purposes of section 
505 of the act. Reports of adequate and well-controlled investigations 
provide the primary basis for determining whether there is ``substantial 
evidence'' to support the claims of effectiveness for new drugs. 
Therefore, the study report should provide sufficient details of study 
design, conduct, and analysis to allow critical evaluation and a 
determination of whether the characteristics of an adequate and well-
controlled study are present.
    (b) An adequate and well-controlled study has the following 
characteristics:
    (1) There is a clear statement of the objectives of the 
investigation and a

[[Page 153]]

summary of the proposed or actual methods of analysis in the protocol 
for the study and in the report of its results. In addition, the 
protocol should contain a description of the proposed methods of 
analysis, and the study report should contain a description of the 
methods of analysis ultimately used. If the protocol does not contain a 
description of the proposed methods of analysis, the study report should 
describe how the methods used were selected.
    (2) The study uses a design that permits a valid comparison with a 
control to provide a quantitative assessment of drug effect. The 
protocol for the study and report of results should describe the study 
design precisely; for example, duration of treatment periods, whether 
treatments are parallel, sequential, or crossover, and whether the 
sample size is predetermined or based upon some interim analysis. 
Generally, the following types of control are recognized:
    (i) Placebo concurrent control. The test drug is compared with an 
inactive preparation designed to resemble the test drug as far as 
possible. A placebo-controlled study may include additional treatment 
groups, such as an active treatment control or a dose-comparison 
control, and usually includes randomization and blinding of patients or 
investigators, or both.
    (ii) Dose-comparison concurrent control. At least two doses of the 
drug are compared. A dose-comparison study may include additional 
treatment groups, such as placebo control or active control. Dose-
comparison trials usually include randomization and blinding of patients 
or investigators, or both.
    (iii) No treatment concurrent control. Where objective measurements 
of effectiveness are available and placebo effect is negligible, the 
test drug is compared with no treatment. No treatment concurrent control 
trials usually include randomization.
    (iv) Active treatment concurrent control. The test drug is compared 
with known effective therapy; for example, where the condition treated 
is such that administration of placebo or no treatment would be contrary 
to the interest of the patient. An active treatment study may include 
additional treatment groups, however, such as a placebo control or a 
dose-comparison control. Active treatment trials usually include 
randomization and blinding of patients or investigators, or both. If the 
intent of the trial is to show similarity of the test and control drugs, 
the report of the study should assess the ability of the study to have 
detected a difference between treatments. Similarity of test drug and 
active control can mean either that both drugs were effective or that 
neither was effective. The analysis of the study should explain why the 
drugs should be considered effective in the study, for example, by 
reference to results in previous placebo-controlled studies of the 
active control drug.
    (v) Historical control. The results of treatment with the test drug 
are compared with experience historically derived from the adequately 
documented natural history of the disease or condition, or from the 
results of active treatment, in comparable patients or populations. 
Because historical control populations usually cannot be as well 
assessed with respect to pertinent variables as can concurrent control 
populations, historical control designs are usually reserved for special 
circumstances. Examples include studies of diseases with high and 
predictable mortality (for example, certain malignancies) and studies in 
which the effect of the drug is self-evident (general anesthetics, drug 
metabolism).
    (3) The method of selection of subjects provides adequate assurance 
that they have the disease or condition being studied, or evidence of 
susceptibility and exposure to the condition against which prophylaxis 
is directed.
    (4) The method of assigning patients to treatment and control groups 
minimizes bias and is intended to assure comparability of the groups 
with respect to pertinent variables such as age, sex, severity of 
disease, duration of disease, and use of drugs or therapy other than the 
test drug. The protocol for the study and the report of its results 
should describe how subjects were assigned to groups. Ordinarily, in a 
concurrently controlled study, assignment is by randomization, with or 
without stratification.

[[Page 154]]

    (5) Adequate measures are taken to minimize bias on the part of the 
subjects, observers, and analysts of the data. The protocol and report 
of the study should describe the procedures used to accomplish this, 
such as blinding.
    (6) The methods of assessment of subjects' response are well-defined 
and reliable. The protocol for the study and the report of results 
should explain the variables measured, the methods of observation, and 
criteria used to assess response.
    (7) There is an analysis of the results of the study adequate to 
assess the effects of the drug. The report of the study should describe 
the results and the analytic methods used to evaluate them, including 
any appropriate statistical methods. The analysis should assess, among 
other things, the comparability of test and control groups with respect 
to pertinent variables, and the effects of any interim data analyses 
performed.
    (c) The Director of the Center for Drug Evaluation and Research may, 
on the Director's own initiative or on the petition of an interested 
person, waive in whole or in part any of the criteria in paragraph (b) 
of this section with respect to a specific clinical investigation, 
either prior to the investigation or in the evaluation of a completed 
study. A petition for a waiver is required to set forth clearly and 
concisely the specific criteria from which waiver is sought, why the 
criteria are not reasonably applicable to the particular clinical 
investigation, what alternative procedures, if any, are to be, or have 
been employed, and what results have been obtained. The petition is also 
required to state why the clinical investigations so conducted will 
yield, or have yielded, substantial evidence of effectiveness, 
notwithstanding nonconformance with the criteria for which waiver is 
requested.
    (d) For an investigation to be considered adequate for approval of a 
new drug, it is required that the test drug be standardized as to 
identity, strength, quality, purity, and dosage form to give 
significance to the results of the investigation.
    (e) Uncontrolled studies or partially controlled studies are not 
acceptable as the sole basis for the approval of claims of 
effectiveness. Such studies carefully conducted and documented, may 
provide corroborative support of well-controlled studies regarding 
efficacy and may yield valuable data regarding safety of the test drug. 
Such studies will be considered on their merits in the light of the 
principles listed here, with the exception of the requirement for the 
comparison of the treated subjects with controls. Isolated case reports, 
random experience, and reports lacking the details which permit 
scientific evaluation will not be considered.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 
FR 11580, Mar. 29, 1990; 64 FR 402, Jan. 5, 1999; 67 FR 9586, Mar. 4, 
2002]



Sec. 314.127  Refusal to approve an abbreviated new drug application.

    (a) FDA will refuse to approve an abbreviated application for a new 
drug under section 505(j) of the act for any of the following reasons:
    (1) The methods used in, or the facilities and controls used for, 
the manufacture, processing, and packing of the drug product are 
inadequate to ensure and preserve its identity, strength, quality, and 
purity.
    (2) Information submitted with the abbreviated new drug application 
is insufficient to show that each of the proposed conditions of use has 
been previously approved for the listed drug referred to in the 
application.
    (3)(i) If the reference listed drug has only one active ingredient, 
information submitted with the abbreviated new drug application is 
insufficient to show that the active ingredient is the same as that of 
the reference listed drug;
    (ii) If the reference listed drug has more than one active 
ingredient, information submitted with the abbreviated new drug 
application is insufficient to show that the active ingredients are the 
same as the active ingredients of the reference listed drug; or
    (iii) If the reference listed drug has more than one active 
ingredient and if the abbreviated new drug application is for a drug 
product that has an active ingredient different from the reference 
listed drug:

[[Page 155]]

    (A) Information submitted with the abbreviated new drug application 
is insufficient to show:
    (1) That the other active ingredients are the same as the active 
ingredients of the reference listed drug; or
    (2) That the different active ingredient is an active ingredient of 
a listed drug or a drug that does not meet the requirements of section 
201(p) of the act; or
    (B) No petition to submit an abbreviated application for the drug 
product with the different active ingredient was approved under Sec. 
314.93.
    (4)(i) If the abbreviated new drug application is for a drug product 
whose route of administration, dosage form, or strength purports to be 
the same as that of the listed drug referred to in the abbreviated new 
drug application, information submitted in the abbreviated new drug 
application is insufficient to show that the route of administration, 
dosage form, or strength is the same as that of the reference listed 
drug; or
    (ii) If the abbreviated new drug application is for a drug product 
whose route of administration, dosage form, or strength is different 
from that of the listed drug referred to in the application, no petition 
to submit an abbreviated new drug application for the drug product with 
the different route of administration, dosage form, or strength was 
approved under Sec. 314.93.
    (5) If the abbreviated new drug application was submitted under the 
approval of a petition under Sec. 314.93, the abbreviated new drug 
application did not contain the information required by FDA with respect 
to the active ingredient, route of administration, dosage form, or 
strength that is not the same as that of the reference listed drug.
    (6)(i) Information submitted in the abbreviated new drug application 
is insufficient to show that the drug product is bioequivalent to the 
listed drug referred to in the abbreviated new drug application; or
    (ii) If the abbreviated new drug application was submitted under a 
petition approved under Sec. 314.93, information submitted in the 
abbreviated new drug application is insufficient to show that the active 
ingredients of the drug product are of the same pharmacological or 
therapeutic class as those of the reference listed drug and that the 
drug product can be expected to have the same therapeutic effect as the 
reference listed drug when administered to patients for each condition 
of use approved for the reference listed drug.
    (7) Information submitted in the abbreviated new drug application is 
insufficient to show that the labeling proposed for the drug is the same 
as the labeling approved for the listed drug referred to in the 
abbreviated new drug application except for changes required because of 
differences approved in a petition under Sec. 314.93 or because the 
drug product and the reference listed drug are produced or distributed 
by different manufacturers or because aspects of the listed drug's 
labeling are protected by patent, or by exclusivity, and such 
differences do not render the proposed drug product less safe or 
effective than the listed drug for all remaining, nonprotected 
conditions of use.
    (8)(i) Information submitted in the abbreviated new drug application 
of any other information available to FDA shows that:
    (A) The inactive ingredients of the drug product are unsafe for use, 
as described in paragraph (a)(8)(ii) of this section, under the 
conditions prescribed, recommended, or suggested in the labeling 
proposed for the drug product; or
    (B) The composition of the drug product is unsafe, as described in 
paragraph (a)(8)(ii) of this section, under the conditions prescribed, 
recommended, or suggested in the proposed labeling because of the type 
or quantity of inactive ingredients included or the manner in which the 
inactive ingredients are included.
    (ii)(A) FDA will consider the inactive ingredients or composition of 
a drug product unsafe and refuse to approve an abbreviated new drug 
application under paragraph (a)(8)(i) of this section if, on the basis 
of information available to the agency, there is a reasonable basis to 
conclude that one or more of the inactive ingredients of the proposed 
drug or its composition raises serious questions of safety or efficacy.

[[Page 156]]

From its experience with reviewing inactive ingredients, and from other 
information available to it, FDA may identify changes in inactive 
ingredients or composition that may adversely affect a drug product's 
safety or efficacy. The inactive ingredients or composition of a 
proposed drug product will be considered to raise serious questions of 
safety or efficacy if the product incorporates one or more of these 
changes. Examples of the changes that may raise serious questions of 
safety or efficacy include, but are not limited to, the following:
    (1) A change in an inactive ingredient so that the product does not 
comply with an official compendium.
    (2) A change in composition to include an inactive ingredient that 
has not been previously approved in a drug product for human use by the 
same route of administration.
    (3) A change in the composition of a parenteral drug product to 
include an inactive ingredient that has not been previously approved in 
a parenteral drug product.
    (4) A change in composition of a drug product for ophthalmic use to 
include an inactive ingredient that has not been previously approved in 
a drug for ophthalmic use.
    (5) The use of a delivery or a modified release mechanism never 
before approved for the drug.
    (6) A change in composition to include a significantly greater 
content of one or more inactive ingredients than previously used in the 
drug product.
    (7) If the drug product is intended for topical administration, a 
change in the properties of the vehicle or base that might increase 
absorption of certain potentially toxic active ingredients thereby 
affecting the safety of the drug product, or a change in the lipophilic 
properties of a vehicle or base, e.g., a change from an oleaginous to a 
water soluble vehicle or base.
    (B) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for parenteral use to be unsafe and will 
refuse to approve the abbreviated new drug application unless it 
contains the same inactive ingredients, other than preservatives, 
buffers, and antioxidants, in the same concentration as the listed drug, 
and, if it differs from the listed drug in a preservative, buffer, or 
antioxidant, the application contains sufficient information to 
demonstrate that the difference does not affect the safety or efficacy 
of the drug product.
    (C) FDA will consider an inactive ingredient in, or the composition 
of, a drug product intended for ophthalmic or otic use unsafe and will 
refuse to approve the abbreviated new drug application unless it 
contains the same inactive ingredients, other than preservatives, 
buffers, substances to adjust tonicity, or thickening agents, in the 
same concentration as the listed drug, and if it differs from the listed 
drug in a preservative, buffer, substance to adjust tonicity, or 
thickening agent, the application contains sufficient information to 
demonstrate that the difference does not affect the safety or efficacy 
of the drug product and the labeling does not claim any therapeutic 
advantage over or difference from the listed drug.
    (9) Approval of the listed drug referred to in the abbreviated new 
drug application has been withdrawn or suspended for grounds described 
in Sec. 314.150(a) or FDA has published a notice of opportunity for 
hearing to withdraw approval of the reference listed drug under Sec. 
314.150(a).
    (10) Approval of the listed drug referred to in the abbreviated new 
drug application has been withdrawn under Sec. 314.151 or FDA has 
proposed to withdraw approval of the reference listed drug under Sec. 
314.151(a).
    (11) FDA has determined that the reference listed drug has been 
withdrawn from sale for safety or effectiveness reasons under Sec. 
314.161, or the reference listed drug has been voluntarily withdrawn 
from sale and the agency has not determined whether the withdrawal is 
for safety or effectiveness reasons, or approval of the reference listed 
drug has been suspended under Sec. 314.153, or the agency has issued an 
initial decision proposing to suspend the reference listed drug under 
Sec. 314.153(a)(1).
    (12) The abbreviated new drug application does not meet any other 
requirement under section 505(j)(2)(A) of the act.

[[Page 157]]

    (13) The abbreviated new drug application contains an untrue 
statement of material fact.
    (b) FDA may refuse to approve an abbreviated application for a new 
drug if the applicant or contract research organization that conducted a 
bioavailability or bioequivalence study described in Sec. 320.63 of 
this chapter that is contained in the abbreviated new drug application 
refuses to permit an inspection of facilities or records relevant to the 
study by a properly authorized officer of employee of the Department of 
Health and Human Services or refuses to submit reserve samples of the 
drug products used in the study when requested by FDA.

[57 FR 17991, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 
FR 25927, Apr. 28, 1993; 67 FR 77672, Dec. 19, 2002]



Sec. 314.150  Withdrawal of approval of an application or abbreviated
application.

    (a) The Food and Drug Administration will notify the applicant, and, 
if appropriate, all other persons who manufacture or distribute 
identical, related, or similar drug products as defined in Sec. Sec. 
310.6 and 314.151(a) of this chapter and for a new drug afford an 
opportunity for a hearing on a proposal to withdraw approval of the 
application or abbreviated new drug application under section 505(e) of 
the act and under the procedure in Sec. 314.200, if any of the 
following apply:
    (1) The Secretary of Health and Human Services has suspended the 
approval of the application or abbreviated application for a new drug on 
a finding that there is an imminent hazard to the public health. FDA 
will promptly afford the applicant an expedited hearing following 
summary suspension on a finding of imminent hazard to health.
    (2) FDA finds:
    (i) That clinical or other experience, tests, or other scientific 
data show that the drug is unsafe for use under the conditions of use 
upon the basis of which the application or abbreviated application was 
approved; or
    (ii) That new evidence of clinical experience, not contained in the 
application or not available to FDA until after the application or 
abbreviated application was approved, or tests by new methods, or tests 
by methods not deemed reasonably applicable when the application or 
abbreviated application was approved, evaluated together with the 
evidence available when the application or abbreviated application was 
approved, reveal that the drug is not shown to be safe for use under the 
conditions of use upon the basis of which the application or abbreviated 
application was approved; or
    (iii) Upon the basis of new information before FDA with respect to 
the drug, evaluated together with the evidence available when the 
application or abbreviated application was approved, that there is a 
lack of substantial evidence from adequate and well-controlled 
investigations as defined in Sec. 314.126, that the drug will have the 
effect it is purported or represented to have under the conditions of 
use prescribed, recommended, or suggested in its labeling; or
    (iv) That the application or abbreviated application contains any 
untrue statement of a material fact; or
    (v) That the patent information prescribed by section 505(c) of the 
act was not submitted within 30 days after the receipt of written notice 
from FDA specifying the failure to submit such information; or
    (b) FDA may notify the applicant, and, if appropriate, all other 
persons who manufacture or distribute identical, related, or similar 
drug products as defined in Sec. 310.6, and for a new drug afford an 
opportunity for a hearing on a proposal to withdraw approval of the 
application or abbreviated new drug application under section 505(e) of 
the act and under the procedure in Sec. 314.200, if the agency finds:
    (1) That the applicant has failed to establish a system for 
maintaining required records, or has repeatedly or deliberately failed 
to maintain required records or to make required reports under section 
505(k) or 507(g) of the act and Sec. 314.80, Sec. 314.81, or Sec. 
314.98, or that the applicant has refused to permit access to, or 
copying or verification of, its records.
    (2) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application or abbreviated 
application

[[Page 158]]

was approved, the methods used in, or the facilities and controls used 
for, the manufacture, processing, and packing of the drug are inadequate 
to ensure and preserve its identity, strength, quality, and purity and 
were not made adequate within a reasonable time after receipt of written 
notice from the agency.
    (3) That on the basis of new information before FDA, evaluated 
together with the evidence available when the application or abbreviated 
application was approved, the labeling of the drug, based on a fair 
evaluation of all material facts, is false or misleading in any 
particular, and the labeling was not corrected by the applicant within a 
reasonable time after receipt of written notice from the agency.
    (4) That the applicant has failed to comply with the notice 
requirements of section 510(j)(2) of the act.
    (5) That the applicant has failed to submit bioavailability or 
bioequivalence data required under part 320 of this chapter.
    (6) The application or abbreviated application does not contain an 
explanation of the omission of a report of any investigation of the drug 
product sponsored by the applicant, or an explanation of the omission of 
other information about the drug pertinent to an evaluation of the 
application or abbreviated application that is received or otherwise 
obtained by the applicant from any source.
    (7) That any nonclinical laboratory study that is described in the 
application or abbreviated application and that is essential to show 
that the drug is safe for use under the conditions prescribed, 
recommended, or suggested in its labeling was not conducted in 
compliance with the good laboratory practice regulations in part 58 of 
this chapter and no reason for the noncompliance was provided or, if it 
was, the differences between the practices used in conducting the study 
and the good laboratory practice regulations do not support the validity 
of the study.
    (8) Any clinical investigation involving human subjects described in 
the application or abbreviated application, subject to the institutional 
review board regulations in part 56 of this chapter or informed consent 
regulations in part 50 of this chapter, was not conducted in compliance 
with those regulations such that the rights or safety of human subjects 
were not adequately protected.
    (9) That the applicant or contract research organization that 
conducted a bioavailability or bioequivalence study described in Sec. 
320.38 or Sec. 320.63 of this chapter that is contained in the 
application or abbreviated application refuses to permit an inspection 
of facilities or records relevant to the study by a properly authorized 
officer or employee of the Department of Health and Human Services or 
refuses to submit reserve samples of the drug products used in the study 
when requested by FDA.
    (10) That the labeling for the drug product that is the subject of 
the abbreviated new drug application is no longer consistent with that 
for the listed drug referred to in the abbreviated new drug application, 
except for differences approved in the abbreviated new drug application 
or those differences resulting from:
    (i) A patent on the listed drug issued after approval of the 
abbreviated new drug application; or
    (ii) Exclusivity accorded to the listed drug after approval of the 
abbreviated new drug application that do not render the drug product 
less safe or effective than the listed drug for any remaining, 
nonprotected condition(s) of use.
    (c) FDA will withdraw approval of an application or abbreviated 
application if the applicant requests its withdrawal because the drug 
subject to the application or abbreviated application is no longer being 
marketed, provided none of the conditions listed in paragraphs (a) and 
(b) of this section applies to the drug. FDA will consider a written 
request for a withdrawal under this paragraph to be a waiver of an 
opportunity for hearing otherwise provided for in this section. 
Withdrawal of approval of an application or abbreviated application 
under this paragraph is without prejudice to refiling.
    (d) FDA may notify an applicant that it believes a potential problem 
associated with a drug is sufficiently serious that the drug should be 
removed from the market and may ask the applicant

[[Page 159]]

to waive the opportunity for hearing otherwise provided for under this 
section, to permit FDA to withdraw approval of the application or 
abbreviated application for the product, and to remove voluntarily the 
product from the market. If the applicant agrees, the agency will not 
make a finding under paragraph (b) of this section, but will withdraw 
approval of the application or abbreviated application in a notice 
published in the Federal Register that contains a brief summary of the 
agency's and the applicant's views of the reasons for withdrawal.

[57 FR 17993, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 
64 FR 402, Jan. 5, 1999]



Sec. 314.151  Withdrawal of approval of an abbreviated new drug 
application under section 505(j)(5) of the act.

    (a) Approval of an abbreviated new drug application approved under 
Sec. 314.105(d) may be withdrawn when the agency withdraws approval, 
under Sec. 314.150(a) or under this section, of the approved drug 
referred to in the abbreviated new drug application. If the agency 
proposed to withdraw approval of a listed drug under Sec. 314.150(a), 
the holder of an approved application for the listed drug has a right to 
notice and opportunity for hearing. The published notice of opportunity 
for hearing will identify all drug products approved under Sec. 
314.105(d) whose applications are subject to withdrawal under this 
section if the listed drug is withdrawn, and will propose to withdraw 
such drugs. Holders of approved applications for the identified drug 
products will be provided notice and an opportunity to respond to the 
proposed withdrawal of their applications as described in paragraphs (b) 
and (c) of this section.
    (b)(1) The published notice of opportunity for hearing on the 
withdrawal of the listed drug will serve as notice to holders of 
identified abbreviated new drug applications of the grounds for the 
proposed withdrawal.
    (2) Holders of applications for drug products identified in the 
notice of opportunity for hearing may submit written comments on the 
notice of opportunity for hearing issued on the proposed withdrawal of 
the listed drug. If an abbreviated new drug application holder submits 
comments on the notice of opportunity for hearing and a hearing is 
granted, the abbreviated new drug application holder may participate in 
the hearing as a nonparty participant as provided for in Sec. 12.89 of 
this chapter.
    (3) Except as provided in paragraphs (c) and (d) of this section, 
the approval of an abbreviated new drug application for a drug product 
identified in the notice of opportunity for hearing on the withdrawal of 
a listed drug will be withdrawn when the agency has completed the 
withdrawal of approval of the listed drug.
    (c)(1) If the holder of an application for a drug identified in the 
notice of opportunity for hearing has submitted timely comments but does 
not have an opportunity to participate in a hearing because a hearing is 
not requested or is settled, the submitted comments will be considered 
by the agency, which will issue an initial decision. The initial 
decision will respond to the comments, and contain the agency's decision 
whether there are grounds to withdraw approval of the listed drug and of 
the abbreviated new drug applications on which timely comments were 
submitted. The initial decision will be sent to each abbreviated new 
drug application holder that has submitted comments.
    (2) Abbreviated new drug application holders to whom the initial 
decision was sent may, within 30 days of the issuance of the initial 
decision, submit written objections.
    (3) The agency may, at its discretion, hold a limited oral hearing 
to resolve dispositive factual issues that cannot be resolved on the 
basis of written submissions.
    (4) If there are no timely objections to the initial decision, it 
will become final at the expiration of 30 days.
    (5) If timely objections are submitted, they will be reviewed and 
responded to in a final decision.
    (6) The written comments received, the initial decision, the 
evidence relied on in the comments and in the initial decision, the 
objections to the initial decision, and, if a limited oral hearing has 
been held, the transcript of that hearing and any documents submitted 
therein, shall form the record upon

[[Page 160]]

which the agency shall make a final decision.
    (7) Except as provided in paragraph (d) of this section, any 
abbreviated new drug application whose holder submitted comments on the 
notice of opportunity for hearing shall be withdrawn upon the issuance 
of a final decision concluding that the listed drug should be withdrawn 
for grounds as described in Sec. 314.150(a). The final decision shall 
be in writing and shall constitute final agency action, reviewable in a 
judicial proceeding.
    (8) Documents in the record will be publicly available in accordance 
with Sec. 10.20(j) of this chapter. Documents available for examination 
or copying will be placed on public display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, room. 1-23, 12420 
Parklawn Dr., Rockville, MD 20857, promptly upon receipt in that office.
    (d) If the agency determines, based upon information submitted by 
the holder of an abbreviated new drug application, that the grounds for 
withdrawal of the listed drug are not applicable to a drug identified in 
the notice of opportunity for hearing, the final decision will state 
that the approval of the abbreviated new drug application for such drug 
is not withdrawn.

[57 FR 17994, Apr. 28, 1992]



Sec. 314.152  Notice of withdrawal of approval of an application
or abbreviated application for a new drug.

    If the Food and Drug Administration withdraws approval of an 
application or abbreviated application for a new drug, FDA will publish 
a notice in the Federal Register announcing the withdrawal of approval. 
If the application or abbreviated application was withdrawn for grounds 
described in Sec. 314.150(a) or Sec. 314.151, the notice will announce 
the removal of the drug from the list of approved drugs published under 
section 505(j)(6) of the act and shall satisfy the requirement of Sec. 
314.162(b).

[57 FR 17994, Apr. 28, 1992]



Sec. 314.153  Suspension of approval of an abbreviated new drug application.

    (a) Suspension of approval. The approval of an abbreviated new drug 
application approved under Sec. 314.105(d) shall be suspended for the 
period stated when:
    (1) The Secretary of the Department of Health and Human Services, 
under the imminent hazard authority of section 505(e) of the act or the 
authority of this paragraph, suspends approval of a listed drug referred 
to in the abbreviated new drug application, for the period of the 
suspension;
    (2) The agency, in the notice described in paragraph (b) of this 
section, or in any subsequent written notice given an abbreviated new 
drug application holder by the agency, concludes that the risk of 
continued marketing and use of the drug is inappropriate, pending 
completion of proceedings to withdraw or suspend approval under Sec. 
314.151 or paragraph (b) of this section; or
    (3) The agency, under the procedures set forth in paragraph (b) of 
this section, issues a final decision stating the determination that the 
abbreviated application is suspended because the listed drug on which 
the approval of the abbreviated new drug application depends has been 
withdrawn from sale for reasons of safety or effectiveness or has been 
suspended under paragraph (b) of this section. The suspension will take 
effect on the date stated in the decision and will remain in effect 
until the agency determines that the marketing of the drug has resumed 
or that the withdrawal is not for safety or effectiveness reasons.
    (b) Procedures for suspension of abbreviated new drug applications 
when a listed drug is voluntarily withdrawn for safety or effectiveness 
reasons. (1) If a listed drug is voluntarily withdrawn from sale, and 
the agency determines that the withdrawal from sale was for reasons of 
safety or effectiveness, the agency will send each holder of an approved 
abbreviated new drug application that is subject to suspension as a 
result of this determination a copy of the agency's initial decision 
setting forth the reasons for the determination. The initial decision 
will also be placed on file with the Division of

[[Page 161]]

Dockets Management (HFA-305), Food and Drug Administration, room 1-23, 
12420 Parklawn Dr., Rockville, MD 20857.
    (2) Each abbreviated new drug application holder will have 30 days 
from the issuance of the initial decision to present, in writing, 
comments and information bearing on the initial decision. If no comments 
or information is received, the initial decision will become final at 
the expiration of 30 days.
    (3) Comments and information received within 30 days of the issuance 
of the initial decision will be considered by the agency and responded 
to in a final decision.
    (4) The agency may, in its discretion, hold a limited oral hearing 
to resolve dispositive factual issues that cannot be resolved on the 
basis of written submissions.
    (5) If the final decision affirms the agency's initial decision that 
the listed drug was withdrawn for reasons of safety or effectiveness, 
the decision will be published in the Federal Register in compliance 
with Sec. 314.152, and will, except as provided in paragraph (b)(6) of 
this section, suspend approval of all abbreviated new drug applications 
identified under paragraph (b)(1) of this section and remove from the 
list the listed drug and any drug whose approval was suspended under 
this paragraph. The notice will satisfy the requirement of Sec. 
314.162(b). The agency's final decision and copies of materials on which 
it relies will also be filed with the Division of Dockets Management 
(address in paragraph (b)(1) of this section).
    (6) If the agency determines in its final decision that the listed 
drug was withdrawn for reasons of safety or effectiveness but, based 
upon information submitted by the holder of an abbreviated new drug 
application, also determines that the reasons for the withdrawal of the 
listed drug are not relevant to the safety and effectiveness of the drug 
subject to such abbreviated new drug application, the final decision 
will state that the approval of such abbreviated new drug application is 
not suspended.
    (7) Documents in the record will be publicly available in accordance 
with Sec. 10.20(j) of this chapter. Documents available for examination 
or copying will be placed on public display in the Division of Dockets 
Management (address in paragraph (b)(1) of this section) promptly upon 
receipt in that office.

[57 FR 17995, Apr. 28, 1992]



Sec. 314.160  Approval of an application or abbreviated application
for which approval was previously refused, suspended, or withdrawn.

    Upon the Food and Drug Administration's own initiative or upon 
request of an applicant, FDA may, on the basis of new data, approve an 
application or abbreviated application which it had previously refused, 
suspended, or withdrawn approval. FDA will publish a notice in the 
Federal Register announcing the approval.

[57 FR 17995, Apr. 28, 1992]



Sec. 314.161  Determination of reasons for voluntary withdrawal of 
a listed drug.

    (a) A determination whether a listed drug that has been voluntarily 
withdrawn from sale was withdrawn for safety or effectiveness reasons 
may be made by the agency at any time after the drug has been 
voluntarily withdrawn from sale, but must be made:
    (1) Prior to approving an abbreviated new drug application that 
refers to the listed drug;
    (2) Whenever a listed drug is voluntarily withdrawn from sale and 
abbreviated new drug applications that referred to the listed drug have 
been approved; and
    (3) When a person petitions for such a determination under 
Sec. Sec. 10.25(a) and 10.30 of this chapter.
    (b) Any person may petition under Sec. Sec. 10.25(a) and 10.30 of 
this chapter for a determination whether a listed drug has been 
voluntarily withdrawn for safety or effectiveness reasons. Any such 
petition must contain all evidence available to the petitioner 
concerning the reason that the drug is withdrawn from sale.
    (c) If the agency determines that a listed drug is withdrawn from 
sale for safety or effectiveness reasons, the agency will, except as 
provided in paragraph (d) of this section, publish a notice of the 
determination in the Federal Register.

[[Page 162]]

    (d) If the agency determines under paragraph (a) of this section 
that a listed drug is withdrawn from sale for safety and effectiveness 
reasons and there are approved abbreviated new drug applications that 
are subject to suspension under section 505(j)(5) of the act, FDA will 
initiate a proceeding in accordance with Sec. 314.153(b).
    (e) A drug that the agency determines is withdrawn for safety or 
effectiveness reasons will be removed from the list, under Sec. 
314.162. The drug may be relisted if the agency has evidence that 
marketing of the drug has resumed or that the withdrawal is not for 
safety or effectiveness reasons. A determination that the drug is not 
withdrawn for safety or effectiveness reasons may be made at any time 
after its removal from the list, upon the agency's initiative, or upon 
the submission of a petition under Sec. Sec. 10.25(a) and 10.30 of this 
chapter. If the agency determines that the drug is not withdrawn for 
safety or effectiveness reasons, the agency shall publish a notice of 
this determination in the Federal Register. The notice will also 
announce that the drug is relisted, under Sec. 314.162(c). The notice 
will also serve to reinstate approval of all suspended abbreviated new 
drug applications that referred to the listed drug.

[57 FR 17995, Apr. 28, 1992]



Sec. 314.162  Removal of a drug product from the list.

    (a) FDA will remove a previously approved new drug product from the 
list for the period stated when:
    (1) The agency withdraws or suspends approval of a new drug 
application or an abbreviated new drug application under Sec. 
314.150(a) or Sec. 314.151 or under the imminent hazard authority of 
section 505(e) of the act, for the same period as the withdrawal or 
suspension of the application; or
    (2) The agency, in accordance with the procedures in Sec. 
314.153(b) or Sec. 314.161, issues a final decision stating that the 
listed drug was withdrawn from sale for safety or effectiveness reasons, 
or suspended under Sec. 314.153(b), until the agency determines that 
the withdrawal from the market has ceased or is not for safety or 
effectiveness reasons.
    (b) FDA will publish in the Federal Register a notice announcing the 
removal of a drug from the list.
    (c) At the end of the period specified in paragraph (a)(1) or (a)(2) 
of this section, FDA will relist a drug that has been removed from the 
list. The agency will publish in the Federal Register a notice 
announcing the relisting of the drug.

[57 FR 17996, Apr. 28, 1992]



Sec. 314.170  Adulteration and misbranding of an approved drug.

    All drugs, including those the Food and Drug Administration approves 
under section 505 of the act and this part, are subject to the 
adulteration and misbranding provisions in sections 501, 502, and 503 of 
the act. FDA is authorized to regulate approved new drugs by regulations 
issued through informal rulemaking under sections 501, 502, and 503 of 
the act.

[50 FR 7493, Feb. 22, 1985. Redesignated at 57 FR 17983, Apr. 28, 1992, 
and amended at 64 FR 402, Jan. 5, 1999]



               Subpart E_Hearing Procedures for New Drugs

    Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. 
Redesignated at 57 FR 17983, Apr. 28, 1992.



Sec. 314.200  Notice of opportunity for hearing; notice of
participation and request for hearing; grant or denial of 

hearing.

    (a) Notice of opportunity for hearing. The Director of the Center 
for Drug Evaluation and Research, Food and Drug Administration, will 
give the applicant, and all other persons who manufacture or distribute 
identical, related, or similar drug products as defined in Sec. 310.6 
of this chapter, notice and an opportunity for a hearing on the Center's 
proposal to refuse to approve an application or to withdraw the approval 
of an application or abbreviated application under section 505(e) of the 
act. The notice will state the reasons for the action and the proposed 
grounds for the order.
    (1) The notice may be general (that is, simply summarizing in a 
general way the information resulting in the

[[Page 163]]

notice) or specific (that is, either referring to specific requirements 
in the statute and regulations with which there is a lack of compliance, 
or providing a detailed description and analysis of the specific facts 
resulting in the notice).
    (2) FDA will publish the notice in the Federal Register and will 
state that the applicant, and other persons subject to the notice under 
Sec. 310.6, who wishes to participate in a hearing, has 30 days after 
the date of publication of the notice to file a written notice of 
participation and request for hearing. The applicant, or other persons 
subject to the notice under Sec. 310.6, who fails to file a written 
notice of participation and request for hearing within 30 days, waives 
the opportunity for a hearing.
    (3) It is the responsibility of every manufacturer and distributor 
of a drug product to review every notice of opportunity for a hearing 
published in the Federal Register to determine whether it covers any 
drug product that person manufactures or distributes. Any person may 
request an opinion of the applicability of a notice to a specific 
product that may be identical, related, or similar to a product listed 
in a notice by writing to the Division of New Drugs and Labeling 
Compliance, Office of Compliance, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002. A person shall request an opinion within 30 days 
of the date of publication of the notice to be eligible for an 
opportunity for a hearing under the notice. If a person requests an 
opinion, that person's time for filing an appearance and request for a 
hearing and supporting studies and analyses begins on the date the 
person receives the opinion from FDA.
    (b) FDA will provide the notice of opportunity for a hearing to 
applicants and to other persons subject to the notice under Sec. 310.6, 
as follows:
    (1) To any person who has submitted an application or abbreviated 
application, by delivering the notice in person or by sending it by 
registered or certified mail to the last address shown in the 
application or abbreviated application.
    (2) To any person who has not submitted an application or 
abbreviated application but who is subject to the notice under Sec. 
310.6 of this chapter, by publication of the notice in the Federal 
Register.
    (c)(1) Notice of participation and request for a hearing, and 
submission of studies and comments. The applicant, or any other person 
subject to the notice under Sec. 310.6, who wishes to participate in a 
hearing, shall file with the Division of Dockets Management (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852, (i) within 30 days after the date of the publication of the 
notice (or of the date of receipt of an opinion requested under 
paragraph (a)(3) of this section) a written notice of participation and 
request for a hearing and (ii) within 60 days after the date of 
publication of the notice, unless a different period of time is 
specified in the notice of opportunity for a hearing, the studies on 
which the person relies to justify a hearing as specified in paragraph 
(d) of this section. The applicant, or other person, may incorporate by 
reference the raw data underlying a study if the data were previously 
submitted to FDA as part of an application, abbreviated application, or 
other report.
    (2) FDA will not consider data or analyses submitted after 60 days 
in determining whether a hearing is warranted unless they are derived 
from well-controlled studies begun before the date of the notice of 
opportunity for hearing and the results of the studies were not 
available within 60 days after the date of publication of the notice. 
Nevertheless, FDA may consider other studies on the basis of a showing 
by the person requesting a hearing of inadvertent omission and hardship. 
The person requesting a hearing shall list in the request for hearing 
all studies in progress, the results of which the person intends later 
to submit in support of the request for a hearing. The person shall 
submit under paragraph (c)(1)(ii) of this section a copy of the complete 
protocol, a list of the participating investigators, and a brief status 
report of the studies.
    (3) Any other interested person who is not subject to the notice of 
opportunity for a hearing may also submit

[[Page 164]]

comments on the proposal to withdraw approval of the application or 
abbreviated application. The comments are requested to be submitted 
within the time and under the conditions specified in this section.
    (d) The person requesting a hearing is required to submit under 
paragraph (c)(1)(ii) of this section the studies (including all 
protocols and underlying raw data) on which the person relies to justify 
a hearing with respect to the drug product. Except, a person who 
requests a hearing on the refusal to approve an application is not 
required to submit additional studies and analyses if the studies upon 
which the person relies have been submitted in the application and in 
the format and containing the summaries required under Sec. 314.50.
    (1) If the grounds for FDA's proposed action concern the 
effectiveness of the drug, each request for hearing is required to be 
supported only by adequate and well-controlled clinical studies meeting 
all of the precise requirements of Sec. 314.126 and, for combination 
drug products, Sec. 300.50, or by other studies not meeting those 
requirements for which a waiver has been previously granted by FDA under 
Sec. 314.126. Each person requesting a hearing shall submit all 
adequate and well-controlled clinical studies on the drug product, 
including any unfavorable analyses, views, or judgments with respect to 
the studies. No other data, information, or studies may be submitted.
    (2) The submission is required to include a factual analysis of all 
the studies submitted. If the grounds for FDA's proposed action concern 
the effectiveness of the drug, the analysis is required to specify how 
each study accords, on a point-by-point basis, with each criterion 
required for an adequate well-controlled clinical investigation 
established under Sec. 314.126 and, if the product is a combination 
drug product, with each of the requirements for a combination drug 
established in Sec. 300.50, or the study is required to be accompanied 
by an appropriate waiver previously granted by FDA. If a study concerns 
a drug or dosage form or condition of use or mode of administration 
other than the one in question, that fact is required to be clearly 
stated. Any study conducted on the final marketed form of the drug 
product is required to be clearly identified.
    (3) Each person requesting a hearing shall submit an analysis of the 
data upon which the person relies, except that the required information 
relating either to safety or to effectiveness may be omitted if the 
notice of opportunity for hearing does not raise any issue with respect 
to that aspect of the drug; information on compliance with Sec. 300.50 
may be omitted if the drug product is not a combination drug product. A 
financial certification or disclosure statement or both as required by 
part 54 of this chapter must accompany all clinical data submitted. FDA 
can most efficiently consider submissions made in the following format.

    I. Safety data.
    A. Animal safety data.
    1. Individual active components.
    a. Controlled studies.
    b. Partially controlled or uncontrolled studies.
    2. Combinations of the individual active components.
    a. Controlled studies.
    b. Partially controlled or uncontrolled studies.
    B. Human safety data.
    1. Individual active components.
    a. Controlled studies.
    b. Partially controlled or uncontrolled studies.
    c. Documented case reports.
    d. Pertinent marketing experiences that may influence a 
determination about the safety of each individual active component.
    2. Combinations of the individual active components.
    a. Controlled studies.
    b. Partially controlled or uncontrolled studies.
    c. Documented case reports.
    d. Pertinent marketing experiences that may influence a 
determination about the safety of each individual active component.
    II. Effectiveness data.
    A. Individual active components: Controlled studies, with an 
analysis showing clearly how each study satisfies, on a point-by-point 
basis, each of the criteria required by Sec. 314.126.
    B. Combinations of individual active components.
    1. Controlled studies with an analysis showing clearly how each 
study satisfies on a point-by-point basis, each of the criteria required 
by Sec. 314.126.
    2. An analysis showing clearly how each requirement of Sec. 300.50 
has been satisfied.

