[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2017 Edition]
[From the U.S. Government Publishing Office]



[[Page i]]

          

          Title 21

Food and Drugs


________________________

Parts 300 to 499

                         Revised as of April 1, 2017

          Containing a codification of documents of general 
          applicability and future effect

          As of April 1, 2017
                    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........................     359
      Alphabetical List of Agencies Appearing in the CFR......     379
      List of CFR Sections Affected...........................     389

[[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 
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    To determine whether a Code volume has been amended since its 
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Register page number of the latest amendment of any given rule.

EFFECTIVE AND EXPIRATION DATES

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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 
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PAST PROVISIONS OF THE CODE

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``[RESERVED]'' TERMINOLOGY

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INCORPORATION BY REFERENCE

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[[Page vii]]

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    Oliver A. Potts,
    Director,
    Office of the Federal Register.
    April 1, 2017.







[[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, 2017.

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

[[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........          51
314             Applications for FDA approval to market a 
                    new drug................................          93
315             Diagnostic radiopharmaceuticals.............         190
316             Orphan drugs................................         192
317             Qualifying pathogens........................         205
320             Bioavailability and bioequivalence 
                    requirements............................         205
328             Over-the-counter drug products intended for 
                    oral ingestion that contain alcohol.....         220
329             Nonprescription human drug products subject 
                    to section 760 of the Federal food, 
                    drug, and cosmetic act..................         222
330             Over-the-counter (OTC) human drugs which are 
                    generally recognized as safe and 
                    effective and not misbranded............         223
331             Antacid products for over-the-counter (OTC) 
                    human use...............................         243
332             Antiflatulent products for over-the-counter 
                    human use...............................         246
333             Topical antimicrobial drug products for 
                    over-the-counter human use..............         247
335             Antidiarrheal drug products for over-the-
                    counter human use.......................         255
336             Antiemetic drug products for over-the-
                    counter human use.......................         257
338             Nighttime sleep-aid drug products for over-
                    the-counter human use...................         259

[[Page 4]]

340             Stimulant drug products for over-the-counter 
                    human use...............................         260
341             Cold, cough, allergy, bronchodilator, and 
                    antiasthmatic drug products for over-
                    the-counter human use...................         261
343             Internal analgesic, antipyretic, and 
                    antirheumatic drug products for over-
                    the-counter human use...................         285
344             Topical otic drug products for over-the-
                    counter human use.......................         292
346             Anorectal drug products for over-the-counter 
                    human use...............................         294
347             Skin protectant drug products for over-the-
                    counter human use.......................         299
348             External analgesic drug products for over-
                    the-counter human use...................         307
349             Ophthalmic drug products for over-the-
                    counter human use.......................         308
350             Antiperspirant drug products for over-the-
                    counter human use.......................         314
352             Sunscreen drug products for over-the-counter 
                    human use [stayed indefinitely].........         316
355             Anticaries drug products for over-the-
                    counter human use.......................         326
357             Miscellaneous internal drug products for 
                    over-the-counter human use..............         331
358             Miscellaneous external drug products for 
                    over-the-counter human use..............         335
361             Prescription drugs for human use generally 
                    recognized as safe and effective and not 
                    misbranded: Drugs used in research......         344
369             Interpretative statements re warnings on 
                    drugs and devices for over-the-counter 
                    sale....................................         349
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.
310.306 Notification of a permanent discontinuance or an interruption in 
          manufacturing of 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, 356c, 356e, 360b-
360f, 360j, 361(a), 371, 374, 375, 379e, 379k-1; 42 U.S.C. 216, 241, 
242(a), 262, 263b-263n.

    Effective Date Note: At 81 FR 61129, Sept. 6, 2016, the authority 
citation for Part 310 was revised, effective Sept. 6, 2017. For the 
convenience of the user, the revised text is set forth as follows:
    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 360j, 
360hh-360ss, 361(a), 371, 374, 375, 379e, 379k-l; 42 U.S.C. 216, 241, 
242(a), 262.



                      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.

[[Page 7]]

    (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.
    (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]

[[Page 8]]



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 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

[[Page 9]]

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. 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.

[[Page 10]]

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]



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

[[Page 11]]

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.
    (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.

[[Page 12]]

    (v) The preparation is labeled with adequate directions for use in 
minor conditions as a simple analgesic.
    (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

[[Page 13]]

3 days, except as directed by a physician.
    (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

[[Page 14]]

week, except as directed by a physician.
    (13)-(15) [Reserved]
    (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.

[[Page 15]]

    (iv) The preparation contains not more than 1.0 percent of pramoxine 
hydrochloride.
    (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.

[[Page 16]]

    (iv) The preparation contains not more than 1.0 percent of dyclonine 
hydrochloride.
    (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.

[[Page 17]]

    (vii) 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) 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

[[Page 18]]

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 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 must 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.
    Individual case safety report (ICSR). A description of an adverse 
drug experience related to an individual patient or subject.
    ICSR attachments. Documents related to the adverse drug experience 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    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

[[Page 19]]

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.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1)(i) of this section must submit to FDA adverse drug experience 
information as described in this section. Except as provided in 
paragraph (e)(2) of this section, 15-day ``Alert reports'' and followup 
reports, including ICSRs and any ICSR attachments, must be submitted to 
the Agency in electronic format as described in paragraph (e)(1) of this 
section.
    (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 must report to FDA each adverse 
drug experience received or otherwise obtained that is both serious and 
unexpected as soon as possible, but no later than 15 calendar days from 
initial receipt of the information by the person whose name appears on 
the label. Each report must be accompanied by the current content of 
labeling in electronic format as an ICSR attachment unless it is already 
on file at FDA.
    (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 must promptly 
investigate all serious, unexpected adverse drug experiences that are 
the subject of these postmarketing 15-day Alert reports and must 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.
    (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 must 
submit, by any appropriate means, each report to the manufacturer within 
5 calendar days of its receipt by the packer or distributor, and the 
manufacturer must 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 must maintain a record of this 
action which must include:
    (i) A copy of each adverse drug experience report;
    (ii) The date the report was received by the packer or distributor;

[[Page 20]]

    (iii) The date the report was submitted to the manufacturer; and
    (iv) The name and address of the manufacturer.
    (4) [Reserved]
    (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 by FDA; however, the person must submit all 
followup information on such reports to FDA.
    (d) Information reported on ICSRs. ICSRs include the following 
information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse drug experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse drug experience.
    (i) Outcome attributed to adverse drug experience;
    (ii) Date of adverse drug experience;
    (iii) Date of ICSR submission;
    (iv) Description of adverse drug experience (including a concise 
medical narrative);
    (v) Adverse drug experience term(s);
    (vi) Description of relevant tests, including dates and laboratory 
data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a combination product as defined in Sec.  
3.2(e) of this chapter;
    (vi) Whether the product is a prescription or nonprescription 
product;
    (vii) Whether adverse drug experience abated after drug use stopped 
or dose reduced;
    (viii) Whether adverse drug experience reappeared after 
reintroduction of drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional; and
    (iii) Occupation, if a health care professional.
    (5) Manufacturer, packer, or distributor information.
    (i) Manufacturer, packer, or distributor name and contact office 
address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date the report was received by manufacturer, packer, or 
distributor;
    (v) Whether the ICSR is a 15-day ``Alert report'';
    (vi) Whether the ICSR is an initial report or followup report; and
    (vii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (e) Electronic format for submissions. (1) Each report required to 
be submitted to FDA under this section, including the ICSR and any ICSR 
attachments, must be submitted in an electronic format that FDA can 
process, review, and archive. FDA will issue guidance on how to provide 
the electronic submission (e.g., method of transmission, media, file 
formats, preparation and organization of files).
    (2) Each person identified in paragraph (c)(1)(i) of this section 
may request, in writing, a temporary waiver of the requirements in 
paragraph (e)(1) of this section. These waivers will be granted on a 
limited basis for good cause shown. FDA will issue guidance on 
requesting a waiver of the requirements in paragraph (e)(1) of this 
section.
    (f) 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 for identification of the patient. The 
manufacturer, packer, and distributor should include the name of the 
reporter from whom the information was received as part of the initial 
reporter information, even when the reporter is the patient. The names 
of patients, individual reporters, health

[[Page 21]]

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.
    (g) Recordkeeping. (1) Each manufacturer, packer, and distributor 
must 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)(3) 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 must 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.
    (h) 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; 79 FR 33087, June 10, 2014]



Sec.  310.306  Notification of a permanent discontinuance or an 
interruption in manufacturing of marketed prescription drugs for human
use without approved new drug applications.

    (a) Applicability. Marketed prescription drug products that are not 
the subject of an approved new drug or abbreviated new drug application 
are subject to this section.
    (b) Notification of a permanent discontinuance or an interruption in 
manufacturing. The manufacturer of each product subject to this section 
must make the notifications required under Sec.  314.81(b)(3)(iii) of 
this chapter and otherwise comply with Sec.  314.81(b)(3)(iii) of this 
chapter. If the manufacturer of a product subject to this section fails 
to provide notification as required under Sec.  314.81(b)(3)(iii), FDA 
will send a letter to the manufacturer and otherwise follow the 
procedures set forth under Sec.  314.81(b)(3)(iii)(e).
    (c) Drug shortages list. FDA will include on the drug shortages list 
required by Sec.  314.81(b)(3)(iii)(d) drug products that are subject to 
this section that it determines to be in shortage. For such drug 
products, FDA will provide the names of each manufacturer rather than 
the names of each applicant. With respect to information collected under 
this paragraph, FDA will observe the confidentiality and disclosure 
provisions set forth in Sec.  314.81(b)(3)(iii)(d)(2).

[80 FR 38938, July 8, 2015]



        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 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.

[[Page 22]]

    (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 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

[[Page 23]]

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.
 Do...................  ......do...............  Placenta localization.
 Do...................  ......do...............  Red blood cell labeling
                                                  and survival studies.

[[Page 24]]

 
 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 25]]

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 Food and Drug Administration, Center for Biologics Evaluation and 
Research, Document Control Center, 10903 New Hampshire Ave., Bldg. 71, 
Rm. G112, Silver Spring, MD 20993-0002, 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,

[[Page 26]]

for which drug a new drug application 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; 80 FR 18091, Apr. 3, 2015]



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.

[[Page 27]]

    (d) This section does not apply to a biological product licensed 
under the 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 28]]



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 29]]

    (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 30]]

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 31]]

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 32]]



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 33]]

    (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 34]]

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 35]]

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 36]]

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 37]]

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 38]]

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 39]]

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 40]]

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 41]]

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 42]]

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 43]]


    (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 44]]

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 45]]

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 46]]


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 47]]


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. (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.

    (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),

[[Page 48]]

(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 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)(i) 
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.

[[Page 49]]

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

[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 Notes: 1. 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.
    2. At 81 FR 61129, Sept. 6, 2016, Sec.  310.545 was amended by 
adding paragraphs (a)(27)(iii) and (iv) and (d)(41), and removing from 
paragraph (d) introductory text the number ``(39)'' and adding in its 
place the number ``(41)'', effective Sept. 6, 2017. For the convenience 
of the user, the added text is set forth as follows:



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

    (a) * * *
    (27) * * *
    (iii) Consumer antiseptic hand wash drug products. Approved as of 
September 6, 2017.

Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (ammonium ether sulfate and polyoxyethylene sorbitan 
monolaurate)
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol (greater than 1.5 percent)
Phenol (less than 1.5 percent)
Poloxamer iodine complex
Povidone-iodine (5 to 10 percent)
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple Dye
Undecoylium chloride iodine complex

    (iv) Consumer antiseptic body wash drug products. Approved as of 
September 6, 2017.

Cloflucarban
Fluorosalan
Hexachlorophene
Hexylresorcinol
Iodine complex (phosphate ester of alkylaryloxy polyethylene glycol)
Iodine tincture
Methylbenzethonium chloride
Nonylphenoxypoly (ethyleneoxy) ethanoliodine
Phenol (greater than 1.5 percent)
Phenol (less than 1.5 percent)
Poloxamer iodine complex
Povidone-iodine (5 to 10 percent)
Secondary amyltricresols
Sodium oxychlorosene
Tribromsalan
Triclocarban
Triclosan
Triple Dye
Undecoylium chloride iodine complex

                                * * * * *

    (d) * * *
    (41) September 6, 2017, for products subject to paragraph 
(a)(27)(iii) or (iv) of this section.



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

[[Page 50]]

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.
    (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]

[[Page 51]]



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.
    (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.

[[Page 52]]

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]

  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 appear 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

[[Page 53]]

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.
    (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.

[[Page 54]]

    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.
    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]

[[Page 55]]



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;
    (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

[[Page 56]]

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 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

[[Page 57]]

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 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

[[Page 58]]

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 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)

[[Page 59]]

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.
    (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.

[[Page 60]]

    (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 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.

[[Page 61]]

    (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 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.

[[Page 62]]

    (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 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.

[[Page 63]]

    (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 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.

[[Page 64]]

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]



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

[[Page 65]]

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 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.

[[Page 66]]

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 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

[[Page 67]]

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 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.

[[Page 68]]

    (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
    (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;

[[Page 69]]

    (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.
    (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

[[Page 70]]

    (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 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

[[Page 71]]

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.
    (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

[[Page 72]]

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 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

[[Page 73]]

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 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

[[Page 74]]

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 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 responsible for selecting qualified investigators, 
providing them

[[Page 75]]

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 
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

[[Page 76]]

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 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

[[Page 77]]

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.
    (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

[[Page 78]]

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.



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,

[[Page 79]]

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 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,

[[Page 80]]

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 repeatedly or deliberately 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 and accepted by the applicable 
Center, the Center will discontinue the disqualification proceeding. If 
an explanation is offered but not accepted by the applicable Center, the 
investigator will be given an opportunity for a regulatory hearing under 
part 16 of this chapter on the question of whether the investigator is 
eligible to receive test articles under this part and eligible to 
conduct any clinical investigation that supports an application for a 
research or marketing permit for products regulated by FDA.
    (b) After evaluating all available information, including any 
explanation presented by the investigator, if the 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 repeatedly or deliberately submitted to FDA or to the 
sponsor false information in any required report, the Commissioner will 
notify the investigator, the sponsor of any investigation in which the 
investigator has been named as a participant, and the reviewing 
institutional review boards (IRBs) that the investigator is not eligible 
to receive test articles under this part. The notification to the 
investigator, sponsor, and IRBs will provide a statement of the basis 
for such determination. The notification also will explain that an 
investigator determined to be ineligible to receive test articles under 
this part will be ineligible to conduct any clinical investigation that 
supports an application for a research or marketing permit for products 
regulated by FDA, including drugs, biologics, devices, new animal drugs, 
foods, including dietary supplements, that bear a nutrient content claim 
or a health claim, infant formulas, food and color additives, and 
tobacco products.
    (c) Each application or submission to FDA under the provisions of 
this chapter containing data reported by an investigator who has been 
determined to be ineligible to receive FDA-regulated test articles is 
subject to examination to determine whether the investigator has 
submitted unreliable data that are essential to the continuation of an 
investigation or essential to the approval of a marketing application, 
or essential to the continued marketing of an FDA-regulated product.
    (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 of this chapter. If a danger to the public health 
exists, however, the Commissioner shall terminate the IND immediately 
and notify the sponsor and the reviewing IRBs of the termination. 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. The determination that an investigation may not be 
considered in support of a research or marketing application or a 
notification or petition submission does not, however, relieve the 
sponsor of any obligation under any other applicable regulation to 
submit to FDA the results of the investigation.
    (e) If the Commissioner determines, after the unreliable data 
submitted by the investigator are eliminated from

[[Page 81]]

consideration, that the continued approval of the product for which the 
data were submitted cannot be justified, the Commissioner will proceed 
to withdraw approval of the product in accordance with the applicable 
provisions of the relevant statutes.
    (f) An investigator who has been determined to be ineligible under 
paragraph (b) of this section may be reinstated as eligible when the 
Commissioner determines that the investigator has presented adequate 
assurances that the investigator will employ all test articles, and will 
conduct any clinical investigation that supports an application for a 
research or marketing permit for products regulated by FDA, solely in 
compliance with the applicable provisions of this chapter.

[77 FR 25359, Apr. 30, 2012]



    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.



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

[[Page 82]]

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 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

[[Page 83]]

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 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

[[Page 84]]

(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;
    (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: [email protected]
    (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),

[[Page 85]]

(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: [email protected]
    (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 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

[[Page 86]]

    (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;
    (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:

[[Page 87]]

    (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 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 Central Document Room, Center for Drug Evaluation and 
Research, Food and Drug Administration, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266.
    (3) For biological products regulated by CBER. Send the IND 
submission to the Food and Drug Administration, Center for Biologics 
Evaluation and Research, Document Control Center, 10903 New Hampshire 
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002.
    (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

[[Page 88]]

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; 80 FR 18091, 
Apr. 3, 2015; 81 FR 17066, Mar. 28, 2016]



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 Food and Drug 
Administration, Center for Biologics Evaluation and Research, Office of 
Communication, Outreach and Development, 10903 New Hampshire Ave., Bldg. 
71, Rm. 3103, Silver Spring, MD 20993-0002.

[65 FR 56479, Sept. 19, 2000, as amended at 74 FR 13113, Mar. 26, 2009; 
80 FR 18091, Apr. 3, 2015]



 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 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

[[Page 89]]

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.



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

[[Page 90]]

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 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.

[[Page 91]]

    (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 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, 240-402-8010 or 1-800-835-4709, e-mail: 
[email protected] 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: 
[email protected] 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: [email protected]
    (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

[[Page 92]]

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; 80 
FR 18091, Apr. 3, 2015]



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 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.

[[Page 93]]

    (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.



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 NDA.
314.52 Notice of certification of invalidity, unenforceability, or 
          noninfringement of a patent.
314.53 Submission of patent information.
314.54 Procedure for submission of a 505(b)(2) 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 NDA.
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

314.92 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 ANDA.
314.95 Notice of certification of invalidity, unenforceability, or 
          noninfringement of a patent.
314.96 Amendments to an unapproved ANDA.
314.97 Supplements and other changes to an approved ANDA.
314.98 Postmarketing reports.
314.99 Other responsibilities of an applicant of an ANDA.

    Subpart D_FDA Action on Applications and Abbreviated Applications

314.100 Timeframes for reviewing applications and abbreviated 
          applications.
314.101 Filing an NDA and receiving an ANDA.

[[Page 94]]

314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an NDA and an ANDA.
314.106 Foreign data.
314.107 Date of approval of a 505(b)(2) application or ANDA.
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 NDA.
314.126 Adequate and well-controlled studies.
314.127 Refusal to approve an ANDA.
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.
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, 355a, 355f, 356, 
356a, 356b, 356c, 356e, 360cc, 371, 374, 379e, 379k-1.

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

    Editorial Note: Nomenclature changes to part 314 appear at 69 FR 
13717, Mar. 24, 2004; 81 FR 69639, Oct. 6, 2016.



                      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.

