[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 2002 Edition]
[From the U.S. Government Printing Office]



[[Page i]]

          

                    21


          Parts 300 to 499

                         Revised as of April 1, 2002

Food and Drugs





          Containing a codification of documents of general 
          applicability and future effect
          As of April 1, 2002
          With Ancillaries
          Published by
          Office of the Federal Register
          National Archives and Records
          Administration

A Special Edition of the Federal Register



[[Page ii]]






                     U.S. GOVERNMENT PRINTING OFFICE
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[[Page iii]]




                            Table of Contents



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

  Title 21:
          Chapter I--Food and Drug Administration, Department 
          of Health and Human Services (Continued)                   3
  Finding Aids:
      Material Approved for Incorporation by Reference........     319
      Table of CFR Titles and Chapters........................     321
      Alphabetical List of Agencies Appearing in the CFR......     339
      List of CFR Sections Affected...........................     349



[[Page iv]]





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

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

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

[[Page v]]



                               EXPLANATION

    The Code of Federal Regulations is a codification of the general and 
permanent rules published in the Federal Register by the Executive 
departments and agencies of the Federal Government. The Code is divided 
into 50 titles which represent broad areas subject to Federal 
regulation. Each title is divided into chapters which usually bear the 
name of the issuing agency. Each chapter is further subdivided into 
parts covering specific regulatory areas.
    Each volume of the Code is revised at least once each calendar year 
and issued on a quarterly basis approximately as follows:

Title 1 through Title 16.................................as of January 1
Title 17 through Title 27..................................as of April 1
Title 28 through Title 41...................................as of July 1
Title 42 through Title 50................................as of October 1

    The appropriate revision date is printed on the cover of each 
volume.

LEGAL STATUS

    The contents of the Federal Register are required to be judicially 
noticed (44 U.S.C. 1507). The Code of Federal Regulations is prima facie 
evidence of the text of the original documents (44 U.S.C. 1510).

HOW TO USE THE CODE OF FEDERAL REGULATIONS

    The Code of Federal Regulations is kept up to date by the individual 
issues of the Federal Register. These two publications must be used 
together to determine the latest version of any given rule.
    To determine whether a Code volume has been amended since its 
revision date (in this case, April 1, 2002), consult the ``List of CFR 
Sections Affected (LSA),'' which is issued monthly, and the ``Cumulative 
List of Parts Affected,'' which appears in the Reader Aids section of 
the daily Federal Register. These two lists will identify the Federal 
Register page number of the latest amendment of any given rule.

EFFECTIVE AND EXPIRATION DATES

    Each volume of the Code contains amendments published in the Federal 
Register since the last revision of that volume of the Code. Source 
citations for the regulations are referred to by volume number and page 
number of the Federal Register and date of publication. Publication 
dates and effective dates are usually not the same and care must be 
exercised by the user in determining the actual effective date. In 
instances where the effective date is beyond the cut-off date for the 
Code a note has been inserted to reflect the future effective date. In 
those instances where a regulation published in the Federal Register 
states a date certain for expiration, an appropriate note will be 
inserted following the text.

OMB CONTROL NUMBERS

    The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires 
Federal agencies to display an OMB control number with their information 
collection request.

[[Page vi]]

Many agencies have begun publishing numerous OMB control numbers as 
amendments to existing regulations in the CFR. These OMB numbers are 
placed as close as possible to the applicable recordkeeping or reporting 
requirements.

OBSOLETE PROVISIONS

    Provisions that become obsolete before the revision date stated on 
the cover of each volume are not carried. Code users may find the text 
of provisions in effect on a given date in the past by using the 
appropriate numerical list of sections affected. For the period before 
January 1, 1986, consult either the List of CFR Sections Affected, 1949-
1963, 1964-1972, or 1973-1985, published in seven separate volumes. For 
the period beginning January 1, 1986, a ``List of CFR Sections 
Affected'' is published at the end of each CFR volume.