[[Page 165]]

    III. A summary of the data and views setting forth the medical 
rationale and purpose for the drug and its ingredients and the 
scientific basis for the conclusion that the drug and its ingredients 
have been proven safe and/or effective for the intended use. If there is 
an absence of controlled studies in the material submitted or the 
requirements of any element of Sec. 300.50 or Sec. 314.126 have not 
been fully met, that fact is required to be stated clearly and a waiver 
obtained under Sec. 314.126 is required to be submitted.
    IV. A statement signed by the person responsible for such submission 
that it includes in full (or incorporates by reference as permitted in 
Sec. 314.200(c)(2)) all studies and information specified in Sec. 
314.200(d).

    (Warning: A willfully false statement is a criminal offense, 18 
U.S.C. 1001.)

    (e) Contentions that a drug product is not subject to the new drug 
requirements. A notice of opportunity for a hearing encompasses all 
issues relating to the legal status of each drug product subject to it, 
including identical, related, and similar drug products as defined in 
Sec. 310.6. A notice of appearance and request for a hearing under 
paragraph (c)(1)(i) of this section is required to contain any 
contention that the product is not a new drug because it is generally 
recognized as safe and effective within the meaning of section 201(p) of 
the act, or because it is exempt from part or all of the new drug 
provisions of the act under the exemption for products marketed before 
June 25, 1938, contained in section 201(p) of the act or under section 
107(c) of the Drug Amendments of 1962, or for any other reason. Each 
contention is required to be supported by a submission under paragraph 
(c)(1)(ii) of this section and the Commissioner of Food and Drugs will 
make an administrative determination on each contention. The failure of 
any person subject to a notice of opportunity for a hearing, including 
any person who manufactures or distributes an identical, related, or 
similar drug product as defined in Sec. 310.6, to submit a notice of 
participation and request for hearing or to raise all such contentions 
constitutes a waiver of any contentions not raised.
    (1) A contention that a drug product is generally recognized as safe 
and effective within the meaning of section 201(p) of the act is 
required to be supported by submission of the same quantity and quality 
of scientific evidence that is required to obtain approval of an 
application for the product, unless FDA has waived a requirement for 
effectiveness (under Sec. 314.126) or safety, or both. The submission 
should be in the format and with the analyses required under paragraph 
(d) of this section. A person who fails to submit the required 
scientific evidence required under paragraph (d) waives the contention. 
General recognition of safety and effectiveness shall ordinarily be 
based upon published studies which may be corroborated by unpublished 
studies and other data and information.
    (2) A contention that a drug product is exempt from part or all of 
the new drug provisions of the act under the exemption for products 
marketed before June 25, 1938, contained in section 201(p) of the act, 
or under section 107(c) of the Drug Amendments of 1962, is required to 
be supported by evidence of past and present quantitative formulas, 
labeling, and evidence of marketing. A person who makes such a 
contention should submit the formulas, labeling, and evidence of 
marketing in the following format.

    I. Formulation.
    A. A copy of each pertinent document or record to establish the 
exact quantitative formulation of the drug (both active and inactive 
ingredients) on the date of initial marketing of the drug.
    B. A statement whether such formulation has at any subsequent time 
been changed in any manner. If any such change has been made, the exact 
date, nature, and rationale for each change in formulation, including 
any deletion or change in the concentration of any active ingredient 
and/or inactive ingredient, should be stated, together with a copy of 
each pertinent document or record to establish the date and nature of 
each such change, including, but not limited to, the formula which 
resulted from each such change. If no such change has been made, a copy 
of representative documents or records showing the formula at 
representative points in time should be submitted to support the 
statement.
    II. Labeling.
    A. A copy of each pertinent document or record to establish the 
identity of each item of written, printed, or graphic matter used as 
labeling on the date the drug was initially marketed.
    B. A statement whether such labeling has at any subsequent time been 
discontinued or changed in any manner. If such discontinuance or change 
has been made, the exact

[[Page 166]]

date, nature, and rationale for each discontinuance or change and a copy 
of each pertinent document or record to establish each such 
discontinuance or change should be submitted, including, but not limited 
to, the labeling which resulted from each such discontinuance or change. 
If no such discontinuance or change has been made, a copy of 
representative documents or records showing labeling at representative 
points in time should be submitted to support the statement.
    III. Marketing.
    A. A copy of each pertinent document or record to establish the 
exact date the drug was initially marketed.
    B. A statement whether such marketing has at any subsequent time 
been discontinued. If such marketing has been discontinued, the exact 
date of each such discontinuance should be submitted, together with a 
copy of each pertinent document or record to establish each such date.
    IV. Verification.
    A statement signed by the person responsible for such submission, 
that all appropriate records have been searched and to the best of that 
person's knowledge and belief it includes a true and accurate 
presentation of the facts.

    (Warning: A willfully false statement is a criminal offense, 18 
U.S.C. 1001.)

    (3) The Food and Drug Administration will not find a drug product, 
including any active ingredient, which is identical, related, or 
similar, as described in Sec. 310.6, to a drug product, including any 
active ingredient for which an application is or at any time has been 
effective or deemed approved, or approved under section 505 of the act, 
to be exempt from part or all of the new drug provisions of the act.
    (4) A contention that a drug product is not a new drug for any other 
reason is required to be supported by submission of the factual records, 
data, and information that are necessary and appropriate to support the 
contention.
    (5) It is the responsibility of every person who manufactures or 
distributes a drug product in reliance upon a ``grandfather'' provision 
of the act to maintain files that contain the data and information 
necessary fully to document and support that status.
    (f) Separation of functions. Separation of functions commences upon 
receipt of a request for hearing. The Director of the Center for Drug 
Evaluation and Research, Food and Drug Administration, will prepare an 
analysis of the request and a proposed order ruling on the matter. The 
analysis and proposed order, the request for hearing, and any proposed 
order denying a hearing and response under paragraph (g) (2) or (3) of 
this section will be submitted to the Office of the Commissioner of Food 
and Drugs for review and decision. When the Center for Drug Evaluation 
and Research recommends denial of a hearing on all issues on which a 
hearing is requested, no representative of the Center will participate 
or advise in the review and decision by the Commissioner. When the 
Center for Drug Evaluation and Research recommends that a hearing be 
granted on one or more issues on which a hearing is requested, 
separation of functions terminates as to those issues, and 
representatives of the Center may participate or advise in the review 
and decision by the Commissioner on those issues. The Commissioner may 
modify the text of the issues, but may not deny a hearing on those 
issues. Separation of functions continues with respect to issues on 
which the Center for Drug Evaluation and Research has recommended denial 
of a hearing. The Commissioner will neither evaluate nor rule on the 
Center's recommendation on such issues and such issues will not be 
included in the notice of hearing. Participants in the hearing may make 
a motion to the presiding officer for the inclusion of any such issue in 
the hearing. The ruling on such a motion is subject to review in 
accordance with Sec. 12.35(b). Failure to so move constitutes a waiver 
of the right to a hearing on such an issue. Separation of functions on 
all issues resumes upon issuance of a notice of hearing. The Office of 
the General Counsel, Department of Health and Human Services, will 
observe the same separation of functions.
    (g) Summary judgment. A person who requests a hearing may not rely 
upon allegations or denials but is required to set forth specific facts 
showing that there is a genuine and substantial issue of fact that 
requires a hearing with respect to a particular drug product specified 
in the request for hearing.
    (1) Where a specific notice of opportunity for hearing (as defined 
in paragraph (a)(1) of this section) is used, the Commissioner will 
enter summary

[[Page 167]]

judgment against a person who requests a hearing, making findings and 
conclusions, denying a hearing, if it conclusively appears from the face 
of the data, information, and factual analyses in the request for the 
hearing that there is no genuine and substantial issue of fact which 
precludes the refusal to approve the application or abbreviated 
application or the withdrawal of approval of the application or 
abbreviated application; for example, no adequate and well-controlled 
clinical investigations meeting each of the precise elements of Sec. 
314.126 and, for a combination drug product, Sec. 300.50 of this 
chapter, showing effectiveness have been identified. Any order entering 
summary judgment is required to set forth the Commissioner's findings 
and conclusions in detail and is required to specify why each study 
submitted fails to meet the requirements of the statute and regulations 
or why the request for hearing does not raise a genuine and substantial 
issue of fact.
    (2) When following a general notice of opportunity for a hearing (as 
defined in paragraph (a)(1) of this section) the Director of the Center 
for Drug Evaluation and Research concludes that summary judgment against 
a person requesting a hearing should be considered, the Director will 
serve upon the person requesting a hearing by registered mail a proposed 
order denying a hearing. This person has 60 days after receipt of the 
proposed order to respond with sufficient data, information, and 
analyses to demonstrate that there is a genuine and substantial issue of 
fact which justifies a hearing.
    (3) When following a general or specific notice of opportunity for a 
hearing a person requesting a hearing submits data or information of a 
type required by the statute and regulations, and the Director of the 
Center for Drug Evaluation and Research concludes that summary judgment 
against the person should be considered, the Director will serve upon 
the person by registered mail a proposed order denying a hearing. The 
person has 60 days after receipt of the proposed order to respond with 
sufficient data, information, and analyses to demonstrate that there is 
a genuine and substantial issue of fact which justifies a hearing.
    (4) If review of the data, information, and analyses submitted show 
that the grounds cited in the notice are not valid, for example, that 
substantial evidence of effectiveness exists, the Commissioner will 
enter summary judgment for the person requesting the hearing, and 
rescind the notice of opportunity for hearing.
    (5) If the Commissioner grants a hearing, it will begin within 90 
days after the expiration of the time for requesting the hearing unless 
the parties otherwise agree in the case of denial of approval, and as 
soon as practicable in the case of withdrawal of approval.
    (6) The Commissioner will grant a hearing if there exists a genuine 
and substantial issue of fact or if the Commissioner concludes that a 
hearing would otherwise be in the public interest.
    (7) If the manufacturer or distributor of an identical, related, or 
similar drug product requests and is granted a hearing, the hearing may 
consider whether the product is in fact identical, related, or similar 
to the drug product named in the notice of opportunity for a hearing.
    (8) A request for a hearing, and any subsequent grant or denial of a 
hearing, applies only to the drug products named in such documents.
    (h) FDA will issue a notice withdrawing approval and declaring all 
products unlawful for drug products subject to a notice of opportunity 
for a hearing, including any identical, related, or similar drug product 
under Sec. 310.6, for which an opportunity for a hearing is waived or 
for which a hearing is denied. The Commissioner may defer or stay the 
action pending a ruling on any related request for a hearing or pending 
any related hearing or other administrative or judicial proceeding.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 
28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, Feb. 2, 1998; 67 FR 
9586, Mar. 4, 2002; 68 FR 24879, May 9, 2003; 69 FR 48775, Aug. 11, 
2004; 74 FR 13113, Mar. 26, 2009]

[[Page 168]]



Sec. 314.201  Procedure for hearings.

    Parts 10 through 16 apply to hearings relating to new drugs under 
section 505 (d) and (e) of the act.



Sec. 314.235  Judicial review.

    (a) The Commissioner of Food and Drugs will certify the transcript 
and record. In any case in which the Commissioner enters an order 
without a hearing under Sec. 314.200(g), the record certified by the 
Commissioner is required to include the requests for hearing together 
with the data and information submitted and the Commissioner's findings 
and conclusion.
    (b) A manufacturer or distributor of an identical, related, or 
similar drug product under Sec. 310.6 may seek judicial review of an 
order withdrawing approval of a new drug application, whether or not a 
hearing has been held, in a United States court of appeals under section 
505(h) of the act.

Subpart F [Reserved]



                   Subpart G_Miscellaneous Provisions

    Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted. 
Redesignated at 57 FR 17983, Apr. 28, 1992.



Sec. 314.410  Imports and exports of new drugs.

    (a) Imports. (1) A new drug may be imported into the United States 
if: (i) It is the subject of an approved application under this part; or 
(ii) it complies with the regulations pertaining to investigational new 
drugs under part 312; and it complies with the general regulations 
pertaining to imports under subpart E of part 1.
    (2) A drug substance intended for use in the manufacture, 
processing, or repacking of a new drug may be imported into the United 
States if it complies with the labeling exemption in Sec. 201.122 
pertaining to shipments of drug substances in domestic commerce.
    (b) Exports. (1) A new drug may be exported if it is the subject of 
an approved application under this part or it complies with the 
regulations pertaining to investigational new drugs under part 312.
    (2) A new drug substance that is covered by an application approved 
under this part for use in the manufacture of an approved drug product 
may be exported by the applicant or any person listed as a supplier in 
the approved application, provided the drug substance intended for 
export meets the specification of, and is shipped with a copy of the 
labeling required for, the approved drug product.
    (3) Insulin or an antibiotic drug may be exported without regard to 
the requirements in section 802 of the act if the insulin or antibiotic 
drug meets the requirements of section 801(e)(1) of the act.

[50 FR 7493, Feb. 22, 1985, unless otherwise noted. Redesignated at 57 
FR 17983, Apr. 28, 1992, and amended at 64 FR 402, Jan. 5, 1999; 69 FR 
18766, Apr. 8, 2004]



Sec. 314.420  Drug master files.

    (a) A drug master file is a submission of information to the Food 
and Drug Administration by a person (the drug master file holder) who 
intends it to be used for one of the following purposes: To permit the 
holder to incorporate the information by reference when the holder 
submits an investigational new drug application under part 312 or 
submits an application or an abbreviated application or an amendment or 
supplement to them under this part, or to permit the holder to authorize 
other persons to rely on the information to support a submission to FDA 
without the holder having to disclose the information to the person. FDA 
ordinarily neither independently reviews drug master files nor approves 
or disapproves submissions to a drug master file. Instead, the agency 
customarily reviews the information only in the context of an 
application under part 312 or this part. A drug master file may contain 
information of the kind required for any submission to the agency, 
including information about the following:
    (1) [Reserved]
    (2) Drug substance, drug substance intermediate, and materials used 
in their preparation, or drug product;
    (3) Packaging materials;
    (4) Excipient, colorant, flavor, essence, or materials used in their 
preparation;

[[Page 169]]

    (5) FDA-accepted reference information. (A person wishing to submit 
information and supporting data in a drug master file (DMF) that is not 
covered by Types II through IV DMF's must first submit a letter of 
intent to the Drug Master File Staff, Food and Drug Administration, 
5901-B Ammendale Rd., Beltsville, MD 20705-1266.) FDA will then contact 
the person to discuss the proposed submission.
    (b) An investigational new drug application or an application, 
abbreviated application, amendment, or supplement may incorporate by 
reference all or part of the contents of any drug master file in support 
of the submission if the holder authorizes the incorporation in writing. 
Each incorporation by reference is required to describe the incorporated 
material by name, reference number, volume, and page number of the drug 
master file.
    (c) A drug master file is required to be submitted in two copies. 
The agency has prepared guidance that provides information about how to 
prepare a well-organized drug master file. If the drug master file 
holder adds, changes, or deletes any information in the file, the holder 
shall notify in writing, each person authorized to reference that 
information. Any addition, change, or deletion of information in a drug 
master file (except the list required under paragraph (d) of this 
section) is required to be submitted in two copies and to describe by 
name, reference number, volume, and page number the information affected 
in the drug master file.
    (d) The drug master file is required to contain a complete list of 
each person currently authorized to incorporate by reference any 
information in the file, identifying by name, reference number, volume, 
and page number the information that each person is authorized to 
incorporate. If the holder restricts the authorization to particular 
drug products, the list is required to include the name of each drug 
product and the application number, if known, to which the authorization 
applies.
    (e) The public availability of data and information in a drug master 
file, including the availability of data and information in the file to 
a person authorized to reference the file, is determined under part 20 
and Sec. 314.430.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 53 
FR 33122, Aug. 30, 1988; 55 FR 28380, July 11, 1990; 65 FR 1780, Jan. 
12, 2000; 65 FR 56479, Sept. 19, 2000; 67 FR 9586, Mar. 4, 2002; 69 FR 
13473, Mar. 23, 2004]



Sec. 314.430  Availability for public disclosure of data and 
information in an application or abbreviated application.

    (a) The Food and Drug Administration will determine the public 
availability of any part of an application or abbreviated application 
under this section and part 20 of this chapter. For purposes of this 
section, the application or abbreviated application includes all data 
and information submitted with or incorporated by reference in the 
application or abbreviated application, including investigational new 
drug applications, drug master files under Sec. 314.420, supplements 
submitted under Sec. 314.70 or Sec. 314.97, reports under Sec. 314.80 
or Sec. 314.98, and other submissions. For purposes of this section, 
safety and effectiveness data include all studies and tests of a drug on 
animals and humans and all studies and tests of the drug for identity, 
stability, purity, potency, and bioavailability.
    (b) FDA will not publicly disclose the existence of an application 
or abbreviated application before an approval letter is sent to the 
applicant under Sec. 314.105 or tentative approval letter is sent to 
the applicant under Sec. 314.107, unless the existence of the 
application or abbreviated application has been previously publicly 
disclosed or acknowledged.
    (c) If the existence of an unapproved application or abbreviated 
application has not been publicly disclosed or acknowledged, no data or 
information in the application or abbreviated application is available 
for public disclosure.
    (d)(1) If the existence of an application or abbreviated application 
has been publicly disclosed or acknowledged before the agency sends an 
approval letter to the applicant, no data or information contained in 
the application or abbreviated application is available for public 
disclosure before the agency sends an approval letter,

[[Page 170]]

but the Commissioner may, in his or her discretion, disclose a summary 
of selected portions of the safety and effectiveness data that are 
appropriate for public consideration of a specific pending issue; for 
example, for consideration of an open session of an FDA advisory 
committee.
    (2) Notwithstanding paragraph (d)(1) of this section, FDA will make 
available to the public upon request the information in the 
investigational new drug application that was required to be filed in 
Docket Number 95S-0158 in the Division of Dockets Management (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852, for investigations involving an exception from informed consent 
under Sec. 50.24 of this chapter. Persons wishing to request this 
information shall submit a request under the Freedom of Information Act.
    (e) After FDA sends an approval letter to the applicant, the 
following data and information in the application or abbreviated 
application are immediately available for public disclosure, unless the 
applicant shows that extraordinary circumstances exist. A list of 
approved applications and abbreviated applications, entitled ``Approved 
Drug Products with Therapeutic Equivalence Evaluations,'' is available 
from the Government Printing Office, Washington, DC 20402. This list is 
updated monthly.
    (1) [Reserved]
    (2) If the application applies to a new drug, all safety and 
effectiveness data previously disclosed to the public as set forth in 
Sec. 20.81 and a summary or summaries of the safety and effectiveness 
data and information submitted with or incorporated by reference in the 
application. The summaries do not constitute the full reports of 
investigations under section 505(b)(1) of the act (21 U.S.C. 355(b)(1)) 
on which the safety or effectiveness of the drug may be approved. The 
summaries consist of the following:
    (i) For an application approved before July 1, 1975, internal agency 
records that describe safety and effectiveness data and information, for 
example, a summary of the basis for approval or internal reviews of the 
data and information, after deletion of the following:
    (a) Names and any information that would identify patients or test 
subjects or investigators.
    (b) Any inappropriate gratuitous comments unnecessary to an 
objective analysis of the data and information.
    (ii) For an application approved on or after July 1, 1975, a Summary 
Basis of Approval (SBA) document that contains a summary of the safety 
and effectiveness data and information evaluated by FDA during the drug 
approval process. The SBA is prepared in one of the following ways:
    (a) Before approval of the application, the applicant may prepare a 
draft SBA which the Center for Drug Evaluation and Research will review 
and may revise. The draft may be submitted with the application or as an 
amendment.
    (b) The Center for Drug Evaluation and Research may prepare the SBA.
    (3) A protocol for a test or study, unless it is shown to fall 
within the exemption established for trade secrets and confidential 
commercial information in Sec. 20.61.
    (4) Adverse reaction reports, product experience reports, consumer 
complaints, and other similar data and information after deletion of the 
following:
    (i) Names and any information that would identify the person using 
the product.
    (ii) Names and any information that would identify any third party 
involved with the report, such as a physician or hospital or other 
institution.
    (5) A list of all active ingredients and any inactive ingredients 
previously disclosed to the public as set forth in Sec. 20.81.
    (6) An assay procedure or other analytical procedure, unless it 
serves no regulatory or compliance purpose and is shown to fall within 
the exemption established for trade secrets and confidential commercial 
information in Sec. 20.61.
    (7) All correspondence and written summaries of oral discussions 
between FDA and the applicant relating to the application, under the 
provisions of part 20.

[[Page 171]]

    (f) All safety and effectiveness data and information which have 
been submitted in an application and which have not previously been 
disclosed to the public are available to the public, upon request, at 
the time any one of the following events occurs unless extraordinary 
circumstances are shown:
    (1) No work is being or will be undertaken to have the application 
approved.
    (2) A final determination is made that the application is not 
approvable and all legal appeals have been exhausted.
    (3) Approval of the application is withdrawn and all legal appeals 
have been exhausted.
    (4) A final determination has been made that the drug is not a new 
drug.
    (5) For applications submitted under section 505(b) of the act, the 
effective date of the approval of the first abbreviated application 
submitted under section 505(j) of the act which refers to such drug, or 
the date on which the approval of an abbreviated application under 
section 505(j) of the act which refers to such drug could be made 
effective if such an abbreviated application had been submitted.
    (6) For abbreviated applications submitted under section 505(j) of 
the act, when FDA sends an approval letter to the applicant.
    (g) The following data and information in an application or 
abbreviated application are not available for public disclosure unless 
they have been previously disclosed to the public as set forth in Sec. 
20.81 of this chapter or they relate to a product or ingredient that has 
been abandoned and they do not represent a trade secret or confidential 
commercial or financial information under Sec. 20.61 of this chapter:
    (1) Manufacturing methods or processes, including quality control 
procedures.
    (2) Production, sales distribution, and similar data and 
information, except that any compilation of that data and information 
aggregated and prepared in a way that does not reveal data or 
information which is not available for public disclosure under this 
provision is available for public disclosure.
    (3) Quantitative or semiquantitative formulas.
    (h) The compilations of information specified in Sec. 20.117 are 
available for public disclosure.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 
FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Oct. 
2, 1996; 64 FR 26698, May 13, 1998; 64 FR 402, Jan. 5, 1999; 66 FR 1832, 
Jan. 10, 2001; 68 FR 24879, May 9, 2003; 69 FR 18766, Apr. 8, 2004; 73 
FR 39610, July 10, 2008]



Sec. 314.440  Addresses for applications and abbreviated applications.

    (a) Applicants shall send applications, abbreviated applications, 
and other correspondence relating to matters covered by this part, 
except for products listed in paragraph (b) of this section, to the 
appropriate office identified below:
    (1) Except as provided in paragraph (a)(4) of this section, an 
application under Sec. 314.50 or Sec. 314.54 submitted for filing 
should be directed to the Central Document Room, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266. Applicants may obtain information about 
folders for binding applications on the Internet at http://www.fda.gov/
cder/ddms/binders.htm. After FDA has filed the application, the agency 
will inform the applicant which division is responsible for the 
application. Amendments, supplements, resubmissions, requests for 
waivers, and other correspondence about an application that has been 
filed should be addressed to 5901-B Ammendale Rd., Beltsville, MD 20705-
1266, to the attention of the appropriate division.
    (2) Except as provided in paragraph (a)(4) of this section, an 
abbreviated application under Sec. 314.94, and amendments, supplements, 
and resubmissions should be directed to the Office of Generic Drugs 
(HFD-600), Center for Drug Evaluation and Research, Food and Drug 
Administration, Metro Park North VII, 7620 Standish Pl., Rockville, MD 
20855. This includes items sent by parcel post or overnight courier 
service. Correspondence not associated with an abbreviated application 
should be addressed specifically to the intended office or division and 
to the person as follows: Office of Generic Drugs,

[[Page 172]]

Center for Drug Evaluation and Research, Food and Drug Administration, 
Attn: [insert name of person], Metro Park North II, HFD-[insert mail 
code of office or division], 7500 Standish Place, rm. 150, Rockville, MD 
20855. The mail code for the Office of Generic Drugs is HFD-600, the 
mail codes for the Divisions of Chemistry I, II, and III are HFD-620, 
HFD-640, and HFD-630, respectively, and the mail code for the Division 
of Bioequivalence is HFD-650.
    (3) A request for an opportunity for a hearing under Sec. 314.110 
on the question of whether there are grounds for denying approval of an 
application, except an application under paragraph (b) of this section, 
should be directed to the Associate Director for Policy (HFD-5).
    (4) The field copy of an application, an abbreviated application, 
amendments, supplements, resubmissions, requests for waivers, and other 
correspondence about an application and an abbreviated application shall 
be sent to the applicant's home FDA district office, except that a 
foreign applicant shall send the field copy to the appropriate address 
identified in paragraphs (a)(1) and (a)(2) of this section.
    (b) Applicants shall send applications and other correspondence 
relating to matters covered by this part for the drug products listed 
below to the Document Control Center (HFM-99), Center for Biologics 
Evaluation and Research, 1401 Rockville Pike, suite 200N, Rockville, MD 
20852-1448, except applicants shall send a request for an opportunity 
for a hearing under Sec. 314.110 on the question of whether there are 
grounds for denying approval of an application to the Director, Center 
for Biologics Evaluation and Research (HFM-1), at the same address.
    (1) Ingredients packaged together with containers intended for the 
collection, processing, or storage of blood and blood components;
    (2) Plasma volume expanders and hydroxyethyl starch for 
leukapheresis;
    (3) Blood component processing solutions and shelf life extenders; 
and
    (4) Oxygen carriers.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 
FR 11581, Mar. 29, 1990; 57 FR 17997, Apr. 28, 1992; 58 FR 47352, Sept. 
8, 1993; 62 FR 43639, Aug. 15, 1997; 69 FR 13473, Mar. 23, 2004; 70 FR 
14981, Mar. 24, 2005; 73 FR 39610, July 10, 2008; 74 FR 13113, Mar. 26, 
2009; 75 FR 37295, June 29, 2010]



Sec. 314.445  Guidance documents.

    (a) FDA has made available guidance documents under Sec. 10.115 of 
this chapter to help you to comply with certain requirements of this 
part.
    (b) The Center for Drug Evaluation and Research (CDER) maintains a 
list of guidance documents that apply to CDER's regulations. The list is 
maintained on the Internet and is published annually in the Federal 
Register. A request for a copy of the CDER list should be directed to 
the Office of Training and Communications, Division of Drug Information, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
10903 New Hampshire Ave., Silver Spring, MD 20993-0002.

[65 FR 56480, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009]



    Subpart H_Accelerated Approval of New Drugs for Serious or Life-
                          Threatening Illnesses

    Source: 57 FR 58958, Dec. 11, 1992, unless otherwise noted.



Sec. 314.500  Scope.

    This subpart applies to certain new drug products that have been 
studied for their safety and effectiveness in treating serious or life-
threatening illnesses and that provide meaningful therapeutic benefit to 
patients over existing treatments (e.g., ability to treat patients 
unresponsive to, or intolerant of, available therapy, or improved 
patient response over available therapy).

[57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999]



Sec. 314.510  Approval based on a surrogate endpoint or on an effect
on a clinical endpoint other than survival or irreversible morbidity.

    FDA may grant marketing approval for a new drug product on the basis 
of

[[Page 173]]

adequate and well-controlled clinical trials establishing that the drug 
product has an effect on a surrogate endpoint that is reasonably likely, 
based on epidemiologic, therapeutic, pathophysiologic, or other 
evidence, to predict clinical benefit or on the basis of an effect on a 
clinical endpoint other than survival or irreversible morbidity. 
Approval under this section will be subject to the requirement that the 
applicant study the drug further, to verify and describe its clinical 
benefit, where there is uncertainty as to the relation of the surrogate 
endpoint to clinical benefit, or of the observed clinical benefit to 
ultimate outcome. Postmarketing studies would usually be studies already 
underway. When required to be conducted, such studies must also be 
adequate and well-controlled. The applicant shall carry out any such 
studies with due diligence.



Sec. 314.520  Approval with restrictions to assure safe use.

    (a) If FDA concludes that a drug product shown to be effective can 
be safely used only if distribution or use is restricted, FDA will 
require such postmarketing restrictions as are needed to assure safe use 
of the drug product, such as:
    (1) Distribution restricted to certain facilities or physicians with 
special training or experience; or
    (2) Distribution conditioned on the performance of specified medical 
procedures.
    (b) The limitations imposed will be commensurate with the specific 
safety concerns presented by the drug product.



Sec. 314.530  Withdrawal procedures.

    (a) For new drugs approved under Sec. Sec. 314.510 and 314.520, FDA 
may withdraw approval, following a hearing as provided in part 15 of 
this chapter, as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical benefit;
    (2) The applicant fails to perform the required postmarketing study 
with due diligence;
    (3) Use after marketing demonstrates that postmarketing restrictions 
are inadequate to assure safe use of the drug product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
agreed upon;
    (5) The promotional materials are false or misleading; or
    (6) Other evidence demonstrates that the drug product is not shown 
to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Drug Evaluation and Research will give the applicant notice of an 
opportunity for a hearing on the Center's proposal to withdraw the 
approval of an application approved under Sec. 314.510 or Sec. 
314.520. The notice, which will ordinarily be a letter, will state 
generally the reasons for the action and the proposed grounds for the 
order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of the 
notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to rely 
at the hearing.
    (d) Separation of functions. Separation of functions (as specified 
in Sec. 10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of the Center may question any person during or at

[[Page 174]]

the conclusion of the person's presentation. No other person attending 
the hearing may question a person making a presentation. The presiding 
officer may, as a matter of discretion, permit questions to be submitted 
to the presiding officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner's decision constitutes final 
agency action from which the applicant may petition for judicial review. 
Before requesting an order from a court for a stay of action pending 
review, an applicant must first submit a petition for a stay of action 
under Sec. 10.35 of this chapter.

[57 FR 58958, Dec. 11, 1992, as amended at 64 FR 402, Jan. 5, 1999]



Sec. 314.540  Postmarketing safety reporting.

    Drug products approved under this program are subject to the 
postmarketing recordkeeping and safety reporting applicable to all 
approved drug products, as provided in Sec. Sec. 314.80 and 314.81.



Sec. 314.550  Promotional materials.

    For drug products being considered for approval under this subpart, 
unless otherwise informed by the agency, applicants must submit to the 
agency for consideration during the preapproval review period copies of 
all promotional materials, including promotional labeling as well as 
advertisements, intended for dissemination or publication within 120 
days following marketing approval. After 120 days following marketing 
approval, unless otherwise informed by the agency, the applicant must 
submit promotional materials at least 30 days prior to the intended time 
of initial dissemination of the labeling or initial publication of the 
advertisement.



Sec. 314.560  Termination of requirements.

    If FDA determines after approval that the requirements established 
in Sec. 314.520, Sec. 314.530, or Sec. 314.550 are no longer 
necessary for the safe and effective use of a drug product, it will so 
notify the applicant. Ordinarily, for drug products approved under Sec. 
314.510, these requirements will no longer apply when FDA determines 
that the required postmarketing study verifies and describes the drug 
product's clinical benefit and the drug product would be appropriate for 
approval under traditional procedures. For drug products approved under 
Sec. 314.520, the restrictions would no longer apply when FDA 
determines that safe use of the drug product can be assured through 
appropriate labeling. FDA also retains the discretion to remove specific 
postapproval requirements upon review of a petition submitted by the 
sponsor in accordance with Sec. 10.30.



  Subpart I_Approval of New Drugs When Human Efficacy Studies Are Not 
                           Ethical or Feasible

    Source: 67 FR 37995, May 31, 2002, unless otherwise noted.



Sec. 314.600  Scope.

    This subpart applies to certain new drug products that have been 
studied for their safety and efficacy in ameliorating or preventing 
serious or life-threatening conditions caused by exposure to lethal or 
permanently disabling toxic biological, chemical, radiological, or 
nuclear substances. This subpart applies only to those new drug products 
for which: Definitive human efficacy studies cannot be conducted because 
it would be unethical to deliberately expose healthy human volunteers to 
a lethal or permanently disabling toxic biological, chemical, 
radiological, or nuclear substance; and field trials to study the 
product's effectiveness after an accidental or hostile exposure have not 
been feasible. This subpart does not apply to products that can be 
approved based on efficacy standards described elsewhere in FDA's 
regulations (e.g., accelerated approval based on surrogate markers or 
clinical endpoints other than survival or irreversible morbidity), nor 
does it address the safety evaluation for the products to which it does 
apply.



Sec. 314.610  Approval based on evidence of effectiveness from 
studies in animals.

    (a) FDA may grant marketing approval for a new drug product for 
which safety has been established and for which the requirements of 
Sec. 314.600 are

[[Page 175]]

met based on adequate and well-controlled animal studies when the 
results of those animal studies establish that the drug product is 
reasonably likely to produce clinical benefit in humans. In assessing 
the sufficiency of animal data, the agency may take into account other 
data, including human data, available to the agency. FDA will rely on 
the evidence from studies in animals to provide substantial evidence of 
the effectiveness of these products only when:
    (1) There is a reasonably well-understood pathophysiological 
mechanism of the toxicity of the substance and its prevention or 
substantial reduction by the product;
    (2) The effect is demonstrated in more than one animal species 
expected to react with a response predictive for humans, unless the 
effect is demonstrated in a single animal species that represents a 
sufficiently well-characterized animal model for predicting the response 
in humans;
    (3) The animal study endpoint is clearly related to the desired 
benefit in humans, generally the enhancement of survival or prevention 
of major morbidity; and
    (4) The data or information on the kinetics and pharmacodynamics of 
the product or other relevant data or information, in animals and 
humans, allows selection of an effective dose in humans.
    (b) Approval under this subpart will be subject to three 
requirements:
    (1) Postmarketing studies. The applicant must conduct postmarketing 
studies, such as field studies, to verify and describe the drug's 
clinical benefit and to assess its safety when used as indicated when 
such studies are feasible and ethical. Such postmarketing studies would 
not be feasible until an exigency arises. When such studies are 
feasible, the applicant must conduct such studies with due diligence. 
Applicants must include as part of their application a plan or approach 
to postmarketing study commitments in the event such studies become 
ethical and feasible.
    (2) Approval with restrictions to ensure safe use. If FDA concludes 
that a drug product shown to be effective under this subpart can be 
safely used only if distribution or use is restricted, FDA will require 
such postmarketing restrictions as are needed to ensure safe use of the 
drug product, commensurate with the specific safety concerns presented 
by the drug product, such as:
    (i) Distribution restricted to certain facilities or health care 
practitioners with special training or experience;
    (ii) Distribution conditioned on the performance of specified 
medical procedures, including medical followup; and
    (iii) Distribution conditioned on specified recordkeeping 
requirements.
    (3) Information to be provided to patient recipients. For drug 
products or specific indications approved under this subpart, applicants 
must prepare, as part of their proposed labeling, labeling to be 
provided to patient recipients. The patient labeling must explain that, 
for ethical or feasibility reasons, the drug's approval was based on 
efficacy studies conducted in animals alone and must give the drug's 
indication(s), directions for use (dosage and administration), 
contraindications, a description of any reasonably foreseeable risks, 
adverse reactions, anticipated benefits, drug interactions, and any 
other relevant information required by FDA at the time of approval. The 
patient labeling must be available with the product to be provided to 
patients prior to administration or dispensing of the drug product for 
the use approved under this subpart, if possible.



Sec. 314.620  Withdrawal procedures.

    (a) Reasons to withdraw approval. For new drugs approved under this 
subpart, FDA may withdraw approval, following a hearing as provided in 
part 15 of this chapter, as modified by this section, if:
    (1) A postmarketing clinical study fails to verify clinical benefit;
    (2) The applicant fails to perform the postmarketing study with due 
diligence;
    (3) Use after marketing demonstrates that postmarketing restrictions 
are inadequate to ensure safe use of the drug product;
    (4) The applicant fails to adhere to the postmarketing restrictions 
applied at the time of approval under this subpart;
    (5) The promotional materials are false or misleading; or

[[Page 176]]

    (6) Other evidence demonstrates that the drug product is not shown 
to be safe or effective under its conditions of use.
    (b) Notice of opportunity for a hearing. The Director of the Center 
for Drug Evaluation and Research (CDER) will give the applicant notice 
of an opportunity for a hearing on CDER's proposal to withdraw the 
approval of an application approved under this subpart. The notice, 
which will ordinarily be a letter, will state generally the reasons for 
the action and the proposed grounds for the order.
    (c) Submission of data and information. (1) If the applicant fails 
to file a written request for a hearing within 15 days of receipt of the 
notice, the applicant waives the opportunity for a hearing.
    (2) If the applicant files a timely request for a hearing, the 
agency will publish a notice of hearing in the Federal Register in 
accordance with Sec. Sec. 12.32(e) and 15.20 of this chapter.
    (3) An applicant who requests a hearing under this section must, 
within 30 days of receipt of the notice of opportunity for a hearing, 
submit the data and information upon which the applicant intends to rely 
at the hearing.
    (d) Separation of functions. Separation of functions (as specified 
in Sec. 10.55 of this chapter) will not apply at any point in 
withdrawal proceedings under this section.
    (e) Procedures for hearings. Hearings held under this section will 
be conducted in accordance with the provisions of part 15 of this 
chapter, with the following modifications:
    (1) An advisory committee duly constituted under part 14 of this 
chapter will be present at the hearing. The committee will be asked to 
review the issues involved and to provide advice and recommendations to 
the Commissioner of Food and Drugs.
    (2) The presiding officer, the advisory committee members, up to 
three representatives of the applicant, and up to three representatives 
of CDER may question any person during or at the conclusion of the 
person's presentation. No other person attending the hearing may 
question a person making a presentation. The presiding officer may, as a 
matter of discretion, permit questions to be submitted to the presiding 
officer for response by a person making a presentation.
    (f) Judicial review. The Commissioner of Food and Drugs' decision 
constitutes final agency action from which the applicant may petition 
for judicial review. Before requesting an order from a court for a stay 
of action pending review, an applicant must first submit a petition for 
a stay of action under Sec. 10.35 of this chapter.



Sec. 314.630  Postmarketing safety reporting.

    Drug products approved under this subpart are subject to the 
postmarketing recordkeeping and safety reporting requirements applicable 
to all approved drug products, as provided in Sec. Sec. 314.80 and 
314.81.



Sec. 314.640  Promotional materials.

    For drug products being considered for approval under this subpart, 
unless otherwise informed by the agency, applicants must submit to the 
agency for consideration during the preapproval review period copies of 
all promotional materials, including promotional labeling as well as 
advertisements, intended for dissemination or publication within 120 
days following marketing approval. After 120 days following marketing 
approval, unless otherwise informed by the agency, the applicant must 
submit promotional materials at least 30 days prior to the intended time 
of initial dissemination of the labeling or initial publication of the 
advertisement.



Sec. 314.650  Termination of requirements.

    If FDA determines after approval under this subpart that the 
requirements established in Sec. Sec. 314.610(b)(2), 314.620, and 
314.630 are no longer necessary for the safe and effective use of a drug 
product, FDA will so notify the applicant. Ordinarily, for drug products 
approved under Sec. 314.610, these requirements will no longer apply 
when FDA determines that the postmarketing study verifies and describes 
the drug product's clinical benefit. For drug products approved under 
Sec. 314.610, the restrictions would no longer apply when FDA 
determines that safe use of the drug product can be ensured through 
appropriate labeling. FDA also

[[Page 177]]

retains the discretion to remove specific postapproval requirements upon 
review of a petition submitted by the sponsor in accordance with Sec. 
10.30 of this chapter.



PART 315_DIAGNOSTIC RADIOPHARMACEUTICALS--Table of Contents



Sec.
315.1 Scope.
315.2 Definition.
315.3 General factors relevant to safety and effectiveness.
315.4 Indications.
315.5 Evaluation of effectiveness.
315.6 Evaluation of safety.

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 374, 379e; 
sec. 122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C. 355 note).

    Source: 64 FR 26667, May 17, 1999, unless otherwise noted.