[[Page 95]]

    (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 Federal Food, Drug, and Cosmetic Act apply to those terms when used 
in this part and part 320 of this chapter.
    (b) The following definitions of terms apply to this part and part 
320 of this chapter:
    180-day exclusivity period is the 180-day period beginning on the 
date of the first commercial marketing of the drug (including the 
commercial marketing of the reference listed drug) by any first 
applicant. The 180-day period ends on the day before the date on which 
an ANDA submitted by an applicant other than a first applicant could be 
approved.
    505(b)(2) application is an NDA submitted under section 505(b)(1) of 
the Federal Food, Drug, and Cosmetic Act for a drug for which at least 
some of the investigations described in section 505(b)(1)(A) of the 
Federal Food, Drug, and Cosmetic Act and relied upon by the applicant 
for approval of the NDA 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.
    Abbreviated application, abbreviated new drug application, or ANDA 
is the application described under Sec.  314.94, including all 
amendments and supplements to the application.
    Acknowledgment letter is a written, postmarked communication from 
FDA to an applicant stating that the Agency has determined that an ANDA 
is sufficiently complete to permit a substantive review. An 
acknowledgment letter indicates that the ANDA is regarded as received.
    Act is the Federal Food, Drug, and Cosmetic Act (section 201 et seq. 
(21 U.S.C. 301 et seq.)).
    Active ingredient is any component 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 body of man or other animals. The term 
includes those components that may undergo chemical change in the 
manufacture of the drug product and be present in the drug product in a 
modified form intended to furnish the specified activity or effect.
    Active moiety is 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.
    ANDA holder is the applicant that owns an approved ANDA.
    Applicant is any person who submits an NDA (including a 505(b)(2) 
application) or ANDA or an amendment or supplement to an NDA or ANDA 
under this part to obtain FDA approval of a new drug and any person who 
owns an approved NDA (including a 505(b)(2) application) or ANDA.
    Application, new drug application, or NDA is the application 
described under Sec.  314.50, including all amendments and supplements 
to the application. An NDA refers to ``stand-alone'' applications 
submitted under section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act and to 505(b)(2) applications.
    Approval letter is a written communication to an applicant from FDA 
approving an NDA or an ANDA.
    Assess the effects of the change is 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

[[Page 96]]

safety or effectiveness of the drug product.
    Authorized generic drug is a listed drug, as defined in this 
section, that has been approved under section 505(c) of the Federal 
Food, Drug, and Cosmetic Act and is marketed, sold, or distributed 
directly or indirectly to the 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.
    Bioavailability is 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 drug action. For drug products that are not 
intended to be absorbed into the bloodstream, bioavailability may be 
assessed by scientifically valid measurements intended to reflect the 
rate and extent to which the active ingredient or active moiety becomes 
available at the site of drug action.
    Bioequivalence is 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. For drug products that 
are not intended to be absorbed into the bloodstream, bioequivalence may 
be assessed by scientifically valid measurements intended to reflect the 
rate and extent to which the active ingredient or active moiety becomes 
available at the site of drug action.
    Bioequivalence requirement is a requirement imposed by FDA for in 
vitro and/or in vivo testing of specified drug products that must be 
satisfied as a condition of marketing.
    Class 1 resubmission is the resubmission of an NDA 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 is the resubmission of an NDA 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.
    Commercial marketing is the introduction or delivery for 
introduction into interstate commerce of a drug product described in an 
ANDA, outside the control of the ANDA applicant, except that the term 
does not include transfer of the drug product for investigational use 
under part 312 of this chapter or transfer of the drug product to 
parties identified in the ANDA for reasons other than sale. Commercial 
marketing includes the introduction or delivery for introduction into 
interstate commerce of the reference listed drug by the ANDA applicant.
    Complete response letter is a written communication to an applicant 
from FDA usually describing all of the deficiencies that the Agency has 
identified in an NDA or ANDA that must be satisfactorily addressed 
before it can be approved.
    Component is any ingredient intended for use in the manufacture of a 
drug product, including those that may not appear in such drug product.

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    Date of approval is the date on the approval letter from FDA stating 
that the NDA or ANDA is approved, except that the date of approval for 
an NDA described in section 505(x)(1) of the Federal Food, Drug, and 
Cosmetic Act is determined as described in section 505(x)(2) of the 
Federal Food, Drug, and Cosmetic Act. ``Date of approval'' refers only 
to a final approval and not to a tentative approval.
    Dosage form is the physical manifestation containing the active and 
inactive ingredients that delivers a dose of the drug product. This 
includes such factors as:
    (1) The physical appearance of the drug product;
    (2) The physical form of the drug product prior to dispensing to the 
patient;
    (3) The way the product is administered; and
    (4) The design features that affect frequency of dosing.
    Drug product is a finished dosage form, e.g., tablet, capsule, or 
solution, that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients.
    Drug substance is 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 used in the synthesis of such ingredient.
    Efficacy supplement is a supplement to an approved NDA 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 this part; or
    (8) Incorporate other information based on at least one adequate and 
well-controlled clinical study.
    FDA or Agency is the Food and Drug Administration.
    First applicant is an ANDA applicant that, on the first day on which 
a substantially complete application containing a paragraph IV 
certification is submitted for approval of a drug, submits a 
substantially complete application that contains, and for which the 
applicant lawfully maintains, a paragraph IV certification for the drug.
    Inactive ingredient is any component other than an active 
ingredient.
    Listed drug is a new drug product that has been approved under 
section 505(c) of the Federal Food, Drug, and Cosmetic Act for safety 
and effectiveness or under section 505(j) of the Federal Food, Drug, and 
Cosmetic Act, which has not been withdrawn or suspended under section 
505(e)(1) through (5) or section 505(j)(6) of the Federal Food, Drug, 
and Cosmetic 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 in the current 
edition of FDA's ``Approved Drug Products With Therapeutic Equivalence 
Evaluations'' (the list) as an approved drug. A drug product is deemed 
to be a listed drug on the date of approval for the NDA or ANDA for that 
drug product.
    NDA holder is the applicant that owns an approved NDA.
    Newly acquired information is data, analyses, or other information 
not previously submitted to the Agency, which may include (but is 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 or original NDA is a pending NDA for which FDA 
has never issued a complete response letter or approval letter, or an 
NDA that was submitted again after FDA had refused

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to file it or after it was withdrawn without being approved.
    Paragraph IV acknowledgment letter is a written, postmarked 
communication from FDA to an applicant stating that the Agency has 
determined that a 505(b)(2) application or ANDA containing a paragraph 
IV certification is sufficiently complete to permit a substantive 
review. A paragraph IV acknowledgment letter indicates that the 
505(b)(2) application is regarded as filed or the ANDA is regarded as 
received.
    Paragraph IV certification is a patent certification of invalidity, 
unenforceability, or noninfringement described in Sec.  
314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4).
    Patent owner is the owner of the patent for which information is 
submitted for an NDA.
    Pharmaceutical alternatives are 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.
    Pharmaceutical equivalents are drug products in identical dosage 
forms and route(s) of administration 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.
    Postmark is an independently verifiable evidentiary record of the 
date on which a document is transmitted, in an unmodifiable format, to 
another party. For postmarks made by the U.S. Postal Service or a 
designated delivery service, the date of transmission is the date on 
which the document is received by the domestic mail service of the U.S. 
Postal Service or by a designated delivery service. For postmarks 
documenting an electronic event, the date of transmission is the date 
(in a particular time zone) that FDA sends the electronic transmission 
on its host system as evidenced by a verifiable record. If the sender 
and the intended recipient are located in different time zones, it is 
the sender's time zone that provides the controlling date of electronic 
transmission.
    Reference listed drug is the listed drug identified by FDA as the 
drug product upon which an applicant relies in seeking approval of its 
ANDA.
    Reference standard is the drug product selected by FDA that an 
applicant seeking approval of an ANDA must use in conducting an in vivo 
bioequivalence study required for approval.
    Resubmission, in the context of a complete response letter, is 
submission by the applicant of all materials needed to fully address all 
deficiencies identified in the complete response letter. An NDA or ANDA 
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 is the authority to rely upon, and 
otherwise use, an investigation for the purpose of obtaining approval of 
an NDA, including the ability to make available the underlying raw data 
from the investigation for FDA audit, if necessary.
    Same drug product formulation is 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.
    Specification is the quality standard (i.e., tests, analytical 
procedures, and acceptance criteria) provided in an approved NDA or ANDA 
to confirm the quality of drug substances, drug products, intermediates, 
raw materials, reagents, components, in-process materials, container 
closure systems, and

[[Page 99]]

other materials used in the production of a drug substance or drug 
product. For the purpose of this definition, acceptance criteria means 
numerical limits, ranges, or other criteria for the tests described.
    Strength is the amount of drug substance contained in, delivered, or 
deliverable from a drug product, which includes:
    (1)(i) The total quantity of drug substance in mass or units of 
activity in a dosage unit or container closure (e.g., weight/unit dose, 
weight/volume or weight/weight in a container closure, or units/volume 
or units/weight in a container closure); and/or, as applicable.
    (ii) The concentration of the drug substance in mass or units of 
activity per unit volume or mass (e.g., weight/weight, weight/volume, or 
units/volume); or
    (2) Such other criteria the Agency establishes for determining the 
amount of drug substance contained in, delivered, or deliverable from a 
drug product if the weights and measures described in paragraph (i) of 
this definition do not apply (e.g., certain drug-device combination 
products for which the amount of drug substance is emitted per use or 
unit time).
    Substantially complete application is an ANDA that on its face is 
sufficiently complete to permit a substantive review. Sufficiently 
complete means that the ANDA contains all the information required under 
section 505(j)(2)(A) of the Federal Food, Drug, and Cosmetic Act and 
does not contain a deficiency described in Sec.  314.101(d) and (e).
    Tentative approval is notification that an NDA or ANDA otherwise 
meets the requirements for approval under the Federal Food, Drug, and 
Cosmetic Act, but cannot be approved because there is a 7-year period of 
orphan exclusivity for a listed drug under section 527 of the Federal 
Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter, or that a 
505(b)(2) application or ANDA otherwise meets the requirements for 
approval under the Federal Food, Drug, and Cosmetic Act, but cannot be 
approved until the conditions in Sec.  314.107(b)(1)(iii), (b)(3), or 
(c) are met; because there is a period of exclusivity for the listed 
drug under Sec.  314.108; because there is a period of pediatric 
exclusivity for the listed drug under section 505A of the Federal Food, 
Drug, and Cosmetic Act; because there is a period of exclusivity for the 
listed drug under section 505E of the Federal Food, Drug, and Cosmetic 
Act; or because a court order pursuant to 35 U.S.C. 271(e)(4)(A) orders 
that the NDA or ANDA may be approved no earlier than the date specified. 
A drug product that is granted tentative approval is not an approved 
drug and will not be approved until FDA issues an approval letter after 
any necessary additional review of the NDA or ANDA.
    The list is the list of approved drug products published in FDA's 
current ``Approved Drug Products With Therapeutic Equivalence 
Evaluations,'' available electronically on FDA's Web site at http://
www.fda.gov/cder.
    Therapeutic equivalents are approved drug products that are 
pharmaceutical equivalents for which bioequivalence has been 
demonstrated, and that can be expected to have the same clinical effect 
and safety profile when administered to patients under the conditions 
specified in the labeling.

[81 FR 69636, Oct. 6, 2016]



                         Subpart B_Applications



Sec.  314.50  Content and format of an NDA.

    NDAs and supplements to approved NDAs 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 
NDA are required: An archival copy, a review copy, and a field copy. An 
NDA 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 NDAs will generally contain only some of 
those items, and information will be limited to that needed to support 
the particular submission. These include an NDA of the type described in 
section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, an 
amendment, and a supplement.

[[Page 100]]

The NDA 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 NDA that is received or otherwise 
obtained by the applicant from any source. FDA will maintain guidance 
documents on the format and content of NDAs to assist applicants in 
their preparation.
    (a) Application form. The applicant must submit a completed and 
signed application form that contains the following:
    (1) The name and address of the applicant; the date of the NDA; the 
NDA number if previously issued (for example, if the NDA is a 
resubmission or an amendment or 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 numbers of all INDs (as defined in Sec.  312.3(b) of this 
chapter) that are referenced in the NDA; the identification numbers of 
all drug master files and other applications under this part that are 
referenced in the NDA; 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 must sign the NDA. If the person signing the NDA 
does not reside or have a place of business within the United States, 
the NDA 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 NDA 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 NDA is required to contain a summary of the NDA 
in enough detail that the reader may gain a good general understanding 
of the data and information in the NDA, including an understanding of 
the quantitative aspects of the data. The summary is not required for 
supplements under Sec.  314.70. Resubmissions of an NDA should contain 
an updated summary, as appropriate. The summary should discuss all 
aspects of the NDA, 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 NDA, FDA may furnish the 
summary to FDA advisory committee members and agency officials whose 
duties require an understanding of the NDA. 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 NDA 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 NDA that support the inclusion of each statement in the 
labeling, and, if the NDA 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

[[Page 101]]

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 NDA.
    (v) A summary of the nonclinical pharmacology and toxicology section 
of the NDA.
    (vi) A summary of the human pharmacokinetics and bioavailability 
section of the NDA.
    (vii) A summary of the microbiology section of the NDA (for anti-
infective drugs only).
    (viii) A summary of the clinical data section of the NDA, 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 NDA 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 NDA or whether 
grounds exist under section 505(d) of the Federal Food, Drug, and 
Cosmetic Act to refuse to approve the NDA. 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 NDA 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 
NDA 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

[[Page 102]]

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.
    (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 NDA 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 NDA. FDA will review such 
early submissions as resources permit.
    (v) The applicant must include a statement certifying that the field 
copy of the NDA 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 NDA 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

[[Page 103]]

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.
    (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 NDA, 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 must be presented by gender, age, 
and racial subgroups and must 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 must be presented.
    (vi) A summary and updates of safety information, as follows:
    (a) The applicant must 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 must be presented by gender, age, and racial 
subgroups. When appropriate, safety data from other subgroups of the 
population of patients treated also must 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 must, under section 505(i) of the Federal Food, 
Drug, and Cosmetic Act, update periodically its pending NDA 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

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this chapter. These ``safety update reports'' must include the same 
kinds of information (from clinical studies, animal studies, and other 
sources) and must be submitted in the same format as the integrated 
summary in paragraph (d)(5)(vi)(a) of this section. In addition, the 
reports must 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 must 
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. Before submitting the first such 
report, applicants 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 
must submit the samples described below to the places identified in the 
Agency's request. FDA generally will 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 NDA to determine whether the drug substance and the 
drug product meet the specifications given in the NDA:

[[Page 105]]

    (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 must submit the following in the archival copy of 
the NDA:
    (i) Three copies of the analytical procedures and related 
descriptive information contained in the chemistry, 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 NDA 
is required to contain the following case report tabulations and case 
report forms:
    (1) Case report tabulations. The NDA 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 NDA. 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 NDA, in accordance with 
paragraph (f)(3) of this section.
    (2) Case report forms. The NDA 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 must submit to FDA additional 
case report forms and tabulations needed to conduct a proper review of 
the NDA, as requested by the director of the FDA division responsible 
for reviewing the NDA. 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) Presentation and format. Applicants are invited to meet with FDA 
before submitting an NDA 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 an 
alternate form.
    (g) Other. The following general requirements apply to the 
submission of information within the summary under paragraph (c) of this 
section and within

[[Page 106]]

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 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 must submit an accurate and complete English 
translation of each part of the NDA that is not in English. The 
applicant must submit a copy of each original literature publication for 
which an English translation is submitted.
    (3) If an applicant who submits an NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic 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 Federal Food, Drug, and Cosmetic 
Act, the applicant must include in its NDA 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 NDA, and provide FDA 
access to, the underlying raw data that provide the basis for the report 
of the investigation submitted in its NDA.
    (h) Patent information. The NDA 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 substance, drug product, or method of use. 
(A) An appropriate patent certification or statement with respect to 
each patent issued by the U.S. Patent and Trademark Office that, in the 
opinion of the applicant and to the best of its knowledge, claims the 
drug substance or drug product on which investigations that are relied 
upon by the applicant for approval of its 505(b)(2) 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 
Federal Food, Drug, and Cosmetic Act and Sec.  314.53. For each such 
patent, the applicant must 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 must entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant must entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant must 
entitle such a certification ``Paragraph III Certification''; or
    (4)(i) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the 505(b)(2) application is submitted. The applicant must entitle such 
a certification ``Paragraph IV Certification''. This certification must 
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 
505(b)(2) application is submitted.

    (ii) The certification must 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 its 
representative and to the NDA holder (or, if the NDA holder does not 
reside or maintain a place of business within the United States, its 
attorney, agent, or other authorized official) for the drug product that 
is claimed by the patent or a use of which is claimed by the patent and 
with the requirements under Sec.  314.52(b) with respect to sending the 
notice and 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 Federal Food, Drug, and 
Cosmetic Act, an appropriate patent certification or

[[Page 107]]

statement 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.
    (C) If, before the date of submission of an original 505(b)(2) 
application, there is a drug product approved in an NDA that is 
pharmaceutically equivalent to the drug product for which the original 
505(b)(2) application is submitted, an appropriate patent certification 
or statement under this section with respect to each patent that claims 
the drug substance or drug product or that claims an approved use for 
one such drug product.
    (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 505(b)(2) 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 Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 is for a method-of-use patent, and the labeling for the 
drug product for which the applicant is seeking approval does not 
include an indication or other condition of use that is covered by the 
method-of-use patent, a statement explaining that the method-of-use 
patent does not claim a proposed indication or other condition of use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a method-of-use patent, the 
applicant must submit an applicable certification under paragraph 
(i)(1)(i) of this section.
    (2) [Reserved]
    (3) Licensing agreements. If a 505(b)(2) application is submitted 
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 
must submit a paragraph IV certification as to that patent and a 
statement that the applicant has been granted a patent license. If the 
patent owner consents to approval of the 505(b)(2) application (if 
otherwise eligible for approval) as of a specific date, the 505(b)(2) 
application must contain a written statement from the patent owner that 
it has a licensing agreement with the applicant and that it consents to 
approval of the 505(b)(2) application as of a specific date.
    (4) Untimely filing of patent information. (i) If a patent described 
in paragraph (i)(1)(i)(A) of this section is issued and the holder of 
the approved NDA for the patented drug does not file with FDA 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 or statement is not required to submit a patent 
certification or statement to address the patent or patent information 
that is late-listed with respect to the pending 505(b)(2) application. 
Except as provided in Sec.  314.53(f)(1), an NDA holder's amendment to 
the description of the approved method(s) of use claimed by the patent 
will be considered untimely filing of patent information unless:
    (A) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of patent 
issuance;
    (B) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of approval of a 
corresponding change to product labeling; or
    (C) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of a decision by 
the U.S. Patent and Trademark Office or by a Federal district court, the 
Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that 
is specific to the patent and alters the construction of a method-of-use 
claim(s) of the patent, and the amendment contains a copy of the 
decision.
    (ii) An applicant whose 505(b)(2) application is submitted after the 
NDA

[[Page 108]]

holder's untimely filing of patent information or whose 505(b)(2) 
application was previously filed but did not contain an appropriate 
patent certification or statement at the time of the patent submission 
must submit a certification under paragraph (i)(1)(i) of this section 
and/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, the applicant must submit an 
appropriate certification or statement for each listed patent.
    (6) Amended certifications. A patent certification or statement 
submitted under paragraphs (i)(1)(i) through (iii) of this section may 
be amended at any time before the approval of the 505(b)(2) application. 
An applicant must submit an amended certification as an amendment to a 
pending 505(b)(2) application. If an applicant with a pending 505(b)(2) 
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 is submitted to change the 
certification, the 505(b)(2) application will no longer be considered to 
contain the prior certification.
    (i) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
and enters a settlement order or consent decree in the action that 
includes a finding that the patent is infringed, unless the final 
decision, settlement order, or consent decree also finds the patent to 
be invalid. In its amendment, the applicant must certify under paragraph 
(i)(1)(i)(A)(3) of this section that the patent will expire on a 
specific date or, with respect to a patent claiming a method of use, the 
applicant may instead provide a statement under paragraph (i)(1)(iii) of 
this section if the applicant amends its 505(b)(2) application such that 
the applicant is no longer seeking approval for a method of use claimed 
by the patent. Once an amendment for the change has been submitted, the 
505(b)(2) application will no longer be considered to contain a 
paragraph IV certification to the patent. If a final decision finds the 
patent to be invalid and infringed, an amended certification is not 
required.
    (ii) After request to remove a patent or patent information from the 
list. If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and no ANDA 
applicant is eligible for 180-day exclusivity based on a paragraph IV 
certification to that patent, the patent or patent information will be 
removed and any applicant with a pending 505(b)(2) application 
(including a tentatively approved 505(b)(2) application) who has made a 
certification with respect to such patent must submit an amendment to 
withdraw its certification. In the amendment, the applicant must state 
the reason for withdrawing the certification or statement (that the 
patent has been removed from the list). If the list reflects that an NDA 
holder has requested that a patent or patent information be removed from 
the list and one or more first applicants are eligible for 180-day 
exclusivity based on a paragraph IV certification to that patent, the 
patent will remain listed until any 180-day exclusivity based on that 
patent has expired or has been extinguished. A 505(b)(2) applicant is 
not required to provide or maintain a certification to a patent or 
patent information that remains listed only for purposes of a first 
applicant's 180-day exclusivity for its ANDA. Once an amendment to 
withdraw the certification has been submitted, the 505(b)(2) application 
will no longer be considered to contain a paragraph IV certification to 
the patent. If removal of a patent from the list results in there being 
no patents listed for the listed drug(s) identified in the 505(b)(2) 
application, the applicant must submit an amended certification 
reflecting that there are no listed patents.