INCORPORATION BY REFERENCE

    What is incorporation by reference? Incorporation by reference was 
established by statute and allows Federal agencies to meet the 
requirement to publish regulations in the Federal Register by referring 
to materials already published elsewhere. For an incorporation to be 
valid, the Director of the Federal Register must approve it. The legal 
effect of incorporation by reference is that the material is treated as 
if it were published in full in the Federal Register (5 U.S.C. 552(a)). 
This material, like any other properly issued regulation, has the force 
of law.
    What is a proper incorporation by reference? The Director of the 
Federal Register will approve an incorporation by reference only when 
the requirements of 1 CFR part 51 are met. Some of the elements on which 
approval is based are:
    (a) The incorporation will substantially reduce the volume of 
material published in the Federal Register.
    (b) The matter incorporated is in fact available to the extent 
necessary to afford fairness and uniformity in the administrative 
process.
    (c) The incorporating document is drafted and submitted for 
publication in accordance with 1 CFR part 51.
    Properly approved incorporations by reference in this volume are 
listed in the Finding Aids at the end of this volume.
    What if the material incorporated by reference cannot be found? If 
you have any problem locating or obtaining a copy of material listed in 
the Finding Aids of this volume as an approved incorporation by 
reference, please contact the agency that issued the regulation 
containing that incorporation. If, after contacting the agency, you find 
the material is not available, please notify the Director of the Federal 
Register, National Archives and Records Administration, Washington DC 
20408, or call (202) 523-4534.

CFR INDEXES AND TABULAR GUIDES

    A subject index to the Code of Federal Regulations is contained in a 
separate volume, revised annually as of January 1, entitled CFR Index 
and Finding Aids. This volume contains the Parallel Table of Statutory 
Authorities and Agency Rules (Table I). A list of CFR titles, chapters, 
and parts and an alphabetical list of agencies publishing in the CFR are 
also included in this volume.
    An index to the text of ``Title 3--The President'' is carried within 
that volume.
    The Federal Register Index is issued monthly in cumulative form. 
This index is based on a consolidation of the ``Contents'' entries in 
the daily Federal Register.
    A List of CFR Sections Affected (LSA) is published monthly, keyed to 
the revision dates of the 50 CFR titles.

[[Page vii]]


REPUBLICATION OF MATERIAL

    There are no restrictions on the republication of material appearing 
in the Code of Federal Regulations.

INQUIRIES

    For a legal interpretation or explanation of any regulation in this 
volume, contact the issuing agency. The issuing agency's name appears at 
the top of odd-numbered pages.
    For inquiries concerning CFR reference assistance, call 202-523-5227 
or write to the Director, Office of the Federal Register, National 
Archives and Records Administration, Washington, DC 20408 or e-mail 
info@fedreg.nara.gov.

SALES

    The Government Printing Office (GPO) processes all sales and 
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Customer Service call 202-512-1803.

ELECTRONIC SERVICES

    The full text of the Code of Federal Regulations, the LSA (List of 
CFR Sections Affected), The United States Government Manual, the Federal 
Register, Public Laws, Public Papers, Weekly Compilation of Presidential 
Documents and the Privacy Act Compilation are available in electronic 
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free). E-mail, gpoaccess@gpo.gov.
    The Office of the Federal Register also offers a free service on the 
National Archives and Records Administration's (NARA) World Wide Web 
site for public law numbers, Federal Register finding aids, and related 
information. Connect to NARA's web site at www.nara.gov/fedreg. The NARA 
site also contains links to GPO Access.

                              Raymond A. Mosley,
                                    Director,
                          Office of the Federal Register.

April 1, 2002.



[[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-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, 2002.

    Redesignation tables for Chapter I--Food and Drug Administration 
appear in the Finding Aids section for the volumes containing parts 170-
199 and 500-599.

[[Page x]]





[[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

Cross References: Food Safety and Inspection Service, Department of 
  Agriculture: See 9 CFR chapter III.

  Federal Trade Commission: See Commercial Practices, 16 CFR chapter I.

  United States Customs Service, Department of the Treasury: See Customs 
Duties, 19 CFR chapter I.

  Internal Revenue Service, Department of the Treasury: See Internal 
Revenue, 26 CFR chapter I.

  Bureau of Alcohol, Tobacco, and Firearms, Department of the Treasury: 
See Alcohol, Tobacco Products and Firearms, 27 CFR chapter I.

[[Page 3]]



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




                           (Parts 300 to 499)

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


  Editorial Note: For nomenclature changes to chapter I see 59 FR 14366, 
Mar. 28, 1994.