Sec. 315.1  Scope.

    The regulations in this part apply to radiopharmaceuticals intended 
for in vivo administration for diagnostic and monitoring use. They do 
not apply to radiopharmaceuticals intended for therapeutic purposes. In 
situations where a particular radiopharmaceutical is proposed for both 
diagnostic and therapeutic uses, the radiopharmaceutical must be 
evaluated taking into account each intended use.



Sec. 315.2  Definition.

    For purposes of this part, diagnostic radiopharmaceutical means:
    (a) An article that is intended for use in the diagnosis or 
monitoring of a disease or a manifestation of a disease in humans and 
that exhibits spontaneous disintegration of unstable nuclei with the 
emission of nuclear particles or photons; or
    (b) Any nonradioactive reagent kit or nuclide generator that is 
intended to be used in the preparation of such article as defined in 
paragraph (a) of this section.



Sec. 315.3  General factors relevant to safety and effectiveness.

    FDA's determination of the safety and effectiveness of a diagnostic 
radiopharmaceutical includes consideration of the following:
    (a) The proposed use of the diagnostic radiopharmaceutical in the 
practice of medicine,
    (b) The pharmacological and toxicological activity of the diagnostic 
radiopharmaceutical (including any carrier or ligand component of the 
diagnostic radiopharmaceutical), and
    (c) The estimated absorbed radiation dose of the diagnostic 
radiopharmaceutical.



Sec. 315.4  Indications.

    (a) For diagnostic radiopharmaceuticals, the categories of proposed 
indications for use include, but are not limited to, the following:
    (1) Structure delineation;
    (2) Functional, physiological, or biochemical assessment;
    (3) Disease or pathology detection or assessment; and
    (4) Diagnostic or therapeutic patient management.
    (b) Where a diagnostic radiopharmaceutical is not intended to 
provide disease-specific information, the proposed indications for use 
may refer to a biochemical, physiological, anatomical, or pathological 
process or to more than one disease or condition.



Sec. 315.5  Evaluation of effectiveness.

    (a) The effectiveness of a diagnostic radiopharmaceutical is 
assessed by evaluating its ability to provide useful clinical 
information related to its proposed indications for use. The method of 
this evaluation varies depending upon the proposed indication(s) and may 
use one or more of the following criteria:
    (1) The claim of structure delineation is established by 
demonstrating in a defined clinical setting the ability to locate 
anatomical structures and to characterize their anatomy.
    (2) The claim of functional, physiological, or biochemical 
assessment is established by demonstrating in a defined clinical setting 
reliable measurement of function(s) or physiological, biochemical, or 
molecular process(es).
    (3) The claim of disease or pathology detection or assessment is 
established by demonstrating in a defined clinical setting that the 
diagnostic radiopharmaceutical has sufficient accuracy

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in identifying or characterizing the disease or pathology.
    (4) The claim of diagnostic or therapeutic patient management is 
established by demonstrating in a defined clinical setting that the test 
is useful in diagnostic or therapeutic patient management.
    (5) For a claim that does not fall within the indication categories 
identified in Sec. 315.4, the applicant or sponsor should consult FDA 
on how to establish the effectiveness of the diagnostic 
radiopharmaceutical for the claim.
    (b) The accuracy and usefulness of the diagnostic information is 
determined by comparison with a reliable assessment of actual clinical 
status. A reliable assessment of actual clinical status may be provided 
by a diagnostic standard or standards of demonstrated accuracy. In the 
absence of such diagnostic standard(s), the actual clinical status must 
be established in another manner, e.g., patient followup.



Sec. 315.6  Evaluation of safety.

    (a) Factors considered in the safety assessment of a diagnostic 
radiopharmaceutical include, among others, the following:
    (1) The radiation dose;
    (2) The pharmacology and toxicology of the radiopharmaceutical, 
including any radionuclide, carrier, or ligand;
    (3) The risks of an incorrect diagnostic determination;
    (4) The adverse reaction profile of the drug;
    (5) Results of human experience with the radiopharmaceutical for 
other uses; and
    (6) Results of any previous human experience with the carrier or 
ligand of the radiopharmaceutical when the same chemical entity as the 
carrier or ligand has been used in a previously studied product.
    (b) The assessment of the adverse reaction profile includes, but is 
not limited to, an evaluation of the potential of the diagnostic 
radiopharmaceutical, including the carrier or ligand, to elicit the 
following:
    (1) Allergic or hypersensitivity responses,
    (2) Immunologic responses,
    (3) Changes in the physiologic or biochemical function of the target 
and nontarget tissues, and
    (4) Clinically detectable signs or symptoms.
    (c)(1) To establish the safety of a diagnostic radiopharmaceutical, 
FDA may require, among other information, the following types of data:
    (i) Pharmacology data,
    (ii) Toxicology data,
    (iii) Clinical adverse event data, and
    (iv) Radiation safety assessment.
    (2) The amount of new safety data required will depend on the 
characteristics of the product and available information regarding the 
safety of the diagnostic radiopharmaceutical, and its carrier or ligand, 
obtained from other studies and uses. Such information may include, but 
is not limited to, the dose, route of administration, frequency of use, 
half-life of the ligand or carrier, half-life of the radionuclide, and 
results of clinical and preclinical studies. FDA will establish 
categories of diagnostic radiopharmaceuticals based on defined 
characteristics relevant to risk and will specify the amount and type of 
safety data that are appropriate for each category (e.g., required 
safety data may be limited for diagnostic radiopharmaceuticals with a 
well established, low-risk profile). Upon reviewing the relevant product 
characteristics and safety information, FDA will place each diagnostic 
radiopharmaceutical into the appropriate safety risk category.
    (d) Radiation safety assessment. The radiation safety assessment 
must establish the radiation dose of a diagnostic radiopharmaceutical by 
radiation dosimetry evaluations in humans and appropriate animal models. 
The maximum tolerated dose need not be established.



PART 316_ORPHAN DRUGS--Table of Contents



                      Subpart A_General Provisions

Sec.
316.1 Scope of this part.
316.2 Purpose.
316.3 Definitions.
316.4 Address for submissions.

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  Subpart B_Written Recommendations for Investigations of Orphan Drugs

316.10 Content and format of a request for written recommendations.
316.12 Providing written recommendations.
316.14 Refusal to provide written recommendations.

                 Subpart C_Designation of an Orphan Drug

316.20 Content and format of a request for orphan-drug designation.
316.21 Verification of orphan-drug status.
316.22 Permanent-resident agent for foreign sponsor.
316.23 Timing of requests for orphan-drug designation; designation of 
          already approved drugs.
316.24 Granting orphan-drug designation.
316.25 Refusal to grant orphan-drug designation.
316.26 Amendment to orphan-drug designation.
316.27 Change in ownership of orphan-drug designation.
316.28 Publication of orphan-drug designations.
316.29 Revocation of orphan-drug designation.
316.30 Annual reports of holder of orphan-drug designation.

                Subpart D_Orphan-drug Exclusive Approval

316.31 Scope of orphan-drug exclusive approval.
316.34 FDA recognition of exclusive approval.
316.36 Insufficient quantities of orphan drugs.

               Subpart E_Open Protocols for Investigations

316.40 Treatment use of a designated orphan drug.

                  Subpart F_Availability of Information

316.50 Guidance documents.
316.52 Availability for public disclosure of data and information in 
          requests and applications.

    Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

    Source: 57 FR 62085, Dec. 29, 1992, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 316 appear at 69 FR 
13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 316.1  Scope of this part.

    (a) This part implements sections 525, 526, 527, and 528 of the act 
and provides procedures to encourage and facilitate the development of 
drugs for rare diseases or conditions, including biological products and 
antibiotics. This part sets forth the procedures and requirements for:
    (1) Submissions to FDA of:
    (i) Requests for recommendations for investigations of drugs for 
rare diseases or conditions;
    (ii) Requests for designation of a drug for a rare disease or 
condition; and
    (iii) Requests for gaining exclusive approval for a drug product for 
a rare disease or condition.
    (2) Allowing a sponsor to provide an investigational drug product 
under a treatment protocol to patients who need the drug for treatment 
of a rare disease or condition.
    (b) This part does not apply to food, medical devices, or drugs for 
veterinary use.
    (c) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21, unless otherwise 
noted.



Sec. 316.2  Purpose.

    The purpose of this part is to establish standards and procedures 
for determining eligibility for the benefits provided for in section 2 
of the Orphan Drug Act, including written recommendations for 
investigations of orphan drugs, a 7-year period of exclusive marketing, 
and treatment use of investigational orphan drugs. This part is also 
intended to satisfy Congress' requirements that FDA promulgate 
procedures for the implementation of sections 525(a) and 526(a) of the 
act.



Sec. 316.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the act apply to those terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Act means the Federal Food, Drug, and Cosmetic Act as amended by 
section 2 of the Orphan Drug Act (sections 525-528 (21 U.S.C. 360aa-
360dd)).

[[Page 180]]

    (2) Active moiety means the molecule or ion, excluding those 
appended portions of the molecule that cause the drug to be an ester, 
salt (including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological action of 
the drug substance.
    (3) Clinically superior means that a drug is shown to provide a 
significant therapeutic advantage over and above that provided by an 
approved orphan drug (that is otherwise the same drug) in one or more of 
the following ways:
    (i) Greater effectiveness than an approved orphan drug (as assessed 
by effect on a clinically meaningful endpoint in adequate and well 
controlled clinical trials). Generally, this would represent the same 
kind of evidence needed to support a comparative effectiveness claim for 
two different drugs; in most cases, direct comparative clinical trials 
would be necessary; or
    (ii) Greater safety in a substantial portion of the target 
populations, for example, by the elimination of an ingredient or 
contaminant that is associated with relatively frequent adverse effects. 
In some cases, direct comparative clinical trials will be necessary; or
    (iii) In unusual cases, where neither greater safety nor greater 
effectiveness has been shown, a demonstration that the drug otherwise 
makes a major contribution to patient care.
    (4) Director means the Director of FDA's Office of Orphan Products 
Development.
    (5) FDA means the Food and Drug Administration.
    (6) Holder means the sponsor in whose name an orphan drug is 
designated and approved.
    (7) IND means an investigational new drug application under part 312 
of this chapter.
    (8) Manufacturer means any person or agency engaged in the 
manufacture of a drug that is subject to investigation and approval 
under the act or the biologics provisions of the Public Health Service 
Act (42 U.S.C. 262-263).
    (9) Marketing application means an application for approval of a new 
drug filed under section 505(b) of the act or an application for a 
biologics license submitted under section 351 of the Public Health 
Service Act (42 U.S.C. 262).
    (10) Orphan drug means a drug intended for use in a rare disease or 
condition as defined in section 526 of the act.
    (11) Orphan-drug designation means FDA's act of granting a request 
for designation under section 526 of the act.
    (12) Orphan-drug exclusive approval or exclusive approval means 
that, effective on the date of FDA approval as stated in the approval 
letter of a marketing application for a sponsor of a designated orphan 
drug, no approval will be given to a subsequent sponsor of the same drug 
product for the same indication for 7 years, except as otherwise 
provided by law or in this part.
    (13) Same drug means:
    (i) If it is a drug composed of small molecules, a drug that 
contains the same active moiety as a previously approved drug and is 
intended for the same use as the previously approved drug, even if the 
particular ester or salt (including a salt with hydrogen or coordination 
bonds) or other noncovalent derivative such as a complex, chelate or 
clathrate has not been previously approved, except that if the 
subsequent drug can be shown to be clinically superior to the first 
drug, it will not be considered to be the same drug.
    (ii) If it is a drug composed of large molecules (macromolecules), a 
drug that contains the same principal molecular structural features (but 
not necessarily all of the same structural features) and is intended for 
the same use as a previously approved drug, except that, if the 
subsequent drug can be shown to be clinically superior, it will not be 
considered to be the same drug. This criterion will be applied as 
follows to different kinds of macromolecules:
    (A) Two protein drugs would be considered the same if the only 
differences in structure between them were due to post-translational 
events or infidelity of translation or transcription or were minor 
differences in amino acid sequence; other potentially important 
differences, such as different glycosylation patterns or different 
tertiary structures, would not cause the drugs to be considered 
different unless the

[[Page 181]]

differences were shown to be clinically superior.
    (B) Two polysaccharide drugs would be considered the same if they 
had identical saccharide repeating units, even if the number of units 
were to vary and even if there were postpolymerization modifications, 
unless the subsequent drug could be shown to be clinically superior.
    (C) Two polynucleotide drugs consisting of two or more distinct 
nucleotides would be considered the same if they had an identical 
sequence of purine and pyrimidine bases (or their derivatives) bound to 
an identical sugar backbone (ribose, deoxyribose, or modifications of 
these sugars), unless the subsequent drug were shown to be clinically 
superior.
    (D) Closely related, complex partly definable drugs with similar 
therapeutic intent, such as two live viral vaccines for the same 
indication, would be considered the same unless the subsequent drug was 
shown to be clinically superior.
    (14) Sponsor means the entity that assumes responsibility for a 
clinical or nonclinical investigation of a drug, including the 
responsibility for compliance with applicable provisions of the act and 
regulations. A sponsor may be an individual, partnership, corporation, 
or Government agency and may be a manufacturer, scientific institution, 
or an investigator regularly and lawfully engaged in the investigation 
of drugs. For purposes of the Orphan Drug Act, FDA considers the real 
party or parties in interest to be a sponsor.

[57 FR 62085, Dec. 29, 1992, as amended at 64 FR 402, Jan. 5, 1999; 64 
FR 56449, Oct. 20, 1999]



Sec. 316.4  Address for submissions.

    All correspondence and requests for FDA action pursuant to the 
provisions of this rule should be addressed as follows: Office of Orphan 
Products Development (HF-35), Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857.



  Subpart B_Written Recommendations for Investigations of Orphan Drugs



Sec. 316.10  Content and format of a request for written recommendations.

    (a) A sponsor's request for written recommendations from FDA 
concerning the nonclinical and clinical investigations necessary for 
approval of a marketing application shall be submitted in the form and 
contain the information required in this section. FDA may require the 
sponsor to submit information in addition to that specified in paragraph 
(b) of this section if FDA determines that the sponsor's initial request 
does not contain adequate information on which to base recommendations.
    (b) A sponsor shall submit two copies of a completed, dated, and 
signed request for written recommendations that contains the following:
    (1) The sponsor's name and address.
    (2) A statement that the sponsor is requesting written 
recommendations on orphan-drug development under section 525 of the act.
    (3) The name of the sponsor's primary contact person and/or resident 
agent, and the person's title, address, and telephone number.
    (4) The generic name and trade name, if any, of the drug and a list 
of the drug product's components or description of the drug product's 
formulation, and chemical and physical properties.
    (5) The proposed dosage form and route of administration.
    (6) A description of the disease or condition for which the drug is 
proposed to be investigated and the proposed indication or indications 
for use for such disease or condition.
    (7) Current regulatory and marketing status and history of the drug 
product, including:
    (i) Whether the product is the subject of an IND or a marketing 
application (if the product is the subject of an IND or a marketing 
application, the IND or marketing application numbers should be stated 
and the investigational or approved indication or indications for use 
specified);
    (ii) Known marketing experience or investigational status outside 
the United States;

[[Page 182]]

    (iii) So far as is known or can be determined, all indications 
previously or currently under investigation anywhere;
    (iv) All adverse regulatory actions taken by the United States or 
foreign authorities.
    (8) The basis for concluding that the drug is for a disease or 
condition that is rare in the United States, including the following:
    (i) The size and other known demographic characteristics of the 
patient population affected and the source of this information.
    (ii) For drugs intended for diseases or conditions affecting 200,000 
or more people in the United States, or for a vaccine, diagnostic drug, 
or preventive drug that would be given to 200,000 or more persons per 
year, a summary of the sponsor's basis for believing that the disease or 
condition described in paragraph (b)(6) of this section occurs so 
infrequently that there is no reasonable expectation that the costs of 
drug development and marketing will be recovered in future sales of the 
drug in the United States. The estimated costs and sales data should be 
submitted as provided for in Sec. 316.21(c).
    (9) A summary and analysis of available data on the pharmacologic 
effects of the drug.
    (10) A summary and analysis of available nonclinical and clinical 
data pertinent to the drug and the disease to be studied including 
copies of pertinent published reports. When a drug proposed for orphan 
drug designation is intended to treat a life-threatening or severely 
debilitating illness, especially where no satisfactory alternative 
therapy exists, the sponsor may wish voluntarily to provide this 
information. A sponsor of such a drug may be entitled to expeditious 
development, evaluation, and marketing under 21 CFR part 312, subpart E.
    (11) An explanation of how the data summarized and analyzed under 
paragraphs (b)(9) and (b)(10) of this section support the rationale for 
use of the drug in the rare disease or condition.
    (12) A definition of the population from which subjects will be 
identified for clinical trials, if known.
    (13) A detailed outline of any protocols under which the drug has 
been or is being studied for the rare disease or condition and a summary 
and analysis of any available data from such studies.
    (14) The sponsor's proposal as to the scope of nonclinical and 
clinical investigations needed to establish the safety and effectiveness 
of the drug.
    (15) Detailed protocols for each proposed United States or foreign 
clinical investigation, if available.
    (16) Specific questions to be addressed by FDA in its 
recommendations for nonclinical laboratory studies and clinical 
investigations.

[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]



Sec. 316.12  Providing written recommendations.

    (a) FDA will provide the sponsor with written recommendations 
concerning the nonclinical laboratory studies and clinical 
investigations necessary for approval of a marketing application if none 
of the reasons described in Sec. 316.14 for refusing to do so applies.
    (b) When a sponsor seeks written recommendations at a stage of drug 
development at which advice on any clinical investigations, or on 
particular investigations would be premature, FDA's response may be 
limited to written recommendations concerning only nonclinical 
laboratory studies, or only certain of the clinical studies (e.g., Phase 
1 studies as described in Sec. 312.21 of this chapter). Prior to 
providing written recommendations for the clinical investigations 
required to achieve marketing approval, FDA may require that the results 
of the nonclinical laboratory studies or completed early clinical 
studies be submitted to FDA for agency review.



Sec. 316.14  Refusal to provide written recommendations.

    (a) FDA may refuse to provide written recommendations concerning the 
nonclinical laboratory studies and clinical investigations necessary for 
approval of a marketing application for any of the following reasons:
    (1) The information required to be submitted by Sec. 316.10(b) has 
not been submitted, or the information submitted is incomplete.

[[Page 183]]

    (2) There is insufficient information about:
    (i) The drug to identify the active moiety and its physical and 
chemical properties, if these characteristics can be determined; or
    (ii) The disease or condition to determine that the disease or 
condition is rare in the United States; or
    (iii) The reasons for believing that the drug may be useful for 
treating the rare disease or condition with that drug; or
    (iv) The regulatory and marketing history of the drug to determine 
the scope and type of investigations that have already been conducted on 
the drug for the rare disease or condition; or
    (v) The plan of study for establishing the safety and effectiveness 
of the drug for treatment of the rare disease or condition.
    (3) The specific questions for which the sponsor seeks the advice of 
the agency are unclear or are not sufficiently specific.
    (4) On the basis of the information submitted and on other 
information available to the agency, FDA determines that the disease or 
condition for which the drug is intended is not rare in the United 
States.
    (5) On the basis of the information submitted and on other 
information available to the agency, FDA determines that there is an 
inadequate basis for permitting investigational use of the drug under 
part 312 of this chapter for the rare disease or condition.
    (6) The request for information contains an untrue statement of 
material fact.
    (b) A refusal to provide written recommendations will be in writing 
and will include a statement of the reason for FDA's refusal. Where 
practicable, FDA will describe the information or material it requires 
or the conditions the sponsor must meet for FDA to provide 
recommendations.
    (c) Within 90 days after the date of a letter from FDA requesting 
additional information or material or setting forth the conditions that 
the sponsor is asked to meet, the sponsor shall either:
    (1) Provide the information or material or amend the request for 
written recommendations to meet the conditions sought by FDA; or
    (2) Withdraw the request for written recommendations. FDA will 
consider a sponsor's failure to respond within 90 days to an FDA letter 
requesting information or material or setting forth conditions to be met 
to be a withdrawal of the request for written recommendations.



                 Subpart C_Designation of an Orphan Drug



Sec. 316.20  Content and format of a request for orphan-drug designation.

    (a) A sponsor that submits a request for orphan-drug designation of 
a drug for a specified rare disease or condition shall submit each 
request in the form and containing the information required in paragraph 
(b) of this section. A sponsor may request orphan-drug designation of a 
previously unapproved drug, or of a new orphan indication for an already 
marketed drug. In addition, a sponsor of a drug that is otherwise the 
same drug as an already approved orphan drug may seek and obtain orphan-
drug designation for the subsequent drug for the same rare disease or 
condition if it can present a plausible hypothesis that its drug may be 
clinically superior to the first drug. More than one sponsor may receive 
orphan-drug designation of the same drug for the same rare disease or 
condition, but each sponsor seeking orphan-drug designation must file a 
complete request for designation as provided in paragraph (b) of this 
section.
    (b) A sponsor shall submit two copies of a completed, dated, and 
signed request for designation that contains the following:
    (1) A statement that the sponsor requests orphan-drug designation 
for a rare disease or condition, which shall be identified with 
specificity.
    (2) The name and address of the sponsor; the name of the sponsor's 
primary contact person and/or resident agent including title, address, 
and telephone number; the generic and trade name, if any, of the drug or 
drug product; and the name and address of the source of the drug if it 
is not manufactured by the sponsor.

[[Page 184]]

    (3) A description of the rare disease or condition for which the 
drug is being or will be investigated, the proposed indication or 
indications for use of the drug, and the reasons why such therapy is 
needed.
    (4) A description of the drug and a discussion of the scientific 
rationale for the use of the drug for the rare disease or condition, 
including all data from nonclinical laboratory studies, clinical 
investigations, and other relevant data that are available to the 
sponsor, whether positive, negative, or inconclusive. Copies of 
pertinent unpublished and published papers are also required.
    (5) Where the sponsor of a drug that is otherwise the same drug as 
an already-approved orphan drug seeks orphan-drug designation for the 
subsequent drug for the same rare disease or condition, an explanation 
of why the proposed variation may be clinically superior to the first 
drug.
    (6) Where a drug is under development for only a subset of persons 
with a particular disease or condition, a demonstration that the subset 
is medically plausible.
    (7) A summary of the regulatory status and marketing history of the 
drug in the United States and in foreign countries, e.g., IND and 
marketing application status and dispositions, what uses are under 
investigation and in what countries; for what indication is the drug 
approved in foreign countries; what adverse regulatory actions have been 
taken against the drug in any country.
    (8) Documentation, with appended authoritative references, to 
demonstrate that:
    (i) The disease or condition for which the drug is intended affects 
fewer than 200,000 people in the United States or, if the drug is a 
vaccine, diagnostic drug, or preventive drug, the persons to whom the 
drug will be administered in the United States are fewer than 200,000 
per year as specified in Sec. 316.21(b), or
    (ii) For a drug intended for diseases or conditions affecting 
200,000 or more people, or for a vaccine, diagnostic drug, or preventive 
drug to be administered to 200,000 or more persons per year in the 
United States, there is no reasonable expectation that costs of research 
and development of the drug for the indication can be recovered by sales 
of the drug in the United States as specified in Sec. 316.21(c).
    (9) A statement as to whether the sponsor submitting the request is 
the real party in interest of the development and the intended or actual 
production and sales of the product.
    (c) Any of the information previously provided by the sponsor to FDA 
under subpart B of this part may be referenced by specific page or 
location if it duplicates information required elsewhere in this 
section.



Sec. 316.21  Verification of orphan-drug status.

    (a) So that FDA can determine whether a drug qualifies for orphan-
drug designation under section 526(a) of the act, the sponsor shall 
include in its request to FDA for orphan-drug designation under Sec. 
316.20 either:
    (1) Documentation as described in paragraph (b) of this section that 
the number of people affected by the disease or condition for which the 
drug product is indicated is fewer than 200,000 persons; or
    (2) Documentation as described in paragraph (c) of this section that 
demonstrates that there is no reasonable expectation that the sales of 
the drug will be sufficient to offset the costs of developing the drug 
for the U.S. market and the costs of making the drug available in the 
United States.
    (b) For the purpose of documenting that the number of people 
affected by the disease or condition for which the drug product is 
indicated is less than 200,000 persons, ``prevalence'' is defined as the 
number of persons in the United States who have been diagnosed as having 
the disease or condition at the time of the submission of the request 
for orphan-drug designation. To document the number of persons in the 
United States who have the disease or condition for which the drug is to 
be indicated, the sponsor shall submit to FDA evidence showing:
    (1) The estimated prevalence of the disease or condition for which 
the drug is being developed, together with a list of the sources 
(including dates of information provided and literature citations) for 
the estimate;

[[Page 185]]

    (2) Upon request by FDA, the estimated prevalence of any other 
disease or condition for which the drug has already been approved or for 
which the drug is currently being developed, together with an 
explanation of the bases of these estimates; and
    (3) The estimated number of people to whom the drug will be 
administered annually if the drug is a vaccine or is a drug intended for 
diagnosis or prevention of a rare disease or condition, together with an 
explanation of the bases of these estimates (including dates of 
information provided and literature citations).
    (c) When submitting documentation that there is no reasonable 
expectation that costs of research and development of the drug for the 
disease or condition can be recovered by sales of the drug in the United 
States, the sponsor shall submit to FDA:
    (1) Data on all costs that the sponsor has incurred in the course of 
developing the drug for the U.S. market. These costs shall include, but 
are not limited to, nonclinical laboratory studies, clinical studies, 
dosage form development, record and report maintenance, meetings with 
FDA, determination of patentability, preparation of designation request, 
IND/marketing application preparation, distribution of the drug under a 
``treatment'' protocol, licensing costs, liability insurance, and 
overhead and depreciation. Furthermore, the sponsor shall demonstrate 
the reasonableness of the cost data. For example, if the sponsor has 
incurred costs for clinical investigations, the sponsor shall provide 
information on the number of investigations, the years in which they 
took place, and on the scope, duration, and number of patients that were 
involved in each investigation.
    (2) If the drug was developed wholly or in part outside the United 
States, in addition to the documentation listed in paragraph (c)(1) of 
this section:
    (i) Data on and justification for all costs that the sponsor has 
incurred outside of the United States in the course of developing the 
drug for the U.S. market. The justification, in addition to 
demonstrating the reasonableness of the cost data, must also explain the 
method that was used to determine which portion of the foreign 
development costs should be applied to the U.S. market, and what percent 
these costs are of total worldwide development costs. Any data submitted 
to foreign government authorities to support drug pricing determinations 
must be included with this information.
    (ii) Data that show which foreign development costs were recovered 
through cost recovery procedures that are allowed during drug 
development in some foreign countries. For example, if the sponsor 
charged patients for the drug during clinical investigations, the 
revenues collected by the sponsor must be reported to FDA.
    (3) In cases where the drug has already been approved for marketing 
for any indication or in cases where the drug is currently under 
investigation for one or more other indications (in addition to the 
indication for which orphan-drug designation is being sought), a clear 
explanation of and justification for the method that is used to 
apportion the development costs among the various indications.
    (4) A statement of and justification for any development costs that 
the sponsor expects to incur after the submission of the designation 
request. In cases where the extent of these future development costs are 
not clear, the sponsor should request FDA's advice and assistance in 
estimating the scope of nonclinical laboratory studies and clinical 
investigations and other data that are needed to support marketing 
approval. Based on these recommendations, a cost estimate should be 
prepared.
    (5) A statement of and justification for production and marketing 
costs that the sponsor has incurred in the past and expects to incur 
during the first 7 years that the drug is marketed.
    (6) An estimate of and justification for the expected revenues from 
sales of the drug in the United States during its first 7 years of 
marketing. The justification should assume that the total market for the 
drug is equal to the prevalence of the disease or condition that the 
drug will be used to treat. The justification should include:
    (i) An estimate of the expected market share of the drug in each of 
the

[[Page 186]]

first 7 years that it is marketed, together with an explanation of the 
basis for that estimate;
    (ii) A projection of and justification for the price at which the 
drug will be sold; and
    (iii) Comparisons with sales of similarly situated drugs, where 
available.
    (7) The name of each country where the drug has already been 
approved for marketing for any indication, the dates of approval, the 
indication for which the drug is approved, and the annual sales and 
number of prescriptions in each country since the first approval date.
    (8) A report of an independent certified public accountant in 
accordance with Statement on Standards for Attestation established by 
the American Institute of Certified Public Accountants on agreed upon 
procedures performed with respect to the data estimates and 
justifications submitted pursuant to this section. Cost data shall be 
determined in accordance with generally accepted accounting principles.
    (d) A sponsor that is requesting orphan-drug designation for a drug 
designed to treat a disease or condition that affects 200,000 or more 
persons shall, at FDA's request, allow FDA or FDA-designated personnel 
to examine at reasonable times and in a reasonable manner all relevant 
financial records and sales data of the sponsor and manufacturer.



Sec. 316.22  Permanent-resident agent for foreign sponsor.

    Every foreign sponsor that seeks orphan-drug designation shall name 
a permanent resident of the United States as the sponsor's agent upon 
whom service of all processes, notices, orders, decisions, requirements, 
and other communications may be made on behalf of the sponsor. 
Notifications of changes in such agents or changes of address of agents 
should preferably be provided in advance, but not later than 60 days 
after the effective date of such changes. The permanent-resident agent 
may be an individual, firm, or domestic corporation and may represent 
any number of sponsors. The name of the permanent-resident agent shall 
be provided to: Office of Orphan Products Development (HF-35), Food and 
Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.



Sec. 316.23  Timing of requests for orphan-drug designation; designation
of already approved drugs.

    (a) A sponsor may request orphan-drug designation at any time in the 
drug development process prior to the submission of a marketing 
application for the drug product for the orphan indication.
    (b) A sponsor may request orphan-drug designation of an already 
approved drug product for an unapproved use without regard to whether 
the prior marketing approval was for an orphan-drug indication.



Sec. 316.24  Granting orphan-drug designation.

    (a) FDA will grant the request for orphan-drug designation if none 
of the reasons described in Sec. 316.25 for requiring or permitting 
refusal to grant such a request applies.
    (b) When a request for orphan-drug designation is granted, FDA will 
notify the sponsor in writing and will publicize the orphan-drug 
designation in accordance with Sec. 316.28.



Sec. 316.25  Refusal to grant orphan-drug designation.

    (a) FDA will refuse to grant a request for orphan-drug designation 
if any of the following reasons apply:
    (1) The drug is not intended for a rare disease or condition 
because:
    (i) There is insufficient evidence to support the estimate that the 
drug is intended for treatment of a disease or condition in fewer than 
200,000 people in the United States, or that the drug is intended for 
use in prevention or in diagnosis in fewer than 200,000 people annually 
in the United States; or
    (ii) Where the drug is intended for prevention, diagnosis, or 
treatment of a disease or condition affecting 200,000 or more people in 
the United States, the sponsor has failed to demonstrate that there is 
no reasonable expectation that development and production costs will be 
recovered from sales of the drug for the orphan indication in the United 
States. A sponsor's failure to comply with Sec. 316.21 shall constitute 
a failure

[[Page 187]]

to make the demonstration required in this paragraph.
    (2) There is insufficient information about the drug, or the disease 
or condition for which it is intended, to establish a medically 
plausible basis for expecting the drug to be effective in the 
prevention, diagnosis, or treatment of that disease or condition.
    (3) A drug that is otherwise the same drug as one that already has 
orphan-drug exclusive approval for the same rare disease or condition 
and the sponsor has not submitted a medically plausible hypothesis for 
the possible clinical superiority of the subsequent drug.
    (b) FDA may refuse to grant a request for orphan-drug designation if 
the request for designation contains an untrue statement of material 
fact or omits material information.



Sec. 316.26  Amendment to orphan-drug designation.

    (a) At any time prior to approval of a marketing application for a 
designated orphan drug, the sponsor holding designation may apply for an 
amendment to the indication stated in the orphan-drug designation if the 
proposed change is due to new and unexpected findings in research on the 
drugs, information arising from FDA recommendations, or unforeseen 
developments in treatment or diagnosis of the disease or condition.
    (b) FDA will grant the amendment if it finds that the initial 
designation request was made in good faith and that the amendment is 
intended to conform the orphan-drug designation indication to the 
results of unanticipated research findings, to unforeseen developments 
in the treatment or diagnosis of the disease or condition, or to changes 
based on FDA recommendations, and that, as of the date of the submission 
of the amendment request, the amendment would not result in exceeding 
the prevalence or cost recovery thresholds in Sec. 316.21 (a)(1) or 
(a)(2) upon which the drug was originally designated.



Sec. 316.27  Change in ownership of orphan-drug designation.

    (a) A sponsor may transfer ownership of or any beneficial interest 
in the orphan-drug designation of a drug to a new sponsor. At the time 
of the transfer, the new and former owners are required to submit the 
following information to FDA:
    (1) The former owner or assignor of rights shall submit a letter or 
other document that states that all or some rights to the orphan-drug 
designation of the drug have been transferred to the new owner or 
assignee and that a complete copy of the request for orphan-drug 
designation, including any amendments to the request, supplements to the 
granted request, and correspondence relevant to the orphan-drug 
designation, has been provided to the new owner or assignee.
    (2) The new owner or assignee of rights shall submit a statement 
accepting orphan-drug designation and a letter or other document 
containing the following:
    (i) The date that the change in ownership or assignment of rights is 
effective;
    (ii) A statement that the new owner has a complete copy of the 
request for orphan-drug designation including any amendments to the 
request, supplements to the granted request, and correspondence relevant 
to the orphan-drug designation; and
    (iii) A specific description of the rights that have been assigned 
and those that have been reserved. This may be satisfied by the 
submission of either a list of rights assigned and reserved or copies of 
all relevant agreements between assignors and assignees; and
    (iv) The name and address of a new primary contact person or 
resident agent.
    (b) No sponsor may relieve itself of responsibilities under the 
Orphan Drug Act or under this part by assigning rights to another person 
without:
    (1) Assuring that the sponsor or the assignee will carry out such 
responsibilities; or
    (2) Obtaining prior permission from FDA.

[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]

[[Page 188]]



Sec. 316.28  Publication of orphan-drug designations.

    Each month FDA will update a publically available list of drugs 
designated as orphan drugs. A cumulative, updated list of all designated 
drugs will be provided annually. These will be placed on file at the FDA 
Division of Dockets Management, and will contain the following 
information:
    (a) The name and address of the manufacturer and sponsor;
    (b) The generic name and trade name, if any, of the drug and the 
date of the granting of orphan-drug designation;
    (c) The rare disease or condition for which orphan-drug designation 
was granted; and
    (d) The proposed indication for use of the drug.



Sec. 316.29  Revocation of orphan-drug designation.

    (a) FDA may revoke orphan-drug designation for any drug if the 
agency finds that:
    (1) The request for designation contained an untrue statement of 
material fact; or
    (2) The request for designation omitted material information 
required by this part; or
    (3) FDA subsequently finds that the drug in fact had not been 
eligible for orphan-drug designation at the time of submission of the 
request therefor.
    (b) For an approved drug, revocation of orphan-drug designation also 
suspends or withdraws the sponsor's exclusive marketing rights for the 
drug but not the approval of the drug's marketing application.
    (c) Where a drug has been designated as an orphan drug because the 
prevalence of a disease or condition (or, in the case of vaccines, 
diagnostic drugs, or preventive drugs, the target population) is under 
200,000 in the United States at the time of designation, its designation 
will not be revoked on the ground that the prevalence of the disease or 
condition (or the target population) becomes more than 200,000 persons.



Sec. 316.30  Annual reports of holder of orphan-drug designation.

    Within 14 months after the date on which a drug was designated as an 
orphan drug and annually thereafter until marketing approval, the 
sponsor of a designated drug shall submit a brief progress report to the 
FDA Office of Orphan Products Development on the drug that includes:
    (a) A short account of the progress of drug development including a 
review of preclinical and clinical studies initiated, ongoing, and 
completed and a short summary of the status or results of such studies.
    (b) A description of the investigational plan for the coming year, 
as well as any anticipated difficulties in development, testing, and 
marketing; and
    (c) A brief discussion of any changes that may affect the orphan-
drug status of the product. For example, for products nearing the end of 
the approval process, sponsors should discuss any disparity between the 
probable marketing indication and the designated indication as related 
to the need for an amendment to the orphan-drug designation pursuant to 
Sec. 316.26.



                Subpart D_Orphan-drug Exclusive Approval



Sec. 316.31  Scope of orphan-drug exclusive approval.

    (a) After approval of a sponsor's marketing application for a 
designated orphan-drug product for treatment of the rare disease or 
condition concerning which orphan-drug designation was granted, FDA will 
not approve another sponsor's marketing application for the same drug 
before the expiration of 7 years from the date of such approval as 
stated in the approval letter from FDA, except that such a marketing 
application can be approved sooner if, and such time as, any of the 
following occurs:
    (1) Withdrawal of exclusive approval or revocation of orphan-drug 
designation by FDA under any provision of this part; or
    (2) Withdrawal for any reason of the marketing application for the 
drug in question; or
    (3) Consent by the holder of exclusive approval to permit another 
marketing application to gain approval; or
    (4) Failure of the holder of exclusive approval to assure a 
sufficient quantity

[[Page 189]]

of the drug under section 527 of the act and Sec. 316.36.
    (b) If a sponsor's marketing application for a drug product is 
determined not to be approvable because approval is barred under section 
527 of the act until the expiration of the period of exclusive marketing 
of another drug product, FDA will so notify the sponsor in writing.



Sec. 316.34  FDA recognition of exclusive approval.

    (a) FDA will send the sponsor (or, the permanent-resident agent, if 
applicable) timely written notice recognizing exclusive approval once 
the marketing application for a designated orphan-drug product has been 
approved. The written notice will inform the sponsor of the requirements 
for maintaining orphan-drug exclusive approval for the full 7-year term 
of exclusive approval.
    (b) When a marketing application is approved for a designated orphan 
drug that qualifies for exclusive approval, FDA will publish in its 
publication entitled ``Approved Drug Products with Therapeutic 
Equivalence Evaluations'' information identifying the sponsor, the drug, 
and the date of termination of the orphan-drug exclusive approval. A 
subscription to this publication and its monthly cumulative supplements 
is available from the Superintendent of Documents, Government Printing 
Office, Washington, DC 20402-9325.



Sec. 316.36  Insufficient quantities of orphan drugs.

    (a) Under section 527 of the act, whenever the Director has reason 
to believe that the holder of exclusive approval cannot assure the 
availability of sufficient quantities of an orphan drug to meet the 
needs of patients with the disease or condition for which the drug was 
designated, the Director will so notify the holder of this possible 
insufficiency and will offer the holder one of the following options, 
which must be exercised by a time that the Director specifies:
    (1) Provide the Director in writing, or orally, or both, at the 
Director's discretion, views and data as to how the holder can assure 
the availability of sufficient quantities of the orphan drug within a 
reasonable time to meet the needs of patients with the disease or 
condition for which the drug was designated; or
    (2) Provide the Director in writing the holder's consent for the 
approval of other marketing applications for the same drug before the 
expiration of the 7-year period of exclusive approval.
    (b) If, within the time that the Director specifies, the holder 
fails to consent to the approval of other marketing applications and if 
the Director finds that the holder has not shown that it can assure the 
availability of sufficient quantities of the orphan drug to meet the 
needs of patients with the disease or condition for which the drug was 
designated, the Director will issue a written order withdrawing the drug 
product's exclusive approval. This order will embody the Director's 
findings and conclusions and will constitute final agency action. An 
order withdrawing the sponsor's exclusive marketing rights may issue 
whether or not there are other sponsors that can assure the availability 
of alternative sources of supply. Once withdrawn under this section, 
exclusive approval may not be reinstated for that drug.



               Subpart E_Open Protocols for Investigations



Sec. 316.40  Treatment use of a designated orphan drug.

    Prospective investigators seeking to obtain treatment use of 
designated orphan drugs may do so as provided in subpart I of this 
chapter.

[74 FR 40945, Aug. 13, 2009]



                  Subpart F_Availability of Information



Sec. 316.50  Guidance documents.

    FDA's Office of Orphan Products Development will maintain and make 
publicly available a list of guidance documents that apply to the 
regulations in this part. The list is maintained on the Internet and is 
published annually in the Federal Register. A request for a copy of the 
list should be directed to the Office of Orphan Products Development 
(HF-35), Food and

[[Page 190]]

Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.