[[Page 109]]

    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4) 
and (i)(6)(iii)(B) of this section:
    (1) An applicant must amend a submitted certification or statement 
if, at any time before the approval of the 505(b)(2) application, the 
applicant learns that the submitted certification or statement is no 
longer accurate; and
    (2) An applicant must submit an appropriate patent certification or 
statement under paragraph (i)(1) of this section if, after submission of 
the 505(b)(2) application, a new patent is issued by the U.S. Patent and 
Trademark Office that, in the opinion of the applicant and to the best 
of its knowledge, claims a listed drug relied upon or that claims an 
approved use for such listed drug for which information is required to 
be filed under section 505(b) and (c) of the Federal Food, Drug, and 
Cosmetic Act and Sec.  314.53.
    (B) An applicant is not required to submit a supplement to change a 
submitted certification when information on an otherwise applicable 
patent is submitted after the approval of 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 must submit with the NDA 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 Federal 
Food, Drug, and Cosmetic 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 NDA contains ``new 
clinical investigations'' that are ``essential to approval of the NDA 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 NDA 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 NDA, 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 IND under which the new 
clinical investigation(s) that is essential to the approval of its NDA 
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 NDA, and information supporting 
the certification. 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 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

[[Page 110]]

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 NDA must 
contain a financial certification or disclosure statement or both as 
required by part 54 of this chapter.
    (l) Format of an original NDA--(1) Archival copy. The applicant must 
submit a complete archival copy of the NDA that contains the information 
required under paragraphs (a) through (f) of this section. FDA will 
maintain the archival copy during the review of the NDA to permit 
individual reviewers to refer to information that is not contained in 
their particular technical sections of the NDA, to give other agency 
personnel access to the NDA for official business, and to maintain in 
one place a complete copy of the NDA. 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 NDA. 
Each of the technical sections, described in paragraphs (d)(1) through 
(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 NDA 
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 NDA.
    (4) Binding folders. The applicant may obtain from FDA sufficient 
folders to bind the archival, the review, and the field copies of the 
NDA.
    (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, unenforceability,
or noninfringement of a patent.

    (a) Notice of certification. For each patent that claims the listed 
drug or drugs relied upon or that claims a use for such listed drug or 
drugs and for which the 505(b)(2) applicant submits a paragraph IV 
certification, the applicant must send notice of such certification by 
registered or certified mail, return receipt requested, or by a 
designated delivery service, as defined in paragraph (g) of this 
section, 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 U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for each drug product which is 
claimed by the patent or a use of which is claimed by

[[Page 111]]

the patent and for which the applicant is seeking approval, or, if the 
NDA holder does not reside or maintain a place of business within the 
United States, the NDA holder's attorney, agent, or other authorized 
official. The name and address of the NDA holder or its attorney, agent, 
or authorized official may be obtained by sending a written or 
electronic communication to the Orange Book Staff, Office of Generic 
Drugs, 7620 Standish Pl., Rockville, MD 20855, or to the Orange Book 
Staff at the email address listed on the Agency's Web site at http://
www.fda.gov.
    (3) This paragraph (a) does not apply to a method-of-use patent that 
does not claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date of filing described 
in Sec.  314.101(a)(2) or (3), as applicable, but not later than 20 days 
after the date of the postmark on the paragraph IV acknowledgment 
letter. The 20-day clock described in this paragraph (b) begins on the 
day after the date of the postmark on the paragraph IV acknowledgment 
letter. When the 20th day falls on Saturday, Sunday, or a Federal 
holiday, the 20th day will be the next day that is not a Saturday, 
Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the date of filing described in Sec.  314.101(a)(2) 
or, if FDA notifies the applicant that FDA has refused to file the 
505(b)(2) application, before the date described in Sec.  314.101(a)(3) 
on which the 505(b)(2) application is filed. The applicant will not have 
complied with this paragraph (b) until it sends valid notice.
    (3) The applicant must submit to FDA an amendment to its 505(b)(2) 
application that includes 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. A copy of the notice itself need not be submitted 
to the Agency.
    (c) Content of a notice. In the notice, the applicant must cite 
section 505(b)(3)(D) of the Federal Food, Drug, and Cosmetic Act and the 
notice must include, but is not limited to, the following information:
    (1) A statement that a 505(b)(2) application that contains any 
required bioavailability or bioequivalence studies has been submitted by 
the applicant and filed by FDA.
    (2) The NDA number.
    (3) The established name, if any, as defined in section 502(e)(3) of 
the Federal Food, Drug, and Cosmetic 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 of each patent on the list 
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 must 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 alleges that the patent will not be infringed 
and the applicant seeks to preserve the option to later file a civil 
action for declaratory judgment in accordance with section 505(c)(3)(D) 
of the Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the 505(b)(2) 
application for the sole and limited purpose of evaluating possible 
infringement of the patent that is the subject of the paragraph IV 
certification.
    (8) 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.

[[Page 112]]

    (d) Amendment or supplement to a 505(b)(2) application. (1) If, 
after the date of filing described in Sec.  314.101(a)(2) or (3), as 
applicable, an applicant submits an amendment or supplement to its 
505(b)(2) application that includes a paragraph IV certification, the 
applicant must send the notice required by paragraph (a) of this section 
at the same time that the amendment or supplement to the 505(b)(2) 
application is submitted to FDA, regardless of whether the applicant has 
already given notice with respect to another such certification 
contained in the 505(b)(2) application or in an amendment or supplement 
to the 505(b)(2) application.
    (2) If, before the date of filing described in Sec.  314.101(a)(2) 
or (3), as applicable, an applicant submits a paragraph IV certification 
in an amendment, the applicant must send the notice required by 
paragraph (a) of this section in accordance with the procedures in 
paragraph (b) of this section.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph IV 
certification in accordance with paragraph (d)(1) or (2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its 505(b)(2) application to provide documentation 
of the date of receipt of the notice required under paragraph (a) of 
this section by each person provided the notice. The amendment must be 
submitted to FDA within 30 days after the last date on which notice was 
received by a person described in paragraph (a) of this section. The 
applicant's amendment also must include documentation that its notice 
was sent on a date that complies with the timeframe required by 
paragraph (b) or (d) of this section, as applicable. FDA will accept, as 
adequate documentation of the date the notice was sent, a copy of the 
registered mail receipt, certified mail receipt, or receipt from a 
designated delivery service, as defined in paragraph (g) of this 
section. FDA will accept as adequate documentation of the date of 
receipt a return receipt, a signature proof of delivery by a designated 
delivery service, 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) Forty-five day period after receipt of notice. If the 
requirements of this section are met, the Agency will presume the notice 
to be complete and sufficient and will count the day following the date 
of receipt of the notice by the patent owner or its representative and 
by the approved NDA holder or its attorney, agent, or other authorized 
official as the first day of the 45-day period provided for in section 
505(c)(3)(C) of the Federal Food, Drug, and Cosmetic Act. FDA may, if 
the applicant amends its 505(b)(2) application with a written statement 
that a later date should be used, count from such later date.
    (g) Designated delivery services. (1) For purposes of this section, 
the term ``designated delivery service'' is any delivery service 
provided by a trade or business that the Agency determines:
    (i) Is available to the general public throughout the United States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item referred 
to in this section is to be delivered, the date on which such item was 
given to such trade or business for delivery; and
    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA may periodically issue guidance regarding designated 
delivery services.

[81 FR 69641, Oct. 6, 2016]



Sec.  314.53  Submission of patent information.

    (a) Who must submit patent information. This section applies to any 
applicant who submits to FDA an NDA or an amendment to it under section 
505(b) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or a 
supplement to an approved NDA 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

[[Page 113]]

paragraph (a) of this section must submit to its NDA the required 
information, on the required FDA 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 NDA 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 must submit information only on those 
patents that claim the drug substance that is the subject of the pending 
or approved NDA or that claim a drug substance that is the same as the 
active ingredient that is the subject of the approved or pending NDA. 
For patents that claim only a polymorph that is the same as the active 
ingredient described in the approved or pending NDA, the applicant must 
certify in the required FDA declaration form 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 NDA. For patents that claim a drug 
product, the applicant must submit information only on those patents 
that claim the drug product, as is defined in Sec.  314.3, that is 
described in the pending or approved NDA. For patents that claim a 
method of use, the applicant must submit information only on those 
patents that claim indications or other conditions of use for which 
approval is sought or has been granted in the NDA. The applicant must 
separately identify each pending or approved method of use and related 
patent claim(s). For approved NDAs, the NDA holder's description of the 
patented method of use required by paragraph (c)(2)(ii)(P)(3) of this 
section must describe only the approved method(s) of use claimed by the 
patent for 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. If the method(s) of 
use claimed by the patent does not cover an indication or other approved 
condition of use in its entirety, the applicant must describe only the 
specific approved method of use claimed by the patent for 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 approved NDAs, the NDA holder submitting 
information on the method-of-use patent must identify with specificity 
the section(s) and subsection(s) of the approved labeling that describes 
the method(s) 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 only 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 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

[[Page 114]]

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 NDA product.
    (c) Reporting requirements--(1) General requirements. An applicant 
described in paragraph (a) of this section must 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 
submitted on the appropriate form, Form FDA 3542 or 3542a, and contains 
the information required in paragraph (c)(2) of this section. 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 
must submit Form FDA 3542a. The following information and verification 
is required, subject to the exceptions listed in paragraph (c)(2)(i)(S) 
of this section:
    (A) NDA number;
    (B) The NDA applicant's name, full address, phone number and, if 
available, fax number and email address;
    (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(s) and route(s) of administration of new drug, and 
whether the applicant proposes to market the new drug for prescription 
use or over-the-counter use;
    (G) U.S. 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 email address;
    (I) The name, full address, phone number and, if available, fax 
number and email 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 section 505(b)(3) and 
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.  
314.52 and 314.95 (if patent owner or NDA 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 NDA or supplement;
    (K) If the patent has been submitted previously for listing, 
identify all change(s) from the previously submitted patent information 
and specify whether the change is related to the patent or related to an 
FDA action or procedure;
    (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 a drug substance that is an active 
ingredient in the drug product described in the NDA or supplement;
    (2) Whether the patent claims only a polymorph that is the same 
active ingredient that is described in the pending NDA or supplement;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the NDA 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:

[[Page 115]]

    (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;
    (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 approval is being sought and a description of each 
pending method of use and related patent claim of the patent being 
submitted;
    (2) Identification of the specific section(s) and subsection(s) of 
the proposed labeling for the drug product that describes the method of 
use claimed by the patent submitted; and
    (3) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(i)(M) or (N) of this 
section, regarding whether that patent also claims either the drug 
substance (active ingredient) or the drug product (composition/
formulation).
    (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 that 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.

    (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 email address; and
    (S) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(i)(M) of this section for a patent that claims the drug substance 
(active ingredient) and meets the requirements for listing on that 
basis, then the applicant is not required to provide the information 
described in paragraph (c)(2)(i)(N) of this section on whether that 
patent also claims the drug product (composition/formulation);
    (2) If an applicant submits the information described in paragraph 
(c)(2)(i)(N) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on that 
basis, then the applicant is not required to provide the information 
described in paragraph (c)(2)(i)(M) of this section on whether that 
patent also claims the drug substance (active ingredient);
    (3) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section, 
then the patent information submission requirements of paragraph 
(d)(2)(ii) of this section apply.
    (ii) Submission of patent information upon and after approval. 
Within 30 days after the date of approval of its NDA or supplement, the 
applicant must submit Form FDA 3542 for each patent that claims the drug 
substance (active ingredient), drug product (formulation and 
composition), or approved method of use. FDA will not list or publish 
patent information if it is not provided on this form or if the patent 
declaration does not contain the required information 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 NDA as 
required in paragraph (c)(2)(ii) of this section. As described in 
paragraph (d)(3) of this section, to be timely filed, patent information 
for patents issued after the date of approval of the NDA 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

[[Page 116]]

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, subject to 
the exceptions listed in paragraph (c)(2)(ii)(T) of this section:
    (A) NDA number;
    (B) The NDA holder's name, full address, phone number and, if 
available, fax number and email address;
    (C) Trade name of new drug;
    (D) Active ingredient(s) of new drug;
    (E) Strength(s) of new drug;
    (F) Dosage form(s) and route(s) of administration of new drug, and 
whether the new drug is approved for prescription use or over-the-
counter use;
    (G) Approval date of NDA or supplement;
    (H) U.S. 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 email address;
    (J) The name, full address, phone number and, if available, fax 
number and email 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 section 505(b)(3) and 
(j)(2)(B) of the Federal Food, Drug, and Cosmetic Act and Sec. Sec.  
314.52 and 314.95 (if patent owner or NDA 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 NDA or supplement;
    (L) If the patent has been submitted previously for listing, 
identify all change(s) from the previously submitted patent information 
and specify whether the change is related to the patent or related to an 
FDA action or procedure;
    (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:
    (1) Whether the patent claims a drug substance that is an active 
ingredient in the drug product described in the approved NDA;
    (2) Whether the patent claims only a polymorph that is the same as 
the active ingredient that is described in the approved NDA;
    (3) Whether the applicant has test data, described in paragraph 
(b)(2) of this section, demonstrating that a drug product containing 
only the polymorph will perform the same as the drug product described 
in the approved NDA 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 and related patent claim of the patent being submitted;
    (2) Identification of the specific section(s) and subsection(s) of 
the approved labeling for the drug product that describes the method of 
use claimed by the patent submitted;
    (3) The description of the patented method of use as required for 
publication, which must contain adequate information to assist 505(b)(2) 
and ANDA applicants in determining whether a listed method-of-use patent 
claims a use for which the 505(b)(2) or ANDA applicant is not seeking 
approval (for example, if the method(s) of use claimed by the patent 
does not cover an indication or other approved condition of use in its 
entirety, then the applicant must describe only the specific approved 
method of use claimed by the patent for which a claim of patent 
infringement could reasonably be asserted if a person not licensed by 
the owner of the

[[Page 117]]

patent engaged in the manufacture, use, or sale of the drug product); 
and
    (4) An applicant that submits information for a patent that claims 
one or more methods of using the drug product must also submit 
information described in either paragraph (c)(2)(ii)(N) or (O) of this 
section, regarding whether that patent also claims either the drug 
substance (active ingredient) or the drug product (composition/
formulation).
    (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 that 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 or response to a request under 21 
CFR 314.53(f)(1) 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.

    (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 email address; and
    (T) Exceptions to required submission of patent information:
    (1) If an applicant submits the information described in paragraph 
(c)(2)(ii)(N) of this section for a patent that claims the drug 
substance (active ingredient) and meets the requirements for listing on 
that basis, then the applicant is not required to provide the 
information described in paragraph (c)(2)(ii)(O) of this section on 
whether that patent also claims the drug product (composition/
formulation).
    (2) If an applicant submits the information described in paragraph 
(c)(2)(ii)(O) of this section for a patent that claims the drug product 
(composition/formulation) and meets the requirements for listing on that 
basis, then the applicant is not required to provide the information 
described in paragraph (c)(2)(ii)(N) of this section on whether that 
patent also claims the drug substance (active ingredient).
    (3) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section, 
then the patent information submission requirements of paragraph 
(d)(2)(ii) of this section apply.
    (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 form, Form FDA 3542 or 3542a.
    (4) Authorized signature. The declarations required by this section 
must 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 NDA. 
An applicant must submit with its original NDA submitted under this 
part, the information described in paragraph (c) of this section on each 
drug substance (active ingredient), drug product (formulation and 
composition), and method-of-use patent issued before the NDA is filed 
with FDA and for which patent information is required to be submitted 
under this section. If a patent is issued after the NDA is filed with 
FDA but before the NDA is approved, the applicant must, within 30 days 
of the date of issuance of the patent, submit the required patent 
information in an amendment to the NDA under Sec.  314.60.
    (2) Supplements. (i) An applicant must submit patent information 
required under paragraph (c) of this section for a patent that claims 
the drug substance, drug product, or method of use

[[Page 118]]

for which approval is sought in any of the following supplements:
    (A) To add or change the dosage form or route of administration;
    (B) To add or change the strength; or
    (C) To change the drug product from prescription use to over-the-
counter use.
    (ii) If the applicant submits a supplement for a change other than 
one of the changes listed under paragraph (d)(2)(i) of this section (for 
example, to change the formulation, to add a new indication or other 
condition of use, or to make any other patented change regarding the 
drug substance, drug product, or any method of use), the following 
patent information submission requirements apply:
    (A) If existing patents for which information required by paragraph 
(c) of this section has already been submitted to FDA for the product 
approved in the original NDA claim the changed product, the applicant is 
not required to resubmit this patent information pursuant to paragraph 
(c) of this section unless the published description of the patented 
method of use would change upon approval of the supplement, and FDA will 
continue to list this patent information for the product;
    (B) If one or more existing patents for which information has 
already been submitted to FDA no longer claim the changed product, the 
applicant must submit a request under paragraph (f)(2)(iv) of this 
section to remove that patent information from the list at the time of 
approval of the supplement;
    (C) If one or more existing drug substance (active ingredient), drug 
product (formulation and composition), or method-of-use patents claim 
the changed product for which approval is sought in the supplement and 
such patent information has not been submitted to FDA, the applicant 
must submit the patent information required under paragraph (c) of this 
section.
    (3) Newly issued patents. If a patent is issued for a drug 
substance, drug product, or method of use after an NDA is approved, the 
applicant must submit to FDA, as described in paragraph (d)(4) of this 
section, the required patent information within 30 days of the date of 
issuance of the patent. If the required patent information is not 
submitted within 30 days of the issuance of the patent, FDA will list 
the patent, but patent certifications or statements will be governed by 
the provisions regarding untimely filed patent information at Sec. Sec.  
314.50(i)(4) and (6) and 314.94(a)(12)(vi) and (viii).
    (4) Submission of Forms FDA 3542a and 3542--(i) Patent information 
submitted with the filing of an NDA, amendment, or supplement. The 
applicant must submit patent information required by paragraphs (c)(1) 
and (c)(2)(i) of this section and Sec.  314.50(h) or Sec.  314.70(f) on 
Form FDA 3542a to the Central Document Room, Center for Drug Evaluation 
and Research, Food and Drug Administration, 5901-B Ammendale Rd., 
Beltsville, MD 20705-1266, or to FDA in an electronic format submission 
that complies with Sec.  314.50(l)(5). Form FDA 3542a should not be 
submitted to the Orange Book Staff in the Office of Generic Drugs.
    (ii) Patent information submitted upon and after approval of an NDA 
or supplement. The applicant must submit patent information required by 
paragraphs (c)(1) and (c)(2)(ii) of this section on Form FDA 3542 to the 
Central Document Room, Center for Drug Evaluation and Research, Food and 
Drug Administration, 5901-B Ammendale Rd., Beltsville, MD 20705-1266, or 
to FDA in an electronic format submission that complies with Sec.  
314.50(l)(5). Form FDA 3542 should not be submitted to the Orange Book 
Staff in the Office of Generic Drugs.
    (5) Submission date. Patent information will be considered to be 
submitted to FDA for purposes of paragraph (d)(3) of this section as of 
the earlier of the date the information submitted on Form FDA 3542 is 
date-stamped by the Central Document Room, or officially received by FDA 
in an electronic format submission that complies with Sec.  
314.50(l)(5).
    (6) Identification. Each submission of patent information, except 
information submitted with an original NDA, must bear prominent 
identification as to its contents, i.e., ``Patent Information,'' or, if 
submitted after approval of an NDA, ``Time Sensitive Patent 
Information.''