                    SUBCHAPTER D--DRUGS FOR HUMAN USE
Part                                                                Page
300             General.....................................           5
310             New drugs...................................           5
312             Investigational new drug application........          57
314             Applications for FDA approval to market a 
                    new drug................................          95
315             Diagnostic radiopharmaceuticals.............         172
316             Orphan drugs................................         174
320             Bioavailability and bioequivalence 
                    requirements............................         185
328             Over-the-counter drug products intended for 
                    oral ingestion that contain alcohol.....         200
329             Habit-forming drugs.........................         201
330             Over-the-counter (OTC) human drugs which are 
                    generally recognized as safe and 
                    effective and not misbranded............         206
331             Antacid products for over-the-counter (OTC) 
                    human use...............................         222
332             Antiflatulent products for over-the-counter 
                    human use...............................         226
333             Topical antimicrobial drug products for 
                    over-the-counter human use..............         227
336             Antiemetic drug products for over-the-
                    counter human use.......................         235
338             Nighttime sleep-aid drug products for over-
                    the-counter human use...................         237
340             Stimulant drug products for over-the-counter 
                    human use...............................         238

[[Page 4]]

341             Cold, cough, allergy, bronchodilator, and 
                    antiasthmatic drug products for over-
                    the-counter human use...................         239
343             Internal analgesic, antipyretic, and 
                    antirheumatic drug products for over-
                    the-counter human use...................         256
344             Topical OTIC drug products for over-the-
                    counter human use.......................         263
346             Anorectal drug products for over-the-counter 
                    human use...............................         265
347             Skin protectant drug products for over-the-
                    counter human use.......................         270
348             External analgesic drug products for over-
                    the-counter human use...................         272
349             Ophthalmic drug products for over-the-
                    counter human use.......................         273
352             Sunscreen drug products for over-the-counter 
                    human use...............................         278
355             Anticaries drug products for over-the-
                    counter human use.......................         288
357             Miscellaneous internal drug products for 
                    over-the-counter human use..............         292
358             Miscellaneous external drug products for 
                    over-the-counter human use..............         296
361             Prescription drugs for human use generally 
                    recognized as safe and effective and not 
                    misbranded: Drugs used in research......         303
369             Interpretative statements re warnings on 
                    drugs and devices for over-the-counter 
                    sale....................................         308
370-499         [Reserved]

[[Page 5]]



                    SUBCHAPTER D--DRUGS FOR HUMAN USE



PART 300--GENERAL--Table of Contents




Subpart A [Reserved]

                      Subpart B--Combination Drugs

Sec.
300.50 Fixed-combination prescription drugs for humans.

          Subpart C--Substances Generally Prohibited From Drugs

300.100 Chlorofluorocarbon propellants.

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

Subpart A [Reserved]



                      Subpart B--Combination Drugs



Sec. 300.50  Fixed-combination prescription drugs for humans.

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

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



          Subpart C--Substances Generally Prohibited From Drugs



Sec. 300.100  Chlorofluorocarbon propellants.

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

[43 FR 11317, Mar. 17, 1978]



PART 310--NEW DRUGS--Table of Contents




                      Subpart A--General Provisions

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

        Subpart B--Specific Administrative Rulings and Decisions

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

 Subpart C--New Drugs Exempted From Prescription-Dispensing Requirements

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

[[Page 6]]

                     Subpart D--Records and Reports

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

        Subpart E--Requirements for Specific New Drugs or Devices

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

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



                      Subpart A--General Provisions



Sec. 310.3  Definitions and interpretations.

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

[[Page 7]]

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

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



Sec. 310.4   Biologics; products subject to license control.

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

[[Page 8]]

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

[64 FR 56448, Oct. 20, 1999]



Sec. 310.6  Applicability of ``new drug'' or safety or effectiveness 
findings in drug efficacy study implementation notices and notices of 
opportunity for hearing to identical, related, and similar drug products.

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

[[Page 9]]

Where the relationships are more subtle and not readily recognized, the 
purchasing agent may request an opinion by writing to the Food and Drug 
Administration at the address shown in paragraph (e) of this section.
    (e) Interested parties may submit to the Food and Drug 
Administration, Center for Drug Evaluation and Research, Office of 
Compliance, HFD-300, 5600 Fishers Lane, Rockville, MD 20857, 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 Secs. 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]



        Subpart B--Specific Administrative Rulings and Decisions



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

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

[39 FR 11680, Mar. 29, 1974]



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

[[Page 10]]

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) ``Caution: Federal law prohibits dispensing without a 
prescription''; 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]

    Effective Date Note: At 67 FR 4907, Feb. 1, 2002, Sec. 310.103 was 
amended in paragraph (a)(3)(i) by removing the phrase `` `Caution: 
Federal law prohibits dispensing without a prescription' '' and by 
adding in its place the phrase `` `Rx only' '', effective Apr. 2, 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)(C) 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)(C) 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)(C) of the act 
may be initiated by the Commissioner or by any interested person. Any 
interested person may file a petition seeking such exemption, which 
petition may be pursuant to part 10 of this chapter, or in the form of a 
supplement to an approved new drug application.
    (c) New drug status of drugs exempted from the prescription 
requirement. A drug exempted from the prescription requirement under the 
provisions of paragraph (b) of this section is a ``new drug'' within the 
meaning of section 201(p) of the act until it has been used to a 
material extent and for a material time under such conditions except as 
provided in paragraph (e) of this section.