[65 FR 56480, Sept. 19, 2000]



Sec. 316.52  Availability for public disclosure of data and information
in requests and applications.

    (a) FDA will not publicly disclose the existence of a request for 
orphan-drug designation under section 526 of the act prior to final FDA 
action on the request unless the existence of the request has been 
previously publicly disclosed or acknowledged.
    (b) Whether or not the existence of a pending request for 
designation has been publicly disclosed or acknowledged, no data or 
information in the request are available for public disclosure prior to 
final FDA action on the request.
    (c) Upon final FDA action on a request for designation, FDA will 
determine the public availability of data and information in the request 
in accordance with part 20 and Sec. 314.430 of this chapter and other 
applicable statutes and regulations.
    (d) In accordance with Sec. 316.28, FDA will make a cumulative list 
of all orphan drug designations available to the public and update such 
list monthly.
    (e) FDA will not publicly disclose the existence of a pending 
marketing application for a designated orphan drug for the use for which 
the drug was designated unless the existence of the application has been 
previously publicly disclosed or acknowledged.
    (f) FDA will determine the public availability of data and 
information contained in pending and approved marketing applications for 
a designated orphan drug for the use for which the drug was designated 
in accordance with part 20 and Sec. 314.430 of this chapter and other 
applicable statutes and regulations.



PART 320_BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS--Table of
Contents



                      Subpart A_General Provisions

Sec.
320.1 Definitions.

      Subpart B_Procedures for Determining the Bioavailability or 
                     Bioequivalence of Drug Products

320.21 Requirements for submission of bioavailability and bioequivalence 
          data.
320.22 Criteria for waiver of evidence of in vivo bioavailability or 
          bioequivalence.
320.23 Basis for measuring in vivo bioavailability or demonstrating 
          bioequivalence.
320.24 Types of evidence to measure bioavailability or establish 
          bioequivalence.
320.25 Guidelines for the conduct of an in vivo bioavailability study.
320.26 Guidelines on the design of a single-dose in vivo bioavailability 
          or bioequivalence study.
320.27 Guidelines on the design of a multiple-dose in vivo 
          bioavailability study.
320.28 Correlation of bioavailability with an acute pharmacological 
          effect or clinical evidence.
320.29 Analytical methods for an in vivo bioavailability or 
          bioequivalence study.
320.30 Inquiries regarding bioavailability and bioequivalence 
          requirements and review of protocols by the Food and Drug 
          Administration.
320.31 Applicability of requirements regarding an ``Investigational New 
          Drug Application.''
320.32 Procedures for establishing or amending a bioequivalence 
          requirement.
320.33 Criteria and evidence to assess actual or potential 
          bioequivalence problems.
320.34 Requirements for batch testing and certification by the Food and 
          Drug Administration.
320.35 Requirements for in vitro testing of each batch.
320.36 Requirements for maintenance of records of bioequivalence 
          testing.
320.38 Retention of bioavailability samples.
320.63 Retention of bioequivalence samples.

    Authority: 21 U.S.C. 321, 351, 352, 355, 371.



                      Subpart A_General Provisions



Sec. 320.1  Definitions.

    (a) Bioavailability means the rate and extent to which the active 
ingredient or active moiety is absorbed from a drug product and becomes 
available at the site of action. For drug products that are not intended 
to be absorbed

[[Page 191]]

into the bloodstream, bioavailability may be assessed by measurements 
intended to reflect the rate and extent to which the active ingredient 
or active moiety becomes available at the site of action.
    (b) Drug product means a finished dosage form, e.g., tablet, 
capsule, or solution, that contains the active drug ingredient, 
generally, but not necessarily, in association with inactive 
ingredients.
    (c) Pharmaceutical equivalents means drug products in identical 
dosage forms that contain identical amounts of the identical active drug 
ingredient, i.e., the same salt or ester of the same therapeutic moiety, 
or, in the case of modified release dosage forms that require a 
reservoir or overage or such forms as prefilled syringes where residual 
volume may vary, that deliver identical amounts of the active drug 
ingredient over the identical dosing period; do not necessarily contain 
the same inactive ingredients; and meet the identical compendial or 
other applicable standard of identity, strength, quality, and purity, 
including potency and, where applicable, content uniformity, 
disintegration times, and/or dissolution rates.
    (d) Pharmaceutical alternatives means drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily in 
the same amount or dosage form or as the same salt or ester. Each such 
drug product individually meets either the identical or its own 
respective compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times and/or dissolution rates.
    (e) Bioequivalence means the absence of a significant difference in 
the rate and extent to which the active ingredient or active moiety in 
pharmaceutical equivalents or pharmaceutical alternatives becomes 
available at the site of drug action when administered at the same molar 
dose under similar conditions in an appropriately designed study. Where 
there is an intentional difference in rate (e.g., in certain extended 
release dosage forms), certain pharmaceutical equivalents or 
alternatives may be considered bioequivalent if there is no significant 
difference in the extent to which the active ingredient or moiety from 
each product becomes available at the site of drug action. This applies 
only if the difference in the rate at which the active ingredient or 
moiety becomes available at the site of drug action is intentional and 
is reflected in the proposed labeling, is not essential to the 
attainment of effective body drug concentrations on chronic use, and is 
considered medically insignificant for the drug.
    (f) Bioequivalence requirement means a requirement imposed by the 
Food and Drug Administration for in vitro and/or in vivo testing of 
specified drug products which must be satisfied as a condition of 
marketing.
    (g) Same drug product formulation means the formulation of the drug 
product submitted for approval and any formulations that have minor 
differences in composition or method of manufacture from the formulation 
submitted for approval, but are similar enough to be relevant to the 
agency's determination of bioequivalence.

[42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 
17997, Apr. 28, 1992; 67 FR 77672, Dec. 19, 2002; 74 FR 2861, Jan. 16, 
2009]



      Subpart B_Procedures for Determining the Bioavailability or 
                     Bioequivalence of Drug Products

    Source: 42 FR 1648, Jan. 7, 1977, unless otherwise noted.



Sec. 320.21  Requirements for submission of bioavailability and 
bioequivalence data.

    (a) Any person submitting a full new drug application to the Food 
and Drug Administration (FDA) shall include in the application either:
    (1) Evidence measuring the in vivo bioavailability of the drug 
product that is the subject of the application; or
    (2) Information to permit FDA to waive the submission of evidence 
measuring in vivo bioavailability.
    (b) Any person submitting an abbreviated new drug application to FDA 
shall include in the application either:
    (1) Evidence demonstrating that the drug product that is the subject 
of the

[[Page 192]]

abbreviated new drug application is bioequivalent to the reference 
listed drug (defined in Sec. 314.3(b) of this chapter). A complete 
study report must be submitted for the bioequivalence study upon which 
the applicant relies for approval. For all other bioequivalence studies 
conducted on the same drug product formulation, the applicant must 
submit either a complete or summary report. If a summary report of a 
bioequivalence study is submitted and FDA determines that there may be 
bioequivalence issues or concerns with the product, FDA may require that 
the applicant submit a complete report of the bioequivalence study to 
FDA; or
    (2) Information to show that the drug product is bioequivalent to 
the reference listed drug which would permit FDA to waive the submission 
of evidence demonstrating in vivo bioequivalence as provided in 
paragraph (f) of this section.
    (c) Any person submitting a supplemental application to FDA shall 
include in the supplemental application the evidence or information set 
forth in paragraphs (a) and (b) of this section if the supplemental 
application proposes any of the following changes:
    (1) A change in the manufacturing site or a change in the 
manufacturing process, including a change in product formulation or 
dosage strength, beyond the variations provided for in the approved 
application.
    (2) A change in the labeling to provide for a new indication for use 
of the drug product, if clinical studies are required to support the new 
indication for use.
    (3) A change in the labeling to provide for a new dosage regimen or 
for an additional dosage regimen for a special patient population, e.g., 
infants, if clinical studies are required to support the new or 
additional dosage regimen.
    (d) FDA may approve a full new drug application, or a supplemental 
application proposing any of the changes set forth in paragraph (c) of 
this section, that does not contain evidence of in vivo bioavailability 
or information to permit waiver of the requirement for in vivo 
bioavailability data, if all of the following conditions are met.
    (1) The application is otherwise approvable.
    (2) The application agrees to submit, within the time specified by 
FDA, either:
    (i) Evidence measuring the in vivo bioavailability and demonstrating 
the in vivo bioequivalence of the drug product that is the subject of 
the application; or
    (ii) Information to permit FDA to waive measurement of in vivo 
bioavailability.
    (e) Evidence measuring the in vivo bioavailability and demonstrating 
the in vivo bioequivalence of a drug product shall be obtained using one 
of the approaches for determining bioavailability set forth in Sec. 
320.24.
    (f) Information to permit FDA to waive the submission of evidence 
measuring the in vivo bioavailability or demonstrating the in vivo 
bioequivalence shall meet the criteria set forth in Sec. 320.22.
    (g) Any person holding an approved full or abbreviated new drug 
application shall submit to FDA a supplemental application containing 
new evidence measuring the in vivo bioavailability or demonstrating the 
in vivo bioequivalence of the drug product that is the subject of the 
application if notified by FDA that:
    (1) There are data demonstrating that the dosage regimen in the 
labeling is based on incorrect assumptions or facts regarding the 
pharmacokinetics of the drug product and that following this dosage 
regimen could potentially result in subtherapeutic or toxic levels; or
    (2) There are data measuring significant intra-batch and batch-to-
batch variability, e.g., plus or minus 25 percent, in the 
bioavailability of the drug product.
    (h) The requirements of this section regarding the submission of 
evidence measuring the in vivo bioavailability or demonstrating the in 
vivo bioequivalence apply only to a full or abbreviated new drug 
application or a supplemental application for a finished dosage 
formulation.

[57 FR 17998, Apr. 28, 1992, as amended at 67 FR 77672, Dec. 19, 2002; 
74 FR 2862, Jan. 16, 2009]

[[Page 193]]



Sec. 320.22  Criteria for waiver of evidence of in vivo bioavailability
or bioequivalence.

    (a) Any person submitting a full or abbreviated new drug 
application, or a supplemental application proposing any of the changes 
set forth in Sec. 320.21(c), may request FDA to waive the requirement 
for the submission of evidence measuring the in vivo bioavailability or 
demonstrating the in vivo bioequivalence of the drug product that is the 
subject of the application. An applicant shall submit a request for 
waiver with the application. Except as provided in paragraph (f) of this 
section, FDA shall waive the requirement for the submission of evidence 
of in vivo bioavailability or bioequivalence if the drug product meets 
any of the provisions of paragraphs (b), (c), (d), or (e) of this 
section.
    (b) For certain drug products, the in vivo bioavailability or 
bioequivalence of the drug product may be self-evident. FDA shall waive 
the requirement for the submission of evidence obtained in vivo 
measuring the bioavailability or demonstrating the bioequivalence of 
these drug products. A drug product's in vivo bioavailability or 
bioequivalence may be considered self-evident based on other data in the 
application if the product meets one of the following criteria:
    (1) The drug product:
    (i) Is a parenteral solution intended solely for administration by 
injection, or an ophthalmic or otic solution; and
    (ii) Contains the same active and inactive ingredients in the same 
concentration as a drug product that is the subject of an approved full 
new drug application or abbreviated new drug application.
    (2) The drug product:
    (i) Is administered by inhalation as a gas, e.g., a medicinal or an 
inhalation anesthetic; and
    (ii) Contains an active ingredient in the same dosage form as a drug 
product that is the subject of an approved full new drug application or 
abbreviated new drug application.
    (3) The drug product:
    (i) Is a solution for application to the skin, an oral solution, 
elixir, syrup, tincture, a solution for aerosolization or nebulization, 
a nasal solution, or similar other solubilized form; and
    (ii) Contains an active drug ingredient in the same concentration 
and dosage form as a drug product that is the subject of an approved 
full new drug application or abbreviated new drug application; and
    (iii) Contains no inactive ingredient or other change in formulation 
from the drug product that is the subject of the approved full new drug 
application or abbreviated new drug application that may significantly 
affect absorption of the active drug ingredient or active moiety for 
products that are systemically absorbed, or that may significantly 
affect systemic or local availability for products intended to act 
locally.
    (c) FDA shall waive the requirement for the submission of evidence 
measuring the in vivo bioavailability or demonstrating the in vivo 
bioequivalence of a solid oral dosage form (other than a delayed release 
or extended release dosage form) of a drug product determined to be 
effective for at least one indication in a Drug Efficacy Study 
Implementation notice or which is identical, related, or similar to such 
a drug product under Sec. 310.6 of this chapter unless FDA has 
evaluated the drug product under the criteria set forth in Sec. 320.33, 
included the drug product in the Approved Drug Products with Therapeutic 
Equivalence Evaluations List, and rated the drug product as having a 
known or potential bioequivalence problem. A drug product so rated 
reflects a determination by FDA that an in vivo bioequivalence study is 
required.
    (d) For certain drug products, bioavailability may be measured or 
bioequivalence may be demonstrated by evidence obtained in vitro in lieu 
of in vivo data. FDA shall waive the requirement for the submission of 
evidence obtained in vivo measuring the bioavailability or demonstrating 
the bioequivalence of the drug product if the drug product meets one of 
the following criteria:
    (1) [Reserved]
    (2) The drug product is in the same dosage form, but in a different 
strength, and is proportionally similar in its active and inactive 
ingredients to

[[Page 194]]

another drug product for which the same manufacturer has obtained 
approval and the conditions in paragraphs (d)(2)(i) through (d)(2)(iii) 
of this section are met:
    (i) The bioavailability of this other drug product has been 
measured;
    (ii) Both drug products meet an appropriate in vitro test approved 
by FDA; and
    (iii) The applicant submits evidence showing that both drug products 
are proportionally similar in their active and inactive ingredients.
    (iv) Paragraph (d) of this section does not apply to delayed release 
or extended release products.
    (3) The drug product is, on the basis of scientific evidence 
submitted in the application, shown to meet an in vitro test that has 
been correlated with in vivo data.
    (4) The drug product is a reformulated product that is identical, 
except for a different color, flavor, or preservative that could not 
affect the bioavailability of the reformulated product, to another drug 
product for which the same manufacturer has obtained approval and the 
following conditions are met:
    (i) The bioavailability of the other product has been measured; and
    (ii) Both drug products meet an appropriate in vitro test approved 
by FDA.
    (e) FDA, for good cause, may waive a requirement for the submission 
of evidence of in vivo bioavailability or bioequivalence if waiver is 
compatible with the protection of the public health. For full new drug 
applications, FDA may defer a requirement for the submission of evidence 
of in vivo bioavailability if deferral is compatible with the protection 
of the public health.
    (f) FDA, for good cause, may require evidence of in vivo 
bioavailability or bioequivalence for any drug product if the agency 
determines that any difference between the drug product and a listed 
drug may affect the bioavailability or bioequivalence of the drug 
product.

[57 FR 17998, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002]



Sec. 320.23  Basis for measuring in vivo bioavailability or 
demonstrating bioequivalence.

    (a)(1) The in vivo bioavailability of a drug product is measured if 
the product's rate and extent of absorption, as determined by comparison 
of measured parameters, e.g., concentration of the active drug 
ingredient in the blood, urinary excretion rates, or pharmacological 
effects, do not indicate a significant difference from the reference 
material's rate and extent of absorption. For drug products that are not 
intended to be absorbed into the bloodstream, bioavailability may be 
assessed by measurements intended to reflect the rate and extent to 
which the active ingredient or active moiety becomes available at the 
site of action.
    (2) Statistical techniques used shall be of sufficient sensitivity 
to detect differences in rate and extent of absorption that are not 
attributable to subject variability.
    (3) A drug product that differs from the reference material in its 
rate of absorption, but not in its extent of absorption, may be 
considered to be bioavailable if the difference in the rate of 
absorption is intentional, is appropriately reflected in the labeling, 
is not essential to the attainment of effective body drug concentrations 
on chronic use, and is considered medically insignificant for the drug 
product.
    (b) Two drug products will be considered bioequivalent drug products 
if they are pharmaceutical equivalents or pharmaceutical alternatives 
whose rate and extent of absorption do not show a significant difference 
when administered at the same molar dose of the active moiety under 
similar experimental conditions, either single dose or multiple dose. 
Some pharmaceutical equivalents or pharmaceutical alternatives may be 
equivalent in the extent of their absorption but not in their rate of 
absorption and yet may be considered bioequivalent because such 
differences in the rate of absorption are

[[Page 195]]

intentional and are reflected in the labeling, are not essential to the 
attainment of effective body drug concentrations on chronic use, and are 
considered medically insignificant for the particular drug product 
studied.

[57 FR 17999, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002]



Sec. 320.24  Types of evidence to measure bioavailability or 
establish bioequivalence.

    (a) Bioavailability may be measured or bioequivalence may be 
demonstrated by several in vivo and in vitro methods. FDA may require in 
vivo or in vitro testing, or both, to measure the bioavailability of a 
drug product or establish the bioequivalence of specific drug products. 
Information on bioequivalence requirements for specific products is 
included in the current edition of FDA's publication ``Approved Drug 
Products with Therapeutic Equivalence Evaluations'' and any current 
supplement to the publication. The selection of the method used to meet 
an in vivo or in vitro testing requirement depends upon the purpose of 
the study, the analytical methods available, and the nature of the drug 
product. Applicants shall conduct bioavailability and bioequivalence 
testing using the most accurate, sensitive, and reproducible approach 
available among those set forth in paragraph (b) of this section. The 
method used must be capable of measuring bioavailability or establishing 
bioequivalence, as appropriate, for the product being tested.
    (b) The following in vivo and in vitro approaches, in descending 
order of accuracy, sensitivity, and reproducibility, are acceptable for 
determining the bioavailability or bioequivalence of a drug product.
    (1)(i) An in vivo test in humans in which the concentration of the 
active ingredient or active moiety, and, when appropriate, its active 
metabolite(s), in whole blood, plasma, serum, or other appropriate 
biological fluid is measured as a function of time. This approach is 
particularly applicable to dosage forms intended to deliver the active 
moiety to the bloodstream for systemic distribution within the body; or
    (ii) An in vitro test that has been correlated with and is 
predictive of human in vivo bioavailability data; or
    (2) An in vivo test in humans in which the urinary excretion of the 
active moiety, and, when appropriate, its active metabolite(s), are 
measured as a function of time. The intervals at which measurements are 
taken should ordinarily be as short as possible so that the measure of 
the rate of elimination is as accurate as possible. Depending on the 
nature of the drug product, this approach may be applicable to the 
category of dosage forms described in paragraph (b)(1)(i) of this 
section. This method is not appropriate where urinary excretion is not a 
significant mechanism of elimination.
    (3) An in vivo test in humans in which an appropriate acute 
pharmacological effect of the active moiety, and, when appropriate, its 
active metabolite(s), are measured as a function of time if such effect 
can be measured with sufficient accuracy, sensitivity, and 
reproducibility. This approach is applicable to the category of dosage 
forms described in paragraph (b)(1)(i) of this section only when 
appropriate methods are not available for measurement of the 
concentration of the moiety, and, when appropriate, its active 
metabolite(s), in biological fluids or excretory products but a method 
is available for the measurement of an appropriate acute pharmacological 
effect. This approach may be particularly applicable to dosage forms 
that are not intended to deliver the active moiety to the bloodstream 
for systemic distribution.
    (4) Well-controlled clinical trials that establish the safety and 
effectiveness of the drug product, for purposes of measuring 
bioavailability, or appropriately designed comparative clinical trials, 
for purposes of demonstrating bioequivalence. This approach is the least 
accurate, sensitive, and reproducible of the general approaches for 
measuring bioavailability or demonstrating bioequivalence. For dosage 
forms intended to deliver the active moiety to the bloodstream for 
systemic distribution, this approach may be considered acceptable only 
when analytical methods cannot be developed to permit use of one of the 
approaches

[[Page 196]]

outlined in paragraphs (b)(1)(i) and (b)(2) of this section, when the 
approaches described in paragraphs (b)(1)(ii), (b)(1)(iii), and (b)(3) 
of this section are not available. This approach may also be considered 
sufficiently accurate for measuring bioavailability or demonstrating 
bioequivalence of dosage forms intended to deliver the active moiety 
locally, e.g., topical preparations for the skin, eye, and mucous 
membranes; oral dosage forms not intended to be absorbed, e.g., an 
antacid or radiopaque medium; and bronchodilators administered by 
inhalation if the onset and duration of pharmacological activity are 
defined.
    (5) A currently available in vitro test acceptable to FDA (usually a 
dissolution rate test) that ensures human in vivo bioavailability.
    (6) Any other approach deemed adequate by FDA to measure 
bioavailability or establish bioequivalence.
    (c) FDA may, notwithstanding prior requirements for measuring 
bioavailability or establishing bioequivalence, require in vivo testing 
in humans of a product at any time if the agency has evidence that the 
product:
    (1) May not produce therapeutic effects comparable to a 
pharmaceutical equivalent or alternative with which it is intended to be 
used interchangeably;
    (2) May not be bioequivalent to a pharmaceutical equivalent or 
alternative with which it is intended to be used interchangeably; or
    (3) Has greater than anticipated potential toxicity related to 
pharmacokinetic or other characteristics.

[57 FR 17999, Apr. 28, 1992; 57 FR 29354, July 1, 1992, as amended at 67 
FR 77673, Dec. 19, 2002]



Sec. 320.25  Guidelines for the conduct of an in vivo bioavailability
study.

    (a) Guiding principles. (1) The basic principle in an in vivo 
bioavailability study is that no unnecessary human research should be 
done.
    (2) An in vivo bioavailability study is generally done in a normal 
adult population under standardized conditions. In some situations, an 
in vivo bioavailability study in humans may preferably and more properly 
be done in suitable patients. Critically ill patients shall not be 
included in an in vivo bioavailability study unless the attending 
physician determines that there is a potential benefit to the patient.
    (b) Basic design. The basic design of an in vivo bioavailability 
study is determined by the following:
    (1) The scientific questions to be answered.
    (2) The nature of the reference material and the dosage form to be 
tested.
    (3) The availability of analytical methods.
    (4) Benefit-risk considerations in regard to testing in humans.
    (c) Comparison to a reference material. In vivo bioavailability 
testing of a drug product shall be in comparison to an appropriate 
reference material unless some other approach is more appropriate for 
valid scientific reasons.
    (d) Previously unmarketed active drug ingredients or therapeutic 
moieties. (1) An in vivo bioavailability study involving a drug product 
containing an active drug ingredient or therapeutic moiety that has not 
been approved for marketing can be used to measure the following 
pharmacokinetic data:
    (i) The bioavailability of the formulation proposed for marketing; 
and
    (ii) The essential pharmacokinetic characteristics of the active 
drug ingredient or therapeutic moiety, such as the rate of absorption, 
the extent of absorption, the half-life of the therapeutic moiety in 
vivo, and the rate of excretion and/or metabolism. Dose proportionality 
of the active drug ingredient or the therapeutic moiety needs to be 
established after single-dose administration and in certain instances 
after multiple-dose administration. This characterization is a necessary 
part of the investigation of the drug to support drug labeling.
    (2) The reference material in such a bioavailability study should be 
a solution or suspension containing the same quantity of the active drug 
ingredient or therapeutic moiety as the formulation proposed for 
marketing.
    (3) The reference material should be administered by the same route 
as the formulation proposed for marketing unless an alternative or 
additional

[[Page 197]]

route is necessary to answer the scientific question under study. For 
example, in the case of an active drug ingredient or therapeutic moiety 
that is poorly absorbed after oral administration, it may be necessary 
to compare the oral dosage form proposed for marketing with the active 
drug ingredient or therapeutic moiety administered in solution both 
orally and intravenously.
    (e) New formulations of active drug ingredients or therapeutic 
moieties approved for marketing. (1) An in vivo bioavailability study 
involving a drug product that is a new dosage form, or a new salt or 
ester of an active drug ingredient or therapeutic moiety that has been 
approved for marketing can be used to:
    (i) Measure the bioavailability of the new formulation, new dosage 
form, or new salt or ester relative to an appropriate reference 
material; and
    (ii) Define the pharmacokinetic parameters of the new formulation, 
new dosage form, or new salt or ester to establish dosage 
recommendation.
    (2) The selection of the reference material(s) in such a 
bioavailability study depends upon the scientific questions to be 
answered, the data needed to establish comparability to a currently 
marketed drug product, and the data needed to establish dosage 
recommendations.
    (3) The reference material should be taken from a current batch of a 
drug product that is the subject of an approved new drug application and 
that contains the same active drug ingredient or therapeutic moiety, if 
the new formulation, new dosage form, or new salt or ester is intended 
to be comparable to or to meet any comparative labeling claims made in 
relation to the drug product that is the subject of an approved new drug 
application.
    (f) Extended release formulations. (1) The purpose of an in vivo 
bioavailability study involving a drug product for which an extended 
release claim is made is to determine if all of the following conditions 
are met:
    (i) The drug product meets the extended release claims made for it.
    (ii) The bioavailability profile established for the drug product 
rules out the occurrence of any dose dumping.
    (iii) The drug product's steady-state performance is equivalent to a 
currently marketed nonextended release or extended release drug product 
that contains the same active drug ingredient or therapeutic moiety and 
that is subject to an approved full new drug application.
    (iv) The drug product's formulation provides consistent 
pharmacokinetic performance between individual dosage units.
    (2) The reference material(s) for such a bioavailability study shall 
be chosen to permit an appropriate scientific evaluation of the extended 
release claims made for the drug product. The reference material shall 
be one of the following or any combination thereof:
    (i) A solution or suspension of the active drug ingredient or 
therapeutic moiety.
    (ii) A currently marketed noncontrolled release drug product 
containing the same active drug ingredient or therapeutic moiety and 
administered according to the dosage recommendations in the labeling of 
the noncontrolled release drug product.
    (iii) A currently marketed extended release drug product subject to 
an approved full new drug application containing the same active drug 
ingredient or therapeutic moiety and administered according to the 
dosage recommendations in the labeling proposed for the extended release 
drug product.
    (iv) A reference material other than one set forth in paragraph 
(f)(2) (i), (ii) or (iii) of this section that is appropriate for valid 
scientific reasons.
    (g) Combination drug products. (1) Generally, the purpose of an in 
vivo bioavailability study involving a combination drug product is to 
determine if the rate and extent of absorption of each active drug 
ingredient or therapeutic moiety in the combination drug product is 
equivalent to the rate and extent of absorption of each active drug 
ingredient or therapeutic moiety administered concurrently in separate 
single-ingredient preparations.
    (2) The reference material in such a bioavailability study should be 
two or more currently marketed, single-ingredient drug products each of 
which contains one of the active drug ingredients

[[Page 198]]

or therapeutic moieties in the combination drug product. The Food and 
Drug Administration may, for valid scientific reasons, specify that the 
reference material shall be a combination drug product that is the 
subject of an approved new drug application.
    (3) The Food and Drug Administration may permit a bioavailability 
study involving a combination drug product to determine the rate and 
extent of absorption of selected, but not all, active drug ingredients 
or therapeutic moieties in the combination drug product. The Food and 
Drug Administration may permit this determination if the 
pharmacokinetics and the interactions of the active drug ingredients or 
therapeutic moieties in the combination drug product are well known and 
the therapeutic activity of the combination drug product is generally 
recognized to reside in only one of the active drug ingredients or 
therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid 
combination drug product.
    (h) Use of a placebo as the reference material. Where appropriate or 
where necessary to demonstrate the sensitivity of the test, the 
reference material in a bioavailability study may be a placebo if:
    (1) The study measures the therapeutic or acute pharmacological 
effect of the active drug ingredient or therapeutic moiety; or
    (2) The study is a clinical trial to establish the safety and 
effectiveness of the drug product.
    (i) Standards for test drug product and reference material. (1) Both 
the drug product to be tested and the reference material, if it is 
another drug product, shall be shown to meet all compendial or other 
applicable standards of identity, strength, quality, and purity, 
including potency and, where applicable, content uniformity, 
disintegration times, and dissolution rates.
    (2) Samples of the drug product to be tested shall be manufactured 
using the same equipment and under the same conditions as those used for 
full-scale production.

[42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]



Sec. 320.26  Guidelines on the design of a single-dose in vivo 
bioavailability or bioequivalence study.

    (a) Basic principles. (1) An in vivo bioavailability or 
bioequivalence study should be a single-dose comparison of the drug 
product to be tested and the appropriate reference material conducted in 
normal adults.
    (2) The test product and the reference material should be 
administered to subjects in the fasting state, unless some other 
approach is more appropriate for valid scientific reasons.
    (b) Study design. (1) A single-dose study should be crossover in 
design, unless a parallel design or other design is more appropriate for 
valid scientific reasons, and should provide for a drug elimination 
period.
    (2) Unless some other approach is appropriate for valid scientific 
reasons, the drug elimination period should be either:
    (i) At least three times the half-life of the active drug ingredient 
or therapeutic moiety, or its metabolite(s), measured in the blood or 
urine; or
    (ii) At least three times the half-life of decay of the acute 
pharmacological effect.
    (c) Collection of blood samples. (1) When comparison of the test 
product and the reference material is to be based on blood concentration 
time curves, unless some other approach is more appropriate for valid 
scientific reasons, blood samples should be taken with sufficient 
frequency to permit an estimate of both:
    (i) The peak concentration in the blood of the active drug 
ingredient or therapeutic moiety, or its metabolite(s), measured; and
    (ii) The total area under the curve for a time period at least three 
times the half-life of the active drug ingredient or therapeutic moiety, 
or its metabolite(s), measured.
    (2) In a study comparing oral dosage forms, the sampling times 
should be identical.
    (3) In a study comparing an intravenous dosage form and an oral 
dosage form, the sampling times should be those needed to describe both:
    (i) The distribution and elimination phase of the intravenous dosage 
form; and

[[Page 199]]

    (ii) The absorption and elimination phase of the oral dosage form.
    (4) In a study comparing drug delivery systems other than oral or 
intravenous dosage forms with an appropriate reference standard, the 
sampling times should be based on valid scientific reasons.
    (d) Collection of urine samples. When comparison of the test product 
and the reference material is to be based on cumulative urinary 
excretion-time curves, unless some other approach is more appropriate 
for valid scientific reasons, samples of the urine should be collected 
with sufficient frequency to permit an estimate of the rate and extent 
of urinary excretion of the active drug ingredient or therapeutic 
moiety, or its metabolite(s), measured.
    (e) Measurement of an acute pharmacological effect. (1) When 
comparison of the test product and the reference material is to be based 
on acute pharmacological effect-time curves, measurements of this effect 
should be made with sufficient frequency to permit a reasonable estimate 
of the total area under the curve for a time period at least three times 
the half-life of decay of the pharmacological effect, unless some other 
approach is more appropriate for valid scientific reasons.
    (2) The use of an acute pharmacological effect to determine 
bioavailability may further require demonstration of dose-related 
response. In such a case, bioavailability may be determined by 
comparison of the dose-response curves as well as the total area under 
the acute pharmacological effect-time curves for any given dose.

[42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]



Sec. 320.27  Guidelines on the design of a multiple-dose in vivo
bioavailability study.

    (a) Basic principles. (1) In selected circumstances it may be 
necessary for the test product and the reference material to be compared 
after repeated administration to determine steady-state levels of the 
active drug ingredient or therapeutic moiety in the body.
    (2) The test product and the reference material should be 
administered to subjects in the fasting or nonfasting state, depending 
upon the conditions reflected in the proposed labeling of the test 
product.
    (3) A multiple-dose study may be required to determine the 
bioavailability of a drug product in the following circumstances:
    (i) There is a difference in the rate of absorption but not in the 
extent of absorption.
    (ii) There is excessive variability in bioavailability from subject 
to subject.
    (iii) The concentration of the active drug ingredient or therapeutic 
moiety, or its metabolite(s), in the blood resulting from a single dose 
is too low for accurate determination by the analytical method.
    (iv) The drug product is an extended release dosage form.
    (b) Study design. (1) A multiple-dose study should be crossover in 
design, unless a parallel design or other design is more appropriate for 
valid scientific reasons, and should provide for a drug elimination 
period if steady-state conditions are not achieved.
    (2) A multiple-dose study is not required to be of crossover design 
if the study is to establish dose proportionality under a multiple-dose 
regimen or to establish the pharmacokinetic profile of a new drug 
product, a new drug delivery system, or an extended release dosage form.
    (3) If a drug elimination period is required, unless some other 
approach is more appropriate for valid scientific reasons, the drug 
elimination period should be either:
    (i) At least five times the half-life of the active drug ingredient 
or therapeutic moiety, or its active metabolite(s), measured in the 
blood or urine; or
    (ii) At least five times the half-life of decay of the acute 
pharmacological effect.
    (c) Achievement of steady-state conditions. Whenever a multiple-dose 
study is conducted, unless some other approach is more appropriate for 
valid scientific reasons, sufficient doses of the test product and 
reference material should be administered in accordance with the 
labeling to achieve steady-state conditions.
    (d) Collection of blood or urine samples. (1) Whenever comparison of 
the test product and the reference material is

[[Page 200]]

to be based on blood concentration-time curves at steady state, 
appropriate dosage administration and sampling should be carried out to 
document attainment of steady state.
    (2) Whenever comparison of the test product and the reference 
material is to be based on cumulative urinary excretion-time curves at 
steady state, appropriate dosage administration and sampling should be 
carried out to document attainment of steady state.
    (3) A more complete characterization of the blood concentration or 
urinary excretion rate during the absorption and elimination phases of a 
single dose administered at steady-state is encouraged to permit 
estimation of the total area under concentration-time curves or 
cumulative urinary excretion-time curves and to obtain pharmacokinetic 
information, e.g., half-life or blood clearance, that is essential in 
preparing adequate labeling for the drug product.
    (e) Steady-state parameters. (1) In certain instances, e.g., in a 
study involving a new drug entity, blood clearances at steady-state 
obtained in a multiple-dose study should be compared to blood clearances 
obtained in a single-dose study to support adequate dosage 
recommendations.
    (2) In a linear system, the area under the blood concentration-time 
curve during a dosing interval in a multiple-dose steady-state study is 
directly proportional to the fraction of the dose absorbed and is equal 
to the corresponding ``zero to infinity'' area under the curve for a 
single-dose study. Therefore, when steady-state conditions are achieved, 
a comparison of blood concentrations during a dosing interval may be 
used to define the fraction of the active drug ingredient or therapeutic 
moiety absorbed.
    (3) Other methods based on valid scientific reasons should be used 
to determine the bioavailability of a drug product having dose-dependent 
kinetics (non-linear system).
    (f) Measurement of an acute pharmacological effect. When comparison 
of the test product and the reference material is to be based on acute 
pharmacological effect-time curves, measurements of this effect should 
be made with sufficient frequency to demonstrate a maximum effect and a 
lack of significant difference between the test product and the 
reference material.

[42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]



Sec. 320.28  Correlation of bioavailability with an acute 
pharmacological effect or clinical evidence.

    Correlation of in vivo bioavailability data with an acute 
pharmacological effect or clinical evidence of safety and effectiveness 
may be required if needed to establish the clinical significance of a 
special claim, e.g., in the case of an extended release preparation.

[42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]



Sec. 320.29  Analytical methods for an in vivo bioavailability or 
bioequivalence study.

    (a) The analytical method used in an in vivo bioavailability or 
bioequivalence study to measure the concentration of the active drug 
ingredient or therapeutic moiety, or its active metabolite(s), in body 
fluids or excretory products, or the method used to measure an acute 
pharmacological effect shall be demonstrated to be accurate and of 
sufficient sensitivity to measure, with appropriate precision, the 
actual concentration of the active drug ingredient or therapeutic 
moiety, or its active metabolite(s), achieved in the body.
    (b) When the analytical method is not sensitive enough to measure 
accurately the concentration of the active drug ingredient or 
therapeutic moiety, or its active metabolite(s), in body fluids or 
excretory products produced by a single dose of the test product, two or 
more single doses may be given together to produce higher concentration 
if the requirements of Sec. 320.31 are met.

[42 FR 1648, Jan. 7, 1977, as amended at 67 FR 77674, Dec. 19, 2002]



Sec. 320.30  Inquiries regarding bioavailability and bioequivalence 
requirements and review of protocols by the Food and Drug Administration.

    (a) The Commissioner of Food and Drugs strongly recommends that, to

[[Page 201]]

avoid the conduct of an improper study and unnecessary human research, 
any person planning to conduct a bioavailability or bioequivalence study 
submit the proposed protocol for the study to FDA for review prior to 
the initiation of the study.
    (b) FDA may review a proposed protocol for a bioavailability or 
bioequivalence study and will offer advice with respect to whether the 
following conditions are met:
    (1) The design of the proposed bioavailability or bioequivalence 
study is appropriate.
    (2) The reference material to be used in the bioavailability or 
bioequivalence study is appropriate.
    (3) The proposed chemical and statistical analytical methods are 
adequate.
    (c)(1) General inquiries relating to in vivo bioavailability 
requirements and methodology shall be submitted to the Food and Drug 
Administration, Center for Drug Evaluation and Research, Office of 
Clinical Pharmacology, 10903 New Hampshire Ave., Silver Spring, MD 
20993-0002.
    (2) General inquiries relating to bioequivalence requirements and 
methodology shall be submitted to the Food and Drug Administration, 
Center for Drug Evaluation and Research, Division of Bioequivalence 
(HFD-650), 7500 Standish Pl., Rockville, MD 20855-2773.

[57 FR 18000, Apr. 28, 1992, as amended at 67 FR 77674, Dec. 19, 2002; 
74 FR 13114, Mar. 26, 2009]



Sec. 320.31  Applicability of requirements regarding an 
``Investigational New Drug Application.''

    (a) Any person planning to conduct an in vivo bioavailability or 
bioequivalence study in humans shall submit an ``Investigational New 
Drug Application'' (IND) if:
    (1) The test product contains a new chemical entity as defined in 
Sec. 314.108(a) of this chapter; or
    (2) The study involves a radioactively labeled drug product; or
    (3) The study involves a cytotoxic drug product.
    (b) Any person planning to conduct a bioavailability or 
bioequivalence study in humans using a drug product that contains an 
already approved, non-new chemical entity shall submit an IND if the 
study is one of the following:
    (1) A single-dose study in normal subjects or patients where either 
the maximum single or total daily dose exceeds that specified in the 
labeling of the drug product that is the subject of an approved new drug 
application or abbreviated new drug application.
    (2) A multiple-dose study in normal subjects or patients where 
either the single or total daily dose exceeds that specified in the 
labeling of the drug product that is the subject of an approved new drug 
application or abbreviated new drug application.
    (3) A multiple-dose study on an extended release product on which no 
single-dose study has been completed.
    (c) The provisions of parts 50, 56, and 312 of this chapter are 
applicable to any bioavailability or bioequivalence study in humans 
conducted under an IND.
    (d) A bioavailability or bioequivalence study in humans other than 
one described in paragraphs (a) through (c) of this section is exempt 
from the requirements of part 312 of this chapter if the following 
conditions are satisfied:
    (1) If the study is one described under Sec. 320.38(b) or Sec. 
320.63, the person conducting the study, including any contract research 
organization, must retain reserve samples of any test article and 
reference standard used in the study and release the reserve samples to 
FDA upon request, in accordance with, and for the period specified in, 
Sec. 320.38;
    (2) An in vivo bioavailability or bioequivalence study in humans 
must be conducted in compliance with the requirements for institutional 
review set forth in part 56 of this chapter, and informed consent set 
forth in part 50 of this chapter; and
    (3) The person conducting the study, including any contract research 
organization, must notify FDA and all participating investigators of any 
serious adverse event, as defined in Sec. 312.32(a), observed during 
the conduct of the study as soon as possible but in no case later than 
15 calendar days after becoming aware of its occurrence. Each report 
must be submitted on FDA Form 3500A or in an electronic format

[[Page 202]]

that FDA can process, review, and archive. FDA will periodically issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation and organization of 
files). Each report must bear prominent identification of its contents, 
i.e., ``bioavailability/bioequivalence safety report.'' The person 
conducting the study, including any contract research organization, must 
also notify FDA of any fatal or life-threatening adverse event from the 
study as soon as possible but in no case later than 7 calendar days 
after becoming aware of its occurrence. Each notification under this 
paragraph must be submitted to the Director, Office of Generic Drugs in 
the Center for Drug Evaluation and Research at FDA. Relevant followup 
information to a bioavailability/bioequivalence safety report must be 
submitted as soon as the information is available and must be identified 
as such, i.e., ``Followup bioavailability/bioequivalence safety 
report.'' Upon request from FDA, the person conducting the study, 
including any contract research organization, must submit to FDA any 
additional data or information that the agency deems necessary, as soon 
as possible, but in no case later than 15 calendar days after receiving 
the request.