[[Page 119]]

    (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 
method-of-use patent, the description of the method of use claimed by 
the patent as required by Sec.  314.53(c)(2)(ii)(P)(3). FDA will publish 
such patent information upon approval of the NDA, or, if the patent 
information is submitted by the applicant after approval of an NDA as 
provided under paragraph (d)(2) of this section, as soon as possible 
after the submission to the Agency of the patent information. A request 
for copies of the submitted patent information must be sent in writing 
to the Freedom of Information Staff at the address listed on the 
Agency's Web site at http://www.fda.gov. The submitted patent 
information, and requests to remove a patent or patent information from 
the list, may be subject to public disclosure.
    (f) Correction of patent information errors--(1) Requests by persons 
other than the NDA holder. 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 NDA holder 
has failed to submit required patent information, that person must first 
notify the Agency in a written or electronic communication titled 
``314.53(f) Patent Listing Dispute.'' The patent listing dispute 
communication must include a statement of dispute that describes the 
specific grounds for disagreement regarding the accuracy or relevance of 
patent information for FDA to send to the applicable NDA holder. For a 
dispute regarding the accuracy or relevance of patent information 
regarding an approved method of using the drug product, this statement 
of dispute must be only a narrative description (no more than 250 words) 
of the person's interpretation of the scope of the patent. This 
statement of dispute must only contain information for which the person 
consents to disclosure because FDA will send the text of the statement 
to the applicable NDA holder without review or redaction. The patent 
listing dispute communication should be directed to the Office of 
Generic Drugs, OGD Document Room, Attention: Orange Book Staff, 7620 
Standish Pl., Rockville, MD 20855, or to the Orange Book Staff at the 
email address listed on the Agency's Web site at http://www.fda.gov.
    (i) Communication with the NDA holder--(A) Drug substance or drug 
product claim. For requests submitted under this paragraph (f)(1) that 
are directed to the accuracy or relevance of submitted patent 
information regarding a drug substance or drug product claim, the Agency 
will send the statement of dispute to the applicable NDA holder. The NDA 
holder must confirm the correctness of the patent information and 
include the signed verification required by paragraph (c)(2)(ii)(R) of 
this section or withdraw or amend the patent information in accordance 
with paragraph (f)(2) of this section within 30 days of the date on 
which the Agency sends the statement of dispute. Unless the NDA holder 
withdraws or amends its patent information in response to the patent 
listing dispute, the Agency will not change the patent information in 
the Orange Book.
    (B) Method-of-use claim. For requests submitted under this paragraph 
(f)(1) that are directed to the accuracy or relevance of submitted 
patent information regarding an approved method of using the drug 
product, FDA will send the statement of dispute to the NDA holder. The 
NDA holder must confirm the correctness of its description of the 
approved method of use claimed by the patent that has been included as 
the ``Use Code'' in the Orange Book, or withdraw or amend the patent 
information in accordance with paragraph (f)(2) of this section, provide 
a narrative description (no more than 250 words) of the NDA holder's 
interpretation of the scope of the patent that explains why the existing 
or amended ``Use Code'' describes only the specific approved method of 
use claimed by the patent for 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, and 
include the signed verification required by paragraph (c)(2)(ii)(R) of 
this section within 30 days of the date on which the Agency sends the 
statement of dispute. The narrative description

[[Page 120]]

must only contain information for which the NDA holder consents to 
disclosure because FDA will send the text of the statement to the person 
who submitted the patent listing dispute without review or redaction.
    (1) If the NDA holder confirms the correctness of the patent 
information, provides the narrative description required by paragraph 
(f)(1)(i)(B) of this section, and includes the signed verification 
required by paragraph (c)(2)(ii)(R) of this section within 30 days of 
the date on which the Agency sends the statement of dispute, the Agency 
will not change the patent information in the Orange Book.
    (2) If the NDA holder responds to the patent listing dispute with 
amended patent information in accordance with paragraph (f)(2) of this 
section, provides the narrative description required by paragraph 
(f)(1)(i)(B) of this section, and includes the signed verification 
required by paragraph (c)(2)(ii)(R) of this section within 30 days of 
the date on which the Agency sends the statement of dispute, FDA will 
update the Orange Book to reflect the amended patent information.
    (ii) Patent certification or statement during and after patent 
listing dispute. A 505(b)(2) application or ANDA must contain an 
appropriate certification or statement for each listed patent, including 
the disputed patent, during and after the patent listing dispute.
    (iii) Information on patent listing disputes. FDA will promptly post 
information on its Web site regarding whether a patent listing dispute 
has been submitted for a published description of a patented method of 
use for a drug product and whether the NDA holder has timely responded 
to the patent listing dispute.
    (2) Requests by the NDA holder--(i) Patents or patent claims that no 
longer meet the statutory requirements for listing. If the NDA holder 
determines that a patent or patent claim no longer meets the 
requirements for listing in section 505(b)(1) or (c)(2) of the Federal 
Food, Drug, and Cosmetic Act (including if there has been a judicial 
finding of invalidity for a listed patent, from which no appeal has been 
or can be taken), the NDA holder is required to promptly notify FDA to 
amend the patent information or withdraw the patent or patent 
information and request that the patent or patent information be removed 
from the list. If the NDA holder is required by court order to amend 
patent information or withdraw a patent from the list, it must submit an 
amendment to its NDA that includes a copy of the order, within 14 days 
of the date the order was entered, to the Central Document Room, Center 
for Drug Evaluation and Research, Food and Drug Administration, 5901-B 
Ammendale Rd., Beltsville, MD 20705-1266. The amendment to the NDA must 
bear the identification described in paragraph (d)(6) of this section. 
FDA will remove a patent or patent information from the list if there is 
no first applicant eligible for 180-day exclusivity based on a paragraph 
IV certification to that patent or after the 180-day exclusivity period 
of a first applicant based on that patent has expired or has been 
extinguished.
    (ii) Patent term restoration. If the term of a listed patent is 
extended pursuant to 35 U.S.C. 156(e), the NDA holder must submit on 
Form FDA 3542 a correction to the expiration date of the patent. This 
correction must be submitted within 30 days of receipt of a certificate 
of extension as described in 35 U.S.C. 156(e)(1) or documentation of an 
extension of the term of the patent as described in 35 U.S.C. 156(e)(2).
    (iii) Submission of corrections or changes to patent information. 
Corrections or changes to previously submitted patent information, other 
than withdrawal of a patent and requests to remove a patent from the 
list, must be submitted on Form FDA 3542 or 3542a, as appropriate, in an 
amendment or supplement to the NDA. The amendment or supplement to the 
NDA must bear the identification described in paragraph (d)(6) of this 
section. We will not accept the corrections or changes unless they are 
submitted on the appropriate forms.
    (iv) Submission of patent withdrawals and requests to remove a 
patent from the list. Withdrawal of a patent and requests to remove a 
patent from the list must be submitted to the same addresses described 
in paragraph (d)(4)(ii) of this section, except that the withdrawal or 
request to remove a patent

[[Page 121]]

from the list is not required to be submitted on Form FDA 3542 and may 
be submitted by letter. Withdrawal of a patent and a request to remove a 
patent from the list must contain the following information:
    (A) The NDA number to which the request applies;
    (B) Each product(s) approved in the NDA to which the request 
applies; and
    (C) The patent number.

[81 FR 69643, Oct. 6, 2016]



Sec.  314.54  Procedure for submission of a 505(b)(2) application
requiring investigations for approval of a new indication for, or other
change from, a listed drug.

    (a) The Federal Food, Drug, and Cosmetic Act does not permit 
approval of an ANDA 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 505(b)(2) application need contain 
only that information needed to support the modification(s) of the 
listed drug.
    (1) The applicant must 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) must 
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 each 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 NDA number. The listed drug(s) identified as relied upon 
must include a drug product approved in an NDA that:
    (A) Is pharmaceutically equivalent to the drug product for which the 
original 505(b)(2) application is submitted; and
    (B) Was approved before the original 505(b)(2) application was 
submitted.
    (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 
Federal Food, Drug, and Cosmetic 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 Federal Food, Drug, and Cosmetic Act with respect to 
any relevant patents that claim the listed drug(s) on which 
investigations relied on by the applicant for approval of the 
application were conducted, or that claim a use for the listed drug(s). 
A 505(b)(2) applicant seeking approval of a drug that is 
pharmaceutically equivalent to a listed drug approved in an NDA 
implicitly relies upon one such pharmaceutically equivalent listed 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 must submit a review copy that contains the 
technical sections described in Sec.  314.50(d)(1), except that the 
section described in Sec.  314.50(d)(1)(ii)(c) must 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

[[Page 122]]

product, and Sec.  314.50(d)(3), and the technical sections described in 
Sec.  314.50(d)(2), (d)(4) through (6), and (f) when needed to support 
the modification. Each of the technical 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 must be satisfied by reference to the listed 
drug under paragraph (a)(1)(iii) of this section.
    (4) The applicant must submit a field copy of the 505(b)(2) 
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 505(b)(2) application.
    (b) A 505(b)(2) application may not be submitted under this section 
for a drug product whose only difference from a 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 
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 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; 81 FR 69647, Oct. 
6, 2016]



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.

[[Page 123]]

    (2) Full waiver. An applicant may request a waiver of the 
requirements of paragraph (a) of this section if the applicant certifies 
that:
    (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 NDA, supplement, or 
resubmission.

    (a) Submission of NDA. FDA generally assumes that when an original 
NDA, supplement to an approved NDA, or resubmission of an NDA or 
supplement is submitted to the Agency for review, the applicant believes 
that the Agency can approve the NDA, supplement, or resubmission as 
submitted. However, the applicant may submit an amendment to an NDA, 
supplement, or resubmission that has been filed under Sec.  314.101 but 
is not yet approved.
    (b) Submission of major amendment. (1) Submission of a major 
amendment to an original NDA, efficacy supplement, or resubmission of an 
NDA 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 Federal Food, Drug, and Cosmetic Act to extend the initial 
review cycle by 3 months. (For

[[Page 124]]

references to a resubmission of an NDA or efficacy supplement in 
paragraph (b) of this section, the timeframe for reviewing the 
resubmission is the ``review cycle'' rather than the ``initial 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 NDA, efficacy supplement, or resubmission under this 
paragraph, the division responsible for reviewing the NDA, supplement, 
or resubmission will notify the applicant of the extension. The initial 
review cycle for an original NDA, efficacy supplement, or resubmission 
of an NDA 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 NDA, efficacy 
supplement, or resubmission of an NDA 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 NDA, efficacy 
supplement, or resubmission of an NDA 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 Federal Food, 
Drug, and Cosmetic 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 NDA, supplement, or 
resubmission, but it may include data to support a minor modification of 
an indication or claim that was included in the original NDA, 
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) Limitation on certain amendments.(1) An unapproved NDA may not 
be amended if all of the following conditions apply:
    (i) The unapproved NDA is for a drug for which a previous NDA has 
been approved and granted a period of exclusivity in accordance with 
section 505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act 
that has not expired;
    (ii) The applicant seeks to amend the unapproved NDA 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 or use 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 NDA.
    (2) The submission of an amendment described in paragraph (c)(1) of 
this section will cause the unapproved NDA to be deemed to be withdrawn 
by the

[[Page 125]]

applicant under Sec.  314.65 on the date of receipt by FDA of the 
amendment. The amendment will be considered a resubmission of the NDA, 
which may not be accepted except as provided in accordance with section 
505(c)(3)(E)(ii) of the Federal Food, Drug, and Cosmetic Act.
    (d) Field copy. The applicant must submit a field copy of each 
amendment to a section of the NDA described in Sec.  314.50(d)(1). The 
applicant must 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.
    (e) Different drug. An applicant may not amend a 505(b)(2) 
application to seek approval of a drug that is a different drug from the 
drug in the original submission of the 505(b)(2) application. For 
purposes of this paragraph (e), a drug is a different drug if it has 
been modified to have a different active ingredient, different route of 
administration, different dosage form, or difference in excipients that 
requires either a separate clinical study to establish safety or 
effectiveness or, for topical products, that requires a separate in vivo 
demonstration of bioequivalence. However, notwithstanding the limitation 
described in this paragraph (e), an applicant may amend the 505(b)(2) 
application to seek approval of a different strength.
    (f) Patent certification requirements. (1) An amendment to a 
505(b)(2) application is required to contain an appropriate patent 
certification or statement described in Sec.  314.50(i) or a 
recertification for a previously submitted paragraph IV certification if 
approval is sought for any of the following types of amendments:
    (i) To add a new indication or other condition of use;
    (ii) To add a new strength;
    (iii) To make other than minor changes in product formulation; or
    (iv) To change the physical form or crystalline structure of the 
active ingredient.
    (2) If the amendment to the 505(b)(2) application does not contain a 
patent certification or statement, the applicant must verify that the 
proposed change described in the amendment is not one of the types of 
amendments described in paragraph (f)(1) of this section.

[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; 81 FR 69648, Oct. 6, 2016]



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 NDA.

    (a) Changes to an approved NDA. (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 NDA 
beyond the variations already provided for in the NDA. 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 NDA 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 NDA under paragraph (d) of this section.

[[Page 126]]

    (2) The NDA holder 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 submission.
    (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, changes in the qualitative or quantitative formulation of the 
drug product, including inactive ingredients, or in the specifications 
provided in the approved NDA;
    (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.

[[Page 127]]

    (viii) Changes to a drug product under an NDA that is subject to a 
validity assessment because of significant questions regarding the 
integrity of the data supporting that NDA.
    (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 should be 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:

[[Page 128]]

    (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 NDA 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;
    (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 NDA, 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 NDA 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 NDA;
    (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

[[Page 129]]

being tested as the analytical procedure described in the approved NDA, 
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 NDA 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.
    (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 NDA, 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 Federal Food, 
Drug, and Cosmetic Act and Sec.  314.53.
    (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).
    (h) Different drug. An applicant may not supplement a 505(b)(2) 
application to seek approval of a drug that is a different drug from the 
drug in the approved 505(b)(2) application. For purposes of this 
paragraph (h), a drug is a different drug if it has been modified to 
have a different active ingredient, different route of administration, 
different dosage form, or difference in excipients that requires either 
a separate clinical study to establish safety or effectiveness or, for 
topical products, that requires a separate in vivo demonstration of 
bioequivalence. However, notwithstanding the limitation described in 
this paragraph (h), an applicant may supplement the 505(b)(2) 
application to seek approval of a different strength.

[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; 81 FR 69648, Oct. 
6, 2016]



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

[[Page 130]]

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:
    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.
    Individual case safety report (ICSR). A description of an adverse 
drug experience related to an individual patient or subject.
    ICSR attachments. Documents related to the adverse drug experience 
described in an ICSR, such as medical records, hospital discharge 
summaries, or other documentation.
    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

[[Page 131]]

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, must 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 must also develop written procedures for the 
surveillance, receipt, evaluation, and reporting of postmarketing 
adverse drug experiences to FDA.
    (c) Reporting requirements. The applicant must submit to FDA adverse 
drug experience information as described in this section. Except as 
provided in paragraph (g)(2) of this section, these reports must be 
submitted to the Agency in electronic format as described in paragraph 
(g)(1) of this section.
    (1)(i) Postmarketing 15-day ``Alert reports''. The applicant must 
report each adverse drug experience that is both serious and unexpected, 
whether foreign or domestic, as soon as possible but no later than 15 
calendar days from initial receipt of the information by the applicant.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The applicant 
must promptly investigate all adverse drug experiences that are the 
subject of these postmarketing 15-day Alert reports and must 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.
    (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, also apply to any person other than 
the applicant whose name appears on the label of an approved drug 
product as a manufacturer, packer, or distributor (nonapplicant). 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 must submit, by any appropriate means, 
each report to the applicant within 5 calendar days of initial receipt 
of the information by the nonapplicant, and the applicant must then 
comply with the requirements of this

[[Page 132]]

section. Under this circumstance, the nonapplicant must maintain a 
record of this action which must 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.
    (2) Periodic adverse drug experience reports. (i) The applicant must 
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 must 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) Descriptive information. (1) A narrative summary and analysis of 
the information in the report;
    (2) 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 code, adverse 
reaction term(s), and date of submission to FDA);
    (3) A history of actions taken since the last report because of 
adverse drug experiences (for example, labeling changes or studies 
initiated); and
    (4) An index consisting of a line listing of the applicant's patient 
identification code, and adverse reaction term(s) for all ICSRs 
submitted under paragraph (c)(2)(ii)(B) of this section.
    (B) ICSRs for serious, expected, and nonserious adverse drug 
experiences. An ICSR for each adverse drug experience not reported under 
paragraph (c)(1)(i) of this section (all serious, expected and 
nonserious adverse drug experiences). All such ICSRs must be submitted 
to FDA (either individually or in one or more batches) within the 
timeframe specified in paragraph (c)(2)(i) of this section. ICSRs must 
only be submitted to FDA once.
    (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. A 15-day Alert report based on 
information in the scientific literature must 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.
    (e) Postmarketing studies. 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.
    (f) Information reported on ICSRs. ICSRs include the following 
information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse drug experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse drug experience.
    (i) Outcome attributed to adverse drug experience;
    (ii) Date of adverse drug experience;
    (iii) Date of ICSR submission;
    (iv) Description of adverse drug experience (including a concise 
medical narrative);

[[Page 133]]

    (v) Adverse drug experience term(s);
    (vi) Description of relevant tests, including dates and laboratory 
data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a prescription or nonprescription 
product;
    (vi) Whether the product is a combination product as defined in 
Sec.  3.2(e) of this chapter;
    (vii) Whether adverse drug experience abated after drug use stopped 
or dose reduced;
    (viii) Whether adverse drug experience reappeared after 
reintroduction of drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional; and
    (iii) Occupation, if a health care professional.
    (5) Applicant information.
    (i) Applicant name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous, literature, or study;
    (iv) Date the report was received by applicant;
    (v) Application number and type;
    (vi) Whether the ICSR is a 15-day ``Alert report'';
    (vii) Whether the ICSR is an initial report or followup report; and
    (viii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (g) Electronic format for submissions. (1) Safety report 
submissions, including ICSRs, ICSR attachments, and the descriptive 
information in periodic reports, must be in an electronic format that 
FDA can process, review, and archive. FDA will issue guidance on how to 
provide the electronic submission (e.g., method of transmission, media, 
file formats, preparation and organization of files).
    (2) An applicant or nonapplicant may request, in writing, a 
temporary waiver of the requirements in paragraph (g)(1) of this 
section. These waivers will be granted on a limited basis for good cause 
shown. FDA will issue guidance on requesting a waiver of the 
requirements in paragraph (g)(1) of this section.
    (h) 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.
    (i) 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 for identification of 
the patient. The applicant should include the name of the reporter from 
whom the information was received as part of the initial reporter 
information, even when the reporter is the patient. The 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 of this 
chapter.
    (j) Recordkeeping. The applicant must 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.
    (k) 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

[[Page 134]]

drug product that is the subject of the application.
    (l) 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 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; 79 FR 33088, June 10, 2014]



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.

[[Page 135]]

    (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 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 [email protected] 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.

[[Page 136]]

    (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.)
    (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

[[Page 137]]

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 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 a permanent discontinuance or an interruption 
in manufacturing. (a) An applicant of a prescription drug product must 
notify FDA in writing of a permanent discontinuance of manufacture of 
the drug product or an interruption in manufacturing of the drug product 
that is likely to lead to a meaningful disruption in supply of that drug 
in the United States if:
    (1) The drug product is life supporting, life sustaining, or 
intended for use in the prevention or treatment of a debilitating 
disease or condition, including any such drug used in emergency medical 
care or during surgery; and
    (2) The drug product is not a radiopharmaceutical drug product.
    (b) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must be submitted to FDA electronically in a format that FDA can 
process, review, and archive:
    (1) At least 6 months prior to the date of the permanent 
discontinuance or interruption in manufacturing; or
    (2) If 6 months' advance notice is not possible because the 
permanent discontinuance or interruption in manufacturing was not 
reasonably anticipated 6 months in advance, as soon as practicable 
thereafter, but in no case later than 5 business days after the 
permanent discontinuance or interruption in manufacturing occurs.
    (c) Notifications required by paragraph (b)(3)(iii)(a) of this 
section must include the following information:

[[Page 138]]

    (1) The name of the drug subject to the notification, including the 
NDC for such drug;
    (2) The name of the applicant;
    (3) Whether the notification relates to a permanent discontinuance 
of the drug or an interruption in manufacturing of the drug;
    (4) A description of the reason for the permanent discontinuance or 
interruption in manufacturing; and
    (5) The estimated duration of the interruption in manufacturing.
    (d)(1) FDA will maintain a publicly available list of drugs that are 
determined by FDA to be in shortage. This drug shortages list will 
include the following information:
    (i) The names and NDC(s) for such drugs;
    (ii) The name of each applicant for such drugs;
    (iii) The reason for the shortage, as determined by FDA from the 
following categories: Requirements related to complying with good 
manufacturing practices; regulatory delay; shortage of an active 
ingredient; shortage of an inactive ingredient component; 
discontinuation of the manufacture of the drug; delay in shipping of the 
drug; demand increase for the drug; or other reason; and
    (iv) The estimated duration of the shortage.
    (2) FDA may choose not to make information collected to implement 
this paragraph available on the drug shortages list or available under 
section 506C(c) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 
356c(c)) if FDA determines that disclosure of such information would 
adversely affect the public health (such as by increasing the 
possibility of hoarding or other disruption of the availability of the 
drug to patients). FDA will also not provide information on the public 
drug shortages list or under section 506C(c) of the Federal Food, Drug, 
and Cosmetic Act that is protected by 18 U.S.C. 1905 or 5 U.S.C. 
552(b)(4), including trade secrets and commercial or financial 
information that is considered confidential or privileged under Sec.  
20.61 of this chapter.
    (e) If an applicant fails to submit a notification as required under 
paragraph (b)(3)(iii)(a) of this section and in accordance with 
paragraph (b)(3)(iii)(b) of this section, FDA will issue a letter to the 
applicant informing it of such failure.
    (1) Not later than 30 calendar days after the issuance of such a 
letter, the applicant must submit to FDA a written response setting 
forth the basis for noncompliance and providing the required 
notification under paragraph (b)(3)(iii)(a) of this section and 
including the information required under paragraph (b)(3)(iii)(c) of 
this section; and
    (2) Not later than 45 calendar days after the issuance of a letter 
under paragraph (b)(3)(iii)(e) of this section, FDA will make the letter 
and the applicant's response to the letter public, unless, after review 
of the applicant's response, FDA determines that the applicant had a 
reasonable basis for not notifying FDA as required under paragraph 
(b)(3)(iii)(a) of this section.
    (f) The following definitions of terms apply to paragraph 
(b)(3)(iii) of this section:
    Drug shortage or shortage means a period of time when the demand or 
projected demand for the drug within the United States exceeds the 
supply of the drug.
    Intended for use in the prevention or treatment of a debilitating 
disease or condition means a drug product intended for use in the 
prevention or treatment of a disease or condition associated with 
mortality or morbidity that has a substantial impact on day-to-day 
functioning.
    Life supporting or life sustaining means a drug product that is 
essential to, or that yields information that is essential to, the 
restoration or continuation of a bodily function important to the 
continuation of human life.
    Meaningful disruption means a change in production that is 
reasonably likely to lead to a reduction in the supply of a drug by a 
manufacturer that is more than negligible and affects the ability of the 
manufacturer to fill orders or meet expected demand for its product, and 
does not include interruptions in manufacturing due to matters such as 
routine maintenance or insignificant changes in manufacturing so long as 
the manufacturer expects to resume operations in a short period of time.