[[Page 11]]

    (d) Prescription legend not allowed on exempted drugs. The use of 
the prescription caution statement quoted in section 503(b) (4) of the 
act, in the labeling of a drug exempted under the provisions of this 
section, constitutes misbranding. Any other statement or suggestion in 
the labeling of a drug exempted under this section, that such drug is 
limited to prescription use, may constitute misbranding.
    (e) Prescription-exemption procedure of OTC drug review. A drug 
limited to prescription use under section 503(b)(1)(C) 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]



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

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

[[Page 12]]

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

[[Page 13]]

hydrochloride) preparations meeting all the following conditions:
    (i) The dicyclomine hydrochloride is prepared with suitable antacid 
and other components, in tablet or other dosage form for oral use in 
self-medication, and containing no drug limited to prescription sale 
under the provisions of section 503(b)(1) of the act.
    (ii) The dicyclomine hydrochloride and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 5 milligrams of 
dicyclomine hydrochloride per dosage unit, or if it is in liquid form 
not more than 0.5 milligram of dicyclomine hydrochloride per milliliter.
    (v) The preparation is labeled with adequate directions for use only 
by adults and children over 12 years of age, in the temporary relief of 
gastric hyperacidity.
    (vi) The dosages recommended or suggested in the directions for use 
do not exceed 10 milligrams of dicyclomine hydrochloride per dose or 30 
milligrams in a 24-hour period.
    (vii) The labeling bears, in juxtaposition with the dosage 
recommendations, clear warning statements against:
    (a) Exceeding the recommended dosage.
    (b) Prolonged use, except as directed by a physician, since 
persistent or recurring symptoms may indicate a serious disease 
requiring medical attention.
    (c) Administration to children under 12 years of age except as 
directed by a physician.
    (9)-(10) [Reserved]
    (11) Hexadenol (a mixture of tetracosanes and their oxidation 
products) preparations meeting all the following conditions:
    (i) The hexadenol is prepared and packaged, with or without other 
drugs, solvents, and propellants, in a form suitable for self-medication 
by external application to the skin as a spray, and containing no drug 
limited to prescription sale under the provisions of section 503(b)(1) 
of the act.
    (ii) The hexadenol and all other components of the preparation meet 
their professed standards of identity, strength, quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 5 percent by weight of 
hexadenol.
    (v) The preparation is labeled with adequate directions for use by 
external application in the treatment of minor burns and minor skin 
irritations.
    (vi) The labeling bears, in juxtaposition with the directions for 
use, clear warning statements against:
    (a) Use on serious burns or skin conditions or prolonged use, except 
as directed by a physician.
    (b) Spraying the preparation in the vicinity of eyes, mouth, nose, 
or ears.
    (12) Sulfur dioxide preparations meeting all the following 
conditions:
    (i) The sulfur dioxide is prepared with or without other drugs, in 
an aqueous solution packaged in a hermetic container suitable for use in 
self-medication by external application to the skin, and containing no 
drug limited to prescription sale under the provisions of section 
503(b)(1) of the act.
    (ii) The sulfur dioxide and all other components of the preparation 
meet their professed standards of identity, strength, quality, and 
purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 5 grams of sulfur 
dioxide per 100 milliliters of solution.
    (v) The preparation is labeled with adequate directions for use by 
external application to the smooth skin in the prevention or treatment 
of minor conditions in which it is indicated.
    (vi) The directions for use recommend or suggest not more than two 
applications a day for not more than 1 week, except as directed by a 
physician.
    (13)-(15) [Reserved]
    (16) Tuaminoheptane sulfate (2-aminoheptane sulfate) preparations 
meeting all the following conditions:
    (i) The tuaminoheptane sulfate is prepared, with or without other 
drugs,

[[Page 14]]