[57 FR 18000, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993; 
67 FR 77674, Dec. 19, 2002; 75 FR 59963, Sept. 29, 2010]



Sec. 320.32  Procedures for establishing or amending a bioequivalence
requirement.

    (a) The Food and Drug Administration, on its own initiative or in 
response to a petition by an interested person, may propose and 
promulgate a regulation to establish a bioequivalence requirement for a 
product not subject to section 505(j) of the act if it finds there is 
well-documented evidence that specific pharmaceutical equivalents or 
pharmaceutical alternatives intended to be used interchangeably for the 
same therapeutic effect:
    (1) Are not bioequivalent drug products; or
    (2) May not be bioequivalent drug products based on the criteria set 
forth in Sec. 320.33; or
    (3) May not be bioequivalent drug products because they are members 
of a class of drug products that have close structural similarity and 
similar physicochemical or pharmacokinetic properties to other drug 
products in the same class that FDA finds are not bioequivalent drug 
products.
    (b) FDA shall include in a proposed rule to establish a 
bioequivalence requirement the evidence and criteria set forth in Sec. 
320.33 that are to be considered in determining whether to issue the 
proposal. If the rulemaking is proposed in response to a petition, FDA 
shall include in the proposal a summary and analysis of the relevant 
information that was submitted in the petition as well as other 
available information to support the establishment of a bioequivalence 
requirement.
    (c) FDA, on its own initiative or in response to a petition by an 
interested person, may propose and promulgate an amendment to a 
bioequivalence requirement established under this subpart.

[57 FR 18000, Apr. 28, 1992]



Sec. 320.33  Criteria and evidence to assess actual or potential 
bioequivalence problems.

    The Commissioner of Food and Drugs shall consider the following 
factors, when supported by well-documented evidence, to identify 
specific pharmaceutical equivalents and pharmaceutical alternatives that 
are not or may not be bioequivalent drug products.
    (a) Evidence from well-controlled clinical trials or controlled 
observations in patients that such drug products do not give comparable 
therapeutic effects.
    (b) Evidence from well-controlled bioequivalence studies that such 
products are not bioequivalent drug products.
    (c) Evidence that the drug products exhibit a narrow therapeutic 
ratio, e.g., there is less than a 2-fold difference in median lethal 
dose (LD50)

[[Page 203]]

and median effective dose (ED50) values, or have less than a 
2-fold difference in the minimum toxic concentrations and minimum 
effective concentrations in the blood, and safe and effective use of the 
drug products requires careful dosage titration and patient monitoring.
    (d) Competent medical determination that a lack of bioequivalence 
would have a serious adverse effect in the treatment or prevention of a 
serious disease or condition.
    (e) Physicochemical evidence that:
    (1) The active drug ingredient has a low solubility in water, e.g., 
less than 5 milligrams per 1 milliliter, or, if dissolution in the 
stomach is critical to absorption, the volume of gastric fluids required 
to dissolve the recommended dose far exceeds the volume of fluids 
present in the stomach (taken to be 100 milliliters for adults and 
prorated for infants and children).
    (2) The dissolution rate of one or more such products is slow, e.g., 
less than 50 percent in 30 minutes when tested using either a general 
method specified in an official compendium or a paddle method at 50 
revolutions per minute in 900 milliliters of distilled or deionized 
water at 37 [deg]C, or differs significantly from that of an appropriate 
reference material such as an identical drug product that is the subject 
of an approved full new drug application.
    (3) The particle size and/or surface area of the active drug 
ingredient is critical in determining its bioavailability.
    (4) Certain physical structural characteristics of the active drug 
ingredient, e.g., polymorphic forms, conforms, solvates, complexes, and 
crystal modifications, dissolve poorly and this poor dissolution may 
affect absorption.
    (5) Such drug products have a high ratio of excipients to active 
ingredients, e.g., greater than 5 to 1.
    (6) Specific inactive ingredients, e.g., hydrophilic or hydrophobic 
excipients and lubricants, either may be required for absorption of the 
active drug ingredient or therapeutic moiety or, alternatively, if 
present, may interfere with such absorption.
    (f) Pharmacokinetic evidence that:
    (1) The active drug ingredient, therapeutic moiety, or its precursor 
is absorbed in large part in a particular segment of the 
gastrointestinal tract or is absorbed from a localized site.
    (2) The degree of absorption of the active drug ingredient, 
therapeutic moiety, or its precursor is poor, e.g., less than 50 
percent, ordinarily in comparison to an intravenous dose, even when it 
is administered in pure form, e.g., in solution.
    (3) There is rapid metabolism of the therapeutic moiety in the 
intestinal wall or liver during the process of absorption (first-class 
metabolism) so the therapeutic effect and/or toxicity of such drug 
product is determined by the rate as well as the degree of absorption.
    (4) The therapeutic moiety is rapidly metabolized or excreted so 
that rapid dissolution and absorption are required for effectiveness.
    (5) The active drug ingredient or therapeutic moiety is unstable in 
specific portions of the gastrointestinal tract and requires special 
coatings or formulations, e.g., buffers, enteric coatings, and film 
coatings, to assure adequate absorption.
    (6) The drug product is subject to dose dependent kinetics in or 
near the therapeutic range, and the rate and extent of absorption are 
important to bioequivalence.

[42 FR 1635, Jan. 7, 1977. Redesignated and amended at 57 FR 18001, Apr. 
28, 1992]



Sec. 320.34  Requirements for batch testing and certification by the
Food and Drug Administration.

    (a) If the Commissioner determines that individual batch testing by 
the Food and Drug Administration is necessary to assure that all batches 
of the same drug product meet an appropriate in vitro test, he shall 
include in the bioequivalence requirement a requirement for 
manufacturers to submit samples of each batch to the Food and Drug 
Administration and to withhold distribution of the batch until notified 
by the Food and Drug Administration that the batch may be introduced 
into interstate commerce.
    (b) The Commissioner will ordinarily terminate a requirement for a 
manufacturer to submit samples for batch testing on a finding that the 
manufacturer has produced four consecutive

[[Page 204]]

batches that were tested by the Food and Drug Administration and found 
to meet the bioequivalence requirement, unless the public health 
requires that batch testing be extended to additional batches.

[42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992]



Sec. 320.35  Requirements for in vitro testing of each batch.

    If a bioequivalence requirement specifies a currently available in 
vitro test or an in vitro bioequivalence standard comparing the drug 
product to a reference standard, the manufacturer shall conduct the test 
on a sample of each batch of the drug product to assure batch-to-batch 
uniformity.

[42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992]



Sec. 320.36  Requirements for maintenance of records of bioequivalence
testing.

    (a) All records of in vivo or in vitro tests conducted on any 
marketed batch of a drug product to assure that the product meets a 
bioequivalence requirement shall be maintained by the manufacturer for 
at least 2 years after the expiration date of the batch and submitted to 
the Food and Drug Administration on request.
    (b) Any person who contracts with another party to conduct a 
bioequivalence study from which the data are intended to be submitted to 
FDA as part of an application submitted under part 314 of this chapter 
shall obtain from the person conducting the study sufficient accurate 
financial information to allow the submission of complete and accurate 
financial certifications or disclosure statements required under part 54 
of this chapter and shall maintain that information and all records 
relating to the compensation given for that study and all other 
financial interest information required under part 54 of this chapter 
for 2 years after the date of approval of the application. The person 
maintaining these records shall, upon request for any properly 
authorized officer or employee of the Food and Drug Administration, at 
reasonable time, permit such officer or employee to have access to and 
copy and verify these records.

[42 FR 1635, Jan. 7, 1977. Redesignated at 57 FR 18001, Apr. 28, 1992, 
as amended at 63 FR 5252, Feb. 2, 1998]



Sec. 320.38  Retention of bioavailability samples.

    (a) The applicant of an application or supplemental application 
submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, 
or, if bioavailability testing was performed under contract, the 
contract research organization shall retain an appropriately identified 
reserve sample of the drug product for which the applicant is seeking 
approval (test article) and of the reference standard used to perform an 
in vivo bioavailability study in accordance with and for the studies 
described in paragraph (b) of this section that is representative of 
each sample of the test article and reference standard provided by the 
applicant for the testing.
    (b) Reserve samples shall be retained for the following test 
articles and reference standards and for the studies described:
    (1) If the formulation of the test article is the same as the 
formulation(s) used in the clinical studies demonstrating substantial 
evidence of safety and effectiveness for the test article's claimed 
indications, a reserve sample of the test article used to conduct an in 
vivo bioavailability study comparing the test article to a reference 
oral solution, suspension, or injection.
    (2) If the formulation of the test article differs from the 
formulation(s) used in the clinical studies demonstrating substantial 
evidence of safety and effectiveness for the test article's claimed 
indications, a reserve sample of the test article and of the reference 
standard used to conduct an in vivo bioequivalence study comparing the 
test article to the formulation(s) (reference standard) used in the 
clinical studies.
    (3) For a new formulation, new dosage form, or a new salt or ester 
of an active drug ingredient or therapeutic moiety that has been 
approved for marketing, a reserve sample of the test article and of the 
reference standard used

[[Page 205]]

to conduct an in vivo bioequivalence study comparing the test article to 
a marketed product (reference standard) that contains the same active 
drug ingredient or therapeutic moiety.
    (c) Each reserve sample shall consist of a sufficient quantity to 
permit FDA to perform five times all of the release tests required in 
the application or supplemental application.
    (d) Each reserve sample shall be adequately identified so that the 
reserve sample can be positively identified as having come from the same 
sample as used in the specific bioavailability study.
    (e) Each reserve sample shall be stored under conditions consistent 
with product labeling and in an area segregated from the area where 
testing is conducted and with access limited to authorized personnel. 
Each reserve sample shall be retained for a period of at least 5 years 
following the date on which the application or supplemental application 
is approved, or, if such application or supplemental application is not 
approved, at least 5 years following the date of completion of the 
bioavailability study in which the sample from which the reserve sample 
was obtained was used.
    (f) Authorized FDA personnel will ordinarily collect reserve samples 
directly from the applicant or contract research organization at the 
storage site during a preapproval inspection. If authorized FDA 
personnel are unable to collect samples, FDA may require the applicant 
or contract research organization to submit the reserve samples to the 
place identified in the agency's request. If FDA has not collected or 
requested delivery of a reserve sample, or if FDA has not collected or 
requested delivery of any portion of a reserve sample, the applicant or 
contract research organization shall retain the sample or remaining 
sample for the 5-year period specified in paragraph (e) of this section.
    (g) Upon release of the reserve samples to FDA, the applicant or 
contract research organization shall provide a written assurance that, 
to the best knowledge and belief of the individual executing the 
assurance, the reserve samples came from the same samples as used in the 
specific bioavailability or bioequivalence study identified by the 
agency. The assurance shall be executed by an individual authorized to 
act for the applicant or contract research organization in releasing the 
reserve samples to FDA.
    (h) A contract research organization may contract with an 
appropriate, independent third party to provide storage of reserve 
samples provided that the sponsor of the study has been notified in 
writing of the name and address of the facility at which the reserve 
samples will be stored.
    (i) If a contract research organization conducting a bioavailability 
or bioequivalence study that requires reserve sample retention under 
this section or Sec. 320.63 goes out of business, it shall transfer its 
reserve samples to an appropriate, independent third party, and shall 
notify in writing the sponsor of the study of the transfer and provide 
the study sponsor with the name and address of the facility to which the 
reserve samples have been transferred.

[58 FR 25927, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999]



Sec. 320.63  Retention of bioequivalence samples.

    The applicant of an abbreviated application or a supplemental 
application submitted under section 505 of the Federal Food, Drug, and 
Cosmetic Act, or, if bioequivalence testing was performed under 
contract, the contract research organization shall retain reserve 
samples of any test article and reference standard used in conducting an 
in vivo or in vitro bioequivalence study required for approval of the 
abbreviated application or supplemental application. The applicant or 
contract research organization shall retain the reserve samples in 
accordance with, and for the period specified in, Sec. 320.38 and shall 
release the reserve samples to FDA upon request in accordance with Sec. 
320.38.

[58 FR 25928, Apr. 28, 1993, as amended at 64 FR 402, Jan. 5, 1999]

[[Page 206]]



PART 328_OVER-THE-COUNTER DRUG PRODUCTS INTENDED FOR ORAL INGESTION 
THAT CONTAIN ALCOHOL--Table of Contents



                      Subpart A_General Provisions

Sec.
328.1 Scope.
328.3 Definitions.

                          Subpart B_Ingredients

328.10 Alcohol.

                           Subpart C_Labeling

328.50 Principal display panel of all OTC drug products intended for 
          oral ingestion that contain alcohol.

    Authority: Secs. 201, 301, 501, 502, 503, 505, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 
371).

    Source: 60 FR 13595, Mar. 13, 1995, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 328 appear at 69 FR 
13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 328.1  Scope.

    Reference in this part to regulatory sections of the Code of Federal 
Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 328.3  Definitions.

    As used in this part:
    (a) Alcohol means the substance known as ethanol, ethyl alcohol, or 
Alcohol, USP.
    (b) Inactive ingredient means any component of a product other than 
an active ingredient as defined in Sec. 210.3(b)(7) of this chapter.



                          Subpart B_Ingredients



Sec. 328.10  Alcohol.

    (a) Any over-the-counter (OTC) drug product intended for oral 
ingestion shall not contain alcohol as an inactive ingredient in 
concentrations that exceed those established in this part, unless a 
specific exemption, as provided in paragraph (e) or (f) of this section, 
has been approved.
    (b) For any OTC drug product intended for oral ingestion and labeled 
for use by adults and children 12 years of age and over, the amount of 
alcohol in the product shall not exceed 10 percent.
    (c) For any OTC drug product intended for oral ingestion and labeled 
for use by children 6 to under 12 years of age, the amount of alcohol in 
the product shall not exceed 5 percent.
    (d) For any OTC drug product intended for oral ingestion and labeled 
for use by children under 6 years of age, the amount of alcohol in the 
product shall not exceed 0.5 percent.
    (e) The Food and Drug Administration will grant an exemption from 
paragraphs (b), (c), and (d) of this section where appropriate, upon 
petition under the provisions of Sec. 10.30 of this chapter. 
Appropriate cause, such as a specific solubility or manufacturing 
problem, must be adequately documented in the petition. Decisions with 
respect to requests for exemption shall be maintained in a permanent 
file for public review by the Division of Dockets Management (HFA-305), 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852.
    (f) Ipecac syrup is exempt from the provisions of paragraph (d) of 
this section.
    (g) The following drugs are temporarily exempt from the provisions 
of paragraphs (b), (c), and (d) of this section:
    (1) Aromatic Cascara Fluidextract.
    (2) Cascara Sagrada Fluidextract.
    (3) Orally ingested homeopathic drug products.

[60 FR 13595, Mar. 13, 1995, as amended at 61 FR 58630, Nov. 18, 1996; 
68 FR 24879, May 9, 2003]



                           Subpart C_Labeling



Sec. 328.50  Principal display panel of all OTC drug products 
intended for oral ingestion that contain alcohol.

    (a) The amount (percentage) of alcohol present in a product shall be 
stated in terms of percent volume of absolute alcohol at 60 [deg]F 
(15.56 [deg]C) in accordance with Sec. 201.10(d)(2) of this chapter.
    (b) A statement expressing the amount (percentage) of alcohol 
present in a product shall appear prominently and conspicuously on the 
``principal display panel,'' as defined in Sec. 201.60 of

[[Page 207]]

this chapter. For products whose principal display panel is on the 
immediate container label and that are not marketed in another retail 
package (e.g., an outer box), the statement of the percentage of alcohol 
present in the product shall appear prominently and conspicuously on the 
``principal display panel'' of the immediate container label.
    (c) For products whose principal display panel is on the retail 
package and the retail package is not the immediate container, the 
statement of the percentage of alcohol present in the product shall also 
appear on the immediate container label; it may appear anywhere on that 
label in accord with section 502(e) of the Federal Food, Drug, and 
Cosmetic Act.
    (d) The statement expressing the amount (percentage) of alcohol 
present in the product shall be in a size reasonably related to the most 
prominent printed matter on the panel or label on which it appears, and 
shall be in lines generally parallel to the base on which the package 
rests as it is designed to be displayed.
    (e) For a product to state in its labeling that it is ``alcohol 
free,'' it must contain no alcohol (0 percent).
    (f) For any OTC drug product intended for oral ingestion containing 
over 5 percent alcohol and labeled for use by adults and children 12 
years of age and over, the labeling shall contain the following 
statement in the directions section: ``Consult a physician for use in 
children under 12 years of age.''
    (g) For any OTC drug product intended for oral ingestion containing 
over 0.5 percent alcohol and labeled for use by children ages 6 to under 
12 years of age, the labeling shall contain the following statement in 
the directions section: ``Consult a physician for use in children under 
6 years of age.''
    (h) When the direction regarding age in paragraph (e) or (f) of this 
section differs from an age-limiting direction contained in any OTC drug 
monograph in this chapter, the direction containing the more stringent 
age limitation shall be used.



PART 330_OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY 
RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED--Table of Contents



                      Subpart A_General Provisions

Sec.
330.1 General conditions for general recognition as safe, effective and 
          not misbranded.
330.2 Pregnancy-nursing warning.
330.3 Imprinting of solid oral dosage form drug products.
330.5 Drug categories.

                   Subpart B_Administrative Procedures

330.10 Procedures for classifying OTC drugs as generally recognized as 
          safe and effective and not misbranded, and for establishing 
          monographs.
330.11 NDA deviations from applicable monograph.
330.12 Status of over-the-counter (OTC) drugs previously reviewed under 
          the Drug Efficacy Study (DESI).
330.13 Conditions for marketing ingredients recommended for over-the-
          counter (OTC) use under the OTC drug review.
330.14 Additional criteria and procedures for classifying OTC drugs as 
          generally recognized as safe and effective and not misbranded.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 39 FR 11741, Mar. 29, 1974, unless otherwise noted.

    Editorial Note: Nomenclature changes to part 330 appear at 69 FR 
13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 330.1  General conditions for general recognition as safe,
effective and not misbranded.

    An over-the-counter (OTC) drug listed in this subchapter is 
generally recognized as safe and effective and is not misbranded if it 
meets each of the conditions contained in this part and each of the 
conditions contained in any applicable monograph. Any product which 
fails to conform to each of the conditions contained in this part and in 
an applicable monograph is liable to regulatory action.

[[Page 208]]

    (a) The product is manufactured in compliance with current good 
manufacturing practices, as established by parts 210 and 211 of this 
chapter.
    (b) The establishment(s) in which the drug product is manufactured 
is registered, and the drug product is listed, in compliance with part 
207 of this chapter. It is requested but not required that the number 
assigned to the product pursuant to part 207 of this chapter appear on 
all drug labels and in all drug labeling. If this number is used, it 
shall be placed in the manner set forth in part 207 of this chapter.
    (c)(1) The product is labeled in compliance with chapter V of the 
Federal Food, Drug, and Cosmetic Act (the act) and subchapter C et seq. 
of this chapter, including the format and content requirements in Sec. 
201.66 of this chapter. An OTC drug product that is not in compliance 
with chapter V and subchapter C, including Sec. 201.66 of this chapter, 
is subject to regulatory action. For purposes of Sec. 201.61(b) of this 
chapter, the statement of identity of the product shall be the term or 
phrase used in the applicable OTC drug monograph established in this 
part.
    (2) The ``Uses'' section of the label and labeling of the product 
shall contain the labeling describing the ``Indications'' that have been 
established in an applicable OTC drug monograph or alternative truthful 
and nonmisleading statements describing only those indications for use 
that have been established in an applicable monograph, subject to the 
provisions of section 502 of the act relating to misbranding and the 
prohibition in section 301(d) of the act against the introduction or 
delivery for introduction into interstate commerce of unapproved new 
drugs in violation of section 505(a) of the act. Any other labeling 
under this subchapter and subchapter C et seq. of this chapter shall be 
stated in the exact language where exact language has been established 
and identified by quotation marks in an applicable OTC drug monograph or 
by regulation (e.g., Sec. 201.63 of this chapter), except as provided 
in paragraphs (i) and (j) of this section.
    (d) The advertising for the product prescribes, recommends, or 
suggests its use only under the conditions stated in the labeling.
    (e) The product contains only suitable inactive ingredients which 
are safe in the amounts administered and do not interfere with the 
effectiveness of the preparation or with suitable tests or assays to 
determine if the product meets its professed standards of identity, 
strength, quality, and purity. Color additives may be used only in 
accordance with section 721 of the act and subchapter A of this chapter.
    (f) The product container and container components meet the 
requirements of Sec. 211.94 of this chapter.
    (g) The labeling for all drugs contains the general warning: ``Keep 
out of reach of children.'' [highlighted in bold type]. The labeling of 
drugs shall also state as follows: For drugs used by oral 
administration, ``In case of overdose, get medical help or contact a 
Poison Control Center right away''; for drugs used topically, rectally, 
or vaginally and not intended for oral ingestion, ``If swallowed, get 
medical help or contact a Poison Control Center right away''; and for 
drugs used topically and intended for oral use, ``If more than used 
for'' (insert intended use, e.g., pain) ``is accidentally swallowed, get 
medical help or contact a Poison Control Center right away.'' The Food 
and Drug Administration will grant an exemption from these general 
warnings where appropriate upon petition, which shall be maintained in a 
permanent file for public review by the Division of Dockets Management, 
Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 
20852.
    (h) Where no maximum daily dosage limit for an active ingredient is 
established in this part, it is used in a product at a level that does 
not exceed the amount reasonably required to achieve its intended 
effect.
    (i) The following terms may be used interchangeably in the labeling 
of OTC drug products, provided such use does not alter the meaning of 
the labeling that has been established and identified in an applicable 
monograph or by regulation. The following terms shall not be used to 
change in any way the title, headings, and subheadings required under 
Sec. 201.66(c)(1) through (c)(9) of this chapter:
    (1) ``Abdominal'' or ``stomach'' (in context only).

[[Page 209]]

    (2) ``Administer'' or ``give''.
    (3) ``Aggravate(s)'' or ``make(s) worse''.
    (4) ``Application of this product'' or ``applying''.
    (5) ``Are uncertain'' or ``do not know''.
    (6) ``Ask'' or ``consult'' or ``contact''.
    (7) ``Asking'' or ``consulting''.
    (8) ``Assistance'' or ``help'' or ``aid''.
    (9) ``Associated with'' or ``due to'' or ``caused by''.
    (10) ``Avoid contact with eyes'' or ``do not get into eyes''.
    (11) ``Avoid inhaling'' or ``do not inhale''.
    (12) ``Before a doctor is consulted'' or ``without first consulting 
your doctor'' or ``consult your doctor before''.
    (13) ``Beverages'' or ``drinks''.
    (14) ``Clean'' or ``cleanse''.
    (15) ``Consulting'' or ``advising''.
    (16) ``Continue(s)'' or ``persist(s)'' or ``is persistent'' or 
``do(es) not go away'' or ``last(s)''.
    (17) ``Daily'' or ``every day''.
    (18) ``Develop(s)'' or ``begin(s)'' or ``occur(s)''.
    (19) ``Difficulty'' or ``trouble''.
    (20) ``Difficulty in urination'' or ``trouble urinating''.
    (21) ``Discard'' or ``throw away''.
    (22) ``Discontinue'' or ``stop'' or ``quit''.
    (23) ``Doctor'' or ``physician''.
    (24) ``Drowsiness'' or ``the drowsiness effect''.
    (25) ``Drowsiness may occur'' or ``you may get drowsy''.
    (26) ``Enlargement of the'' or ``an enlarged''.
    (27) ``Especially in children'' or especially children''.
    (28) ``Exceed'' or ``use more than'' or ``go beyond''.
    (29) ``Exceed recommended dosage'' or ``use more than directed''.
    (30) ``Excessive'' or ``too much''.
    (31) ``Excitability may occur'' or ``you may get excited''.
    (32) ``Experience'' or ``feel''.
    (33) ``For relief of'' or ``relieves''.
    (34) ``For temporary reduction of'' or ``temporarily reduces''.
    (35) ``For the temporary relief of'' or ``temporarily relieves''.
    (36) ``For the treatment of'' or ``treats''.
    (37) ``Frequently'' or ``often''.
    (38) ``Give to'' or ``use in''.
    (39) ``Immediately'' or ``right away'' or ``directly''.
    (40) ``Immediately'' or ``as soon as''.
    (41) ``Immediately following'' or ``right after''.
    (42) ``Improve(s)'' or ``get(s) better'' or ``make(s) better''.
    (43) ``Increased'' or ``more''.
    (44) ``Increase your risk of'' or ``cause''.
    (45) ``Indication(s)'' or ``Use(s)''.
    (46) ``Inhalation'' or ``puff''.
    (47) ``In persons who'' or ``if you'' or ``if the child''.
    (48) ``Instill'' or ``put''.
    (49) ``Is (are) accompanied by'' or ``you also have'' (in context 
only) or ``(optional: that) occur(s) with''.
    (50) ``Longer'' or ``more''.
    (51) ``Lung'' or ``pulmonary''.
    (52) ``Medication(s)'' or ``medicine(s)'' or ``drug(s)''.
    (53) ``Nervousness, dizziness, or sleeplessness occurs'' or ``you 
get nervous, dizzy, or sleepless''.
    (54) ``Not to exceed'' or ``do not exceed'' or ``not more than''.
    (55) ``Obtain(s)'' or ``get(s)''.
    (56) ``Passages'' or ``passageways'' or ``tubes''.
    (57) ``Perforation of'' or ``hole in''.
    (58) ``Persistent'' or ``that does not go away'' or ``that 
continues'' or ``that lasts''.
    (59) ``Per day'' or ``daily''.
    (60) ``Presently'' or ``now''.
    (61) ``Produce(s)'' or ``cause(s)''.
    (62) ``Prompt(ly)'' or ``quick(ly)'' or ``right away''.
    (63) ``Reduce'' or ``minimize''.
    (64) ``Referred to as'' or ``of''.
    (65) ``Sensation'' or ``feeling''.
    (66) ``Solution'' or ``liquid''.
    (67) ``Specifically'' or ``definitely''.
    (68) ``Take'' or ``use'' or ``give''.
    (69) ``Tend(s) to recur'' or ``reoccur(s)'' or ``return(s)'' or 
``come(s) back''.
    (70) ``To avoid contamination'' or ``avoid contamination'' or ``do 
not contaminate''.
    (71) ``To help'' or ``helps''.
    (72) ``Unless directed by a doctor'' or ``except under the advice of 
a doctor'' or ``unless told to do so by a doctor''.
    (73) ``Use caution'' or ``be careful''.
    (74) ``Usually'' or ``generally'' (in context only).

[[Page 210]]

    (75) ``You'' (``Your'') or ``the child'' (``the child's'').
    (76) ``You also have'' or ``occurs with''.
    (77) ``When practical'' or ``if possible''.
    (78) ``Whether'' or ``if''.
    (79) ``Worsen(s)'' or ``get(s) worse'' or ``make(s) worse''.
    (j) The following connecting terms may be deleted from the labeling 
of OTC drug products, provided such deletion does not alter the meaning 
of the labeling that has been established and identified in an 
applicable monograph or by regulation. The following terms shall not be 
used to change in any way the specific title, headings, and subheadings 
required under Sec. 201.66(c)(1) through (c)(9) of this chapter:
    (l) ``And''.
    (2) ``As may occur with''.
    (3) ``Associated'' or ``to be associated''.
    (4) ``Consult a doctor''.
    (5) ``Discontinue use''.
    (6) ``Drug Interaction Precaution''.
    (7) ``Due to''.
    (8) ``Except under the advice and supervision of a physician''.
    (9) ``If this occurs''.
    (10) ``In case of''.
    (11) ``Notice''.
    (12) ``Or''.
    (13) ``Occurring with''.
    (14) ``Or as directed by a doctor''.
    (15) ``Such as''.
    (16) ``Such as occurs with''.
    (17) ``Tends to''.
    (18) ``This product''.
    (19) ``Unless directed by a doctor''.
    (20) ``While taking this product'' or ``before taking this 
product''.
    (21) ``Within''.

[39 FR 11741, Mar. 29, 1974, as amended at 40 FR 11718, Mar. 13, 1975; 
40 FR 13496, Mar. 27, 1975; 42 FR 15674, Mar. 22, 1977; 46 FR 8459, Jan. 
27, 1981; 50 FR 8996, Mar. 6, 1985; 51 FR 16266, May 1, 1986; 55 FR 
11581, Mar. 29, 1990; 59 FR 4000, Jan. 28, 1994; 59 FR 14365, Mar. 28, 
1994; 64 FR 13294, Mar. 17, 1999; 68 FR 24879, May 9, 2003]



Sec. 330.2  Pregnancy-nursing warning.

    A pregnancy-nursing warning for OTC drugs is set forth under Sec. 
201.63 of this chapter.

[47 FR 54758, Dec. 3, 1982]



Sec. 330.3  Imprinting of solid oral dosage form drug products.

    A requirement to imprint an identification code on solid oral dosage 
form drug products is set forth under part 206 of this chapter.

[58 FR 47959, Sept. 13, 1993]



Sec. 330.5  Drug categories.

    Monographs promulgated pursuant to the provisions of this part shall 
be established in this part 330 and following parts and shall cover the 
following designated categories:
    (a) Antacids.
    (b) Laxatives.
    (c) Antidiarrheal products.
    (d) Emetics.
    (e) Antiemetics.
    (f) Antiperspirants.
    (g) Sunburn prevention and treatment products.
    (h) Vitamin-mineral products.
    (i) Antimicrobial products.
    (j) Dandruff products.
    (k) Oral hygiene aids.
    (l) Hemorrhoidal products.
    (m) Hematinics.
    (n) Bronchodilator and antiasthmatic products.
    (o) Analgesics.
    (p) Sedatives and sleep aids.
    (q) Stimulants.
    (r) Antitussives.
    (s) Allergy treatment products.
    (t) Cold remedies.
    (u) Antirheumatic products.
    (v) Ophthalmic products.
    (w) Contraceptive products.
    (x) Miscellaneous dermatologic products.
    (y) Dentifrices and dental products such as analgesics, antiseptics, 
etc.
    (z) Miscellaneous (all other OTC drugs not falling within one of the 
above therapeutic categories).



                   Subpart B_Administrative Procedures



Sec. 330.10  Procedures for classifying OTC drugs as generally 
recognized as safe and effective and not misbranded, and for 

establishing monographs.

    For purposes of classifying over-the-counter (OTC) drugs as drugs 
generally recognized among qualified experts as safe and effective for 
use and as not

[[Page 211]]

misbranded drugs, the following regulations shall apply:
    (a) Procedure for establishing OTC drug monographs--(1) Advisory 
review panels. The Commissioner shall appoint advisory review panels of 
qualified experts to evaluate the safety and effectiveness of OTC drugs, 
to review OTC drug labeling, and to advise him on the promulgation of 
monographs establishing conditions under which OTC drugs are generally 
recognized as safe and effective and not misbranded. A single advisory 
review panel shall be established for each designated category of OTC 
drugs and every OTC drug category will be considered by a panel. The 
members of a panel shall be qualified experts (appointed by the 
Commissioner) and may include persons from lists submitted by 
organizations representing professional, consumer, and industry 
interests. The Commissioner shall designate the chairman of each panel. 
Summary minutes of all meetings shall be made.
    (2) Request for data and views. The Commissioner will publish a 
notice in the Federal Register requesting interested persons to submit, 
for review and evaluation by an advisory review panel, published and 
unpublished data and information pertinent to a designated category of 
OTC drugs. Data and information submitted pursuant to a published 
notice, and falling within the confidentiality provisions of 18 U.S.C. 
1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j), shall be handled by the 
advisory review panel and the Food and Drug Administration as 
confidential until publication of a proposed monograph and the full 
report(s) of the panel or until the Commissioner places the panel's 
recommendations on public display at the office of the Division of 
Dockets Management. Thirty days thereafter such data and information 
shall be made publicly available and may be viewed at the office of the 
Division of Dockets Management of the Food and Drug Administration, 
except to the extent that the person submitting it demonstrates that it 
still falls within the confidentiality provisions of one or more of 
those statutes. To be considered, eight copies of the data and/or views 
on any marketed drug within the class must be submitted, preferably 
bound, indexed, and on standard sized paper (approximately 8\1/2\x11 
inches). When requested, abbreviated submissions should be sent. All 
submissions must be in the following format:

                       OTC Drug Review Information

    I. Label(s) and all labeling (preferably mounted and filed with the 
other data--facsimile labeling is acceptable in lieu of actual container 
labeling).
    II. A statement setting forth the quantities of active ingredients 
of the drug.
    III. Animal safety data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    C. Finished drug product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    IV. Human safety data.
    A. Individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of combinations of the individual active 
components.
    5. Pertinent medical and scientific literature.
    C. Finished drug product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination as to the safety of the finished drug product.
    5. Pertinent medical and scientific literature.
    V. Efficacy data.
    A. Individual active components.
    1. Controlled studies.

[[Page 212]]

    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of each individual active component.
    5. Pertinent medical and scientific literature.
    B. Combinations of the individual active components.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of combinations of the individual active 
components.
    5. Pertinent medical and scientific literature.
    C. Finished drug product.
    1. Controlled studies.
    2. Partially controlled or uncontrolled studies.
    3. Documented case reports. Identify expected or frequently reported 
side effects.
    4. Pertinent marketing experiences that may influence a 
determination on the efficacy of the finished drug product.
    5. Pertinent medical and scientific literature.
    VI. A summary of the data and views setting forth the medical 
rationale and purpose (or lack thereof) for the drug and its ingredients 
and the scientific basis (or lack thereof) for the conclusion that the 
drug and its ingredients have been proven safe and effective for the 
intended use. If there is an absence of controlled studies in the 
material submitted, an explanation as to why such studies are not 
considered necessary must be included.
    VII. An official United States Pharmacopeia (USP)-National Formulary 
(NF) drug monograph for the active ingredient(s) or botanical drug 
substance(s), or a proposed standard for inclusion in an article to be 
recognized in an official USP-NF drug monograph for the active 
ingredient(s) or botanical drug substance(s). Include information 
showing that the official or proposed compendial monograph for the 
active ingredient or botanical drug substance is consistent with the 
active ingredient or botanical drug substance used in the studies 
establishing safety and effectiveness and with the active ingredient or 
botanical drug substance marketed in the OTC product(s) to a material 
extent and for a material time. If differences exist, explain why.