[[Page 139]]

    (iv) Withdrawal of approved drug product from sale. (a) Within 30 
calendar days of the withdrawal of an approved drug from sale, 
applicants who are manufacturers, repackers, or relabelers subject to 
part 207 of this chapter must submit the following information about the 
drug, in accordance with the applicable requirements described in 
Sec. Sec.  207.61 and 207.65:
    (1) The National Drug Code (NDC);
    (2) The identity of the drug by established name and by proprietary 
name, if any;
    (3) The new drug application number or abbreviated application 
number;
    (4) The date on which the drug is expected to be no longer in 
commercial distribution. FDA requests that the reason for withdrawal of 
the drug from sale be included with the information.
    (b) Within 30 calendar days of the withdrawal of an approved drug 
from sale, applicants who are not subject to part 207 of this chapter 
must submit the information listed in paragraphs (b)(3)(iv)(a)(1) 
through (4) of this section. The information must be submitted either 
electronically or in writing to the Drug Registration and Listing 
Office, Food and Drug Administration, Center for Drug Evaluation and 
Research.
    (c) Reporting under paragraph (b)(3)(iv)(a) of this section 
constitutes compliance with the requirements of Sec.  207.57 of this 
chapter to update drug listing information with respect to the 
withdrawal from sale.
    (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; 80 FR 38938, July 8, 2015; 81 FR 
60221, Aug. 31, 2016]



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 NDA, or 
in an amendment or supplement to an NDA. 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

[[Page 140]]

agency to evaluate the NDA or compliance cannot be achieved;
    (2) The applicant's alternative submission satisfies the 
requirement; or
    (3) The applicant's submission otherwise justifies a waiver.
    (c) If FDA grants the applicant's waiver request with respect to a 
requirement under Sec. Sec.  314.50 through 314.81, the waived 
requirement will not constitute a basis for refusal to approve an NDA 
under Sec.  314.125.

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 67 
FR 9586, Mar. 4, 2002; 81 FR 69649, Oct. 6, 2016]



                   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 ANDAs for other 
changes from a listed drug will not be approved.
    (b) A person who wants to submit an ANDA 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 ANDA.
    (c) To obtain permission to submit an ANDA 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 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

[[Page 141]]

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(p) of the Federal 
Food, Drug, and Cosmetic 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 Federal Food, Drug, and Cosmetic 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; or
    (vi) A drug product is approved in an NDA for the change described 
in the petition.
    (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 ANDA for the drug product. FDA may, at any 
time during the course of its review of an ANDA, request additional 
information required to evaluate the change approved under the petition.
    (f)(1) 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.
    (2) If, after approval of a petition and before approval of an ANDA 
submitted pursuant to the approved petition, a drug product is approved 
in an NDA for the change described in the petition,

[[Page 142]]

the petition and the listed drug identified in the petition can no 
longer be the basis for ANDA submission, irrespective of whether FDA has 
withdrawn approval of the petition. A person seeking approval for such 
drug product must submit a new ANDA that identifies the pharmaceutically 
equivalent reference listed drug as the basis for ANDA submission and 
comply with applicable regulatory requirements.

[57 FR 17983, Apr. 28, 1992, as amended at 81 FR 69649, Oct. 6, 2016]



Sec.  314.94  Content and format of an ANDA.

    ANDAs are required to be submitted in the form and contain the 
information required under this section. Three copies of the ANDA are 
required, an archival copy, a review copy, and a field copy. FDA will 
maintain guidance documents on the format and content of ANDAs to assist 
applicants in their preparation.
    (a) ANDAs. Except as provided in paragraph (b) of this section, the 
applicant must submit a complete archival copy of the abbreviated new 
drug application that includes the following:
    (1) Application form. The applicant must 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 must state 
whether the submission is an ANDA under this section or a supplement to 
an ANDA under Sec.  314.97.
    (2) Table of contents. The archival copy of the ANDA 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 ANDA submission. An ANDA 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 ANDA must contain:
    (i) The name of the reference listed drug, including its dosage form 
and strength. For an ANDA based on an approved petition under Sec.  
10.30 of this chapter and Sec.  314.93, the reference listed drug must 
be the same as the listed drug referenced in the approved 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)(5)(F) of the Federal Food, 
Drug, and Cosmetic Act.
    (iii) For an ANDA based on an approved petition under Sec.  10.30 of 
this chapter and Sec.  314.93, a reference to the 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 ANDA 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

[[Page 143]]

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 Federal Food, Drug, and Cosmetic 
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 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 ANDA 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.  314.3(b), 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 ANDA is submitted pursuant to a petition approved under 
Sec.  314.93, the results of any bioavailability or 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 
Federal Food, Drug, and Cosmetic Act.
    (iii) For each in vivo or in vitro bioequivalence study contained in 
the ANDA:
    (A) A description of the analytical and statistical methods used in 
each study; and
    (B) With respect to each study involving human subjects, a statement 
that the study 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

[[Page 144]]

this chapter, and that it 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 ANDA, if the ANDA relies on a reference listed drug.
    (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 Federal Food, 
Drug, and Cosmetic Act.
    (9) Chemistry, manufacturing, and controls. (i) The information 
required under Sec.  314.50(d)(1), except that the information required 
under Sec.  314.50(d)(1)(ii)(c) must 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 must 
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 must 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 must 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

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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 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 ANDA 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 substance, drug 
product, or method of use. (A) An appropriate patent certification or 
statement with respect to each patent issued by the U.S. 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 Federal Food, Drug, and Cosmetic Act and for which 
information is required to be filed under section 505(b) and (c) of the 
Federal Food, Drug, and Cosmetic Act and Sec.  314.53. For each such 
patent, the applicant must 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 must entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant must entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant must 
entitle such a certification ``Paragraph III Certification''; or
    (4)(i) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the ANDA is submitted. The applicant must entitle such a certification 
``Paragraph IV Certification''. This certification must 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 ANDA is 
submitted.

    (ii) The certification must 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 its 
representative and to the NDA holder (or, if the NDA holder does not 
reside or maintain a place of business within the United States, its 
attorney, agent, or other authorized official) for the listed drug, with 
the requirements under Sec.  314.95(b) with respect to sending the 
notice, and with the requirements under Sec.  314.95(c) with respect to 
the content of the notice.
    (B) If the ANDA refers to a listed drug that is itself a licensed 
generic product of a patented drug first approved under section 505(b) 
of the Federal Food, Drug, and Cosmetic Act, an appropriate patent 
certification or statement under paragraph (a)(12)(i) and/or (iii) 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 ANDA 
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 Federal Food, Drug, and Cosmetic Act 
and Sec.  314.53 for a patent claiming a method

[[Page 146]]

of using the listed drug, and the labeling for the drug product for 
which the applicant is seeking approval does not include an indication 
or other condition of use that is covered by the method-of-use patent, a 
statement explaining that the method-of-use patent does not claim a 
proposed indication or other condition of use.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication or other condition of use that, 
according to the patent information submitted under section 505(b) or 
(c) of the Federal Food, Drug, and Cosmetic Act and Sec.  314.53 or in 
the opinion of the applicant, is claimed by a method-of-use patent, an 
applicable certification under paragraph (a)(12)(i) of this section.
    (iv) [Reserved]
    (v) Licensing agreements. If the ANDA 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 must submit a paragraph 
IV certification as to that patent and a statement that the applicant 
has been granted a patent license. If the patent owner consents to 
approval of the ANDA (if otherwise eligible for approval) as of a 
specific date, the ANDA must contain a written statement from the patent 
owner that it has a licensing agreement with the applicant and that it 
consents to approval of the ANDA as of a specific date.
    (vi) Untimely filing of patent information. (A) If a patent on the 
listed drug is issued and the holder of the approved NDA for the listed 
drug does not file with FDA the required information on the patent 
within 30 days of issuance of the patent, an applicant who submitted an 
ANDA for that drug that contained an appropriate patent certification or 
statement before the submission of the patent information is not 
required to submit a patent certification or statement to address the 
patent or patent information that is late-listed with respect to the 
pending ANDA. Except as provided in Sec.  314.53(f)(1), an NDA holder's 
amendment to the description of the approved method(s) of use claimed by 
the patent will be considered untimely filing of patent information 
unless:
    (1) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of patent 
issuance;
    (2) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of approval of a 
corresponding change to product labeling; or
    (3) The amendment to the description of the approved method(s) of 
use claimed by the patent is submitted within 30 days of a decision by 
the U.S. Patent and Trademark Office or by a Federal district court, the 
Court of Appeals for the Federal Circuit, or the U.S. Supreme Court that 
is specific to the patent and alters the construction of a method-of-use 
claim(s) of the patent, and the amendment contains a copy of the 
decision.
    (B) An applicant whose ANDA is submitted after the NDA holder's 
untimely filing of patent information, or whose pending ANDA was 
previously submitted but did not contain an appropriate patent 
certification or statement at the time of the patent submission, must 
submit a certification under paragraph (a)(12)(i) of this section and/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, the applicant must submit an 
appropriate certification or statement for each listed patent.
    (viii) Amended certifications. A patent certification or statement 
submitted under paragraphs (a)(12)(i) through (iii) of this section may 
be amended at any time before the approval of the ANDA. If an applicant 
with a pending ANDA voluntarily makes a patent certification for an 
untimely filed patent, the applicant may withdraw the patent 
certification for the untimely filed patent. An applicant must submit an

[[Page 147]]

amended certification as an amendment to a pending ANDA. Once an 
amendment is submitted to change a certification, the ANDA will no 
longer be considered to contain the prior certification.
    (A) After finding of infringement. An applicant who has submitted a 
paragraph IV certification and is sued for patent infringement must 
submit an amendment to change its certification if a court enters a 
final decision from which no appeal has been or can be taken, or signs 
and enters a settlement order or consent decree in the action that 
includes a finding that the patent is infringed, unless the final 
decision, settlement order, or consent decree also finds the patent to 
be invalid. In its amendment, the applicant must certify under paragraph 
(a)(12)(i)(A)(3) of this section that the patent will expire on a 
specific date or, with respect to a patent claiming a method of use, the 
applicant may instead provide a statement under paragraph (a)(12)(iii) 
of this section if the applicant amends its ANDA such that the applicant 
is no longer seeking approval for a method of use claimed by the patent. 
Once an amendment for the change has been submitted, the ANDA will no 
longer be considered to contain a paragraph IV certification to the 
patent. If a final judgment finds the patent to be invalid and 
infringed, an amended certification is not required.
    (B) After request to remove a patent or patent information from the 
list. If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and no ANDA 
applicant is eligible for 180-day exclusivity based on a paragraph IV 
certification to that patent, the patent or patent information will be 
removed and any applicant with a pending ANDA (including a tentatively 
approved ANDA) who has made a certification with respect to such patent 
must submit an amendment to withdraw its certification. In the 
amendment, the applicant must state the reason for withdrawing the 
certification or statement (that the patent has been removed from the 
list). If the list reflects that an NDA holder has requested that a 
patent or patent information be removed from the list and one or more 
first applicants are eligible for 180-day exclusivity based on a 
paragraph IV certification to that patent, the patent will remain listed 
until any 180-day exclusivity based on that patent has expired or has 
been extinguished. After any applicable 180-day exclusivity has expired 
or has been extinguished, the patent or patent information will be 
removed and any applicant with a pending ANDA (including a tentatively 
approved ANDA) who has made a certification with respect to such patent 
must submit an amendment to withdraw its certification. Once an 
amendment to withdraw the certification has been submitted, the ANDA 
will no longer be considered to contain a paragraph IV certification to 
the patent. If removal of a patent from the list results in there being 
no patents listed for the listed drug identified in the ANDA, the 
applicant must submit an amended certification reflecting that there are 
no relevant patents.
    (C) Other amendments. (1) Except as provided in paragraphs 
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section:
    (i) An applicant must amend a submitted certification or statement 
if, at any time before the date of approval of the ANDA, the applicant 
learns that the submitted certification or statement is no longer 
accurate; and
    (ii) An applicant must submit an appropriate patent certification or 
statement under paragraph (a)(12)(i) and/or (iii) of this section if, 
after submission of the ANDA, a new patent is issued by the U.S. 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 
an approved use for such reference listed drug and for which information 
is required to be filed under section 505(b) and (c) of the Federal 
Food, Drug, and Cosmetic Act and Sec.  314.53. For a paragraph IV 
certification, the certification must not be submitted earlier than the 
first working day after the day the patent is published in the list.
    (2) An applicant is not required to submit a supplement to change a 
submitted certification when information on a patent on the listed drug 
is submitted after the approval of the ANDA.

[[Page 148]]

    (13) Financial certification or disclosure statement. An ANDA must 
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 ANDA 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 must comply with 
the provisions of paragraph (a) of this section.
    (c) [Reserved]
    (d) Format of an ANDA. (1) The applicant must submit a complete 
archival copy of the ANDA as required under paragraphs (a) and (c) of 
this section. FDA will maintain the archival copy during the review of 
the ANDA to permit individual reviewers to refer to information that is 
not contained in their particular technical sections of the ANDA, to 
give other Agency personnel access to the ANDA for official business, 
and to maintain in one place a complete copy of the ANDA.
    (i) Format of submission. An applicant may submit portions of the 
archival copy of the ANDA 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 ANDAs, the applicant must submit a review copy of the ANDA 
that contains two separate sections. One section must contain the 
information described under paragraphs (a)(2) through (6) and (8) and 
(9) of this section and section 505(j)(2)(A)(vii) of the Federal Food, 
Drug, and Cosmetic Act and a 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 must contain the information 
described under paragraphs (a)(3), (7), and (8) of this section. Each of 
the sections in the review copy is required to contain a copy of the 
application form described under paragraph (a) of this section.
    (3) [Reserved]
    (4) The applicant may obtain from FDA sufficient folders to bind the 
archival, the review, and the field copies of the ANDA.
    (5) The applicant must submit a field copy of the ANDA 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 ANDA.

[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; 81 FR 69649, Oct. 6, 2016]



Sec.  314.95   Notice of certification of invalidity, unenforceability,
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 for which the applicant submits a paragraph IV 
certification, the

[[Page 149]]

applicant must send notice of such certification by registered or 
certified mail, return receipt requested, or by a designated delivery 
service, as defined in paragraph (g) of this section 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 U.S. Patent and Trademark 
Office; and
    (2) The holder of the approved NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic Act for the listed drug that is claimed 
by the patent and for which the applicant is seeking approval, or, if 
the NDA holder does not reside or maintain a place of business within 
the United States, the NDA holder's attorney, agent, or other authorized 
official. The name and address of the NDA holder or its attorney, agent, 
or authorized official may be obtained by sending a written or 
electronic communication to the Orange Book Staff, Office of Generic 
Drugs, 7620 Standish Pl., Rockville, MD 20855 or to the Orange Book 
Staff at the email address listed on the Agency's Web site at http://
www.fda.gov.
    (3) This paragraph (a) does not apply to a method-of-use patent that 
does not claim a use for which the applicant is seeking approval.
    (4) An applicant may send notice by an alternative method only if 
FDA has agreed in advance that the method will produce an acceptable 
form of documentation.
    (b) Sending the notice. (1) Except as provided under paragraph (d) 
of this section, the applicant must send the notice required by 
paragraph (a) of this section on or after the date it receives a 
paragraph IV acknowledgment letter from FDA, but not later than 20 days 
after the date of the postmark on the paragraph IV acknowledgment 
letter. The 20-day clock described in this paragraph (b) begins on the 
day after the date of the postmark on the paragraph IV acknowledgment 
letter. When the 20th day falls on Saturday, Sunday, or a Federal 
holiday, the 20th day will be the next day that is not a Saturday, 
Sunday, or Federal holiday.
    (2) Any notice required by paragraph (a) of this section is invalid 
if it is sent before the applicant's receipt of a paragraph IV 
acknowledgment letter, or before the first working day after the day the 
patent is published in the list. The applicant will not have complied 
with this paragraph (b) until it sends valid notice.
    (3) The applicant must submit to FDA an amendment to its ANDA that 
includes 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. 
A copy of the notice itself need not be submitted to the Agency.
    (c) Contents of a notice. In the notice, the applicant must cite 
section 505(j)(2)(B)(iv) of the Federal Food, Drug, and Cosmetic Act and 
the notice must include, but is not limited to, the following 
information:
    (1) A statement that FDA has received an ANDA submitted by the 
applicant containing any required bioavailability or bioequivalence data 
or information.
    (2) The ANDA number.
    (3) A statement that the applicant has received the paragraph IV 
acknowledgment letter for the ANDA.
    (4) The established name, if any, as defined in section 502(e)(3) of 
the Federal Food, Drug, and Cosmetic Act, of the proposed drug product.
    (5) The active ingredient, strength, and dosage form of the proposed 
drug product.
    (6) The patent number and expiration date of each listed patent for 
the reference listed drug alleged to be invalid, unenforceable, or not 
infringed.
    (7) 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 must 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 150]]

    (8) If the applicant alleges that the patent will not be infringed 
and the applicant seeks to preserve the option to later file a civil 
action for declaratory judgment in accordance with section 505(j)(5)(C) 
of the Federal Food, Drug, and Cosmetic Act, then the notice must be 
accompanied by an offer of confidential access to the ANDA for the sole 
and limited purpose of evaluating possible infringement of the patent 
that is the subject of the paragraph IV certification.
    (9) 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 or supplement to an ANDA. (1) If, after receipt of a 
paragraph IV acknowledgment letter or acknowledgment letter, an 
applicant submits an amendment or supplement to its ANDA that includes a 
paragraph IV certification, the applicant must send the notice required 
by paragraph (a) of this section at the same time that the amendment or 
supplement to the ANDA is submitted to FDA, regardless of whether the 
applicant has already given notice with respect to another such 
certification contained in the ANDA or in an amendment or supplement to 
the ANDA.
    (2) If, before receipt of a paragraph IV acknowledgment letter, an 
applicant submits an amendment to its ANDA that includes a paragraph IV 
certification, the applicant must send the notice required by paragraph 
(a) of this section in accordance with the procedures in paragraph (b) 
of this section. If an ANDA applicant's notice of its paragraph IV 
certification is timely provided in accordance with paragraph (b) of 
this section and the applicant has not submitted a previous paragraph IV 
certification, FDA will base its determination of whether the applicant 
is a first applicant on the date of submission of the amendment 
containing the paragraph IV certification.
    (3) An applicant that submits an amendment or supplement to seek 
approval of a different strength must provide notice of any paragraph IV 
certification in accordance with paragraph (d)(1) or (2) of this 
section, as applicable.
    (e) Documentation of timely sending and receipt of notice. The 
applicant must amend its ANDA to provide documentation of the date of 
receipt of the notice required under paragraph (a) of this section by 
each person provided the notice. The amendment must be submitted to FDA 
within 30 days after the last date on which notice was received by a 
person described in paragraph (a) of this section. The applicant's 
amendment also must include documentation that its notice was sent on a 
date that complies with the timeframe required by paragraph (b) or (d) 
of this section, as applicable, and a dated printout of the entry for 
the reference listed drug in FDA's ``Approved Drug Products With 
Therapeutic Equivalence Evaluations'' (the list) that includes the 
patent that is the subject of the paragraph IV certification. FDA will 
accept, as adequate documentation of the date the notice was sent, a 
copy of the registered mail receipt, certified mail receipt, or receipt 
from a designated delivery service as defined in paragraph (g) of this 
section. FDA will accept as adequate documentation of the date of 
receipt a return receipt, signature proof of delivery by a designated 
delivery service, 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) Forty-five day period after receipt of notice. 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 NDA holder or its attorney, agent, or other authorized 
official as the first day of the 45-day period provided for in section 
505(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act. FDA may, 
if the applicant provides a written statement to FDA that a later date 
should be used, count from such later date.
    (g) Designated delivery services. (1) For purposes of this section, 
the term

[[Page 151]]

``designated delivery service'' means any delivery service provided by a 
trade or business that the Agency determines:
    (i) Is available to the general public throughout the United States;
    (ii) Records electronically to its database, kept in the regular 
course of its business, or marks on the cover in which any item referred 
to in this section is to be delivered, the date on which such item was 
given to such trade or business for delivery; and
    (iii) Provides overnight or 2-day delivery service throughout the 
United States.
    (2) FDA may periodically issue guidance regarding designated 
delivery services.