    (3) Deliberations of an advisory review panel. An advisory review 
panel will meet as often and for as long as is appropriate to review the 
data submitted to it and to prepare a report containing its conclusions 
and recommendations to the Commissioner with respect to the safety and 
effectiveness of the drugs in a designated category of OTC drugs. A 
panel may consult any individual or group. Any interested person may 
request an opportunity to present oral views to the panel; such request 
may be granted or denied by the panel. Such requests for oral 
presentations should be in written form including a summarization of the 
data to be presented to the panel. Any interested person may present 
written data and views which shall be considered by the panel. This 
information shall be presented to the panel in the format set forth in 
paragraph (a)(2) of this section and within the time period established 
for the drug category in the notice for review by a panel.
    (4) Standards for safety, effectiveness, and labeling. The advisory 
review panel, in reviewing the data submitted to it and preparing its 
conclusions and recommendations, and the Commissioner, in reviewing the 
conclusions and recommendations of the panel and the published proposed, 
tentative, and the final monographs, shall apply the following standards 
to determine general recognition that a category of OTC drugs is safe 
and effective and not misbranded:
    (i) Safety means a low incidence of adverse reactions or significant 
side effects under adequate directions for use and warnings against 
unsafe use as well as low potential for harm which may result from abuse 
under conditions of widespread availability. Proof of safety shall 
consist of adequate tests by methods reasonably applicable to show the 
drug is safe under the prescribed, recommended, or suggested conditions 
of use. This proof shall include results of significant human experience 
during marketing. General recognition of safety shall ordinarily be 
based upon published studies which may be corroborated by unpublished 
studies and other data.
    (ii) Effectiveness means a reasonable expectation that, in a 
significant proportion of the target population, the pharmacological 
effect of the drug, when used under adequate directions for use and 
warnings against unsafe use, will provide clinically significant

[[Page 213]]

relief of the type claimed. Proof of effectiveness shall consist of 
controlled clinical investigations as defined in Sec. 314.126(b) of 
this chapter, unless this requirement is waived on the basis of a 
showing that it is not reasonably applicable to the drug or essential to 
the validity of the investigation and that an alternative method of 
investigation is adequate to substantiate effectiveness. Investigations 
may be corroborated by partially controlled or uncontrolled studies, 
documented clinical studies by qualified experts, and reports of 
significant human experience during marketing. Isolated case reports, 
random experience, and reports lacking the details which permit 
scientific evaluation will not be considered. General recognition of 
effectiveness shall ordinarily be based upon published studies which may 
be corroborated by unpublished studies and other data.
    (iii) The benefit-to-risk ratio of a drug shall be considered in 
determining safety and effectiveness.
    (iv) An OTC drug may combine two or more safe and effective active 
ingredients and may be generally recognized as safe and effective when 
each active ingredient makes a contribution to the claimed effect(s); 
when combining of the active ingredients does not decrease the safety or 
effectiveness of any of the individual active ingredients; and when the 
combination, when used under adequate directions for use and warnings 
against unsafe use, provides rational concurrent therapy for a 
significant proportion of the target population.
    (v) Labeling shall be clear and truthful in all respects and may not 
be false or misleading in any particular. It shall state the intended 
uses and results of the product; adequate directions for proper use; and 
warnings against unsafe use, side effects, and adverse reactions in such 
terms as to render them likely to be read and understood by the ordinary 
individual, including individuals of low comprehension, under customary 
conditions of purchase and use.
    (vi) A drug shall be permitted for OTC sale and use by the laity 
unless, because of its toxicity or other potential for harmful effect or 
because of the method or collateral measures necessary to its use, it 
may safely be sold and used only under the supervision of a practitioner 
licensed by law to administer such drugs.
    (5) Advisory review panel report to the Commissioner. An advisory 
review panel may submit to the Commissioner a report containing its 
conclusions and recommendations with respect to the conditions under 
which OTC drugs falling within the category covered by the panel are 
generally recognized as safe and effective and not misbranded. Included 
within this report shall be:
    (i) A recommended monograph or monographs covering the category of 
OTC drugs and establishing conditions under which the drugs involved are 
generally recognized as safe and effective and not misbranded (Category 
I). This monograph may include any conditions relating to active 
ingredients, labeling indications, warnings and adequate directions for 
use, prescription or OTC status, and any other conditions necessary and 
appropriate for the safety and effectiveness of drugs covered by the 
monograph.
    (ii) A statement of active ingredients, labeling claims or other 
statements, or other conditions reviewed and excluded from the monograph 
on the basis of the panel's determination that they would result in the 
drug's not being generally recognized as safe and effective or would 
result in misbranding (Category II).
    (iii) A statement of active ingredients, labeling claims or other 
statements, or other conditions reviewed and excluded from the monograph 
on the basis of the panel's determination that the available data are 
insufficient to classify such condition under either paragraph (a)(5) 
(i) or (ii) of this section and for which further testing is therefore 
required (Category III). The report may recommend the type of further 
testing required and the time period within which it might reasonably be 
concluded.
    (6) Proposed monograph. After reviewing the conclusions and 
recommendations of the advisory review panel, the Commissioner shall 
publish in the Federal Register a proposed order containing:
    (i) A monograph or monographs establishing conditions under which a

[[Page 214]]

category of OTC drugs or a specific or specific OTC drugs are generally 
recognized as safe and effective and not misbranded (Category I).
    (ii) A statement of the conditions excluded from the monograph on 
the basis of the Commissioner's determination that they would result in 
the drug's not being generally recognized as safe and effective or would 
result in misbranding (Category II).
    (iii) A statement of the conditions excluded from the monograph on 
the basis of the Commissioner's determination that the available data 
are insufficient to classify such conditions under either paragraph 
(a)(6)(i) or (ii) of this section (Category III).
    (iv) The full report(s) of the panel to the Commissioner. The 
proposed order shall specify a reasonable period of time within which 
conditions falling within paragraph (a)(6)(iii) of this section may be 
continued in marketed products while the data necessary to support them 
are being obtained for evaluation by the Food and Drug Administration. 
The summary minutes of the panel meetings shall be made available to 
interested persons upon request. Any interested person may, within 90 
days after publication of the proposed order in the Federal Register, 
file with the Division of Dockets Management of the Food and Drug 
Administration written comments in triplicate. Comments may be 
accompanied by a memorandum or brief in support thereof. All comments 
may be reviewed at the office of the Division of Dockets Management 
between the hours of 9 a.m. and 4 p.m., Monday through Friday. Within 30 
days after the final day for submission of comments, reply comments may 
be filed with the Division of Dockets Management; these comments shall 
be utilized to reply to comments made by other interested persons and 
not to reiterate a position. The Commissioner may satisfy this 
requirement by publishing in the Federal Register a proposed order 
summarizing the full report of the advisory review panel, containing its 
conclusions and recommendations, to obtain full public comment before 
undertaking his own evaluation and decision on the matters involved.
    (7) Tentative final monograph. (i) After reviewing all comments, 
reply comments, and any new data and information or, alternatively, 
after reviewing a panel's recommendations, the Commissioner shall 
publish in the Federal Register a tentative order containing a monograph 
establishing conditions under which a category of OTC drugs or specific 
OTC drugs are generally recognized as safe and effective and not 
misbranded. Within 90 days, any interested person may file with the 
Division of Dockets Management, Food and Drug Administration, written 
comments or written objections specifying with particularity the 
omissions or additions requested. These objections are to be supported 
by a brief statement of the grounds therefor. A request for an oral 
hearing may accompany such objections.
    (ii) The Commissioner may also publish in the Federal Register a 
separate tentative order containing a statement of those active 
ingredients reviewed and proposed to be excluded from the monograph on 
the basis of the Commissioner's determination that they would result in 
a drug product not being generally recognized as safe and effective or 
would result in misbranding. This order may be published when no 
substantive comments in opposition to the panel report or new data and 
information were received by the Food and Drug Administration under 
paragraph (a)(6)(iv) of this section or when the Commissioner has 
evaluated and concurs with a panel's recommendation that a condition be 
excluded from the monograph. Within 90 days, any interested person may 
file with the Division of Dockets Management, Food and Drug 
Administration, written objections specifying with particularity the 
provision of the tentative order to which objection is made. These 
objections are to be supported by a brief statement of the grounds 
therefor. A request for an oral hearing may accompany such objections.
    (iii) Within 12 months after publishing a tentative order pursuant 
to paragraph (a)(7)(i) of this section, any interested person may file 
with the Division of Dockets Management, Food and Drug Administration, 
new data

[[Page 215]]

and information to support a condition excluded from the monograph in 
the tentative order.
    (iv) Within 60 days after the final day for submission of new data 
and information, comments on the new data and information may be filed 
with the Division of Dockets Management, Food and Drug Administration.
    (v) New data and information submitted after the time specified in 
this paragraph but prior to the establishment of a final monograph will 
be considered as a petition to amend the monograph and will be 
considered by the Commissioner only after a final monograph has been 
published in the Federal Register unless the Commisisoner finds that 
good cause has been shown that warrants earlier consideration.
    (8) Oral hearing before the Commissioner. After reviewing objections 
filed in response to the tentative final monograph, the Commissioner, if 
he finds reasonable grounds in support thereof, shall by notice in the 
Federal Register schedule an oral hearing. The notice scheduling an oral 
hearing shall specify the length of the hearing and how the time shall 
be divided among the parties requesting the hearing. The hearing shall 
be conducted by the Commissioner and may not be delegated.
    (9) Final monograph. After reviewing the objections, the entire 
administrative record including all new data and information and 
comments, and considering the arguments made at any oral hearing, the 
Commissioner shall publish in the Federal Register a final order 
containing a monograph establishing conditions under which a category of 
OTC drugs or a specific or specific OTC drugs are generally recognized 
as safe and effective and not misbranded. The monograph shall become 
effective as specified in the order.
    (10) Administrative record. (i) All data and information to be 
considered in any proceeding pursuant to this section shall be submitted 
in response to the request for data and views pursuant to paragraph 
(a)(2) of this section, in response to any other notice published in the 
Federal Register, or accepted by the panel during its deliberations 
pursuant to paragraph (a)(3) of this section or submitted to the 
Division of Dockets Management as part of the comments during the 90-day 
period and 30-day rebuttal comment period permitted pursuant to 
paragraph (a)(6) of this section or submitted to the Division of Dockets 
Management during the 12-month period or as part of the comments during 
the 60-day period permitted pursuant to paragraph (a)(7) of this 
section.
    (ii) The Commissioner shall make all decisions and issue all orders 
pursuant to this section solely on the basis of the administrative 
record, and shall not consider data or information not included as part 
of the administrative record.
    (iii) The administrative record shall consist solely of the 
following material: All notices and orders published in the Federal 
Register, all data and views submitted in response to the request 
published pursuant to paragraph (a)(2) of this section, in response to 
any other notice published in the Federal Register, or accepted by the 
panel during its deliberations pursuant to paragraph (a)(3) of this 
section, all minutes of panel meetings, the panel report(s), all 
comments and rebuttal comments submitted on the proposed monograph and 
all new data and information submitted pursuant to paragraph (a)(6) of 
this section, all objections submitted on the tentative final monograph 
and all new data and information and comments submitted pursuant to 
paragraph (a)(7) of this section, the complete record of any oral public 
hearing conducted pursuant to paragraph (a)(8) of this section, all 
other comments requested at any time by the Commissioner, all data and 
information for which the Commissioner has reopened the administrative 
record, and all other material that the Commissioner includes in the 
administrative record as part of the basis for the Commissioner's 
decision.
    (11) Court appeal. The monograph contained in the final order 
constitutes final agency action from which appeal lies to the courts. 
The Food and Drug Administration will request consolidation of all 
appeals in a single court. Upon court appeal, the Commissioner

[[Page 216]]

may, at his discretion, stay the effective date for part or all of the 
monograph pending appeal and final court adjudication.
    (12) Amendment of monographs. (i) The Commissioner may propose on 
the Commissioner's own initiative to amend or repeal any monograph 
established pursuant to this section. Any interested person may petition 
the Commissioner for such proposal pursuant to Sec. 10.30 of this 
chapter. The Commissioner may deny the petition if the Commissioner 
finds a lack of safety or effectiveness employing the standards in 
paragraph (a)(4) of this section (in which case the appeal provisions of 
paragraph (a)(11) of this section shall apply), or the Commissioner may 
publish a proposed amendment or repeal in the Federal Register if the 
Commissioner finds general recognition of safety and effectiveness 
employing the standards in paragraph (a)(4) of this section. Any 
interested person may, within 90 days after publication of the proposed 
order in the Federal Register, file with the Division of Dockets 
Management, Food and Drug Administration, written comments in 
triplicate. Comments may be accompanied by a memorandum or brief in 
support thereof. All comments may be reviewed in the Division of Dockets 
Management between the hours of 9 a.m. and 4 p.m., Monday through 
Friday. After reviewing the comments, the Commissioner shall publish a 
final order amending the monograph established under the provisions of 
paragraph (a)(9) of this section or withdraw the proposal if comments 
opposing the amendment are persuasive. A new drug application may be 
submitted in lieu of, or in addition to, a petition under this 
paragraph.
    (ii) A new drug application may be submitted in lieu of a petition 
to amend the OTC drug monograh only if the drug product with the 
condition that is the subject of the new drug application has not been 
marketed on an interim basis (such as under the provisions of paragraph 
(a)(6)(iii) of this section), all clinical testing has been conducted 
pursuant to a new drug application plan, and no marketing of the product 
with the condition for which approval is sought is undertaken prior to 
approval of the new drug application. The Food and Drug Administration 
shall handle a new drug application as a petition for amendment of a 
monograph, and shall review it on that basis, if the provisions of this 
paragraph preclude approval of a new drug application but permit the 
granting of such a petition.
    (b) Regulatory action. Any product which fails to conform to an 
applicable monograph after its effective date is liable to regulatory 
action.
    (c) Information and data submitted under this section shall include, 
with respect to each nonclinical laboratory study contained in the 
application, either a statement that the study was conducted in 
compliance with the good laboratory practice regulations set forth in 
part 58 of this chapter, or, if the study was not conducted in 
compliance with such regulations, a brief statement of the reason for 
the noncompliance.
    (d) [Reserved]
    (e) Institutional review and informed consent. Information and data 
submitted under this section after July 27, 1981, shall include 
statements regarding each clinical investigation involving human 
subjects, from which the information and data are derived, that it 
either was conducted in compliance with the requirements for 
institutional review set forth in part 56 of this chapter, or was not 
subject to such requirements in accordance with Sec. Sec. 56.104 or 
56.105, and that it was conducted in compliance with the requirements 
for informed consent set forth in part 50 of this chapter.
    (f) Financial certification or disclosure statement. Any clinical 
data submitted under this section must be accompanied by financial 
certifications or disclosure statements or both as required by part 54 
of this chapter.

[39 FR 11741, Mar. 29, 1974, as amended at 39 FR 39556, Nov. 8, 1974; 42 
FR 19141, Apr. 12, 1977; 42 FR 54800, Oct. 11, 1977; 46 FR 8460, 8955, 
Jan. 27, 1981; 46 FR 14340, Feb. 27, 1981; 46 FR 21360, Apr. 10, 1981; 
46 FR 47738, Sept. 29, 1981; 50 FR 7516, Feb. 22, 1985; 55 FR 11581, 
Mar. 29, 1990; 63 FR 5253, Feb. 2, 1998; 67 FR 3073, Jan. 23, 2002]

[[Page 217]]



Sec. 330.11  NDA deviations from applicable monograph.

    A new drug application requesting approval of an OTC drug deviating 
in any respect from a monograph that has become final shall be in the 
form required by Sec. 314.50 of this chapter, but shall include a 
statement that the product meets all conditions of the applicable 
monograph except for the deviation for which approval is requested and 
may omit all information except that pertinent to the deviation.

[39 FR 11741, Mar. 29, 1974, as amended at 55 FR 11581, Mar. 29, 1990]



Sec. 330.12  Status of over-the-counter (OTC) drugs previously 
reviewed under the Drug Efficacy Study (DESI).

    (a) There were 420 OTC drugs reviewed in the Drug Efficacy Study (a 
review of drugs introduced to the market through new drug procedures 
between 1938 and 1962). A careful review has been made of the reports on 
these drugs to determine those drugs for which implementation may be 
deferred without significant risk to the public health, pending review 
by appropriate OTC drug advisory review panels and promulgation of a 
monograph.
    (b) On and after April 20, 1972, a number of notices were published 
in the Federal Register concerning previously unpublished OTC drugs 
reviewed by the National Academy of Sciences-National Research Council 
Drug Efficacy Study Group. Only the evaluations and comments of the 
panels were published, with no conclusions of the Commissioner of Food 
and Drugs. Those publications were for the purpose of giving interested 
persons the benefit of the Academy's opinions. For those products, and 
also for OTC drug products previously published with the Commissioner's 
conclusions (except for the products listed in paragraphs (b) (1) and 
(2) of this section, all requests for data, revised labeling, requests 
for new drug applications, abbreviated new drug applications, updating 
supplements, data to support less than effective claims, if any, etc., 
are deferred, and such OTC drug products are instead subject to the OTC 
drug review in their appropriate classes pursuant to the procedures 
established in this subpart.
    (1) The requirements of the following DESI announcements are not 
deferred (the reference document may also pertain to prescription 
drugs):
    (i) Certain Surgical Sutures (DESI 4725), published in the Federal 
Register of November 11, 1971 (36 FR 21612).
    (ii) Absorbable Dusting Powder (DESI 6264), published in the Federal 
Register of May 25, 1971 (36 FR 9475).
    (iii) Certain Insulin Preparations (DESI 4286), published in the 
Federal Register of April 9, 1971 (36 FR 6842).
    (iv) Sulfo-Van Ointment (DESI 2230), published in the Federal 
Register of October 8, 1970 (35 FR 15860).
    (v) Antiperspirants and Deodorants Containing Neomycin Sulfate (DESI 
11048) for which an order revoking provisions for certification or 
release was published in the Federal Register of December 5, 1972 (37 FR 
25820) and has been stayed by the filing of objections.
    (vi) Thorexin Cough Medicine (DESI 11160) for which a notice of 
opportunity for hearing was published in the Federal Register of 
February 2, 1973 (38 FR 3210).
    (vii) Antibiotic susceptibility discs (DESI 90235) for which an 
order providing for certain discs to be certified and removing 
provisions for certification of other discs was published in the Federal 
Register of September 30, 1972 (37 FR 20525) and has been stayed by the 
filing of objections notice of which was published in the Federal 
Register of March 15, 1973 (38 FR 7007).
    (2) Deferral of requirements is not appropriate when an announcement 
has been published and has been followed by a final order classifying a 
drug either as lacking substantial evidence of effectiveness or as not 
shown to be safe. These products will be removed from the market, if 
they have not already been removed. Regulatory action will also be 
undertaken against identical, similar and related products (21 CFR 
310.6). Deferral of requirements is not appropriate for the following 
(the referenced document may also pertain to prescription drugs):
    (i) Certain Sulfonamide-Decongestant Nasal Preparation (DESI 4850), 
for

[[Page 218]]

which notice of withdrawal of approval of new drug applications was 
published in the Federal Register of October 24, 1970 (35 FR 16605, 
16606).
    (ii) Eskay's Theranates, containing strychnine, sodium, and calcium 
glycerophosphates, thiamine hydrochloride, alcohol, and phosphoric acid 
(DESI 2220), for which notice of withdrawal of approval of the new drug 
application was published in the Federal Register of February 18, 1971 
(36 FR 3152).
    (iii) The following topical drugs (DESI 1726), for which notice of 
withdrawal of new drug applications was published in the Federal 
Register of August 28, 1971 (36 FR 17368):
    (a) Rhulitol Solution, containing tannic acid, chlorobutanol, 
phenol, camphor, alum, and isopropyl alcohol.
    (b) Zirnox Topical Lotion, containing phenyitoloxamine citrate and 
zirconium oxide.
    (iv) Menacyl Tablets, containing aspirin, menadione, and ascorbic 
acid (DESI 6363), for which notice of withdrawal of approval of the new 
drug application was published in the Federal Register of July 23, 1970 
(35 FR 11827).
    (v) Curad Medicated Adhesive Bandage containing sulfathiazole (DESI 
4964), for which notice of withdrawal of approval of the new drug 
application was published in the Federal Register of December 31, 1969 
(34 FR 20441).
    (vi) Drugs Containing Rutin, Quercetin, Hesperidin, or any 
Bioflavonoids (DESI 5960), for which notice of withdrawal of approval of 
new drug applications was published in the Federal Register of July 3, 
1970 (35 FR 10872, 10873) and October 17, 1970 (35 FR 16332). A further 
notice of opportunity for hearing with respect to the drugs covered by 
the October 17, 1970 Federal Register notice will be published at a 
later date.
    (vii) Antibiotics in Combination with Other Drugs for Nasal Use 
(DESI 7561), for which an order revoking provision for certification was 
published in the Federal Register of August 6, 1971 (36 FR 14469) and 
confirmed in the Federal Register of October 28, 1971 (36 FR 20686).
    (viii) Antibiotic Troches (DESI 8328), for which an order revoking 
provision for certification was published in the Federal Register of 
July 14, 1971 (36 FR 13089) and confirmed in the Federal Register of 
October 9, 1971 (36 FR 19695).
    (ix) Certain Drugs Containing Oxyphenisatin or Oxyphenisatin Acetate 
(DESI 10732), for which notices of withdrawal of approval of new drug 
applications were published in the Federal Register of February 1, 1972 
(37 FR 2460), and March 9, 1973 (38 FR 6419).
    (x) Curad Medicated Adhesive Bandage containing tyrothricin-
nitrofurazone (DESI 6898), for which an order revoking provision for 
certification was published March 14, 1972 (37 FR 5294), and confirmed 
in the Federal Register of July 6, 1972 (37 FR 13254).
    (xi) Candette Cough Gel (DESI 11562), for which notice of withdrawal 
of approval of the new drug application was published in the Federal 
Register of November 19, 1972 (37 FR 25249).
    (xii) Certain OTC Multiple-Vitamin Preparations for Oral Use 
containing excessive amounts of vitamin D and/or vitamin A (DESI 97), 
for which notice of withdrawal of approval of the new drug applications 
was published in the Federal Register of November 29, 1972 (37 FR 
25249).
    (xiii) Certain Sulfonamide-Containing Preparations for Topical 
Ophthalmic or Otic Use (DESI 368, for which a notice of withdrawal of 
approval was published in the Federal Register of February 2, 1973 (38 
FR 3208).
    (xiv) Those parts of the publication entitled ``Certain Mouthwash 
and Gargle Preparations'' (DESI 2855) pertaining to Tyrolaris Mouthwash, 
containing tyrothricin, panthenol, and alcohol, for which an order 
revoking provision for certification was published in the Federal 
Register of February 2, 1967 (32 FR 1172) prior to the drug efficacy 
study implementation.
    (c) Manufacturers and distributors should take notice that the 
information on OTC drugs provided by the Drug Efficacy Study review is 
valuable information as to the deficiencies in the data available to 
support indications for use. They are encouraged to perform studies to 
obtain adequate evidence of effectiveness for the review of OTC drugs 
which is already in progress.

[[Page 219]]

In the interim it is in the public interest that manufacturers and 
distributors of all OTC drugs effect changes in their formulations and/
or labeling to bring the products into conformity with current medical 
knowledge and experience.
    (d) Manufacturers and distributors of OTC drugs may be reluctant to 
make appropriate formulation and/or labeling changes for fear of losing 
the protection of the so-called ``grandfather'' provisions of the 1938 
Federal Food, Drug, and Cosmetic Act (sec. 201(p)(1)) and the 1962 
amendments to the act (sec. 107(c) of those amendments). To encourage 
and facilitate prompt changes, the Food and Drug Administration will not 
take legal action against any OTC drug, other than those not deferred, 
based on a charge that the product is a new drug and not grandfathered 
under the act as a result of the changes if the changes in formulation 
and/or labeling are of the following kind:
    (1) The addition to the labeling of warning, contraindications, side 
effects, and/or precaution information.
    (2) The deletion from the labeling of false, misleading, or 
unsupported indications for use or claims of effectiveness.
    (3) Changes in the components or composition of the drug that will 
give increased assurance that the drug will have its intended effect, 
yet not raise or contribute any added safety questions.
    (4) Changes in the components or composition of the drug which may 
reasonably be concluded to improve the safety of the drug, without 
diminishing its effectiveness.
    (e) The forbearance from legal action for lack of grandfather 
protection is an interim procedure designed to encourage appropriate 
change in formulation and/or labeling during the time period required to 
review the various classes of OTC drugs. At such time as an applicable 
OTC drug monograph becomes effective, the interim procedure will 
automatically be terminated and any appropriate regulatory action will 
be initiated.



Sec. 330.13  Conditions for marketing ingredients recommended for 
over-the-counter (OTC) use under the OTC drug review.

    (a) Before the publication in the Federal Register of an applicable 
proposed monograph, an OTC drug product that contains: (1) An active 
ingredient limited, on or after May 11, 1972, to prescription use for 
the indication and route of administration under consideration by an OTC 
advisory review panel, and not thereafter exempted from such limitation 
pursuant to Sec. 310.200 of this chapter, or
    (2) An active ingredient at a dosage level higher than that 
available in an OTC drug product on December 4, 1975, shall be regarded 
as a new drug within the meaning of section 201(p) of the act for which 
an approved new drug application is required.
    (b)(1) An OTC drug product that contains: (i) An active ingredient 
limited, on or after May 11, 1972, to prescription use for the 
indication and route of administration under consideration by an OTC 
advisory review panel, and not thereafter exempted from such limitation 
pursuant to Sec. 310.200 of this chapter, or
    (ii) An active ingredient at a dosage level higher than that 
available in an OTC drug product on December 4, 1975, which ingredient 
and/or dosage level is classified by the panel in category I (conditions 
subject to Sec. 330.10(a)(6)(i)) shall be regarded as a new drug within 
the meaning of section 201(p) of the act for which an approved new drug 
application is required if marketed for OTC use prior to the date of 
publication in the Federal Register of a proposed monograph.
    (2) An OTC drug product covered by paragraph (b)(1) of this section 
which is marketed after the date of publication in the Federal Register 
of a proposed monograph but prior to the effective date of a final 
monograph shall be subject to the risk that the Commissioner may not 
accept the panel's recommendation and may instead adopt a different 
position that may require relabeling, recall, or other regulatory 
action. The Commissioner may state such position at any time by notice 
in the Federal Register, either separately or as part of another 
document;

[[Page 220]]

appropriate regulatory action will commence immediately and will not 
await publication of a final monograph. Marketing of such a product with 
a formulation or labeling not in accord with a proposed monograph or 
tentative final monograph also may result in regulatory action against 
the product, the marketer, or both.
    (c) An OTC drug product that contains: (1) An active ingredient 
limited, on or after May 11, 1972, to prescription use for the 
indication and route of administration under consideration by an OTC 
advisory review panel, and not thereafter exempted from such limitation 
pursuant to Sec. 310.200 of this chapter, or
    (2) An active ingredient at a dosage level higher than that 
available in any OTC drug product on December 4, 1975, which ingredient 
and/or dosage level is classified by the panel in category II 
(conditions subject to Sec. 330.10(a)(6)(ii)), may be marketed only 
after:
    (i) The Center for Drug Evaluation and Research or the Commissioner 
tentatively determines that the ingredient is generally recognized as 
safe and effective, and the Commissioner states by notice in the Federal 
Register (separately or as part of another document) that marketing 
under specified conditions will be permitted;
    (ii) The ingredient is determined by the Commissioner to be 
generally recognized as safe and effective and is included in the 
appropriate published OTC drug final monograph; or
    (iii) A new drug application for the product has been approved.
    (d) An OTC drug product that contains: (1) An active ingredient 
limited, on or after May 11, 1972, to prescription use for the 
indication and route of administration under consideration by an OTC 
advisory review panel, and not thereafter exempted from such limitation 
pursuant to Sec. 310.200 of this chapter, or
    (2) An active ingredient at a dosage level higher than that 
available in any OTC drug product on December 4, 1975, which ingredient 
and/or dosage level is classified by the panel in category III 
(conditions subject to Sec. 330.10(a)(6)(iii)), may be marketed only 
after:
    (i) The Center for Drug Evaluation and Research or the Commissioner 
tentatively determines that the ingredient is generally recognized as 
safe and effective, and the Commissioner states by notice in the Federal 
Register (separately or as part of another document) that marketing 
under specified conditions will be permitted;
    (ii) The ingredient is determined by the Commissioner to be 
generally recognized as safe and effective and is included in the 
appropriate published OTC drug final monograph; or
    (iii) A new drug application for the product has been approved.
    (e) This section applies only to conditions under consideration as 
part of the OTC drug review initiated on May 11, 1972, and evaluated 
under the procedures set forth in Sec. 330.10. Section 330.14(h) 
applies to the marketing of all conditions under consideration and 
evaluated using the criteria and procedures set forth in Sec. 330.14.

[41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 
FR 8996, Mar. 6, 1985; 55 FR 11581, Mar. 29, 1990; 67 FR 3074, Jan. 23, 
2002]



Sec. 330.14  Additional criteria and procedures for classifying OTC 
drugs as generally recognized as safe and effective and not misbranded.

    (a) Introduction. This section sets forth additional criteria and 
procedures by which over the counter (OTC) drugs initially marketed in 
the United States after the OTC drug review began in 1972 and OTC drugs 
without any U.S. marketing experience can be considered in the OTC drug 
monograph system. This section also addresses conditions regulated as a 
cosmetic or dietary supplement in a foreign country that would be 
regulated as OTC drugs in the United States. For purposes of this 
section, ``condition'' means an active ingredient or botanical drug 
substance (or a combination of active ingredients or botanical drug 
substances), dosage form, dosage strength, or route of administration, 
marketed for a specific OTC use, except as excluded in paragraph (b)(2) 
of this section. For purposes of this part, ``botanical drug substance'' 
means a drug substance derived from one or more plants, algae, or 
macroscopic fungi, but does not include a highly purified or

[[Page 221]]

chemically modified substance derived from such a source.
    (b) Criteria. To be considered for inclusion in the OTC drug 
monograph system, the condition must meet the following criteria:
    (1) The condition must be marketed for OTC purchase by consumers. If 
the condition is marketed in another country in a class of OTC drug 
products that may be sold only in a pharmacy, with or without the 
personal involvement of a pharmacist, it must be established that this 
marketing restriction does not indicate safety concerns about the 
condition's toxicity or other potentiality for harmful effect, the 
method of its use, or the collateral measures necessary to its use.
    (2) The condition must have been marketed OTC for a minimum of 5 
continuous years in the same country and in sufficient quantity, as 
determined in paragraphs (c)(2)(ii), (c)(2)(iii), and (c)(2)(iv) of this 
section. Depending on the condition's extent of marketing in only one 
country with 5 continuous years of marketing, marketing in more than one 
country may be necessary.
    (c) Time and extent application. Certain information must be 
provided when requesting that a condition subject to this section be 
considered for inclusion in the OTC drug monograph system. The following 
information must be provided in the format of a time and extent 
application (TEA):
    (1) Basic information about the condition that includes a 
description of the active ingredient(s) or botanical drug substance(s), 
pharmacologic class(es), intended OTC use(s), OTC strength(s) and dosage 
form(s), route(s) of administration, directions for use, and the 
applicable existing OTC drug monograph(s) under which the condition 
would be marketed or the request and rationale for creation of a new OTC 
drug monograph(s).
    (i) A detailed chemical description of the active ingredient(s) that 
includes a full description of the drug substance, including its 
physical and chemical characteristics, the method of synthesis (or 
isolation) and purification of the drug substance, and any 
specifications and analytical methods necessary to ensure the identity, 
strength, quality, and purity of the drug substance.
    (ii) For a botanical drug substance(s), a detailed description of 
the botanical ingredient (including proper identification of the plant, 
plant part(s), alga, or macroscopic fungus used; a certificate of 
authenticity; and information on the grower/supplier, growing 
conditions, harvest location and harvest time); a qualitative 
description (including the name, appearance, physical/chemical 
properties, chemical constituents, active constituent(s) (if known), and 
biological activity (if known)); a quantitative description of the 
chemical constituents, including the active constituent(s) or other 
chemical marker(s) (if known and measurable); the type of manufacturing 
process (e.g., aqueous extraction, pulverization); and information on 
any further processing of the botanical substance (e.g., addition of 
excipients or blending).
    (iii) Reference to the current edition of the U.S. Pharmacopeia 
(USP)-National Formulary (NF) or foreign compendiums may help satisfy 
the requirements in this section.
    (2) A list of all countries in which the condition has been 
marketed. Include the following information for each country. (For a 
condition that has been marketed OTC in 5 or more countries with a 
minimum of 5 continuous years of marketing in at least one country, the 
sponsor may submit information in accordance with paragraph (c)(4) of 
this section):
    (i) How the condition has been marketed (e.g., OTC general sales 
direct-to-consumer; sold only in a pharmacy, with or without the 
personal involvement of a pharmacist; dietary supplement; or cosmetic). 
If the condition has been marketed as a nonprescription pharmacy-only 
product, establish that this marketing restriction does not indicate 
safety concerns about its toxicity or other potentiality for harmful 
effect, the method of its use, or the collateral measures necessary to 
its use.
    (ii) The cumulative total number of dosage units (e.g., tablets, 
capsules, ounces) sold for each dosage form of the condition. 
Manufacturers or suppliers of OTC active ingredients may provide dosage 
unit information as the total weight of active ingredient sold. List the 
various package sizes for each dosage form in which the condition is

[[Page 222]]

marketed OTC. Provide an estimate of the minimum number of potential 
consumer exposures to the condition using one of the following 
calculations:
    (A) Divide the total number of dosage units sold by the number of 
dosage units in the largest package size marketed, or
    (B) Divide the total weight of the active ingredient sold by the 
total weight of the active ingredient in the largest package size 
marketed.
    (iii) A description of the population demographics (percentage of 
various racial/ethnic groups) and the source(s) from which this 
information has been compiled, to ensure that the condition's use(s) can 
be reasonably extrapolated to the U.S. population.
    (iv) If the use pattern (i.e., how often it is to be used (according 
to the label) and for how long) varies between countries based on the 
condition's packaging and labeling, or changes in use pattern have 
occurred over time in one or more countries, describe the use pattern 
for each country and explain why there are differences or changes.
    (v) A description of the country's system for identifying adverse 
drug experiences, especially those found in OTC marketing experience, 
including method of collection if applicable.
    (3) A statement of how long the condition has been marketed in each 
country and how long the current product labeling has been in use, 
accompanied by a copy of the current product labeling. All labeling that 
is not in English must be translated to English in accordance with Sec. 
10.20(c)(2) of this chapter. State whether the current product labeling 
has or has not been authorized, accepted, or approved by a regulatory 
body in each country where the condition is marketed.
    (4) For a condition that has been marketed OTC in five or more 
countries with a minimum of 5 continuous years of marketing in at least 
one country, the sponsor may select at least five of these countries 
from which to submit information in accord with paragraphs (c)(2)(i) 
through (c)(2)(iv) of this section. Selected countries must include the 
country with a minimum of 5 continuous years of OTC marketing, countries 
that have the longest duration of marketing, and countries having the 
most support for extent of marketing, i.e., a large volume of sales with 
cultural diversity among users of the product. If the condition meets 
these criteria in countries listed in section 802(b)(1)(A) of the 
Federal Food, Drug, and Cosmetic Act, some of these countries should be 
included among the five selected. Sponsors should provide information 
from more than five countries if they believe that it is needed to 
support eligibility. Sponsors should explain the basis for the countries 
selected in the TEA.
    (5) A list of all countries where the condition is marketed only as 
a prescription drug and the reasons why its marketing is restricted to 
prescription in these countries.
    (6) A list of all countries in which the condition has been 
withdrawn from marketing or in which an application for OTC marketing 
approval has been denied. Include the reasons for such withdrawal or 
application denial.
    (7) The information requested in paragraphs (c)(2), (c)(2)(i) 
through (c)(2)(iv), and (c)(3) of this section must be provided in a 
table format. The labeling required by paragraph (c)(3) of this section 
must be attached to the table.
    (8) For OTC drugs that have been marketed for more than 5 years in 
the United States under a new drug application, the information 
requested in paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), (c)(3), and 
(c)(5) of this section need not be provided.
    (d) Submission of information; confidentiality. The sponsor must 
submit three copies of the TEA to the Central Document Room, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852. The Food and Drug 
Administration will handle the TEA as confidential until such time as a 
decision is made on the eligibility of the condition for consideration 
in the OTC drug monograph system. If the condition is found eligible, 
the TEA will be placed on public display in the Division of Dockets 
Management after deletion of information deemed confidential under 18 
U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Sponsors must 
identify information that is considered confidential under these 
statutory provisions. If the condition is not found eligible, the TEA 
will not be

[[Page 223]]

placed on public display, but a letter from the agency to the sponsor 
stating why the condition was not found acceptable will be placed on 
public display in the Division of Dockets Management.
    (e) Notice of eligibility. If the condition is found eligible, the 
agency will publish a notice of eligibility in the Federal Register and 
provide the sponsor and other interested parties an opportunity to 
submit data to demonstrate safety and effectiveness. When the notice of 
eligibility is published, the agency will place the TEA on public 
display in the Division of Dockets Management.
    (f) Request for data and views. The notice of eligibility shall 
request interested persons to submit published and unpublished data to 
demonstrate the safety and effectiveness of the condition for its 
intended OTC use(s). These data shall be submitted to a docket 
established in the Division of Dockets Management and shall be publicly 
available for viewing at that office, except data deemed confidential 
under 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Data 
considered confidential under these provisions must be clearly 
identified. Any proposed compendial standards for the condition shall 
not be considered confidential. The safety and effectiveness submissions 
shall include the following:
    (1) All data and information listed in Sec. 330.10(a)(2) under the 
outline ``OTC Drug Review Information,'' items III through VII.
    (2) All serious adverse drug experiences as defined in Sec. Sec. 
310.305 and 314.80 of this chapter, from each country where the 
condition has been or is currently marketed as a prescription drug or as 
an OTC drug or product. Provide individual adverse drug experience 
reports (FDA Form 3500A or equivalent) along with a summary of all 
serious adverse drug experiences and expected or frequently reported 
side effects for the condition. Individual reports that are not in 
English must be translated to English in accordance with Sec. 
10.20(c)(2) of this chapter.
    (g) Administrative procedures. The agency may use an advisory review 
panel to evaluate the safety and effectiveness data in accord with the 
provisions of Sec. 330.10(a)(3). Alternatively, the agency may evaluate 
the data in conjunction with the advisory review panel or on its own 
without using an advisory review panel. The agency will use the safety, 
effectiveness, and labeling standards in Sec. 330.10(a)(4)(i) through 
(a)(4)(vi) in evaluating the data.
    (1) If the agency uses an advisory review panel to evaluate the 
data, the panel may submit its recommendations in its official minutes 
of meeting(s) or by a report under the provisions of Sec. 330.10(a)(5).
    (2) The agency may act on an advisory review panel's recommendations 
using the procedures in Sec. Sec. 330.10(a)(2) and 330.10(a)(6) through 
(a)(10).
    (3) If the condition is initially determined to be generally 
recognized as safe and effective for OTC use in the United States, the 
agency will propose to include it in an appropriate OTC drug 
monograph(s), either by amending an existing monograph(s) or 
establishing a new monograph(s), if necessary.
    (4) If the condition is initially determined not to be generally 
recognized as safe and effective for OTC use in the United States, the 
agency will inform the sponsor and other interested parties who have 
submitted data of its determination by letter, a copy of which will be 
placed on public display in the docket established in the Division of 
Dockets Management. The agency will publish a notice of proposed 
rulemaking to include the condition in Sec. 310.502 of this chapter.
    (5) Interested parties will have an opportunity to submit comments 
and new data. The agency will subsequently publish a final rule (or 
reproposal if necessary) in the Federal Register.
    (h) Marketing. A condition submitted under this section for 
consideration in the OTC drug monograph system may be marketed in 
accordance with an applicable final OTC drug monograph(s) only after the 
agency determines that the condition is generally recognized as safe and 
effective and includes it in the appropriate OTC drug final 
monograph(s), and the condition complies with paragraph (i) of this 
section. When an OTC drug monograph has not been finalized and 
finalization is not

[[Page 224]]

imminent, after the agency has evaluated the comments to a proposed rule 
to include a new condition in a tentative final monograph as generally 
recognized as safe and effective and the agency has not changed its 
position as a result of the comments, and the condition complies with 
paragraph (i) of this section, the agency may publish a notice of 
enforcement policy that allows marketing to begin pending completion of 
the final monograph subject to the risk that the agency may, prior to or 
in the final monograph, adopt a different position that could require 
relabeling, recall, or other regulatory action.
    (i) Compendial monograph. Any active ingredient or botanical drug 
substance included in a final OTC drug monograph or the subject of an 
enforcement notice described in paragraph (h) of this section must be 
recognized in an official USP-NF drug monograph that sets forth its 
standards of identity, strength, quality, and purity. Sponsors must 
include an official or proposed compendial monograph as part of the 
safety and effectiveness data submission listed in Sec. 330.10(a)(2) 
under item VII of the outline entitled ``OTC DRUG REVIEW INFORMATION.''

[67 FR 3074, Jan. 23, 2002]



PART 331_ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE--Table
of Contents



                      Subpart A_General Provisions

Sec.
331.1 Scope.

                      Subpart B_Active Ingredients

331.10 Antacid active ingredients.
331.11 Listing of specific active ingredients.
331.15 Combination with nonantacid active ingredients.

                      Subpart C_Testing Procedures

331.20 Determination of percent contribution of active ingredients.
331.21 Test Modifications.

                           Subpart D_Labeling

331.30 Labeling of antacid products.
331.80 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 39 FR 19874, June 4, 1974, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 331.1  Scope.

    An over-the-counter antacid product in a form suitable for oral 
administration is generally recognized as safe and effective and is not 
misbranded if it meets each of the following conditions and each of the 
general conditions established in Sec. 330.1 of this chapter.



                      Subpart B_Active Ingredients



Sec. 331.10  Antacid active ingredients.

    (a) The active antacid ingredients of the product consist of one or 
more of the ingredients permitted in Sec. 331.11 within any maximum 
daily dosage limit established, each ingredient is included at a level 
that contributes at least 25 percent of the total acid neutralizing 
capacity of the product, and the finished product contains at least 5 
meq of acid neutralizing capacity as measured by the procedure provided 
in the United States Pharmacopeia 23/National Formulary 18. The method 
established in Sec. 331.20 shall be used to determine the percent 
contribution of each antacid active ingredient.
    (b) This section does not apply to an antacid ingredient 
specifically added as a corrective to prevent a laxative or constipating 
effect.

[39 FR 19874, June 4, 1974, as amended at 61 FR 4822, Feb. 8, 1996]



Sec. 331.11  Listing of specific active ingredients.

    (a) Aluminum-containing active ingredients:
    (1) Basic aluminum carbonate gel.
    (2) Aluminum hydroxide (or as aluminum hydroxide-hexitol stabilized 
polymer, aluminum hydroxide-magnesium carbonate codried gel, aluminum 
hydroxide-magnesium trisilicate codried gel, aluminum-hydroxide sucrose 
powder hydrated).
    (3) Dihydroxyaluminum aminoacetate and dihydroxyaluminum aminoacetic 
acid.

[[Page 225]]

    (4) Aluminum phosphate gel when used as part of an antacid 
combination product and contributing at least 25 percent of the total 
acid neutralizing capacity; maximum daily dosage limit is 8 grams.
    (5) Dihydroxyaluminum sodium carbonate.
    (b) Bicarbonate-containing active ingredients: Bicarbonate ion; 
maximum daily dosage limit 200 mEq. for persons up to 60 years old and 
100 mEq. for persons 60 years or older.
    (c) Bismuth-containing active ingredients:
    (1) Bismuth aluminate.
    (2) Bismuth carbonate.
    (3) Bismuth subcarbonate.
    (4) Bismuth subgallate.
    (5) Bismuth subnitrate.
    (d) Calcium-containing active ingredients: Calcium, as carbonate or 
phosphate; maximum daily dosage limit 160 mEq. calcium (e.g., 8 grams 
calcium carbonate).
    (e) Citrate-containing active ingredients: Citrate ion, as citric 
acid or salt; maximum daily dosage limit 8 grams.
    (f) Glycine (aminoacetic acid).
    (g) Magnesium-containing active ingredients:
    (1) Hydrate magnesium aluminate activated sulfate.
    (2) Magaldrate.
    (3) Magnesium aluminosilicates.
    (4) Magnesium carbonate.
    (5) Magnesium glycinate.
    (6) Magnesium hydroxide.
    (7) Magnesium oxide.
    (8) Magnesium trisilicate.
    (h) Milk solids, dried.
    (i) Phosphate-containing active ingredients:
    (1) Aluminum phosphate; maximum daily dosage limit 8 grams.
    (2) Mono or dibasic calcium salt; maximum daily dosage limit 2 
grams.
    (3) Tricalcium phosphate; maximum daily dosage limit 24 grams.
    (j) Potassium-containing active ingredients:
    (1) Potassium bicarbonate (or carbonate when used as a component of 
an effervescent preparation); maximum daily dosage limit 200 mEq. of 
bicarbonate ion for persons up to 60 years old and 100 mEq. of 
bicarbonate ion for persons 60 years or older.
    (2) Sodium potassium tartrate.
    (k) Sodium-containing active ingredients:
    (1) Sodium bicarbonate (or carbonate when used as a component of an 
effervescent preparation); maximum daily dosage limit 200 mEq. of sodium 
for persons up to 60 years old and 100 mEq. of sodium for persons 60 
years or older, and 200 mEq. of bicarbonate ion for persons up to 60 
years old and 100 mEq. of bicarbonate ion for persons 60 years or older. 
That part of the warning required by Sec. 330.1(g), which states, 
``Keep this and all drugs out of the reach of children'' is not required 
on a product which contains only sodium bicarbonate powder and which is 
intended primarily for other than drug uses.
    (2) Sodium potassium tartrate.
    (l) Silicates:
    (1) Magnesium aluminosilicates.
    (2) Magnesium trisilicate.
    (m) Tartrate-containing active ingredients. Tartaric acid or its 
salts; maximum daily dosage limit 200 mEq. (15 grams) of tartrate.