[81 FR 69651, Oct. 6, 2016]



Sec.  314.96   Amendments to an unapproved ANDA.

    (a) ANDA. (1) An applicant may amend an ANDA 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 ANDA. 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.  314.3 
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) Field copy. The applicant must submit a field copy of each 
amendment under Sec.  314.94(a)(9). The applicant, other than a foreign 
applicant, must 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.
    (c) Different listed drug. An applicant may not amend an ANDA to 
seek approval of a drug referring to a listed drug that is different 
from the reference listed drug identified in the ANDA. This paragraph 
(c) applies if, at any time before the approval of the ANDA, a different 
listed drug is approved that is the pharmaceutical equivalent to the 
product in the ANDA and is designated as a reference listed drug. This 
paragraph (c) also applies if changes are proposed in an amendment to 
the ANDA such that the proposed product is a pharmaceutical equivalent 
to a different listed drug than the reference listed drug identified in 
the ANDA. A change of the reference listed drug must be submitted in a 
new ANDA. However, notwithstanding the limitation described in this 
paragraph (c), an applicant may amend the ANDA to seek approval of a 
different strength.
    (d)(1) Patent certification requirements. An amendment to an ANDA is 
required to contain an appropriate patent certification or statement 
described in Sec.  314.94(a)(12) or a recertification for a previously 
submitted paragraph IV certification if approval is sought for any of 
the following types of amendments:
    (i) To add a new indication or other condition of use;
    (ii) To add a new strength;
    (iii) To make other than minor changes in product formulation; or
    (iv) To change the physical form or crystalline structure of the 
active ingredient.
    (2) If the amendment to the ANDA does not contain a patent 
certification or statement, the applicant must verify that the proposed 
change described in the amendment is not one of

[[Page 152]]

the types of amendments described in paragraph (d)(1) of this section.

[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; 81 FR 69652, Oct. 6, 2016]



Sec.  314.97  Supplements and other changes to an approved ANDA.

    (a) General requirements. The applicant must comply with the 
requirements of Sec. Sec.  314.70 and 314.71 regarding the submission of 
supplemental ANDAs and other changes to an approved ANDA.
    (b) Different listed drug. An applicant may not supplement an ANDA 
to seek approval of a drug referring to a listed drug that is different 
from the current reference listed drug identified in the ANDA. This 
paragraph (b) applies if changes are proposed in a supplement to the 
ANDA such that the proposed product is a pharmaceutical equivalent to a 
different listed drug than the reference listed drug identified in the 
ANDA. A change of reference listed drug must be submitted in a new ANDA. 
However, notwithstanding the limitation described in this paragraph (b), 
an applicant may supplement the ANDA to seek approval of a different 
strength.

[81 FR 69653, Oct. 6, 2016]



Sec.  314.98  Postmarketing reports.

    (a) Each applicant having an approved abbreviated new drug 
application under Sec.  314.94 that is effective must comply with the 
requirements of Sec.  314.80 regarding the reporting and recordkeeping 
of adverse drug experiences.
    (b) Each applicant must make the reports required under Sec.  314.81 
and section 505(k) of the Federal Food, Drug, and Cosmetic Act for each 
of its approved abbreviated applications.

[79 FR 33089, June 10, 2014]



Sec.  314.99  Other responsibilities of an applicant of an ANDA.

    (a) An applicant must comply with the requirements of Sec.  314.65 
regarding withdrawal by the applicant of an unapproved ANDA and Sec.  
314.72 regarding a change in ownership of an ANDA.
    (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 must comply with the requirements for a 
waiver under Sec.  314.90. If FDA grants the applicant's waiver request 
with respect to a requirement under Sec. Sec.  314.92 through 314.99, 
the waived requirement will not constitute a basis for refusal to 
approve an ANDA under Sec.  314.127.

81 FR 69653, Oct. 6, 2016]



    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 NDA and receiving an ANDA.

    (a) Filing an NDA. (1) Within 60 days after FDA receives an NDA, the 
Agency will determine whether the NDA may be filed. The filing of an NDA 
means that FDA has made a threshold determination that the NDA is 
sufficiently complete to permit a substantive review.

[[Page 153]]

    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for refusing to file the NDA apply, the Agency will file 
the NDA and notify the applicant in writing. In the case of a 505(b)(2) 
application that contains a paragraph IV certification, the applicant 
will be notified via a paragraph IV acknowledgment letter. The date of 
filing will be the date 60 days after the date FDA received the NDA. The 
date of filing begins the 180-day period described in section 505(c) of 
the Federal Food, Drug, and Cosmetic Act. This 180-day period is called 
the ``filing clock.''
    (3) If FDA refuses to file the NDA, 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 NDA 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 NDA. 
If, following the informal conference, the applicant requests that FDA 
file the NDA (with or without amendments to correct the deficiencies), 
the Agency will file the NDA over protest under paragraph (a)(2) of this 
section, notify the applicant in writing, and review it as filed. If the 
NDA 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 an NDA that is filed over protest. 
If FDA refuses to file the NDA under paragraph (e) of this section, the 
applicant may amend the NDA and resubmit it, and the Agency will make a 
determination under this section whether it may be filed.
    (b)(1) Receiving an ANDA. An ANDA will be evaluated after it is 
submitted to determine whether the ANDA may be received. Receipt of an 
ANDA means that FDA has made a threshold determination that the 
abbreviated application is substantially complete.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for considering the ANDA not to have been received 
applies, the ANDA is substantially complete and the Agency will receive 
the ANDA and notify the applicant in writing. If FDA determines, upon 
evaluation, that an ANDA was substantially complete as of the date it 
was submitted to FDA, FDA will consider the ANDA to have been received 
as of the date of submission. In the case of an ANDA that contains a 
paragraph IV certification, the applicant will be notified via a 
paragraph IV acknowledgment letter.
    (3) If FDA considers the ANDA not to have been received under 
paragraph (d) or (e) of this section, FDA will notify the applicant of 
the refuse-to-receive decision. The applicant may then:
    (i) Withdraw the ANDA under Sec.  314.99; or
    (ii) Correct the deficiencies and resubmit the ANDA; or
    (iii) Take no action, in which case FDA may consider the ANDA 
withdrawn after 1 year.
    (c) [Reserved]
    (d) NDA or ANDA deficiencies. FDA may refuse to file an NDA or may 
not consider an ANDA to be received if any of the following applies:
    (1) The NDA or ANDA does not contain a completed application form.
    (2) The NDA or ANDA is not submitted in the form required under 
Sec.  314.50 or Sec.  314.94.
    (3) The NDA or ANDA is incomplete because it does not on its face 
contain information required under section 505(b) or section 505(j) of 
the Federal Food, Drug, and Cosmetic Act and Sec.  314.50 or Sec.  
314.94. In determining whether an ANDA is incomplete on its face, FDA 
will consider the nature (e.g., major or minor) of the deficiencies, 
including the number of deficiencies in the ANDA.
    (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 NDA or ANDA does not contain an accurate and complete 
English translation of each part of the NDA or ANDA that is not in 
English.
    (6) The NDA or ANDA does not contain a statement for each 
nonclinical laboratory study that the study was

[[Page 154]]

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 NDA or ANDA does not contain a statement for each clinical 
study that the study 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 NDA or ANDA 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 NDA or ANDA and the applicant of the 
submission:
    (i) Has an approved NDA or ANDA for the same drug product; or
    (ii) Is merely a distributor and/or repackager of the already 
approved drug product.
    (9) The NDA 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 Federal Food, Drug, and Cosmetic Act.
    (e) Regulatory deficiencies. The Agency will refuse to file an NDA 
or will consider an ANDA 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.
    (2) Submission of a 505(b)(2) application or an ANDA is not 
permitted under section 505(c)(3)(E)(ii), 505(j)(5)(F)(ii), 
505A(b)(1)(A)(i)(I), 505A(c)(1)(A)(i)(I), or 505E(a) of the Federal 
Food, Drug, and Cosmetic Act.
    (f) Outcome of FDA review. (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 NDA; 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 NDA 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 ANDA. If FDA disapproves the ANDA, FDA will issue a 
notice of opportunity for hearing if the applicant asked FDA to provide 
it an opportunity for a hearing on an ANDA in response to a complete 
response letter.
    (3) This paragraph (f) does not apply to NDAs or ANDAs that have 
been withdrawn from FDA review by the applicant.

[81 FR 69653, Oct. 6, 2016]



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

[[Page 155]]

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 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

[[Page 156]]

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 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 NDA and an ANDA.

    (a) FDA will approve an NDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.125 for refusing to approve 
the NDA applies. FDA will issue a tentative approval letter if an NDA 
otherwise meets the requirements for approval under the Federal Food, 
Drug, and Cosmetic Act, but cannot be approved because there is a 7-year 
period of orphan exclusivity for the listed drug under section 527 of 
the Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this 
chapter, or if a 505(b)(2) application otherwise meets the requirements 
for approval under the Federal Food, Drug, and Cosmetic Act, but cannot 
be approved until the conditions in Sec.  314.107(b)(3) are met; because 
there is a period of exclusivity for the listed drug under Sec.  
314.108; because there is a period of pediatric exclusivity for the 
listed drug under section 505A of the Federal Food, Drug, and Cosmetic 
Act; or because there is a period of exclusivity for the listed drug 
under section 505E of the Federal Food, Drug, and Cosmetic Act. A drug 
product that is granted tentative approval is not an approved drug and 
will not be approved until FDA issues an approval after any necessary 
additional review of the NDA. FDA's tentative approval of a drug product 
is based on information available to FDA at the time of the tentative 
approval letter (i.e., information in the 505(b)(2) application and the 
status of current good manufacturing practices of the facilities used in 
the manufacturing and testing of the drug product) and is therefore 
subject to change on the basis of new information that may come to FDA's 
attention. A new drug product may not be marketed until the date of 
approval.
    (b) FDA will approve an NDA and issue the applicant an approval 
letter on the basis of draft labeling if the only deficiencies in the 
NDA 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 NDA after it determines that the drug meets 
the statutory standards for safety and effectiveness, manufacturing and 
controls, and labeling, and an ANDA after it determines that the drug 
meets the statutory standards for manufacturing and controls, labeling, 
and, where applicable, bioequivalence. While the

[[Page 157]]

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 ANDA and send the applicant an approval 
letter if none of the reasons in Sec.  314.127 for refusing to approve 
the ANDA applies. FDA will issue a tentative approval letter if an ANDA 
otherwise meets the requirements for approval under the Federal Food, 
Drug, and Cosmetic Act, but cannot be approved because there is a 7-year 
period of orphan exclusivity for the listed drug under section 527 of 
the Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this 
chapter, or cannot be approved until the conditions in Sec.  
314.107(b)(3) or (c) are met; because there is a period of exclusivity 
for the listed drug under Sec.  314.108; because there is a period of 
pediatric exclusivity for the listed drug under section 505A of the 
Federal Food, Drug, and Cosmetic Act; or because there is a period of 
exclusivity for the listed drug under section 505E of the Federal Food, 
Drug, and Cosmetic Act. A drug product that is granted tentative 
approval is not an approved drug and will not be approved until FDA 
issues an approval after any necessary additional review of the ANDA. 
FDA's tentative approval of a drug product is based on information 
available to FDA at the time of the tentative approval letter (i.e., 
information in the ANDA and the status of current good manufacturing 
practices of the facilities used in the manufacturing and testing of the 
drug product) and is therefore subject to change on the basis of new 
information that may come to FDA's attention. A new drug product may not 
be marketed until the date of approval.

[81 FR 69654, Oct. 6, 2016]



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. 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  Date of approval of a 505(b)(2) application or ANDA.

    (a) General. A drug product may be introduced or delivered for 
introduction into interstate commerce when the 505(b)(2) application or 
ANDA for the drug product is approved. A 505(b)(2) application or ANDA 
for a drug product is approved on the date FDA issues an approval letter 
under Sec.  314.105 for the 505(b)(2) application or ANDA.
    (b) Effect of patent(s) on the listed drug. As described in 
paragraphs (b)(1) and (2) of this section, the status of patents listed 
for the listed drug(s) relied upon or reference listed drug, as 
applicable, must be considered in determining the first possible date on 
which a 505(b)(2) application or ANDA can be approved. The criteria in 
paragraphs (b)(1) and (2) of this section will be used to determine, for 
each relevant

[[Page 158]]

patent, the date that patent will no longer prevent approval. The first 
possible date on which the 505(b)(2) application or ANDA can be approved 
will be calculated for each patent, and the 505(b)(2) application or 
ANDA may be approved on the last applicable date.
    (1) Timing of approval based on patent certification or statement. 
If none of the reasons in Sec.  314.125 or Sec.  314.127, as applicable, 
for refusing to approve the 505(b)(2) application or ANDA applies, and 
none of the reasons in paragraph (d) of this section for delaying 
approval applies, the 505(b)(2) application or ANDA may be approved as 
follows:
    (i) Immediately, if the applicant certifies under Sec.  314.50(i) or 
Sec.  314.94(a)(12) that:
    (A) The applicant is aware of a relevant patent but the patent 
information required under section 505(b) or (c) of the Federal Food, 
Drug, and Cosmetic Act has not been submitted to FDA; or
    (B) The relevant patent has expired; or
    (C) The relevant patent is invalid, unenforceable, or will not be 
infringed, except as provided in paragraphs (b)(3) and (c) of this 
section, and the 45-day period provided for in section 505(c)(3)(C) and 
(j)(5)(B)(iii) of the Federal Food, Drug, and Cosmetic Act has expired; 
or
    (D) There are no relevant patents.
    (ii) Immediately, if the applicant submits an appropriate statement 
under Sec.  314.50(i) or Sec.  314.94(a)(12) explaining that a method-
of-use patent does not claim an indication or other condition of use for 
which the applicant is seeking approval, except that if the applicant 
also submits a paragraph IV certification to the patent, then the 
505(b)(2) application or ANDA may be approved as provided in paragraph 
(b)(1)(i)(C) of this section.
    (iii) On the date specified, 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.
    (2) Patent information filed after submission of 505(b)(2) 
application or ANDA. If the holder of the approved NDA for the listed 
drug submits patent information required under Sec.  314.53 after the 
date on which the 505(b)(2) application or ANDA was submitted to FDA, 
the 505(b)(2) applicant or ANDA applicant must comply with the 
requirements of Sec.  314.50(i)(4) and (6) and Sec.  314.94(a)(12)(vi) 
and (viii) regarding submission of an appropriate patent certification 
or statement. If the applicant submits an amendment certifying under 
Sec.  314.50(i)(1)(i)(A)(4) or Sec.  314.94(a)(12)(i)(A)(4) that the 
relevant patent is invalid, unenforceable, or will not be infringed, and 
complies with the requirements of Sec.  314.52 or Sec.  314.95, the 
505(b)(2) application or ANDA may be approved immediately upon 
submission of documentation of receipt of notice of paragraph IV 
certification under Sec.  314.52(e) or Sec.  314.95(e). The 45-day 
period provided for in section 505(c)(3)(C) and (j)(5)(B)(iii) of the 
Federal Food, Drug, and Cosmetic Act does not apply in these 
circumstances.
    (3) Disposition of patent litigation--(i) Approval upon expiration 
of 30-month period or 7\1/2\ years from date of listed drug approval. 
(A) Except as provided in paragraphs (b)(3)(ii) through (viii) of this 
section, if, with respect to patents for which required information was 
submitted under Sec.  314.53 before the date on which the 505(b)(2) 
application or ANDA was submitted to FDA (excluding an amendment or 
supplement to the 505(b)(2) application or ANDA), 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 of the 
notice of certification from the applicant under Sec.  314.52 or Sec.  
314.95, the 505(b)(2) application or ANDA may be approved 30 months 
after the later of the date of the receipt of the notice of 
certification by any owner of the listed patent or by the NDA holder (or 
its representative(s)) 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

[[Page 159]]

date of approval of the patented drug and within 45 days of receipt of 
the notice of certification from the applicant under Sec.  314.52 or 
Sec.  314.95, the 505(b)(2) application or ANDA may be approved at the 
expiration of the 7\1/2\ years from the date of approval of the NDA for 
the patented drug product.
    (ii) Federal district court decision of invalidity, 
unenforceability, or non-infringement. If before the expiration of the 
30-month period, or 7\1/2\ years where applicable, the district court 
decides that the patent is invalid, unenforceable, or not infringed 
(including any substantive determination that there is no cause of 
action for patent infringement or invalidity), the 505(b)(2) application 
or ANDA may be approved on:
    (A) The date on which the court enters judgment reflecting the 
decision; or
    (B) The date of a settlement order or consent decree signed and 
entered by the court stating that the patent that is the subject of the 
certification is invalid, unenforceable, or not infringed.
    (iii) Appeal of Federal district court judgment of infringement. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court decides that the patent has been 
infringed, and if the judgment of the district court is appealed, the 
505(b)(2) application or ANDA may be approved on:
    (A) The date on which the mandate is issued by the court of appeals 
entering judgment that the patent is invalid, unenforceable, or not 
infringed (including any substantive determination that there is no 
cause of action for patent infringement or invalidity); or
    (B) The date of a settlement order or consent decree signed and 
entered by the court of appeals stating that the patent that is the 
subject of the certification is invalid, unenforceable, or not 
infringed.
    (iv) Affirmation or non-appeal of Federal district court judgment of 
infringement. If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the district court decides that the patent has 
been infringed, and if the judgment of the district court is not 
appealed or is affirmed, the 505(b)(2) application or ANDA may be 
approved no earlier than the date specified by the district court in an 
order under 35 U.S.C. 271(e)(4)(A).
    (v) Grant of preliminary injunction by Federal district court. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the district court grants a preliminary injunction 
prohibiting the applicant 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:
    (A) The patent is invalid, unenforceable, or not infringed, the 
505(b)(2) application or ANDA may be approved as provided in paragraph 
(b)(3)(ii) of this section; or
    (B) The patent is infringed, the 505(b)(2) application or ANDA may 
be approved as provided in paragraph (b)(3)(iii) or (iv) of this 
section, whichever is applicable.
    (vi) Written consent to approval by patent owner or exclusive patent 
licensee. If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the patent owner or the exclusive patent 
licensee (or their representatives) agrees in writing that the 505(b)(2) 
application or ANDA may be approved any time on or after the date of the 
consent, approval may be granted on or after that date.
    (vii) Court order terminating 30-month or 7\1/2\-year period. If 
before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court enters an order requiring the 30-month or 7\1/2\-
year period to be terminated, the 505(b)(2) application or ANDA may be 
approved in accordance with the court's order.
    (viii) Court order of dismissal without a finding of infringement. 
If before the expiration of the 30-month period, or 7\1/2\ years where 
applicable, the court(s) enter(s) an order of dismissal, with or without 
prejudice, without a finding of infringement in each pending suit for 
patent infringement brought within 45 days of receipt of the notice of 
paragraph IV certification sent by the 505(b)(2) or ANDA applicant, the 
505(b)(2) application or ANDA may be approved on or after the date of 
the order.