[39 FR 19874, June 4, 1974, as amended at 51 FR 27763, Aug. 1, 1986; 55 
FR 19859, May 11, 1990]



Sec. 331.15  Combination with nonantacid active ingredients.

    (a) An antacid may contain any generally recognized as safe and 
effective nonantacid laxative ingredient to correct for constipation 
caused by the antacid. No labeling claim of the laxative effect may be 
used for such a product.
    (b) An antacid may contain any generally recognized as safe and 
effective analgesic ingredient(s), if it is indicated for use solely for 
the concurrent symptoms involved, e.g., headache and acid indigestion, 
and is marketed in a form intended for ingestion as a solution.
    (c) An antacid may contain any generally recognized as safe and 
effective antiflatulent ingredient if it is indicated for use solely for 
the concurrent symptoms of gas associated with heartburn, sour stomach 
or acid indigestion.



                      Subpart C_Testing Procedures



Sec. 331.20  Determination of percent contribution of active ingredients.

    To determine the percent contribution of an antacid active 
ingredient,

[[Page 226]]

place an accurately weighed amount of the antacid active ingredient 
equal to the amount present in a unit dose of the product into a 250-
milliliter (mL) beaker. If wetting is desired, add not more than 5 mL of 
alcohol (neutralized to an apparent pH of 3.5), and mix to wet the 
sample thoroughly. Add 70 mL of water, and mix on a magnetic stirrer at 
300 30 r.p.m. for 1 minute. Analyze the acid 
neutralizing capacity of the sample according to the procedure provided 
in the United States Pharmacopeia 23/National Formulary 18 and calculate 
the percent contribution of the antacid active ingredient in the total 
product as follows:
    Percent contribution =(Total mEq. Antacid Active Ingredientx100)/
(Total mEq. Antacid Product).

[61 FR 4823, Feb. 8, 1996]



Sec. 331.21  Test modifications.

    The formulation or mode of administration of certain products may 
require a modification of the United States Pharmacopeia 23/National 
Formulary 18 acid neutralizing capacity test. Any proposed modification 
and the data to support it shall be submitted as a petition under the 
rules established in Sec. 10.30 of this chapter. All information 
submitted will be subject to the disclosure rules in part 20 of this 
chapter.

[61 FR 4823, Feb. 8, 1996]



                           Subpart D_Labeling



Sec. 331.30  Labeling of antacid products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antacid.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``For the relief of'' (optional, 
any or all of the following:) ``heartburn,'' ``sour stomach,'' and/or 
``acid indigestion'' (which may be followed by the optional statement:) 
``and upset stomach associated with'' (optional, as appropriate) ``this 
symptom'' or ``these symptoms.'' Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in this paragraph (b), may also be used, as 
provided in Sec. 330.1(c)(2) of this chapter, subject to the provisions 
of section 502 of the act relating to misbranding and the prohibition in 
section 301(d) of the act against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings, under the heading ``Warnings'', which may be combined but not 
rearranged to eliminate duplicative words or phrases if the resulting 
warning is clear and understandable:
    (1) ``Do not take more than (maximum recommended daily dosage, 
broken down by age groups if appropriate, expressed in units such as 
tablets or teaspoonfuls) in a 24-hour period, or use the maximum dosage 
of this product for more than 2 weeks, except under the advice and 
supervision of a physician.''
    (2) For products which cause constipation in 5 percent or more of 
persons who take the maximum recommended dosage: ``May cause 
constipation.''
    (3) For products which cause laxation in 5 percent or more of 
persons who take the maximum recommended dosage: ``May have laxative 
effect.''
    (4) For products containing more than 5 gm per day lactose in a 
maximum daily dosage: ``Do not use this product except under advice and 
supervision of a physician if you are allergic to milk or milk 
products.''
    (d) Drug interaction precaution. The labeling of the product 
contains the following statement ``Ask a doctor or pharmacist before use 
if you are [bullet] \1\ presently taking a prescription drug. Antacids 
may interact with certain prescription drugs.''
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter.
---------------------------------------------------------------------------

    (e) Directions for use. The labeling of the product contains the 
recommended dosage, under the heading ``Directions'', per time interval 
(e.g., every 4 hours) or time period (e.g., 4 times a day) broken down 
by age groups if appropriate, followed by ``or as directed by a 
physician.''
    (f) Exemption from the general accidental overdose warning. The 
labeling for antacid drug products containing

[[Page 227]]

the active ingredients identified in Sec. 331.11(a), (b), and (d) 
through (m); permitted combinations of these ingredients provided for in 
Sec. 331.10; and any of these ingredients or combinations of these 
ingredients in combination with simethicone (identified in Sec. 332.10 
of this chapter and provided for in Sec. 331.15(c)), are exempt from 
the requirement in Sec. 330.1(g) of this chapter that the labeling bear 
the general warning statement ``In case of accidental overdose, seek 
professional assistance or contact a poison control center 
immediately.'' With the exception of sodium bicarbonate powder products 
identified in Sec. 331.11(k)(1), the labeling must continue to bear the 
first part of the general warning in Sec. 330.1(g) of this chapter, 
which states, ``Keep this and all drugs out of the reach of children.''
    (g) [Reserved]
    (h) The word ``doctor'' may be substituted for the word 
``physician'' in any of the labeling statements in this section.

[39 FR 19874, June 4, 1974, as amended at 47 FR 38484, Aug. 31, 1982; 51 
FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar. 13, 
1987; 55 FR 11581, Mar. 29, 1990; 58 FR 45208, Aug. 26, 1993; 59 FR 
60556, Nov. 25, 1994; 61 FR 17806, Apr. 22, 1996; 64 FR 13295, Mar. 17, 
1999; 69 FR 13734, Mar. 24, 2004]



Sec. 331.80  Professional labeling.

    (a) The labeling of the product provided to health professionals 
(but not to the general public):
    (1) Shall contain the neutralizing capacity of the product as 
calculated using the procedure set forth in United States Pharmacopeia 
23/National Formulary 18 expressed in terms of the dosage recommended 
per minimum time interval or, if the labeling recommends more than one 
dosage, in terms of the minimum dosage recommended per minimum time 
interval.
    (2) May contain an indication for the symptomatic relief of 
hyperacidity associated with the diagnosis of peptic ulcer, gastritis, 
peptic esophagitis, gastric hyperacidity, and hiatal hernia.
    (3) For products containing basic aluminum carbonate gel identified 
in Sec. 331.11(a)(1)--Indication. ``For the treatment, control, or 
management of hyperphosphatemia, or for use with a low phosphate diet to 
prevent formation of phosphate urinary stones, through the reduction of 
phosphates in the serum and urine.''
    (4) For products containing aluminum identified in Sec. 331.11(a)--
Warnings. (i) Prolonged use of aluminum-containing antacids in patients 
with renal failure may result in or worsen dialysis osteomalacia. 
Elevated tissue aluminum levels contribute to the development of the 
dialysis encephalopathy and osteomalacia syndromes. Small amounts of 
aluminum are absorbed from the gastrointestinal tract and renal 
excretion of aluminum is impaired in renal failure. Aluminum is not well 
removed by dialysis because it is bound to albumin and transferrin, 
which do not cross dialysis membranes. As a result, aluminum is 
deposited in bone, and dialysis osteomalacia may develop when large 
amounts of aluminum are ingested orally by patients with impaired renal 
function.
    (ii) Aluminum forms insoluble complexes with phosphate in the 
gastrointestinal tract, thus decreasing phosphate absorption. Prolonged 
use of aluminum-containing antacids by normophosphatemic patients may 
result in hypophosphatemia if phosphate intake is not adequate. In its 
more severe forms, hypophosphatemia can lead to anorexia, malaise, 
muscle weakness, and osteomalacia.
    (b) Professional labeling for an antacid-antiflatulent combination 
may contain the information allowed for health professionals for 
antacids and antiflatulents.

[39 FR 19874, June 4, 1974. Redesignated and amended at 55 FR 19859, May 
11, 1990]



PART 332_ANTIFLATULENT PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table
of Contents



                      Subpart A_General Provisions

Sec.
332.1 Scope.
332.3 Definitions.

                      Subpart B_Active Ingredients

332.10 Antiflatulent active ingredients.
332.15 Combination with non-antiflatulent active ingredients.

[[Page 228]]

                           Subpart C_Labeling

332.30 Labeling of antiflatulent products.
332.31 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 39 FR 19877, June 4, 1974, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 332.1  Scope.

    An over-the-counter antiflatulent product in a form suitable for 
oral administration is generally recognized as safe and effective and is 
not misbranded if it meets each of the following conditions and each of 
the general conditions established in Sec. 330.1 of this chapter.



Sec. 332.3  Definitions.

    As used in this part:
    Antigas. A term that may be used interchangeably with the term 
antiflatulent. Neither term should be considered as describing the 
mechanism of action of the active ingredient contained in the product.

[61 FR 8838, Mar. 5, 1996]



                      Subpart B_Active Ingredients



Sec. 332.10  Antiflatulent active ingredients.

    Simethicone; maximum daily dose 500 mg. There is no dosage 
limitation at this time for professional labeling.



Sec. 332.15  Combination with non-antiflatulent active ingredients.

    An antiflatulent may contain any generally recognized as safe and 
effective antacid ingredient(s) if it is indicated for use solely for 
the concurrent symptoms of gas associated with heartburn, sour stomach 
or acid indigestion.



                           Subpart C_Labeling



Sec. 332.30  Labeling of antiflatulent drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antiflatulent,'' ``antigas,'' or ``antiflatulent (antigas).''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' one or more of the phrases listed in this 
paragraph (b), as appropriate. Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in this paragraph (b), may also be used, as 
provided in Sec. 330.1(c)(2) of this chapter, subject to the provisions 
of section 502 of the Federal Food, Drug, and Cosmetic Act (the act) 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) (Select one of the following: ``Alleviates or Relieves'') ``the 
symptoms referred to as gas.''
    (2) (Select one of the following: ``Alleviates'' or ``Relieves'') 
(select one or more of the following: ``bloating,'' ``pressure,'' 
``fullness,'' or ``stuffed feeling'') ``commonly referred to as gas.''
    (c) Exemption from the general accidental overdose warning. The 
labeling for antiflatulent drug products containing simethicone 
identified in Sec. 332.10 and antacid/antiflatulent combination drug 
products provided for in Sec. 332.15, containing the active ingredients 
identified in Sec. 331.11(a), (b), and (d) through (m) of this chapter 
are exempt from the requirement in Sec. 330.1(g) of this chapter that 
the labeling bear the general warning statement ``In case of accidental 
overdose, seek professional assistance or contact a poison control 
center immediately.'' The labeling must continue to bear the first part 
of the general warning in Sec. 330.1(g) of this chapter, which states, 
``Keep this and all drugs out of the reach of children.''

[39 FR 19877, June 4, 1974, as amended at 40 FR 11719, Mar. 13, 1975; 51 
FR 16266, May 1, 1986; 51 FR 27763, Aug. 1, 1986; 52 FR 7830, Mar. 13, 
1987; 61 FR 8838, Mar. 5, 1996]



Sec. 332.31  Professional labeling.

    (a) The labeling of the product provided to health professionals 
(but not to the general public) may contain as additional indications 
postoperative gas pain or for use in endoscopic examination.
    (b) Professional labeling for an antiflatulent-antacid combination 
may

[[Page 229]]

contain information allowed for health professionals for antacids and 
antiflatulents.



PART 333_TOPICAL ANTIMICROBIAL DRUG PRODUCTS FOR OVER-THE-COUNTER 
HUMAN USE--Table of Contents



Subpart A [Reserved]

              Subpart B_First Aid Antibiotic Drug Products

Sec.
333.101 Scope.
333.103 Definitions.
333.110 First aid antibiotic active ingredients.
333.120 Permitted combinations of active ingredients.
333.150 Labeling of first aid antibiotic drug products.
333.160 Labeling of permitted combinations of active ingredients.

               Subpart C_Topical Antifungal Drug Products

333.201 Scope.
333.203 Definitions.
333.210 Antifungal active ingredients.
333.250 Labeling of antifungal drug products.
333.280 Professional labeling.

                  Subpart D_Topical Acne Drug Products

333.301 Scope.
333.303 Definitions.
333.310 Acne active ingredients.
333.320 Permitted combinations of active ingredients.
333.350 Labeling of acne drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 52 FR 47322, Dec. 11, 1987, unless otherwise noted.

Subpart A [Reserved]



              Subpart B_First Aid Antibiotic Drug Products



Sec. 333.101  Scope.

    (a) An over-the-counter first aid antibiotic drug product in a form 
suitable for topical administration is generally recognized as safe and 
effective and is not misbranded if it meets each of the conditions in 
this subpart and each of the general conditions established in Sec. 
330.1.
    (b) References in this subpart to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 333.103  Definitions.

    As used in this subpart:
    First aid antibiotic. An antibiotic-containing drug product applied 
topically to the skin to help prevent infection in minor cuts, scrapes, 
and burns.

[52 FR 47322, Dec. 11, 1987, as amended at 64 FR 403, Jan. 5, 1999]



Sec. 333.110  First aid antibiotic active ingredients.

    The product consists of any of the following active ingredients 
within the specified concentration established for each ingredient and 
in the specified dosage form:
    (a) Bacitracin ointment containing, in each gram, 500 units of 
bacitracin in a suitable ointment base.
    (b) Bacitracin zinc ointment containing, in each gram, 500 units of 
bacitracin zinc in a suitable ointment base.
    (c) Chlortetracycline hydrochloride ointment containing, in each 
gram, 30 milligrams of chlortetracycline hydrochloride in a suitable 
ointment base.
    (d) Neomycin sulfate ointment containing, in each gram, 3.5 
milligrams of neomycin in a suitable water soluble or oleaginous 
ointment base.
    (e) Neomycin sulfate cream containing, in each gram, 3.5 milligrams 
of neomycin in a suitable cream base.
    (f) Tetracycline hydrochloride ointment containing, in each gram, 30 
milligrams of tetracycline hydrochloride in a suitable ointment base.

[52 FR 47322, Dec. 11, 1987, as amended at 53 FR 18838, May 25, 1988; 64 
FR 403, Jan. 5, 1999]



Sec. 333.120  Permitted combinations of active ingredients.

    The following combinations are permitted provided each active 
ingredient is present within the established concentration and in the 
specified dosage form, and the product is labeled in accordance with 
Sec. 333.160.
    (a) Combinations of antibiotic active ingredients. (1) Bacitracin-
neomycin sulfate ointment containing, in each gram, 500 units of 
bacitracin and 3.5

[[Page 230]]

milligrams of neomycin in a suitable ointment base.
    (2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment 
containing, in each gram, in a suitable ointment base the following:
    (i) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 
units of polymyxin B; or
    (ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 
units of polymyxin B;
    (3) Bacitracin-polymyxin B sulfate topical aerosol containing, in 
each gram, 500 units of bacitracin and 5,000 units of polymyxin B in a 
suitable vehicle, packaged in a pressurized container with suitable 
inert gases.
    (4) Bacitracin zinc-neomycin sulfate ointment containing, in each 
gram, 500 units of bacitracin and 3.5 milligrams of neomycin in a 
suitable ointment base.
    (5) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment 
containing, in each gram, in a suitable ointment base the following:
    (i) 400 units of bacitracin, 3 milligrams of neomycin, and 8,000 
units of polymyxin B; or
    (ii) 400 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 
units of polymyxin B; or
    (iii) 500 units of bacitracin, 3.5 milligrams of neomycin, and 5,000 
units of polymyxin B; or
    (iv) 500 units of bacitracin, 3.5 milligrams of neomycin, and 10,000 
units of polymyxin B;
    (6) Bacitracin zinc-polymyxin B sulfate ointment containing, in each 
gram, 500 units of bacitracin and 10,000 units of polymyxin B in a 
suitable ointment base.
    (7) Bacitracin zinc-polymyxin B sulfate topical aerosol containing, 
in each gram, 120 units of bacitracin and 2,350 units of polymyxin B in 
a suitable vehicle, packaged in a pressurized container with suitable 
inert gases.
    (8) Bacitracin zinc-polymyxin B sulfate topical powder containing, 
in each gram, 500 units of bacitracin and 10,000 units of polymyxin B in 
a suitable base.
    (9) Neomycin sulfate-polymyxin B sulfate ointment containing, in 
each gram, 3.5 milligrams of neomycin and 5,000 units of polymyxin B in 
a suitable water miscible base.
    (10) Neomycin sulfate-polymyxin B sulfate cream containing, in each 
gram, 3.5 milligrams of neomycin and 10,000 units of polymyxin B in a 
suitable vehicle.
    (11) Oxytetracycline hydrochloride-polymyxin B sulfate ointment 
containing, in each gram, 30 milligrams of oxytetracycline and 10,000 
units of polymyxin B in a suitable ointment base.
    (12) Oxytetracycline hydrochloride-polymyxin B sulfate topical 
powder containing, in each gram, 30 milligrams of oxytetracycline and 
10,000 units of polymyxin B with a suitable filler.
    (b) Combinations of first aid antibiotic active ingredients and 
local anesthetic active ingredients. (1) Bacitracin ointment containing, 
in each gram, 500 units of bacitracin and any single generally 
recognized as safe and effective amine or ``caine''-type local 
anesthetic active ingredient in a suitable ointment base.
    (2) Bacitracin-neomycin sulfate-polymyxin B sulfate ointment 
containing, in each gram, in a suitable ointment base the following:
    (i) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 units 
of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient; or
    (ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 
units of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient.
    (3) Bacitracin-polymyxin B sulfate topical aerosol containing, in 
each gram, 500 units of bacitracin and 5,000 units of polymyxin B and 
any single generally recognized as safe and effective amine or 
``caine''-type local anesthetic active ingredient in a suitable vehicle, 
packaged in a pressurized container with suitable inert gases.
    (4) Bacitracin zinc-neomycin sulfate-polymyxin B sulfate ointment 
containing, in each gram, in a suitable ointment base the following:

[[Page 231]]

    (i) 400 units of bacitracin, 3 milligrams of neomycin, 8,000 units 
of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient; or
    (ii) 400 units of bacitracin, 3.5 milligrams of neomycin, 5,000 
units of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient; or
    (iii) 500 units of bacitracin, 3.5 milligrams of neomycin, 5,000 
units of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient; or
    (iv) 500 units of bacitracin, 3.5 milligrams of neomycin, 10,000 
units of polymyxin B, and any single generally recognized as safe and 
effective amine or ``caine''-type local anesthetic active ingredient;
    (5) Bacitracin zinc-polymyxin B sulfate ointment containing, in each 
gram, 500 units of bacitracin, 10,000 units of polymyxin B, and any 
single generally recognized as safe and effective amine or ``caine''-
type local anesthetic active ingredient in a suitable ointment base.
    (6) Neomycin sulfate-polymyxin B sulfate cream containing, in each 
gram, 3.5 milligrams of neomycin, 10,000 units of polymyxin B, and any 
single generally recognized as safe and effective amine or ``caine''-
type local anesthetic active ingredient in a suitable vehicle.

[52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. 24, 1987, as amended at 
53 FR 18838, May 25, 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, Oct. 
3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR 403, Jan. 5, 1999]



Sec. 333.150  Labeling of first aid antibiotic drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``first aid antibiotic.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``First aid to help'' [select 
one of the following: ``prevent,'' (``decrease'' (``the risk of'' or 
``the chance of'')), (``reduce'' (``the risk of'' or ``the chance 
of'')), ``guard against,'' or ``protect against''] [select one of the 
following: ``infection,'' ``bacterial contamination,'' or ``skin 
infection''] ``in minor cuts, scrapes, and burns.'' Other truthful and 
nonmisleading statements describing only the indications for use that 
have been established and listed in this paragraph (b), may also be 
used, as provided in Sec. 330.1(c)(2), subject to the provisions of 
section 502 of the act relating to misbranding and the prohibition in 
section 301(d) of the act against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``For external use only. Do not use in the eyes or apply over 
large areas of the body. In case of deep or puncture wounds, animal 
bites, or serious burns, consult a doctor.''
    (2) For products containing chlortetracycline hydrochloride or 
tetracycline hydrochloride.``Stop use and consult a doctor if the 
condition persists or gets worse. Do not use longer than 1 week unless 
directed by doctor.''
    (3) For any product containing bacitracin, bacitracin zinc, 
neomycin, neomycin sulfate, polymyxin B, and/or polymyxin B sulfate. 
``Stop use and consult a doctor if the condition persists or gets worse, 
or if a rash or other allergic reaction develops. Do not use if you are 
allergic to any of the ingredients. Do not use longer than 1 week unless 
directed by a doctor.''
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'': (1) For ointment and cream 
products. ``Clean the affected area. Apply a small amount of this 
product (an amount equal to the surface area of the tip of a finger) on 
the area 1 to 3 times daily. May be covered with a sterile bandage.''
    (2) For powder products. ``Clean the affected area. Apply a light 
dusting of the powder on the area 1 to 3 times daily. May be covered 
with a sterile bandage.''
    (3) For aerosol products. ``Clean the affected area. Spray a small 
amount of this product on the area 1 to 3 times

[[Page 232]]

daily. May be covered with a sterile bandage.''
    (e) The word ``doctor'' may be substituted for the word 
``physician'' in any of the labeling statements in this subpart.

[52 FR 47332, Dec. 11, 1987, as amended at 61 FR 58472, Nov. 15, 1996]



Sec. 333.160  Labeling of permitted combinations of active ingredients.

    Statements of identity, indications, warnings, and directions for 
use, respectively, applicable to each ingredient in the product may be 
combined to eliminate duplicative words or phrases so that the resulting 
information is clear and understandable.
    (a) Statement of identity. For a combination drug product that has 
an established name, the labeling of the product states the established 
name of the combination drug product, followed by the statement of 
identity for each ingredient in the combination, as established in the 
statement of identity sections of the applicable OTC drug monographs. 
For a combination drug product that does not have an established name, 
the labeling of the product states the statement of identity for each 
ingredient in the combination, as established in the statement of 
identity sections of the applicable OTC drug monographs.
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the indication(s) for each ingredient in the 
combination, as established in the ``Indications'' sections of the 
applicable OTC drug monographs, unless otherwise stated in this 
paragraph. Other truthful and nonmisleading statements, describing only 
the indications for use that have been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2), 
subject to the provisions of section 502 of the act relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (1) For permitted combinations identified in Sec. 333.120(a). The 
indications in Sec. 333.150 should be used.
    (2) For permitted combinations identified in Sec. 333.120(b). In 
addition to the required indication identified in Sec. 333.150, the 
labeling of the product may state, under the heading ``Indications,'' 
the following additional indication: ``First aid for the temporary 
relief of'' (select one of the following: ``pain,'' ``discomfort,'' 
``pain or discomfort'' or ``pain and itching'') ``in minor cuts, 
scrapes, and burns.''
    (c) Warnings. The labeling of the product states, under the heading 
``Warnings,'' the warning(s) for each ingredient in the combination, as 
established in the warnings sections of the applicable OTC drug 
monographs.
    (d) Directions. The labeling of the product states, under the 
heading ``Directions,'' directions that conform to the directions 
established for each ingredient in the directions sections of the 
applicable OTC drug monographs. When the time intervals or age 
limitations for administrations of the individual ingredients differ, 
the directions for the combination product may not exceed any maximum 
dosage limits established for the individual ingredients in the 
applicable OTC drug monograph.



               Subpart C_Topical Antifungal Drug Products

    Source: 58 FR 49898, Sept. 23, 1993, unless otherwise noted.



Sec. 333.201  Scope.

    (a) An over-the-counter antifungal drug product in a form suitable 
for topical administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this subpart 
and each general condition established in Sec. 330.1 of this chapter.
    (b) Reference in this subpart to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 333.203  Definitions.

    As used in this subpart:
    (a) Antifungal. A drug which inhibits the growth and reproduction of 
fungal cells and decreases the number of fungi present.

[[Page 233]]

    (b) Athlete's foot. An infection of the feet caused by certain 
dermatophytic fungi.
    (c) Dermatophyte. A fungus that invades and lives upon the skin or 
in the hair or nails.
    (d) Fungus. Any of a large division of plants, including 
dermatophytes, yeasts, and molds, characterized by a simple cell 
structure and the absence of chlorophyll.
    (e) Jock itch. A chronic and recurrent infection caused by certain 
dermatophytic fungi; affects the upper, inner thighs and sometimes 
extends to the groin and the pubic area; the condition most frequently 
occurs in men, but may also occur in women.
    (f) Ringworm. A skin infection caused by certain dermatophytic 
fungi.



Sec. 333.210  Antifungal active ingredients.

    The active ingredient of the product consists of any one of the 
following within the specified concentration established for each 
ingredient:
    (a) Clioquinol 3 percent.
    (b) Haloprogin 1 percent.
    (c) Miconazole nitrate 2 percent.
    (d) Povidone-iodine 10 percent.
    (e) Tolnaftate 1 percent.
    (f) Undecylenic acid, calcium undecylenate, copper undecylenate, and 
zinc undecylenate may be used individually or in any ratio that provides 
a total undecylenate concentration of 10 to 25 percent.
    (g) Clotrimazole 1 percent.

[58 FR 49898, Sept. 23, 1993, as amended at 67 FR 5943, Feb. 8, 2002]



Sec. 333.250  Labeling of antifungal drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antifungal.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the phrase listed in paragraph (b)(1)(i) of 
this section and may contain the additional phrase listed in paragraph 
(b)(1)(ii) of this section. Other truthful and nonmisleading statements, 
describing only the indications for use that have been established in 
paragraph (b) of this section, may also be used, as provided in Sec. 
330.1(c)(2) of this chapter, subject to the provisions of section 502 of 
the Federal Food, Drug, and Cosmetic Act (the act) relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (1) For products containing any ingredient identified in Sec. 
333.210 labeled for the treatment of athlete's foot, jock itch, and 
ringworm. (i) (Select one of the following: ``Treats,'' ``For the 
treatment of,'' ``For effective treatment of,'' ``Cures,'' ``For the 
cure of,'' ``Clears up,'' or ``Proven clinically effective in the 
treatment of'') ``most'' (select one condition from any one or more of 
the following groups of conditions:
    (A) ``Athlete's foot,'' athlete's foot (dermatophytosis),'' 
``athlete's foot (tinea pedis),'' or ``tinea pedis (athlete's foot)'';
    (B) ``Jock itch,'' ``jock itch (tinea cruris),'' or ``tinea cruris 
(jock itch)''; or
    (C) ``Ringworm,'' ``ringworm (tinea corporis),'' or ``tinea corporis 
(ringworm).'')
    (ii) In addition to the information identified in paragraph 
(b)(1)(i) of this section, the labeling of the product may contain the 
following statement: (Select one of the following: ``Relieves,'' ``For 
relief of,'' ``For effective relief of,'' or ``Soothes,'') (select one 
or more of the following: ``Itching,'' ``scaling,'' ``cracking,'' 
``burning,'' ``redness,'' ``soreness,'' ``irritation,'' ``discomfort,'' 
``chafing associated with jock itch,'' ``itchy, scaly skin between the 
toes,'' or ``itching, burning feet'').
    (2) For products containing the ingredient identified in Sec. 
333.210(e) labeled for the prevention of athlete's foot. (i) (Select one 
of the following: ``Clinically proven to prevent,'' ``Prevents,'' 
``Proven effective in the prevention of,'' ``Helps prevent,'' ``For the 
prevention of,'' ``For the prophylaxis (prevention) of,'' ``Guards 
against,'' or ``Prevents the recurrence of'') ``most'' (select one of 
the following: ``Athlete's foot,'' ``athlete's foot (dermatophytosis),'' 
``athlete's foot (tinea pedis),'' or ``tinea pedis (athlete's foot)'') 
``with daily use.''

[[Page 234]]

    (ii) In addition to the information identified in paragraph 
(b)(2)(i) of this section, the labeling of the product may contain the 
following statement: ``Clears up most athlete's foot infection and with 
daily use helps keep it from coming back.''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredient identified in Sec. 
330.210. (i) ``Do not use on children under 2 years of age unless 
directed by a doctor.''
    (ii) ``For external use only.''
    (iii) ``Avoid contact with the eyes.''
    (2) For products labeled according to paragraph (b)(1) of this 
section for the treatment of athlete's foot and ringworm. ``If 
irritation occurs or if there is no improvement within 4 weeks, 
discontinue use and consult a doctor.''
    (3) For products labeled according to paragraph (b)(1) of this 
section for the treatment of jock itch. ``If irritation occurs or if 
there is no improvement within 2 weeks, discontinue use and consult a 
doctor.''
    (4) For products labeled according to paragraph (b)(2) of this 
section for the prevention of athlete's foot. ``If irritation occurs, 
discontinue use and consult a doctor.''
    (5) For products containing the ingredient identified in Sec. 
333.210(a) labeled according to paragraph (b)(1) of this section. The 
following statements must appear in boldface type as the first warnings 
under the ``Warnings'' heading. (i) ``Do not use on children under 2 
years of age.'' (This warning is to be used in place of the warning in 
paragraph (c)(1)(i) of this section.)
    (ii) ``Do not use for diaper rash.''
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'':
    (1) For products labeled according to paragraph (b)(1) of this 
section for the treatment of athlete's foot, jock itch, and ringworm. 
[Select one of the following: ``Clean'' or ``Wash''] ``the affected area 
and dry thoroughly. Apply'' (the word ``spray'' may be used to replace 
the word ``apply'' for aerosol products) ``a thin layer of the product 
over affected area twice daily (morning and night) or as directed by a 
doctor. Supervise children in the use of this product. For athlete's 
foot: Pay special attention to spaces between the toes; wear well-
fitting, ventilated shoes, and change shoes and socks at least once 
daily. For athlete's foot and ringworm, use daily for 4 weeks; for jock 
itch, use daily for 2 weeks. If condition persists longer, consult a 
doctor. This product is not effective on the scalp or nails.''
    (2) For products labeled according to paragraph (b)(2) of this 
section for the prevention of athlete's foot. ``To prevent athlete's 
foot,'' (select one of the following: ``clean'' or ``wash'') ``the feet 
and dry thoroughly. Apply'' (the word ``spray'' may be used to replace 
the word ``apply'' for aerosol products) ``a thin layer of the product 
to the feet once or twice daily (morning and/or night). Supervise 
children in the use of this product. Pay special attention to spaces 
between the toes; wear well-fitting, ventilated shoes, and change shoes 
and socks at least once daily.''
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[58 FR 49898, Sept. 23, 1993, as amended at 65 FR 52305, Aug. 29, 2000]



Sec. 333.280  Professional labeling.

    The labeling provided to health professionals (but not to the 
general public) may contain the following additional indication:
    (a) For products containing haloprogin or miconazole nitrate 
identified in Sec. 333.210 (a) and (c). ``For the treatment of 
superficial skin infections caused by yeast (Candida albicans).''
    (b) [Reserved]



                  Subpart D_Topical Acne Drug Products

    Source: 56 FR 41019, Aug. 16, 1991, unless otherwise noted.



Sec. 333.301  Scope.

    (a) An over-the-counter acne drug product in a form suitable for 
topical application is generally recognized as safe and effective and is 
not misbranded if it meets each of the conditions in this subpart and 
each general condition established in Sec. 330.1 of this chapter.

[[Page 235]]

    (b) References in this subpart to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 333.303  Definitions.

    As used in this subpart:
    (a) Acne. A disease involving the oil glands and hair follicles of 
the skin which is manifested by blackheads, whiteheads, acne pimples, 
and acne blemishes.
    (b) Acne blemish. A flaw in the skin resulting from acne.
    (c) Acne drug product. A drug product used to reduce the number of 
acne blemishes, acne pimples, blackheads, and whiteheads.
    (d) Acne pimple. A small, prominent, inflamed elevation of the skin 
resulting from acne.
    (e) Blackhead. A condition of the skin that occurs in acne and is 
characterized by a black tip.
    (f) Whitehead. A condition of the skin that occurs in acne and is 
characterized by a small, firm, whitish elevation of the skin.



Sec. 333.310  Acne active ingredients.

    The active ingredient of the product consists of any of the 
following:
    (a) Benzoyl peroxide, 2.5 to 10 percent.
    (b) Resorcinol, 2 percent, when combined with sulfur in accordance 
with Sec. 333.320(a).
    (c) Resorcinol monoacetate, 3 percent, when combined with sulfur in 
accordance with Sec. 333.320(b).
    (d) Salicylic acid, 0.5 to 2 percent.
    (e) Sulfur, 3 to 10 percent.
    (f) Sulfur, 3 to 8 percent, when combined with resorcinol or 
resorcinol monoacetate in accordance with Sec. 333.320.

[75 FR 9776, Mar. 4, 2010]



Sec. 333.320  Permitted combinations of active ingredients.

    (a) Resorcinol identified in Sec. 333.310(b) may be combined with 
sulfur identified in Sec. 333.310(f).
    (b) Resorcinol monoacetate identified in Sec. 333.310(c) may be 
combined with sulfur identified in Sec. 333.310(f).

[75 FR 9776, Mar. 4, 2010]



Sec. 333.350  Labeling of acne drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``acne medication,'' ``acne treatment,'' ``acne medication'' (insert 
dosage form, e.g., ``cream,'' ``gel,'' ``lotion,'' or ``ointment''), or 
``acne treatment'' (insert dosage form, e.g., ``cream,'' ``gel,'' 
``lotion,'' or ``ointment'').
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the phrase listed in paragraph (b)(1) of this 
section and may contain any of the additional phrases listed in 
paragraph (b)(2) of this section. Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in paragraph (b) of this section, may also be 
used, as provided in Sec. 330.1(c)(2) of this chapter, subject to the 
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act 
(the act) relating to misbranding and the prohibition in section 301(d) 
of the act against the introduction or delivery for introduction into 
interstate commerce of unapproved new drugs in violation of section 
505(a) of the act.
    (1) ``For the'' (select one of the following: ``management'' or 
``treatment'') ``of acne.''
    (2) In addition to the information identified in paragraph (b)(1) of 
this section, the labeling of the product may contain any one or more of 
the following statements:
    (i) (Select one of the following: ``Clears,'' ``Clears up,'' 
``Clears up most,'' ``Dries,'' ``Dries up,'' ``Dries and clears,'' 
``Helps clear,'' ``Helps clear up,'' ``Reduces the number of,'' or 
``Reduces the severity of'') (select one or more of the following: 
``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or ``whiteheads'') 
which may be followed by ``and allows skin to heal.''
    (ii) ``Penetrates pores to'' (select one of the following: 
``eliminate most,'' ``control,'' ``clear most,'' or ``reduce the number 
of'') (select one or more of the following: ``acne blemishes,'' ``acne 
pimples,'' ``blackheads,'' or ``whiteheads'').
    (iii) ``Helps keep skin clear of new'' (select one or more of the 
following:

[[Page 236]]

``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or 
``whiteheads'').
    (iv) ``Helps prevent new'' (select one or more of the following: 
``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or ``whiteheads'') 
which may be followed by ``from forming.''
    (v) ``Helps prevent the development of new'' (select one or more of 
the following: ``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or 
``whiteheads'').
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredients identified in Sec. 
330.310.
    (i) The labeling states ``For external use only.''
    (ii) The labeling states ``When using this product [bullet] skin 
irritation and dryness is more likely to occur if you use another 
topical acne medication at the same time. If irritation occurs, only use 
one topical acne medication at a time.''
    (2) For products containing sulfur identified in Sec. 333.310(e) 
and (f).
    (i) The labeling states ``Do not use on [bullet] broken skin 
[bullet] large areas of the skin.''
    (ii) The labeling states ``When using this product [bullet] apply 
only to areas with acne.''
    (3) For products containing any combination identified in Sec. 
333.320. (i) The labeling states ``When using this product [bullet] 
rinse right away with water if it gets in eyes.''
    (ii) The labeling states ``Stop use and ask a doctor [bullet] if 
skin irritation occurs or gets worse.''
    (4) For products containing benzoyl peroxide identified in Sec. 
333.310(a).
    (i) The labeling states ``Do not use if you [bullet] have very 
sensitive skin [bullet] are sensitive to benzoyl peroxide.''
    (ii) The labeling states ``When using this product [bullet] avoid 
unnecessary sun exposure and use a sunscreen [bullet] avoid contact with 
the eyes, lips, and mouth [bullet] avoid contact with hair and dyed 
fabrics, which may be bleached by this product [bullet] skin irritation 
may occur, characterized by redness, burning, itching, peeling, or 
possibly swelling. Irritation may be reduced by using the product less 
frequently or in a lower concentration.''
    (iii) The labeling states ``Stop use and ask a doctor if [bullet] 
irritation becomes severe.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products applied containing any ingredient identified in 
Sec. 333.310. The labeling states ``[bullet] clean the skin thoroughly 
before applying this product [bullet] cover the entire affected area 
with a thin layer one to three times daily [bullet] because excessive 
drying of the skin may occur, start with one application daily, then 
gradually increase to two or three times daily if needed or as directed 
by a doctor [bullet] if bothersome dryness or peeling occurs, reduce 
application to once a day or every other day.''
    (2) For products applied and left on the skin containing benzoyl 
peroxide identified in Sec. 333.310(a).
    (i) The labeling states the directions in paragraph (d)(1) of this 
section.
    (ii) The labeling states ``[bullet] if going outside, apply 
sunscreen after using this product. If irritation or sensitivity 
develops, stop use of both products and ask a doctor.''
    (3) For products applied and removed from the skin containing any 
ingredient identified in Sec. 333.310. Products, such as soaps and 
masks, may be applied and removed and should include appropriate 
directions. All products containing benzoyl peroxide should include the 
directions in paragraph (d)(2)(ii) of this section.
    (4) Optional directions. In addition to the required directions in 
paragraphs (d)(1) and (d)(2) of this section, the product may contain 
the following optional labeling: ``Sensitivity Test for a New User. 
Apply product sparingly to one or two small affected areas during the 
first 3 days. If no discomfort occurs, follow the directions stated 
(select one of the following: `elsewhere on this label,' `above,' or 
`below').''

[56 FR 41019, Aug. 16, 1991, as amended at 75 FR 9776, Mar. 4, 2010]

[[Page 237]]



PART 335_ANTIDIARRHEAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE--Table of Contents



                      Subpart A_General Provisions

Sec.
335.1 Scope.
335.3 Definitions.

                      Subpart B_Active Ingredients

335.10 Antidiarrheal active ingredients.

                           Subpart C_Labeling

335.50 Labeling of antidiarrheal drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 68 FR 18881, April 17, 2003, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 335.1  Scope.

    (a) An over-the-counter antidiarrheal drug product in a form 
suitable for oral administration is generally recognized as safe and 
effective and is not misbranded if it meets each condition in this part 
and each general condition established in Sec. 330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 335.3  Definitions.

    As used in this part:
    (a) Antidiarrheal. A drug that can be shown by objective measurement 
to treat or control (stop) the symptoms of diarrhea.
    (b) Diarrhea. A condition characterized by increased frequency of 
loose, watery stools (three or more daily) during a limited period (24 
to 48 hours), usually with no identifiable cause.
    (c) Travelers' diarrhea. A subset of diarrhea occurring in travelers 
that is most commonly caused by an infectious agent.

[68 FR 18881, April 17, 2003, as amended at 69 FR 26302, May 12, 2004]



                      Subpart B_Active Ingredients



Sec. 335.10  Antidiarrheal active ingredients.

    The active ingredient of the product consists of any one of the 
following when used within the dosage limits established for each 
ingredient in Sec. 335.50(d):
    (a) Bismuth subsalicylate.
    (b) Kaolin.