[[Page 160]]

    (4) Tentative approval. FDA will issue a tentative approval letter 
when tentative approval is appropriate in accordance with this section. 
In order for a 505(b)(2) application or ANDA to be approved under 
paragraph (b)(3) of this section, the applicant must receive an approval 
letter from the Agency. Tentative approval of an NDA or ANDA does not 
constitute ``approval'' of an NDA or ANDA and cannot, absent an approval 
letter from the Agency, result in an approval under paragraph (b)(3) of 
this section.
    (c) Timing of approval of subsequent ANDA. (1) If an ANDA contains a 
paragraph IV certification for a relevant patent and the ANDA is not 
that of a first applicant, the ANDA is regarded as the ANDA of a 
subsequent applicant. The ANDA of a subsequent applicant will not be 
approved during the period when any first applicant is eligible for 180-
day exclusivity or during the 180-day exclusivity period of a first 
applicant. Any applicable 180-day exclusivity period cannot extend 
beyond the expiration of the patent upon which the 180-day exclusivity 
period was based.
    (2) A first applicant must submit correspondence to its ANDA 
notifying FDA within 30 days of the date of its first commercial 
marketing of its drug product or the reference listed drug. If an 
applicant does not notify FDA, as required in this paragraph (c)(2), of 
this date, the date of first commercial marketing will be deemed to be 
the date of the drug product's approval.
    (3) If FDA concludes that a first applicant is not actively pursuing 
approval of its ANDA, FDA may immediately approve an ANDA(s) of a 
subsequent applicant(s) if the ANDA(s) is otherwise eligible for 
approval.
    (d) Delay due to exclusivity. The Agency will also delay the 
approval of a 505(b)(2) application or ANDA if delay is required by the 
exclusivity provisions in Sec.  314.108; section 527 of the Federal 
Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter; section 
505A of the Federal Food, Drug, and Cosmetic Act; or section 505E of the 
Federal Food, Drug, and Cosmetic Act. When the approval of a 505(b)(2) 
application or ANDA is delayed under this section and Sec.  314.108; 
section 527 of the Federal Food, Drug, and Cosmetic Act and Sec.  316.31 
of this chapter; section 505A of the Federal Food, Drug, and Cosmetic 
Act; or section 505E of the Federal Food, Drug, and Cosmetic Act, the 
505(b)(2) application or ANDA will be approved on the latest of the days 
specified under this section and Sec.  314.108; section 527 of the 
Federal Food, Drug, and Cosmetic Act and Sec.  316.31 of this chapter; 
section 505A of the Federal Food, Drug, and Cosmetic Act; or section 
505E of the Federal Food, Drug, and Cosmetic Act, as applicable.
    (e) Notification of court actions or written consent to approval. 
(1) The applicant must submit the following information to FDA, as 
applicable:
    (i) A copy of any judgment by the court (district court or mandate 
of the court of appeals) or settlement order or consent decree signed 
and entered by the court (district court or court of appeals) finding a 
patent described in paragraph (b)(3) of this section invalid, 
unenforceable, or not infringed, or finding the patent valid and 
infringed;
    (ii) Written notification of whether or not any action by the court 
described in paragraph (e)(1)(i) of this section has been appealed 
within the time permitted for an appeal;
    (iii) A copy of any order entered by the court terminating the 30-
month or 7\1/2\-year period as described in paragraph (b)(3)(i), (ii), 
(vii), or (viii) of this section;
    (iv) A copy of any written consent to approval by the patent owner 
or exclusive patent licensee described in paragraph (b)(3)(vi) of this 
section;
    (v) A copy of any preliminary injunction described in paragraph 
(b)(3)(v) of this section, and a copy of any subsequent court order 
lifting the injunction; and
    (vi) A copy of any court order pursuant to 35 U.S.C. 271(e)(4)(A) 
ordering that a 505(b)(2) application or ANDA may be approved no earlier 
than the date specified (irrespective of whether the injunction relates 
to a patent described in paragraph (b)(3) of this section).
    (2) All information required by paragraph (e)(1) of this section 
must be sent to the applicant's NDA or ANDA, as appropriate, within 14 
days of the date of entry by the court, the date of appeal

[[Page 161]]

or expiration of the time for appeal, or the date of written consent to 
approval, as applicable.
    (f) Forty-five day period after receipt of notice of paragraph IV 
certification--(1) Computation of 45-day time clock. The 45-day clock 
described in paragraph (b)(3) of this section as to each recipient 
required to receive notice of paragraph IV certification under Sec.  
314.52 or Sec.  314.95 begins on the day after the date of receipt of 
the applicant's notice of paragraph IV certification by the recipient. 
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) Notification of filing of legal action. (i) The 505(b)(2) or 
ANDA applicant must notify FDA in writing within 14 days of the filing 
of any legal action filed within 45 days of receipt of the notice of 
paragraph IV certification by any recipient. A 505(b)(2) applicant must 
send the notification to its NDA. An ANDA applicant must send the 
notification to its ANDA. The notification to FDA of the legal action 
must include:
    (A) The 505(b)(2) application or ANDA number.
    (B) The name of the 505(b)(2) or ANDA applicant.
    (C) 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.
    (D) A statement that an action for patent infringement, identified 
by court, case number, and the patent number(s) of the patent(s) at 
issue in the action, has been filed in an appropriate court on a 
specified date.
    (ii) A patent owner or NDA holder (or its representative(s)) 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 paragraph (f)(2)(i) of this 
section.
    (iii) If the 505(b)(2) or ANDA applicant, the patent owner(s), the 
NDA holder, or its representative(s) 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 505(b)(2) application or ANDA, whichever occurs 
later, that a legal action for patent infringement was filed within 45 
days of receipt of the notice of paragraph IV certification, the 
505(b)(2) application or ANDA may be approved upon expiration of the 45-
day period (if the 505(b)(2) or ANDA applicant confirms that a legal 
action for patent infringement has not been filed) or upon completion of 
the Agency's review of the 505(b)(2) application or ANDA, whichever is 
later.
    (3) Waiver. If the patent owner or NDA holder who is an exclusive 
patent licensee (or its representative(s)) 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 NDA holder who is 
an exclusive patent licensee (or its representative(s)) submits to FDA a 
valid waiver before the 45 days elapse, the 505(b)(2) application or 
ANDA may be approved upon completion of the Agency's review of the NDA 
or ANDA. FDA will only accept a waiver in the following form:

    (Name of patent owner or NDA holder who is an exclusive patent 
licensee or its representative(s)) has received notice from (name of 
applicant) under (section 505(b)(3) or 505(j)(2)(B) of the Federal Food, 
Drug, and Cosmetic 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 elapse). (Name of patent owner or 
NDA holder who is an exclusive patent licensee) waives the opportunity 
provided by (section 505(c)(3)(C) or 505(j)(5)(B)(iii) of the Federal 
Food, Drug, and Cosmetic Act) and does not object to FDA's approval of 
(name of applicant)'s (505(b)(2) application or ANDA) for (name of drug) 
with an approval date on or after the date of this submission.

    (g) Conversion of approval to tentative approval. If FDA issues an 
approval letter in error or a court enters an order requiring, in the 
case of an already approved 505(b)(2) application or ANDA, that the date 
of approval be delayed, FDA will convert the approval to a tentative 
approval if appropriate.

[81 FR 69655, Oct. 6, 2016]



Sec.  314.108  New drug product exclusivity.

    (a) Definitions. The definitions in Sec.  314.3 and the following 
definitions of terms apply to this section:

[[Page 162]]

    Approved under section 505(b) means an NDA submitted under section 
505(b) and approved on or after October 10, 1962, or an application that 
was ``deemed approved'' under section 107(c)(2) of Public Law 87-781.
    Bioavailability study means a study to determine the bioavailability 
or the pharmacokinetics of a drug.
    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.
    Essential to approval means, with regard to an investigation, that 
there are no other data available that could support approval of the 
NDA.
    New chemical entity means a drug that contains no active moiety that 
has been approved by FDA in any other NDA submitted under section 505(b) 
of the Federal Food, Drug, and Cosmetic 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 timing of approval of a 505(b)(2) application 
or ANDA. (1) [Reserved]
    (2) If a drug product that contains a new chemical entity was 
approved after September 24, 1984, in an NDA submitted under section 
505(b) of the Federal Food, Drug, and Cosmetic Act, no person may submit 
a 505(b)(2) application or ANDA under section 505(j) of the Federal 
Food, Drug, and Cosmetic 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 NDA, except that the 
505(b)(2) application or ANDA 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 ANDA described in 
paragraph (b)(2) of this section will occur as provided in Sec.  
314.107(b)(1) or (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 NDA for the new 
chemical entity and within 45 days after receipt of the notice described 
at Sec.  314.52 or Sec.  314.95, in which case, approval of the 
505(b)(2) application or ANDA will occur as provided in Sec.  
314.107(b)(3).
    (4) If an NDA:
    (i) Was submitted under section 505(b) of the Federal Food, Drug, 
and Cosmetic Act;
    (ii) Was approved after September 24, 1984;

[[Page 163]]

    (iii) Was for a drug product that contains an active moiety that has 
been previously approved in another NDA under section 505(b) of the 
Federal Food, Drug, and Cosmetic 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, for a period of 3 years 
after the date of approval of the application, the Agency will not 
approve a 505(b)(2) application or an ANDA for the conditions of 
approval of the NDA, or an ANDA submitted pursuant to an approved 
petition under section 505(j)(2)(C) of the Federal Food, Drug, and 
Cosmetic Act that relies on the information supporting the conditions of 
approval of an original NDA.
    (5) If a supplemental NDA:
    (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 NDA, for a 
period of 3 years after the date of approval of the supplemental 
application, the Agency will not approve a 505(b)(2) application or an 
ANDA for a change, or an ANDA submitted pursuant to an approved petition 
under section 505(j)(2)(C) of the Federal Food, Drug, and Cosmetic Act 
that relies on the information supporting a change approved in the 
supplemental NDA.

[59 FR 50368, Oct. 3, 1994, as amended at 81 FR 69657, Oct. 6, 2016]



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 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.

[[Page 164]]

    (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 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

[[Page 165]]

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 NDA.

    (a) The Food and Drug Administration will refuse to approve the NDA 
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 NDA under section 505(d) of the 
Federal Food, Drug, and Cosmetic 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 NDA 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 NDA for any of the following 
reasons, unless the requirement has been waived under Sec.  314.90:
    (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 Federal 
Food, Drug, and Cosmetic 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 NDA 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 NDA 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 NDA under Sec.  
314.101(d), if the deficiency is not corrected.
    (11) The drug will be manufactured in whole or in part in an 
establishment that is not registered and not exempt from registration 
under section 510 of the Federal Food, Drug, and Cosmetic 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 NDA.

[[Page 166]]

    (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 NDA 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 NDA that is received or 
otherwise obtained by the applicant from any source.
    (15) A nonclinical laboratory study that is described in the NDA 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 NDA, 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 NDA 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 NDA failed to contain the patent 
information required by section 505(b)(1) of the Federal Food, Drug, and 
Cosmetic Act.
    (19) The 505(b)(2) application failed to contain a patent 
certification or statement with respect to each listed patent for a drug 
product approved in an NDA that:
    (i) Is pharmaceutically equivalent to the drug product for which the 
original 505(b)(2) application is submitted; and
    (ii) Was approved before the original 505(b)(2) application was 
submitted.
    (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; 81 FR 60221, 
Aug. 31, 2016; 81 FR 69658, Oct. 6, 2016]



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 summary of the proposed or actual

[[Page 167]]

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.
    (5) Adequate measures are taken to minimize bias on the part of the 
subjects, observers, and analysts of the

[[Page 168]]

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 ANDA.

    (a) FDA will refuse to approve an ANDA for a new drug under section 
505(j) of the Federal Food, Drug, and Cosmetic Act for any of the 
following reasons, unless the requirement has been waived under Sec.  
314.99:
    (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 ANDA is insufficient to show that 
each of the proposed conditions of use has been previously approved for 
the listed drug referred to in the ANDA.
    (3)(i) If the reference listed drug has only one active ingredient, 
information submitted with the ANDA 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 ANDA 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 ANDAis for a drug product that has an active 
ingredient different from the reference listed drug:
    (A) Information submitted with the ANDA is insufficient to show:
    (1) That the other active ingredients are the same as the active 
ingredients of the reference listed drug; or

[[Page 169]]

    (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 Federal Food, Drug, and Cosmetic Act; or
    (B) No petition to submit an ANDA for the drug product with the 
different active ingredient was approved under Sec.  314.93.
    (4)(i) If the ANDA 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 ANDA, 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 ANDA 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 
ANDA for the drug product with the different route of administration, 
dosage form, or strength was approved under Sec.  314.93.
    (5) If the ANDA was submitted under the approval of a petition under 
Sec.  314.93, the ANDA 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 ANDA is insufficient to show 
that the drug product is bioequivalent to the listed drug referred to in 
the ANDA; or
    (ii) If the ANDA was submitted under a petition approved under Sec.  
314.93, information submitted in the ANDA 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 ANDA 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 ANDA 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 ANDA or 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 ANDA 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. 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.

[[Page 170]]

    (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 ANDA 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 ANDA 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 ANDA 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 ANDA 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 ANDA 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 ANDA 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 Federal Food, Drug, and 
Cosmetic Act.
    (13) The abbreviated new drug application contains an untrue 
statement of material fact.
    (14) For an ANDA submitted pursuant to an approved petition under 
Sec.  10.30 of this chapter and Sec.  314.93, an NDA subsequently has 
been approved for the change described in the approved petition.
    (b) FDA may refuse to approve an ANDA 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 ANDA 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

[[Page 171]]

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; 81 FR 69658, Oct. 
6, 2016]



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 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,

[[Page 172]]

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 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

[[Page 173]]

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 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.

[[Page 174]]

    (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 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.

[[Page 175]]

    (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.
    (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

[[Page 176]]

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 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

[[Page 177]]

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 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

[[Page 178]]

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.
    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.)


[[Page 179]]


    (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 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.

[[Page 180]]

    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 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

[[Page 181]]

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]



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.

[[Page 182]]

    (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. 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;
    (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

[[Page 183]]

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, 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

[[Page 184]]

(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.
    (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.

[[Page 185]]

    (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, 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

[[Page 186]]

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 Food and Drug Administration, Center for Biologics 
Evaluation and Research, Document Control Center, 10903 New Hampshire 
Ave., Bldg. 71, Rm. G112, Silver Spring, MD 20993-0002, 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 Center for Biologics Evaluation and 
Research, ATTN: Director, 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; 80 FR 18091, Apr. 3, 2015]



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 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

[[Page 187]]

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 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]

[[Page 188]]



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 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

[[Page 189]]

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
    (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

[[Page 190]]

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 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.

[[Page 191]]

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 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

[[Page 192]]

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.

  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.

[[Page 193]]

316.23 Timing of requests for orphan-drug designation; designation of 
          already approved drugs.
316.24 Deficiency letters and 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 for a rare 
disease or condition.
    (2) Allowing a sponsor to provide an investigational drug 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.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35132, June 12, 2013]



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)).
    (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

[[Page 194]]

that provided by an approved drug (that is otherwise the same drug) in 
one or more of the following ways:
    (i) Greater effectiveness than an approved 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 
for the same use or indication for 7 years, except as otherwise provided 
by law or in this part. A designated drug will receive orphan-drug 
exclusive approval only if the same drug has not already been approved 
for the same use or indication.
    (13) Orphan subset of a non-rare disease or condition (``orphan 
subset'') means that use of the drug in a subset of persons with a non-
rare disease or condition may be appropriate but use of the drug outside 
of that subset (in the remaining persons with the non-rare disease or 
condition) would be inappropriate owing to some property(ies) of the 
drug, for example, drug toxicity, mechanism of action, or previous 
clinical experience with the drug.
    (14) 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

[[Page 195]]

structures, would not cause the drugs to be considered different unless 
the 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.
    (15) 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; 78 FR 35132, June 12, 2013]



Sec.  316.4  Address for submissions.

    All correspondence and requests for FDA action under the provisions 
of this rule should be addressed as follows: Office of Orphan Products 
Development, Food and Drug Administration, Bldg. 32, Rm. 5271, 10903 New 
Hampshire Ave., Silver Spring, MD 20993.

[78 FR 35133, June 12, 2013]



  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 196]]

    (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 197]]

    (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 use for an already marketed 
drug. In addition, a sponsor of a drug that is otherwise the same drug 
as an already approved 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, 
telephone number, and email address; the generic and trade name, if any, 
of the drug, or, if neither is available, the chemical name or a 
meaningful descriptive name of the drug; and the name and address of the 
source of the drug if it is not manufactured by the sponsor.

[[Page 198]]

    (3) A description of the rare disease or condition for which the 
drug is being or will be investigated, the proposed use of the drug, and 
the reasons why such therapy is needed.
    (4) A description of the drug, to include the identity of the active 
moiety if it is a drug composed of small molecules, or of the principal 
molecular structural features if it is composed of macromolecules; its 
physical and chemical properties, if these characteristics can be 
determined; and a discussion of the scientific rationale to establish a 
medically plausible basis for the use of the drug for the rare disease 
or condition, including all relevant data from in vitro laboratory 
studies, preclinical efficacy studies conducted in an animal model for 
the human disease or condition, and clinical experience with the drug in 
the rare disease or condition that are available to the sponsor, whether 
positive, negative, or inconclusive. Animal toxicology studies are 
generally not relevant to a request for orphan-drug designation. 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 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 sponsor requests orphan-drug designation for a drug for 
only a subset of persons with a particular disease or condition that 
otherwise affects 200,000 or more people (``orphan subset''), a 
demonstration that, due to one or more properties of the drug, the 
remaining persons with such disease or condition would not be 
appropriate candidates for use of the drug.
    (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).
    (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.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]



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 is to be developed 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 is to be 
developed is less than 200,000 persons, ``prevalence'' is defined as the 
number of persons in the United

[[Page 199]]

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 developed, 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;
    (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

[[Page 200]]

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 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.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]



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, 
address, telephone number, and email address shall be provided to: 
Office of Orphan Products Development, Food and Drug Administration, 
Bldg. 32, rm. 5271, 10903 New Hampshire Ave., Silver Spring, MD 20993.

[78 FR 35133, June 12, 2013]



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 its 
drug development process prior to the time that sponsor submits a 
marketing application for the drug for the same rare disease or 
condition.
    (b) A sponsor may request orphan-drug designation of an already 
approved drug for an unapproved use without regard to whether the prior 
marketing approval was for a rare disease or condition.

[78 FR 35133, June 12, 2013]



Sec.  316.24  Deficiency letters and granting orphan-drug designation.

    (a) FDA will send a deficiency letter to the sponsor if the request 
for orphan-drug designation lacks information required under Sec. Sec.  
316.20 and 316.21, or contains inaccurate or incomplete information. FDA 
may consider a designation request voluntarily withdrawn if the sponsor 
fails to respond to the deficiency letter within 1 year of issuance of 
the deficiency letter, unless within that same timeframe the sponsor 
requests in writing an extension of time to respond. This request must 
include the reason(s) for the requested extension and the length of time 
of the requested extension. FDA will grant all

[[Page 201]]

reasonable requests for an extension. In the event FDA denies a request 
for an extension of time, FDA may consider the designation request 
voluntarily withdrawn. In the event FDA considers a designation request 
voluntarily withdrawn, FDA will so notify the sponsor in writing.
    (b) 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.
    (c) 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.
    (d) A sponsor may voluntarily withdraw an orphan-drug designation 
request or an orphan-drug designation at any time after the request is 
submitted or granted, respectively, by submitting a written request for 
withdrawal to FDA. FDA will acknowledge such withdrawal in a letter to 
the sponsor. Any benefits attendant to designation (such as orphan-
exclusive approval) will cease once designation is voluntarily 
withdrawn, from the date of FDA's acknowledgement letter. If a sponsor 
voluntarily withdraws designation, FDA will publicize such withdrawal in 
accordance with Sec.  316.28.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]



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 such disease or condition in the 
United States. A sponsor's failure to comply with Sec.  316.21 shall 
constitute a failure 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) The drug is otherwise the same drug as an already approved drug 
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 or if the request is otherwise 
ineligible under this part.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35133, June 12, 2013]



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 designated use if the proposed change is due to new and 
unexpected findings in research on the drug, 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 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

[[Page 202]]

Sec.  316.21(a)(1) or (a)(2) upon which the drug was originally 
designated.

[78 FR 35134, June 12, 2013]



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]



Sec.  316.28  Publication of orphan-drug designations.

    Each month FDA will update a publicly available cumulative posting 
of all drugs designated as orphan drugs. These postings will contain the 
following information:
    (a) The name and address of the sponsor;
    (b) The generic name and trade name, if any, or, if neither is 
available, the chemical name or a meaningful descriptive name of the 
drug;
    (c) The date of the granting of orphan-drug designation;
    (d) The designated use in the rare disease or condition; and
    (e) If the drug loses designation after August 12, 2013, the date of 
it no longer having designation.

[78 FR 35134, June 12, 2013]



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

[[Page 203]]

ground that the prevalence of the disease or condition (or the target 
population) becomes more than 200,000 persons.
    (d) If FDA revokes orphan-drug designation, FDA will publicize that 
the drug is no longer designated in accordance with Sec.  316.28(e).