                           Subpart C_Labeling



Sec. 335.50  Labeling of antidiarrheal drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product either 
as an ``antidiarrheal'' or ``for diarrhea.''
    (b) Indications. The labeling of the product states, under the 
heading ``Use,'' one or more of the phrases listed in this paragraph 
(b), as appropriate. Other truthful and nonmisleading statements, 
describing only the indications for use that have been established and 
listed in this paragraph (b) may also be used, as provided in Sec. 
330.1(c)(2) of this chapter, subject to the provisions of section 502 of 
the Federal Food, Drug, and Cosmetic Act (the act) relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (1) For products containing bismuth subsalicylate identified in 
Sec. 335.10(a). The labeling states [select one of the following: 
``controls'' or ``relieves''] [select one or both of the following: 
``diarrhea'' or ``travelers' diarrhea'']. If both ``diarrhea'' and 
``travelers' diarrhea'' are selected, each shall be preceded by a bullet 
in accordance with Sec. 201.66(b)(4) and (d)(4) of this chapter and the 
heading ``Uses'' shall be used.
    (2) For products containing kaolin identified in Sec. 335.10(b). 
The labeling states ``helps firm stool within 24 to 48 hours''.
    (3) Additional indications--(i) When any additional indications are 
used, the heading ``Uses'' shall be used and each listed use shall be 
preceded by a

[[Page 238]]

bullet in accord with Sec. 201.66(b)(4) of this chapter.
    (ii) In addition to the indication in paragraph (b)(1) of this 
section, one or both of the following may be used for products 
containing bismuth subsalicylate in Sec. 335.10(a): ``[bullet] reduces 
number of bowel movements'' ``[bullet] helps firm stool''.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredient identified in Sec. 
335.10. (i) ``Do not use if you have [bullet] bloody or black stool''.
    (ii) ``Ask a doctor before use if you have [bullet] fever [bullet] 
mucus in the stool''.
    (2) For products containing bismuth subsalicylate identified in 
Sec. 335.10(a). (i) The following shall appear in accordance with Sec. 
201.66(c)(5)(ii) of this chapter.
    (A) The Reye's syndrome warning in Sec. 201.314(h) of this chapter.
    (B) ``Allergy alert: Contains salicylate. Do not take if you are 
[bullet] allergic to salicylates (including aspirin), [bullet] taking 
other salicylate products''.
    (ii) ``Do not use if you have [bullet] an ulcer [bullet] a bleeding 
problem''.
    (iii) ``Ask a doctor or pharmacist before use if you are taking any 
drug for [bullet] anticoagulation (thinning the blood) [bullet] diabetes 
[bullet] gout [bullet] arthritis''.
    (iv) ``When using this product a temporary, but harmless, darkening 
of the stool and/or tongue may occur''.
    (v) ``Stop use and ask a doctor if [bullet] symptoms get worse 
[bullet] ringing in the ears or loss of hearing occurs [bullet] diarrhea 
lasts more than 2 days''.
    (3) For products containing kaolin identified in Sec. 335.10(b). 
(i) ``Ask a doctor or pharmacist before use if you are taking any other 
drugs. Try to use at least 3 hours before or after taking any other 
drugs.''
    (ii) ``Stop use and ask a doctor if [bullet] symptoms get worse 
[bullet] diarrhea lasts more than 2 days''.
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing any ingredient identified in Sec. 
335.10. The labeling states ``[bullet] drink plenty of clear fluids to 
help prevent dehydration caused by diarrhea''.
    (2) For products containing bismuth subsalicylate identified in 
Sec. 335.10(a). The labeling states ``[bullet] adults and children 12 
years and over:'' 525 milligrams ``every 1/2 to 1 hour, or'' 1,050 
milligrams ``every hour as needed [bullet] do not exceed'' 4,200 
milligrams ``in 24 hours [bullet] use until diarrhea stops but not more 
than 2 days [bullet] children under 12 years: ask a doctor''.
    (3) For products containing kaolin identified in Sec. 335.10(b). 
The labeling states ``[bullet] adults and children 12 years and over:'' 
26.2 grams ``after each loose stool [bullet] continue to take every 6 
hours until stool is firm but not more than 2 days [bullet] do not 
exceed'' [262 grams] ``in 24 hours [bullet] children under 12 years of 
age: ask a doctor''.
    (e) Products that meet the criteria established in Sec. 
201.66(d)(10) of this chapter. The information described in Sec. 
201.66(c) of this chapter shall be printed in accordance with the 
following specifications.
    (1) The labeling shall meet the requirements of Sec. 201.66(c) of 
this chapter except that the information in Sec. 201.66(c)(3) of this 
chapter may be omitted, and the information in Sec. 201.66(c)(5) and 
(c)(6) of this chapter may be presented as follows:
    (i) The words ``Contains salicylate.'' may be omitted from the 
warning in Sec. 335.50(c)(2)(i)(B).
    (ii) The subheading ``When using this product'' in Sec. 
335.50(c)(2)(iv) may be omitted.
    (iii) The words ``continue to'' may be omitted from the directions 
in Sec. 335.50(d)(3).
    (2) The labeling shall be printed in accordance with the 
requirements of Sec. 201.66(d) of this chapter except that any 
requirements related to Sec. 201.66(c)(3) of this chapter and the 
bullet in the warning in Sec. 335.50(c)(1)(i) may be omitted.

[68 FR 18881, April 17, 2003, as amended at 69 FR 26302, May 12, 2004]

[[Page 239]]



PART 336_ANTIEMETIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table
of Contents



                      Subpart A_General Provisions

Sec.
336.1 Scope.
336.3 Definition.

                      Subpart B_Active Ingredients

336.10 Antiemetic active ingredients.

                           Subpart C_Labeling

336.50 Labeling of antiemetic drug products.
336.80 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 52 FR 15892, Apr. 30, 1987, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 336.1  Scope.

    (a) An over-the-counter antiemetic drug product in a form suitable 
for oral administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this part 
and each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 336.3  Definition.

    As used in this part:
    Antiemetic. An agent that prevents or treats nausea and vomiting.



                      Subpart B_Active Ingredients



Sec. 336.10  Antiemetic active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient in Sec. 336.50(d):
    (a) Cyclizine hydrochloride.
    (b) Dimenhydrinate.
    (c) Diphenhydramine hydrochloride.
    (d) Meclizine hydrochloride.



                           Subpart C_Labeling



Sec. 336.50  Labeling of antiemetic drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antiemetic.''
    (b) Indications. The labeling of the product states the following 
under the heading ``Indications,'' ``For the prevention and treatment of 
the nausea, vomiting, or dizziness associated with motion sickness.'' 
Other truthful and nonmisleading statements, describing only the 
indications for use that have been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2), 
subject to the provisions of section 502 of the act relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings:''
    (1) For products containing any ingredient identified in Sec. 
336.10--(i) When labeled for use in adults and for those products that 
can be and are labeled for use in children under 12 years of age. ``Do 
not take this product, unless directed by a doctor, if you have a 
breathing problem such as emphysema or chronic bronchitis, or if you 
have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (ii) For those products that can be and are labeled only for 
children under 12 years of age. ``Do not give this product to children 
who have a breathing problem such as chronic bronchitis or who have 
glaucoma, without first consulting the child's doctor.''
    (2) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a). ``Do not give to children under 6 years of age unless 
directed by a doctor.''
    (3) For products containing dimenhydrinate identified in Sec. 
336.10(b). ``Do not give to children under 2 years of age unless 
directed by a doctor.''
    (4) For products containing diphenhydramine hydrochloride identified 
in Sec. 336.10(c). ``Do not give to children

[[Page 240]]

under 6 years of age unless directed by a doctor.''
    (5) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). ``Do not give to children under 12 years of age unless 
directed by a doctor.''
    (6) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a) or meclizine hydrochloride identified in Sec. 
330.10(d). ``May cause drowsiness; alcohol, sedatives, and tranquilizers 
may increase the drowsiness effect. Avoid alcoholic beverages while 
taking this product. Do not take this product if you are taking 
sedatives or tranquilizers, without first consulting your doctor. Use 
caution when driving a motor vehicle or operating machinery.''
    (7) For products containing dimenhydrinate identified in Sec. 
336.10(b) or diphenhydramine hydrochloride identified in Sec. 
336.10(c). ``May cause marked drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (8) For products containing diphenhydramine hydrochloride identified 
in Sec. 336.10(c). ``Do not use [bullet] \1\ with any other product 
containing diphenhydramine, including one used on skin''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a). Adults and children 12 years of age and over: Oral 
dosage is 50 milligrams every 4 to 6 hours, not to exceed 200 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: Oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor.
    (2) For products containing dimenhydrinate identified in Sec. 
336.10(b). Adults and children 12 years of age and over: Oral dosage is 
50 to 100 milligrams every 4 to 6 hours, not to exceed 400 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: Oral dosage is 25 to 50 milligrams every 6 to 8 hours, not to 
exceed 150 milligrams in 24 hours, or as directed by a doctor. Children 
2 to under 6 years of age: Oral dosage is 12.5 to 25 milligrams every 6 
to 8 hours, not to exceed 75 milligrams in 24 hours, or as directed by a 
doctor.
    (3) For products containing diphenhydramine hydrochloride identified 
in Sec. 336.10(c). Adults and children 12 years of age and over: Oral 
dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: Oral dosage is 12.5 to 25 milligrams every 4 to 6 
hours, not to exceed 150 milligrams in 24 hours, or as directed by a 
doctor.
    (4) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). Adults and children 12 years of age and over: Oral 
dosage is 25 to 50 milligrams once daily, or as directed by a doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[52 FR 15892, Apr. 30, 1987, as amended at 53 FR 35809, Sept. 15, 1988; 
59 FR 16982, Apr. 11, 1994; 67 FR 72559, Dec. 6, 2003]



Sec. 336.80  Professional labeling.

    The labeling provided to health professionals (but not to the 
general public) may contain the following additional indications.
    (a) For products containing cyclizine hydrochloride, dimenhydrinate, 
and diphenhydramine hydrochloride identified in Sec. 336.10 (a), (b), 
and (c). ``For the treatment of vertigo of motion sickness.''
    (b) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). ``For the treatment of vertigo.''



PART 338_NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN 
USE--Table of Contents



                      Subpart A_General Provisions

Sec.
338.1 Scope.

[[Page 241]]

338.3 Definition.

                      Subpart B_Active Ingredients

338.10 Nighttime sleep-aid active ingredients.

                           Subpart C_Labeling

338.50 Labeling of nighttime sleep-aid drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 54 FR 6826, Feb. 14, 1989, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 338.1  Scope.

    (a) An over-the-counter nighttime sleep-aid drug product in a form 
suitable for oral administration is generally recognized as safe and 
effective and is not misbranded if it meets each condition in this part 
and each general condition established in Sec. 330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 338.3  Definition.

    As used in this part:
    Nighttime sleep-aid. A drug that is useful for the relief of 
occasional sleeplessness by individuals who have difficulty falling 
asleep.



                      Subpart B_Active Ingredients



Sec. 338.10  Nighttime sleep-aid active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient in Sec. 338.50(d):
    (a) Diphenhydramine hydrochloride.
    (b) Diphenhydramine citrate.



                           Subpart C_Labeling



Sec. 338.50  Labeling of nighttime sleep-aid drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``nighttime sleep-aid.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' one or more of the phrases listed in this 
paragraph. Other truthful and nonmisleading statements, describing only 
the indications for use that have been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2) of 
this chapter, subject to the provisions of section 502 of the act 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) (``Helps you'' or ``Reduces time to'') ``fall asleep if you have 
difficulty falling asleep.''
    (2) ``For relief of occasional sleeplessness.''
    (3) ``Helps to reduce difficulty falling asleep.''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``Do not give to children under 12 years of age.''
    (2) ``If sleeplessness persists continuously for more than 2 weeks, 
consult your doctor. Insomnia may be a symptom of serious underlying 
medical illness.''
    (3) ``Do not take this product, unless directed by a doctor, if you 
have a breathing problem such as emphysema or chronic bronchitis, or if 
you have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (4) ``Avoid alcoholic beverages while taking this product. Do not 
take this product if you are taking sedatives or tranquilizers, without 
first consulting your doctor.''
    (5) ``Do not use [bullet] \1\ with any other product containing 
diphenhydramine, even one used on skin''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing diphenhydramine hydrochloride identified 
in Sec. 338.10(a). Adults and children 12 years of age and over: Oral 
dosage is 50 milligrams at bedtime if needed, or as directed by a 
doctor.

[[Page 242]]

    (2) For products containing diphenhydramine citrate identified in 
Sec. 338.10(b). Adults and children 12 years of age and over: Oral 
dosage is 76 milligrams at bedtime if needed, or as directed by a 
doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[54 FR 6826, Feb. 14, 1989, as amended at 59 FR 16983, Apr. 11, 1994; 67 
FR 72559, Dec. 6, 2002]



PART 340_STIMULANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table
of Contents



                      Subpart A_General Provisions

Sec.
340.1 Scope.
340.3 Definition.

                       Subpart B_Active Ingredient

340.10 Stimulant active ingredient.

                           Subpart C_Labeling

340.50 Labeling of stimulant drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 53 FR 6105, Feb. 29, 1988, unless otherwise noted.



                      Subpart A_General Provisions



Sec. 340.1  Scope.

    (a) An over-the-counter stimulant drug product in a form suitable 
for oral administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this part 
and each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 340.3  Definition.

    As used in this part:
    Stimulant. A drug which helps restore mental alertness or 
wakefulness during fatigue or drowsiness.



                       Subpart B_Active Ingredient



Sec. 340.10  Stimulant active ingredient.

    The active ingredient of the product consists of caffeine when used 
within the dosage limits established in Sec. 340.50(d).



                           Subpart C_Labeling



Sec. 340.50  Labeling of stimulant drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``altertness aid'' or a ``stimulant.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``Helps restore mental alertness 
or wakefulness when experiencing fatigue or drowsiness.'' Other truthful 
and nonmisleading statements, describing only the indications for use 
that have been established and listed in this paragraph (b), may also be 
used, as provided in Sec. 330.1(c)(2), subject to the provisions of 
section 502 of the Act relating to misbranding and the prohibition in 
section 301(d) of the Act against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the Act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``The recommended dose of this product contains about as much 
caffeine as a cup of coffee. Limit the use of caffeine-containing 
medications, foods, or beverages while taking this product because too 
much caffeine may cause nervousness, irritability, sleeplessness, and, 
occasionally, rapid heart beat.''
    (2) ``For occasional use only. Not intended for use as a substitute 
for sleep. If fatigue or drowsiness persists or continues to recur, 
consult a'' (select one of the following: ``physician'' or ``doctor'').
    (3) ``Do not give to children under 12 years of age.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': Adults and children 12 
years of

[[Page 243]]

age and over: Oral dosage is 100 to 200 milligrams not more often than 
every 3 to 4 hours.



PART 341_COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG
PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents



                      Subpart A_General Provisions

Sec.
341.1 Scope.
341.3 Definitions.

                      Subpart B_Active Ingredients

341.12 Antihistamine active ingredients.
341.14 Antitussive active ingredients.
341.16 Bronchodilator active ingredients.
341.18 Expectorant active ingredient.
341.20 Nasal decongestant active ingredients.
341.40 Permitted combinations of active ingredients.

                           Subpart C_Labeling

341.70 Labeling of OTC drug products containing ingredients that are 
          used for treating concurrent symptoms (in either a single-
          ingredient or combination drug product).
341.72 Labeling of antihistamine drug products.
341.74 Labeling of antitussive drug products.
341.76 Labeling of bronchodilator drug products.
341.78 Labeling of expectorant drug products.
341.80 Labeling of nasal decongestant drug products.
341.85 Labeling of permitted combinations of active ingredients.
341.90 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Editorial Note: Nomenclature changes to part 341 appear at 69 FR 
13717, Mar. 24, 2004.



                      Subpart A_General Provisions



Sec. 341.1  Scope.

    (a) An over-the-counter cold, cough, allergy, bronchodilator, or 
antiasthmatic drug product in a form suitable for oral, inhalant, or 
topical administration is generally recognized as safe and effective and 
is not misbranded if it meets each of the conditions in this part and 
each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.

[51 FR 35339, Oct. 2, 1986]



Sec. 341.3  Definitions.

    As used in this part:
    (a) Bronchodilator drug. A drug used to overcome spasms that cause 
narrowing of the bronchial air tubes, such as in the symptomatic 
treatment of the wheezing and shortness of breath of asthma.
    (b) Oral antitussive drug. A drug that either is taken by mouth or 
is dissolved in the mouth in the form of a lozenge and acts systemically 
to relieve cough.
    (c) Topical antitussive drug. A drug that relieves cough when 
inhaled after being applied topically to the throat or chest in the form 
of an ointment or from a steam vaporizer, or when dissolved in the mouth 
in the form of a lozenge for a local effect.
    (d) Expectorant drug. A drug taken orally to promote or facilitate 
the removal of secretions from the respiratory airways.
    (e) Antihistamine drug. A drug used for the relief of the symptoms 
of hay fever and upper respiratory allergies (allergic rhinitis).
    (f) Oral nasal decongestant drug. A drug that is taken by mouth and 
acts systemically to reduce nasal congestion caused by acute or chronic 
rhinitis.
    (g) Topical nasal decongestant drug. A drug that when applied 
topically inside the nose, in the form of drops, jellies, or sprays, or 
when inhaled intranasally reduces nasal congestion caused by acute or 
chronic rhinitis.
    (h) Calibrated dropper. A dropper calibrated such that the volume 
error incurred in measuring any liquid does not exceed 15 percent under 
normal use conditions.
    (i) Effervescent dosage form. A dosage form intended to be dissolved 
in water before administration. It contains, in addition to the active 
ingredient(s), mixtures of acids (citric acid, tartaric acid) and sodium 
bicarbonate, which

[[Page 244]]

release carbon dioxide when dissolved in water.

[51 FR 35339, Oct. 2, 1986, as amended at 54 FR 8509, Feb. 28, 1989; 55 
FR 40382, Oct. 3, 1990; 57 FR 58374, Dec. 9, 1992; 59 FR 43409, Aug. 23, 
1994; 71 FR 43362, Aug. 1, 2006]



                      Subpart B_Active Ingredients



Sec. 341.12  Antihistamine active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient:
    (a) Brompheniramine maleate.
    (b) Chlorcyclizine hydrochloride.
    (c) Chlorpheniramine maleate.
    (d) Dexbrompheniramine maleate.
    (e) Dexchlorpheniramine maleate.
    (f) Diphenhydramine citrate.
    (g) Diphenhydramine hydrochloride.
    (h) Doxylamine succinate.
    (i) Phenindamine tartrate.
    (j) Pheniramine maleate.
    (k) Pyrilamine maleate.
    (l) Thonzylamine hydrochloride.
    (m) Triprolidine hydrochloride.

[57 FR 58374, Dec. 9, 1992, as amended at 59 FR 4218, Jan. 28, 1994]



Sec. 341.14  Antitussive active ingredients.

    The active ingredients of the product consist of any of the 
following when used within the dosage limits and in the dosage forms 
established for each ingredient in Sec. 341.74(d):
    (a) Oral antitussives. (1) Chlophedianol hydrochloride.
    (2) Codeine ingredients. The following ingredients may be used only 
in combination in accordance with Sec. 290.2 and 21 CFR 1308.15(c).
    (i) Codeine.
    (ii) Codeine phosphate.
    (iii) Codeine sulfate.
    (3) Dextromethorphan.
    (4) Dextromethorphan hydrobromide.
    (5) Diphenhydramine citrate.
    (6) Diphenhydramine hydrochloride.
    (b) Topical antitussives. (1) Camphor.
    (2) Menthol.

[52 FR 30055, Aug. 12, 1987, as amended at 59 FR 29174, June 3, 1994; 67 
FR 4907, Feb. 1, 2002]



Sec. 341.16  Bronchodilator active ingredients.

    The active ingredients of the product consist of any of the 
following when used within the dosage limits established for each 
ingredient:
    (a) Ephedrine.
    (b) Ephedrine hydrochloride.
    (c) Ephedrine sulfate.
    (d) Epinephrine.
    (e) Epinephrine bitartrate.
    (f) Racephedrine hydrochloride.
    (g) Racepinephrine hydrochloride.

[51 FR 35339, Oct. 2, 1986]



Sec. 341.18  Expectorant active ingredient.

    The active ingredient of the product is guaifenesin when used within 
the dosage limits established in Sec. 341.78(d).

[54 FR 8509, Feb. 28, 1989]



Sec. 341.20  Nasal decongestant active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits and in the dosage forms 
established for each ingredient:
    (a) Oral nasal decongestants. (1) Phenylephrine hydrochloride.
    (2) Pseudoephedrine hydrochloride.
    (3) Pseudoephedrine sulfate.
    (4) Phenylephrine bitartrate in an effervescent dosage form.
    (b) Topical nasal decongestants. (1) Levmetamfetamine.
    (2) Ephedrine.
    (3) Ephedrine hydrochloride.
    (4) Ephedrine sulfate.
    (5) [Reserved]
    (6) Naphazoline hydrochloride.
    (7) Oxymetazoline hydrochloride.
    (8) Phenylephrine hydrochloride.
    (9) Propylhexedrine.
    (10) Xylometazoline hydrochloride.

[59 FR 43409, Aug. 23, 1994, as amended at 63 FR 40650, July 30, 1998; 
71 FR 43362, Aug. 1, 2006]



Sec. 341.40  Permitted combinations of active ingredients.

    The following combinations are permitted provided each active 
ingredient is present within the dosage limits established in parts 341, 
343, and 356 of this chapter and the product is labeled in accordance 
with Sec. Sec. 341.70 or 341.85:

[[Page 245]]

    (a) Any single antihistamine active ingredient identified in Sec. 
341.12 may be combined with any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (b) Any single antihistamine active ingredient identified in Sec. 
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec. 341.20(a) provided that the product is 
labeled according to Sec. 341.85.
    (c) Any single antihistamine active ingredient identified in Sec. 
341.12 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec. 341.20(a) and any generally recognized as 
safe and effective single analgesic-antipyretic active ingredient, or 
any combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (d) Any single antihistamine active ingredient identified in Sec. 
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec. 
341.14(a)(1) through (a)(4) provided that the product is labeled 
according to Sec. 341.85(c)(4). Diphenhydramine citrate in Sec. Sec. 
341.12(f) and 341.14(a)(5) or diphenhydramine hydrochloride in 
Sec. Sec. 341.12(g) and 341.14(a)(6) may be both the antihistamine and 
the antitussive active ingredient provided that the product is labeled 
according to Sec. 341.70(a).
    (e) Any single antihistamine active ingredient identified in Sec. 
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec. 
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a) provided that the 
product is labeled according to Sec. 341.85(c)(4). Diphenhydramine 
citrate in Sec. Sec. 341.12(f) and 341.14(a)(5) or diphenhydramine 
hydrochloride in Sec. Sec. 341.12(g) and 341.14(a)(6) may be both the 
antihistamine and the antitussive active ingredient provided that the 
product is labeled according to Sec. 341.70(a).
    (f) Any single antihistamine active ingredient identified in Sec. 
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec. 
341.14(a)(1) through (a)(4) and any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85(c)(4). Diphenhydramine 
citrate in Sec. Sec. 341.12(f) and 341.14(a)(5) or diphenhydramine 
hydrochloride in Sec. Sec. 341.12(g) and 341.14(a)(6) may be both the 
antihistamine and the antitussive active ingredient provided that the 
product is labeled according to Sec. 341.70(a).
    (g) Any single antihistamine active ingredient identified in Sec. 
341.12(a) through (e) and (h) through (m) may be combined with any 
single oral antitussive active ingredient identified in Sec. 
341.14(a)(1) through (a)(4) and any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a) and any generally 
recognized as safe and effective single analgesic-antipyretic active 
ingredient, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients, or any aspirin and antacid combination 
provided that the product is labeled according to Sec. 341.85(c)(4). 
Diphenhydramine citrate in Sec. Sec. 341.12(f) and 341.14(a)(5) or 
diphenhydramine hydrochloride in Sec. Sec. 341.12(g) and 341.14(a)(6) 
may be both the antihistamine and the antitussive active ingredient 
provided that the product is labeled according to Sec. 341.70(a).
    (h) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) may be combined with any single 
expectorant active ingredient identified in Sec. 341.18 provided that 
the product is labeled according to Sec. 341.85.
    (i) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a) provided that the 
product is labeled according to Sec. 341.85.

[[Page 246]]

    (j) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single expectorant active ingredient identified in Sec. 341.18 
provided that the product is labeled according to Sec. 341.85.
    (k) Any single antitussive active ingredient identified in Sec. 
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral anesthetic/analgesic active ingredient, 
or any combination of anesthetic/analgesic active ingredients provided 
that the product is available in either a liquid (to be swallowed) or a 
solid dosage form (to be dissolved in the mouth and swallowed) and 
provided that the product is labeled according to Sec. 341.85. If the 
combination contains a topical antitussive, the product must be 
formulated in a solid dosage form to be dissolved in the mouth. Menthol 
in Sec. 341.14(b)(2) and part 356 of this chapter may be both the 
antitussive and the anesthetic/analgesic active ingredient provided that 
the product is labeled according to Sec. 341.70(b).
    (l) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a) may be combined with any generally recognized as safe 
and effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (m) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a) may be combined with any single oral nasal decongestant 
active ingredient identified in Sec. 341.20(a) and any generally 
recognized as safe and effective single analgesic-antipyretic active 
ingredient, or any combination of acetaminophen with other analgesic-
antipyretic active ingredients, or any aspirin and antacid combination 
provided that the product is labeled according to Sec. 341.85.
    (n) Any single oral antitussive active ingredient identified in 
Sec. 341.14(a)(1) through (a)(4) may be combined with any single oral 
nasal decongestant active ingredient identified in Sec. 341.20(a) and 
any single expectorant active ingredient identified in Sec. 341.18 and 
any generally recognized as safe and effective single analgesic-
antipyretic active ingredient, or any combination of acetaminophen with 
other analgesic-antipyretic active ingredients, or any aspirin and 
antacid combination provided that the product is labeled according to 
Sec. 341.85.
    (o) Any single expectorant active ingredient identified in Sec. 
341.18 may be combined with any generally recognized as safe and 
effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (p) Any single expectorant active ingredient identified in Sec. 
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec. 341.20(a) provided that the product is 
labeled according to Sec. 341.85.
    (q) Any single expectorant active ingredient identified in Sec. 
341.18 may be combined with any single oral nasal decongestant active 
ingredient identified in Sec. 341.20(a) and any generally recognized as 
safe and effective single analgesic-antipyretic active ingredient, or 
any combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (r) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any generally recognized as safe 
and effective single analgesic-antipyretic active ingredient, or any 
combination of acetaminophen with other analgesic-antipyretic active 
ingredients, or any aspirin and antacid combination provided that the 
product is labeled according to Sec. 341.85.
    (s) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any generally recognized as safe 
and effective single oral anesthetic/analgesic active ingredient 
identified, or any combination of anesthetic/analgesic active 
ingredients provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to

[[Page 247]]

be dissolved in the mouth and swallowed) and provided that the product 
is labeled according to Sec. 341.85.
    (t) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any single antitussive active 
ingredient identified in Sec. 341.14(a) or (b)(2) and any generally 
recognized as safe and effective single oral anesthetic/analgesic active 
ingredient, or any combination of anesthetic/analgesic active 
ingredients provided that the product is available in either a liquid 
(to be swallowed) or a solid dosage form (to be dissolved in the mouth 
and swallowed) and provided that the product is labeled according to 
Sec. 341.85. If the combination contains a topical antitussive, the 
product must be formulated in a solid dosage form to be dissolved in the 
mouth.
    (u) Camphor identified in Sec. 341.14(b)(1) may be combined with 
menthol identified in Sec. 341.14(b)(2) and eucalyptus oil (1.2 to 1.3 
percent) provided that the product is available only in a suitable 
ointment vehicle and provided that the product is labeled according to 
Sec. 341.85.
    (v) Levmetamfetamine identified in Sec. 341.20(b)(1) may be 
combined with aromatics (camphor (54 milligrams (mg)), menthol (80 mg), 
methyl salicylate (11 mg), and lavender oil (4 mg)) provided that the 
product is available only as a nasal inhaler and provided that the 
product is labeled according to Sec. 341.85.
    (w) Any single antitussive active ingredient identified in Sec. 
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral demulcent active ingredient provided that 
the product is available in either a liquid (to be swallowed) or a solid 
dosage form (to be dissolved in the mouth and swallowed) and provided 
that the product is labeled according to Sec. 341.85. If the 
combination contains a topical antitussive, the product must be 
formulated in a solid dosage form to be dissolved in the mouth.
    (x) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any generally recognized as safe 
and effective single oral demulcent active ingredient provided that the 
product is available in either a liquid (to be swallowed) or a solid 
dosage form (to be dissolved in the mouth and swallowed) and provided 
that the product is labeled according to Sec. 341.85.
    (y) Any single antitussive active ingredient identified in Sec. 
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec. 341.20(a) and any 
generally recognized as safe and effective single oral demulcent active 
ingredient provided that the product is available in either a liquid (to 
be swallowed) or a solid dosage form (to be dissolved in the mouth and 
swallowed) and provided that the product is labeled according to Sec. 
341.85. If the combination contains a topical antitussive, the product 
must be formulated in a solid dosage form to be dissolved in the mouth.
    (z) Any single antitussive active ingredient identified in Sec. 
341.14(a) or (b)(2) may be combined with any generally recognized as 
safe and effective single oral anesthetic/analgesic active ingredient or 
any combination of anesthetic/analgesic active ingredients and any 
generally recognized as safe and effective single oral demulcent active 
ingredient provided that the product is available in either a liquid (to 
be swallowed) or a solid dosage form (to be dissolved in the mouth and 
swallowed) and provided that the product is labeled according to Sec. 
341.85. If the combination contains a topical antitussive, the product 
must be formulated in a solid dosage form to be dissolved in the mouth.
    (aa) Any single oral nasal decongestant active ingredient identified 
in Sec. 341.20(a) may be combined with any generally recognized as safe 
and effective single oral anesthetic/analgesic active ingredient or any 
combination of oral anesthetic/analgesic active ingredients and any 
generally recognized as safe and effective single oral demulcent active 
ingredient provided that the product is available in either a liquid (to 
be swallowed) or a solid dosage form (to be dissolved in the mouth and 
swallowed) and provided that the product is labeled according to Sec. 
341.85.
    (bb) Any single antitussive active ingredient identified in Sec. 
341.14(a) or (b)(2) may be combined with any single oral nasal 
decongestant active ingredient identified in Sec. 341.20(a) and any 
generally recognized as safe and effective single oral anesthetic/
analgesic active

[[Page 248]]

ingredient identified or any combination of anesthetic/analgesic active 
ingredients and any generally recognized as safe and effective single 
oral demulcent active ingredient provided that the product is available 
in either a liquid (to be swallowed) or a solid dosage form (to be 
dissolved in the mouth and swallowed) and provided that the product is 
labeled according to Sec. 341.85. If the combination contains a topical 
antitussive, the product must be formulated in a solid dosage form to be 
dissolved in the mouth.

[67 FR 78168, Dec. 23, 2002]



                           Subpart C_Labeling



Sec. 341.70  Labeling of OTC drug products containing ingredients that
are used for treating concurrent symptoms (in either a single-ingredient

or combination drug product).

    The statements of identity, indications, warnings, and directions 
for use, respectively, applicable to each ingredient in the product may 
be combined to eliminate duplicative words or phrases so that the 
resulting information is clear and understandable.
    (a) For products containing diphenhydramine citrate and 
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and 
(a)(6). The labeling of the product contains the established name of the 
drug, if any, and identifies the product as an ``antihistamine/cough 
suppressant'' or ``antihistamine/antitussive (cough suppressant).'' The 
indications shall be combined from Sec. Sec. 341.72(b) and 341.74(b). 
The warnings shall be combined from Sec. Sec. 341.72(c)(1), (c)(2), 
(c)(4), and (c)(6) and 341.74(c)(1), (c)(2), (c)(3), and (c)(4). 
Alternatively, all of the warnings in Sec. 341.74(c) shall be used. The 
directions for OTC labeling shall follow Sec. Sec. 341.74(d)(1)(iv) or 
(d)(1)(v), as applicable. The directions for professional labeling shall 
follow Sec. 341.90(j) or (k), as applicable.
    (b) For products containing menthol identified in Sec. Sec. 
341.14(b)(2) and 356.12(f) of this chapter. The product contains 5 to 10 
milligrams menthol. The labeling of the product contains the established 
name of the drug, if any, and identifies the product as a ``cough 
suppressant/oral anesthetic'' or ``antitussive (cough suppressant)/oral 
anesthetic.'' The indications shall be combined from Sec. 341.74(b) and 
part 356 of this chapter. The warnings shall be combined from Sec. 
341.74(c)(1), (c)(2), and (c)(3) and part 356 of this chapter. The 
directions shall be: ``Directions [in bold type] [bullet] \1\ adults and 
children 2 years and over: dissolve lozenge slowly in the mouth. Repeat 
every 2 hours as needed or as directed by a doctor. [bullet] children 
under 2 years of age: ask a doctor''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet 
symbol.

[61 FR 15703, Apr. 9, 1996, as amended at 67 FR 78170, Dec. 23, 2002; 68 
FR 17881, Apr. 14, 2003]



Sec. 341.72  Labeling of antihistamine drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antihistamine.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' any of the phrases listed in paragraph (b) of 
this section, as appropriate. Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in this paragraph, may also be used, as provided 
in Sec. 330.1(c)(2) of this chapter, subject to the provisions of 
section 502 of the Federal Food, Drug, and Cosmetic Act (the act) 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) ``Temporarily'' (select one of the following: ``relieves,'' 
``alleviates,'' ``decreases,'' ``reduces,'' or ``dries'') ``runny nose 
and'' (select one of the following: ``relieves,'' ``alleviates,'' 
``decreases,'' or ``reduces'') ``sneezing, itching of the nose or 
throat, and itchy, watery eyes due to hay fever'' (which may be followed 
by one or both of the following: ``or other upper respiratory 
allergies'' or ``(allergic rhinitis)'').
    (2) ``For the temporary relief of runny nose, sneezing, itching of 
the nose or throat, and itchy, watery eyes due to hay fever'' (which may 
be followed by one or both of the following:

[[Page 249]]

``or other upper respiratory allergies'' or ``(allergic rhinitis)'').
    (c) Warnings. The labeling of the product contains the following 
warnings, under the heading ``Warnings'':
    (1) ``May cause excitability especially in children.''
    (2) ``Do not take this product, unless directed by a doctor, if you 
have a breathing problem such as emphysema or chronic bronchitis, or if 
you have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (3) For products containing brompheniramine maleate, chlorcyclizine 
hydrochloride, chlorpheniramine maleate, dexbrompheniramine maleate, 
dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, 
pyrilamine maleate, thonzylamine hydrochloride, or triprolidine 
hydrochloride identified in Sec. 341.12(a), (b), (c), (d), (e), (i), 
(j), (k), (l), and (m). ``May cause drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (4) For products containing diphenhydramine citrate, diphenhydramine 
hydrochloride, or doxylamine succinate identified in Sec. 341.12(f), 
(g), and (h). ``May cause marked drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (5) For products containing phenindamine tartrate identified in 
Sec. 341.12(i). ``May cause nervousness and insomnia in some 
individuals.''
    (6) For products that are labeled only for use by children under 12 
years of age. The labeling of the product contains only the warnings 
identified in paragraphs (c)(1) and (c)(5) of this section as well as 
the following:
    (i) ``Do not give this product to children who have a breathing 
problem such as chronic bronchitis, or who have glaucoma, without first 
consulting the child's doctor.''
    (ii) For products containing brompheniramine maleate, 
chlorpheniramine maleate, dexbrompheniramine maleate, 
dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, 
pyrilamine maleate, thonzylamine hydrochloride, or triprolidine 
hydrochloride identified in Sec. 341.12(a), (c), (d), (e), (i), (j), 
(k), (l), and (m). ``May cause drowsiness. Sedatives and tranquilizers 
may increase the drowsiness effect. Do not give this product to children 
who are taking sedatives or tranquilizers, without first consulting the 
child's doctor.''
    (iii) For products containing diphenhydramine citrate, 
diphenhydramine hydrochloride, or doxylamine succinate identified in 
Sec. 341.12(f), (g), and (h). ``May cause marked drowsiness. Sedatives 
and tranquilizers may increase the drowsiness effect. Do not give this 
product to children who are taking sedatives or tranquilizers, without 
first consulting the child's doctor.''
    (iv) For products containing diphenhydramine citrate or 
diphenhydramine hydrochloride identified in Sec. 341.12(f) and (g). 
``Do not use [bullet] \1\ with any other product containing 
diphenhydramine, even one used on skin''.
---------------------------------------------------------------------------

    \1\ See Sec. 201.66(b)(4) of this chapter for definition of bullet 
symbol.
---------------------------------------------------------------------------

    (7) For products containing diphenhydramine citrate or 
diphenhydramine hydrochloride identified in Sec. 341.12(f) and (g). 
``Do not use [bullet] with any other product containing diphenhydramine, 
even one used on skin''.
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing brompheniramine maleate identified in 
Sec. 341.12(a). Adults and children 12 years of age and over: oral 
dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed

[[Page 250]]

12 milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (2) For products containing chlorcyclizine hydrochloride identified 
in Sec. 341.12(b). Adults and children 12 years of age and over: oral 
dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 milligrams 
in 24 hours, or as directed by a doctor. Children under 12 years of age: 
consult a doctor.
    (3) For products containing chlorpheniramine maleate identified in 
Sec. 341.12(c). Adults and children 12 years of age and over: oral 
dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (4) For products containing dexbrompheniramine maleate identified in 
Sec. 341.12(d). Adults and children 12 years of age and over: oral 
dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 1 milligram every 4 to 6 hours, not to exceed 6 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (5) For products containing dexchlorpheniramine maleate identified 
in Sec. 341.12(e). Adults and children 12 years of age and over: oral 
dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 1 milligram every 4 to 6 hours, not to exceed 6 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (6) For products containing diphenhydramine citrate identified in 
Sec. 341.12(f). Adults and children 12 years of age and over: oral 
dosage is 38 to 76 milligrams every 4 to 6 hours, not to exceed 456 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 19 to 38 milligrams every 4 to 6 hours, 
not to exceed 228 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.
    (7) For products containing diphenhydramine hydrochloride identified 
in Sec. 341.12(g). Adults and children 12 years of age and over: oral 
dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 12.5 to 25 milligrams every 4 to 6 
hours, not to exceed 150 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
    (8) For products containing doxylamine succinate identified in Sec. 
341.12(h). Adults and children 12 years of age and over: oral dosage is 
7.5 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 3.75 to 6.25 milligrams every 4 to 6 hours, not to 
exceed 37.5 milligrams in 24 hours, or as directed by a doctor. Children 
under 6 years of age: consult a doctor.
    (9) For products containing phenindamine tartrate identified in 
Sec. 341.12(i). Adults and children 12 years of age and over: oral 
dosage is 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 12.5 milligrams every 4 to 6 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (10) For products containing pheniramine maleate identified in Sec. 
341.12(j). Adults and children 12 years of age and over: oral dosage is 
12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 6.25 to 12.5 milligrams every 4 to 6 hours, not to 
exceed 75 milligrams in 24 hours, or as directed by a doctor. Children 
under 6 years of age: consult a doctor.
    (11) For products containing pyrilamine maleate identified in Sec. 
341.12(k). Adults and children 12 years of age and over: oral dosage is 
25 to 50 milligrams every 6 to 8 hours, not to exceed 200 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 12.5 to 25 milligrams every 6 to 8 hours, not to 
exceed 100

[[Page 251]]

milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (12) For products containing thonzylamine hydrochloride identified 
in Sec. 341.12(l). Adults and children 12 years of age and over: oral 
dosage is 50 to 100 milligrams every 4 to 6 hours, not to exceed 600 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 25 to 50 milligrams every 4 to 6 hours, 
not to exceed 300 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.
    (13) For products containing triprolidine hydrochloride identified 
in Sec. 341.12(m). Adults and children 12 years of age and over: oral 
dosage is 2.5 milligrams every 4 to 6 hours, not to exceed 10 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 1.25 milligrams every 4 to 6 hours, not to exceed 5 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[57 FR 58374, Dec. 9, 1992, as amended at 59 FR 4218, Jan. 28, 1994; 67 
FR 72559, Dec. 6, 2002]



Sec. 341.74  Labeling of antitussive drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``cough suppressant'' or an ``antitussive (cough suppressant).''
    (b) Indications. The labeling of the product states, under t