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35134, June 12, 2013]



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) FDA may approve a sponsor's marketing application for a 
designated orphan drug for use in the rare disease or condition for 
which the drug was designated, or for select indication(s) or use(s) 
within the rare disease or condition for which the drug was designated. 
Unless FDA previously approved the same drug for the same use or 
indication, FDA will not approve another sponsor's marketing application 
for the same drug for the same use or indication 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 at 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 of the drug under section 527 of the act and Sec.  
316.36.
    (b) Orphan-drug exclusive approval protects only the approved 
indication or use of a designated drug. If such approval is limited to 
only particular indication(s) or uses(s) within the rare disease or 
condition for which the drug was designated, FDA may later approve the 
drug for additional indication(s) or uses(s) within the rare disease or 
condition not protected by the exclusive approval. If the sponsor who 
obtains approval for these new indication(s) or uses(s) has orphan-drug 
designation for the drug for the rare disease or condition, FDA will 
recognize a new orphan-drug exclusive approval for these new (not 
previously approved) indication(s) or use(s) from the date of approval 
of the drug for such new indication(s) or use(s).
    (c) 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 Federal Food, Drug, and Cosmetic Act until the expiration of 
the period of exclusive marketing of another drug, FDA will so notify 
the sponsor in writing.

[57 FR 62085, Dec. 29, 1992, as amended at 78 FR 35134, June 12, 2013]



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

[[Page 204]]

application for a designated orphan-drug product has been approved, if 
the same drug has not already been approved for the same use or 
indication. 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 under section 505 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) 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, and is 
also available online at http://www.accessdata.fda.gov/scripts/cder/ob/
default.cfm.
    (c) If a drug is otherwise the same drug as a previously approved 
drug for the same use or indication, FDA will not recognize orphan-drug 
exclusive approval if the sponsor fails to demonstrate upon approval 
that the drug is clinically superior to the previously approved drug.

[78 FR 35135, June 12, 2013]



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, 
Food and Drug Administration, Bldg. 32, rm. 5271, 10903

[[Page 205]]

New Hampshire Ave., Silver Spring, MD 20993.

[78 FR 35135, June 12, 2013]



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 317_QUALIFYING PATHOGENS--Table of Contents



Sec.
317.1 [Reserved]
317.2 List of qualifying pathogens that have the potential to pose a 
          serious threat to public health.

    Authority: 21 U.S.C. 355f, 371.

    Source: 79 FR 32480, June 5, 2014, unless otherwise noted.



Sec.  317.1  [Reserved]



Sec.  317.2  List of qualifying pathogens that have the potential to pose
a serious threat to public health.

    The term ``qualifying pathogen'' in section 505E(f) of the Federal 
Food, Drug, and Cosmetic Act is defined to mean any of the following:
    (a) Acinetobacter species.
    (b) Aspergillus species.
    (c) Burkholderia cepacia complex.
    (d) Campylobacter species.
    (e) Candida species.
    (f) Clostridium difficile.
    (g) Coccidioides species.
    (h) Cryptococcus species.
    (i) Enterobacteriaceae.
    (j) Enterococcus species.
    (k) Helicobacter pylori.
    (l) Mycobacterium tuberculosis complex.
    (m) Neisseria gonorrhoeae.
    (n) Neisseria meningitidis.
    (o) Non-tuberculous mycobacteria species.
    (p) Pseudomonas species.
    (q) Staphylococcus aureus.
    (r) Streptococcus agalactiae.
    (s) Streptococcus pneumoniae.
    (t) Streptococcus pyogenes.
    (u) Vibrio cholerae.



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.

[[Page 206]]

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.

    The definitions contained in Sec.  314.3 of this chapter apply to 
those terms when used in this part.

[81 FR 69658, Oct. 6, 2016]



      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 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.

[[Page 207]]

    (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]



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

[[Page 208]]

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 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]

[[Page 209]]



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 scientifically valid 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 must 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)(1) 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 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.
    (2) For drug products that are not intended to be absorbed into the 
bloodstream, bioequivalence may be demonstrated by scientifically valid 
methods that are expected to detect a significant difference between the 
drug and the listed drug in safety and therapeutic effect.

[57 FR 17999, Apr. 28, 1992, as amended at 67 FR 77673, Dec. 19, 2002, 
81 FR 69658, Oct. 6, 2016]



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

[[Page 210]]

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 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.

[[Page 211]]

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 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.

[[Page 212]]

    (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 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]

[[Page 213]]



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
    (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

[[Page 214]]

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 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

[[Page 215]]

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 
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

[[Page 216]]

    (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 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

[[Page 217]]

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) 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

[[Page 218]]

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-pass 
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; 81 FR 17066, Mar. 28, 2016]



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 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

[[Page 219]]

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 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

[[Page 220]]

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]



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

[[Page 221]]

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 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.

[[Page 222]]



PART 329_NONPRESCRIPTION HUMAN DRUG PRODUCTS SUBJECT TO SECTION 760 OF
THE FEDERAL FOOD, DRUG, AND COSMETIC ACT--Table of Contents



    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371, 379aa.

    Source: 79 FR 33089, June 10, 2014, unless otherwise noted.



Sec.  329.100  Postmarketing reporting of adverse drug events under
section 760 of the Federal Food, Drug, and Cosmetic Act.

    (a) Reporting requirements. Reports of serious adverse events 
required by section 760 of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) must include the information specified in this section, as 
applicable. Except as provided in paragraph (c)(2) of this section, 
these reports must be submitted to the Agency in electronic format as 
described in paragraph (c)(1) of this section.
    (b) Contents of reports. For purposes of reporting serious adverse 
events under section 760 of the FD&C Act, an individual case safety 
report (ICSR) constitutes the MedWatch form required to be submitted by 
section 760(d) of the FD&C Act. ICSRs include the following information:
    (1) Patient information.
    (i) Patient identification code;
    (ii) Patient age at the time of adverse drug experience, or date of 
birth;
    (iii) Patient gender; and
    (iv) Patient weight.
    (2) Adverse event.
    (i) Outcome attributed to adverse drug event;
    (ii) Date of adverse drug event;
    (iii) Date of ICSR submission;
    (iv) Description of adverse drug event (including a concise medical 
narrative);
    (v) Adverse drug event term(s);
    (vi) Description of relevant tests, including dates and laboratory 
data; and
    (vii) Other relevant patient history, including preexisting medical 
conditions.
    (3) Suspect medical product(s).
    (i) Name;
    (ii) Dose, frequency, and route of administration used;
    (iii) Therapy dates;
    (iv) Diagnosis for use (indication);
    (v) Whether the product is a combination product as defined in Sec.  
3.2(e) of this chapter;
    (vi) Whether the product is a prescription or nonprescription 
product;
    (vii) Whether adverse drug event abated after drug use stopped or 
dose reduced;
    (viii) Whether adverse drug event reappeared after reintroduction of 
drug;
    (ix) Lot number;
    (x) Expiration date;
    (xi) National Drug Code (NDC) number; and
    (xii) Concomitant medical products and therapy dates.
    (4) Initial reporter information.
    (i) Name, address, and telephone number;
    (ii) Whether the initial reporter is a health care professional; and
    (iii) Occupation, if a health care professional.
    (5) Responsible person (as defined in section 760(b) of the FD&C 
Act) information.
    (i) Name and contact office address;
    (ii) Telephone number;
    (iii) Report source, such as spontaneous;
    (iv) Date the report was received by responsible person;
    (v) Whether the ICSR is a 15-day report;
    (vi) Whether the ICSR is an initial report or followup report; and
    (vii) Unique case identification number, which must be the same in 
the initial report and any subsequent followup report(s).
    (c) Electronic format for submissions. (1) Each report required to 
be submitted to FDA under section 760 of the FD&C Act, accompanied by a 
copy of the label on or within the retail package of the drug and any 
other documentation (as ICSR attachments), must be in an electronic 
format that FDA can process, review, and archive. FDA will issue 
guidance on how to provide the electronic submission (e.g., method of 
transmission, media, file formats, preparation, and organization of 
files).
    (2) The responsible person may request, in writing, a temporary 
waiver of the requirements in paragraph (c)(1) of this section. These 
waivers will be

[[Page 223]]

granted on a limited basis for good cause shown. FDA will issue guidance 
on requesting a waiver of the requirements in paragraph (c)(1) of this 
section.
    (d) Patient privacy. The responsible person should not include in 
reports under this section the names and addresses of individual 
patients; instead, the responsible person should assign a unique code 
for identification of the patient. The responsible person should include 
the name of the reporter from whom the information was received as part 
of the initial reporter information, even when the reporter is the 
patient. The names of patients, health care professionals, hospitals, 
and geographical identifiers in adverse drug event reports are not 
releasable to the public under FDA's public information regulations in 
part 20 of this chapter.



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.
330.15 Timelines for FDA review and action on time and extent 
          applications and safety and effectiveness data submissions.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360fff-6, 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.
    (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

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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).
    (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''.

[[Page 225]]

    (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).
    (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''.

[[Page 226]]

    (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 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

[[Page 227]]

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\ x 11 
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.
    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

[[Page 228]]

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 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

[[Page 229]]

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 
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

[[Page 230]]

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 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.

[[Page 231]]

    (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 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

[[Page 232]]

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]



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

[[Page 233]]

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 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

[[Page 234]]

(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. 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.

[[Page 235]]

    (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; 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.

[[Page 236]]

    (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.

    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. Section 330.15 sets forth timelines for FDA 
review and action.
    (a) Definitions. The definitions and interpretations contained in 
section 201 of the Federal Food, Drug, and Cosmetic Act and the 
following definitions of terms apply to this section and to Sec.  
330.15.
    (1) 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 chemically modified substance derived from such a 
source.
    (2) 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.
    (3) Date of filing means the date of the notice from FDA stating 
that FDA has made a threshold determination that the safety and 
effectiveness data submission is sufficiently complete to permit a 
substantive review; or, if the submission is filed over protest in 
accordance with paragraph (j)(3) of this section, the date of filing is 
the date of the notice from FDA stating that FDA has filed the 
submission over protest (this date will be no later than 30 days after 
the request that FDA file the submission over protest).
    (4) Feedback letter means a letter issued by the agency in 
accordance with paragraph (g)(4) of this section that informs the 
sponsor and other interested persons who have submitted data under 
paragraph (f) of this section that a condition is initially determined 
not to be generally recognized as safe and effective (GRASE).
    (5) Safety and effectiveness data submission means a data package 
submitted by a sponsor or other interested person that includes safety 
and effectiveness data and information under paragraph (f) of this 
section and that is represented by the submitter as being a complete 
submission.

[[Page 237]]

    (6) Sponsor means the person that submitted a time and extent 
application (TEA) under paragraph (c) of this section.
    (7) Time and extent application (TEA) means a submission by a 
sponsor under paragraph (c) of this section, which will be evaluated by 
the agency to determine eligibility of a condition for consideration in 
the OTC drug monograph system.
    (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

[[Page 238]]

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 
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

[[Page 239]]

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 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) Safety and effectiveness data submission. The notice of 
eligibility will request a safety and effectiveness data submission that 
includes published and unpublished data to demonstrate the safety and 
effectiveness of the condition for its intended OTC use(s), as well as 
the submission of any other relevant data and views. These data will be 
submitted to a docket established in the Division of Dockets Management 
and will 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 
will not be considered confidential. The safety and effectiveness data 
submission must be sufficiently complete to be filed by the agency under 
paragraph (j)(2) of this section. Safety and effectiveness data and 
other information submitted under this paragraph are subject to the 
requirements in Sec.  330.10(c), (e), and (f). The safety and 
effectiveness data submission must 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 GRASE for OTC 
use in the United States, the agency will inform the sponsor and other 
interested persons who have submitted data of its determination by 
feedback letter, a copy of which will be placed on public display in the 
docket established in the Division of Dockets Management. The

[[Page 240]]

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 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.''
    (j) Filing determination. (1) After FDA receives a safety and 
effectiveness data submission, the agency will determine whether the 
submission may be filed. The filing of a submission means that FDA has 
made a threshold determination that the submission is sufficiently 
complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraph (j)(4) of 
this section for refusing to file the safety and effectiveness data 
submission apply, the agency will file the submission and notify the 
submitter in writing. FDA will post a copy of the notice to the docket. 
The date of filing begins the FDA timelines described in Sec.  
330.15(c)(3) and (4). Data submitted after the date of filing will be 
considered before the issuance of a notice of proposed rulemaking if 
there is adequate time for review; otherwise, the data will be 
considered as comments to the proposed rule after issuance of a notice 
of proposed rulemaking.
    (3) If FDA refuses to file the safety and effectiveness data 
submission, the agency will notify the submitter in writing and state 
the reason(s) under paragraph (j)(4) of this section for the refusal. 
The submitter may request in writing, within 30 days of the date of the 
agency's notification, a meeting with the agency about whether the 
agency should file the submission, and FDA will convene the meeting 
within 30 days of the request. If, within 120 days after the meeting, 
the submitter requests that FDA file the submission (with or without 
correcting the deficiencies), the agency will file the safety and 
effectiveness data submission over protest under paragraph (j)(2) of 
this section, notify the submitter in writing and post a copy to the 
docket, and review the submission as filed. The submitter must have a 
meeting before requesting that FDA file the submission over protest but 
need not resubmit a copy of a safety and effectiveness data submission 
that is filed over protest. A safety and effectiveness data submission 
and the corresponding TEA-eligible condition are both not deemed under 
consideration if FDA refuses to file the safety and effectiveness data 
submission, and it is not filed over protest; the condition remains 
eligible for consideration and the sponsor or any interested person can 
pursue consideration of the condition in the future by submitting a new 
safety and effectiveness data submission.

[[Page 241]]

    (4) FDA may refuse to file a safety and effectiveness data 
submission if any of the following applies:
    (i) The submission is incomplete because it does not contain 
information required under paragraph (f) of this section. If the 
submission does not contain required information because such 
information or data are not relevant to the condition, the submission 
must clearly identify and provide an explanation for the omission.
    (ii) The submission is not organized or formatted in a manner to 
enable the agency to readily determine whether it is sufficiently 
complete to permit a substantive review.
    (iii) The submission does not contain a signed statement that the 
submission represents a complete safety and effectiveness data 
submission and that the submission includes all the safety and 
effectiveness data and information available to the submitter at the 
time of the submission, whether positive or negative.
    (iv) The submission does not contain an analysis and summary of the 
data and other supporting information, organized by clinical or 
nonclinical area, such as clinical efficacy data, clinical safety data, 
clinical pharmacology, adverse event reports, animal toxicology, 
chemistry data, and compendial status.
    (v) The submission does not contain a supporting document 
summarizing the strategy used for literature searches, including search 
terms, sources, dates accessed, and years reviewed.
    (vi) The submission does not contain a reference list of supporting 
information, such as published literature, unpublished information, 
abstracts and case reports, and a copy of the supporting information.
    (vii) The submission includes data or information relevant for 
making a GRASE determination marked as confidential without a statement 
that the information may be released to the public.
    (viii) The submission does not contain a complete environmental 
assessment 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.
    (ix) The submission does not contain a statement for each 
nonclinical laboratory study that the study was conducted in compliance 
with the requirements set forth in part 58 of this chapter, or, if it 
was not conducted in compliance with part 58 of this chapter, a brief 
statement of the reason for the noncompliance.
    (x) The submission does not contain a statement for each clinical 
investigation involving human subjects that the investigation 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 the investigation was conducted in compliance with the informed 
consent regulations in part 50 of this chapter.
    (xi) The submission does not include financial certification or 
disclosure statements, or both, as required by part 54 of this chapter, 
accompanying any clinical data submitted.
    (k) Withdrawal of consideration. (1) Notwithstanding paragraph (g) 
of this section, FDA may withdraw consideration of a TEA submission or a 
safety and effectiveness data submission if:
    (i) The person that submitted the submission requests that its 
submission be withdrawn from consideration; or
    (ii) FDA deems the submission to be withdrawn from consideration due 
to the submitter's failure to respond to communications from FDA.
    (2) Before FDA deems a submission withdrawn under paragraph 
(k)(1)(ii) of this section, FDA will notify the person that submitted 
the submission. If, within 90 days from the date of the notice from FDA, 
the submitter requests that FDA not withdraw consideration of the 
submission, FDA will not deem the submission to be withdrawn.
    (3) If FDA withdraws consideration of a submission under paragraph 
(k)(1) of this section, FDA will post a notice of withdrawal to the 
docket, except in the case of a TEA submission that is withdrawn from 
consideration before issuance of a notice of eligibility, in which case, 
the notice of withdrawal will only be provided to the sponsor. 
Information that has been posted to the public docket for the condition 
at the time of the withdrawal (such as a

[[Page 242]]

notice of eligibility or a safety and effectiveness data submission that 
has been accepted for filing and posted to the docket) will remain in 
the public docket. If the condition has been found eligible through 
issuance of a notice of eligibility, the condition remains eligible for 
consideration and the sponsor or any interested person can pursue 
consideration of the condition in the future by submitting a new safety 
and effectiveness data submission.
    (4) If FDA withdraws consideration of a submission under paragraph 
(k)(1) of this section, the timelines under Sec.  330.15(c) will no 
longer apply as of the date of withdrawal, and the submission will not 
be included in the metrics under Sec.  330.15(b).

[67 FR 3074, Jan. 23, 2002, as amended at 81 FR 84475, Nov. 23, 2016]



Sec.  330.15  Timelines for FDA review and action on time and extent
applications and safety and effectiveness data submissions.

    (a) Applicability. This section applies to the review of a condition 
in a time and extent application (TEA) submitted under Sec.  330.14 for 
consideration in the over-the-counter (OTC) drug monograph system. This 
section does not apply to:
    (1) A sunscreen active ingredient or combination of sunscreen active 
ingredients, and other conditions for such ingredients; or
    (2) A non-sunscreen active ingredient or combination of non-
sunscreen active ingredients, and other conditions for such ingredients 
submitted in a TEA under Sec.  330.14 before November 27, 2014, subject 
to section 586F(a)(1)(C) of the Federal Food, Drug, and Cosmetic Act.
    (b) Metrics. FDA will maintain and update annually, a publicly 
available posting of metrics for the review of TEAs and safety and 
effectiveness data submissions that are subject to the timelines in this 
section. The posting will contain the following information for tracking 
the extent to which the timelines set forth in paragraph (c) of this 
section were met during the previous calendar year.
    (1) Number and percent of eligibility notices or ineligibility 
letters issued within 180 days of submission of a TEA;
    (2) Number and percent of filing determinations issued within 90 
days of submission of a safety and effectiveness data submission;
    (3) If applicable, number and percent of feedback letters issued 
within 730 days from the date of filing;
    (4) Number and percent of notices for proposed rulemaking issued 
within 1,095 days from the date of filing;
    (5) Number and percent of final rules issued within 912 days of 
closing of the docket of the proposed rulemaking; and
    (6) Total number of TEAs submitted under Sec.  330.14.
    (c) Timelines for FDA review and action. FDA will review and take an 
action within the following timelines:
    (1) Within 180 days of submission of a TEA under Sec.  330.14(c), 
FDA will issue a notice of eligibility or post to the docket a letter of 
ineligibility, in accordance with Sec.  330.14(d) and (e).
    (2) Within 90 days of submission of a safety and effectiveness data 
submission, in accordance with Sec.  330.14(j), FDA will issue a filing 
determination. The date of filing begins the FDA timelines in paragraphs 
(c)(3) and (4) of this section.
    (3) Within 730 days from the date of filing, if the condition is 
initially determined not to be GRASE for OTC use in the United States, 
FDA will inform the sponsor and other interested persons who have 
submitted data of its determination by feedback letter in accordance 
with Sec.  330.14(g)(4).
    (4) Within 1,095 days from the date of filing of a safety and 
effectiveness data submission, FDA will issue a notice of proposed 
rulemaking to either:
    (i) Include the condition in an appropriate OTC monograph(s), either 
by amending an existing monograph(s) or establishing a new monograph(s), 
if necessary; or
    (ii) Include the condition in Sec.  310.502 of this chapter.
    (5) Within 912 days of the closing of the docket of the proposed 
rulemaking under paragraph (c)(4) of this section, FDA will issue a 
final rule.

[81 FR 84477, Nov. 23, 2016]

[[Page 243]]



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.
    (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.

[[Page 244]]

    (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, 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 Ingredient x 100)/
(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]

[[Page 245]]



                           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 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]

[[Page 246]]



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.

                           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]

[[Page 247]]



                      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 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.

[[Page 248]]

                  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 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

[[Page 249]]

    (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:
    (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

[[Page 250]]

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'')), (``