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 -
morpholinopropyl ether hydrochloride) preparations meeting all the 
following conditions:
    (i) The pramoxine hydrochloride is prepared, with or without other 
drugs, in a dosage form suitable for use in self-medication by external 
application to the skin, and containing no drug limited to prescription 
sale under the provisions of section 503(b)(1) of the act.
    (ii) The pramoxine hydrochloride and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 1.0 percent of pramoxine 
hydrochloride.
    (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

[[Page 15]]

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) Carbetapentane citrate (2-(2-diethylaminoethoxy)-ethyl-1-
phenyl- cyclopentyl-1-carboxylate citrate) preparations meeting all the 
following conditions:
    (i) The carbetanentane 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 carbetapentane 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, and application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 25 milligrams of 
carbetapentane citrate per dosage unit; or if it is in liquid form, not 
more than 1.5 milligrams of carbetapentane citrate 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, 30 milligrams of carbetapentane citrate per dose or 
120 milligrams of carbetapentane citrate per 24-hour period; for 
children 4 to 12 years of age, 7.5 milligrams per dose or 30 milligrams 
per 24-hour period; for children 2 to 4 years of age, 4.0 milligrams per 
dose or 16.0 milligrams per 24-hour period.
    (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 2 years of age, unless directed by a physician.
    (b) Clear warning statements 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.
    (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.

[[Page 16]]

    (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--piperidonopropiophenone 
hydrochloride) preparations meeting all the following conditions:
    (i) The dyclonine hydrochloride is prepared, with or without other 
drugs, in a dosage form suitable for use as a cream or ointment in self-
medication by external application to the skin, or rectally, and 
contains no drug limited to prescription sale under the provisions of 
section 503(b)(1) of the act.
    (ii) The dyclonine hydrochloride and all other components of the 
preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 1.0 percent of dyclonine 
hydrochloride.
    (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

[[Page 17]]

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 (-(o-methoxyphenyl)-
isopropyl-methylamine hydrochloride; 1-(o-methoxyphenyl)- 2-methylamino-
propane hydrochloride) preparations meeting all the following 
conditions:
    (i) The methoxyphenamine hydrochloride is prepared with appropriate 
amounts of a suitable antitussive, with or without other drugs, in a 
dosage form suitable for oral use in self-medication, and containing no 
drug limited to prescription sale under the provisions of section 
503(b)(1) of the act.
    (ii) The methoxyphenamine hydrochloride and all other components of 
the preparation meet their professed standards of identity, strength, 
quality, and purity.
    (iii) If the preparation is a new drug, an application pursuant to 
section 505(b) of the act is approved for it.
    (iv) The preparation contains not more than 3.5 milligrams of 
methoxyphenamine hydrochloride per milliliter.
    (v) The preparation is labeled with adequate directions for use in 
the temporary relief of cough due to minor conditions in which it is 
indicated.
    (vi) The dosages recommended or suggested in the labeling do not 
exceed: For adults, 35 milligrams of methoxyphenamine hydrochloride per 
dose or 140 milligrams of methoxyphenamine hydrochloride per 24-hour 
period; for children 6 to 12 years of age, one-half of the maximum adult 
dose or dosage.
    (vii) The label bears a conspicuous warning to keep the drug out of 
the reach of children, and the labeling 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 (-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.

[[Page 18]]

    (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]



                     Subpart D--Records and Reports



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

    (a) A new drug may not be approved for marketing unless it has been 
shown to be safe and effective for its intended use(s). After approval, 
the applicant is required to establish and maintain records and make 
reports related to clinical experience or other data or information 
necessary to make or facilitate a determination of whether there are or 
may be grounds under section 505(e) of the act for suspending or 
withdrawing approval of the application. Some drugs, because of the 
nature of 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 
adversedrug experiences associated with the use of their drug products. 
Any person subject to the reporting requirements of paragraph (c) of 
this section shall also develop written procedures for the surveillance, 
receipt, evaluation, and reporting of postmarketing adverse drug 
experiences to FDA.
    (b) Definitions. The following definitions of terms apply to this 
section:-

[[Page 19]]

    Adverse drug experience. Any adverse event associated with the use 
of a drug in humans, whether or not considered drug related, including 
the following: An adverse event occurring in the course of the use of a 
drug product in professional practice; an adverse event occurring from 
drug overdose whether accidental or intentional; an adverse event 
occurring from drug abuse; an adverse event occurring from drug 
withdrawal; and any failure of expected pharmacological action.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial reporter, 
at immediate risk of death from the adverse drug experience as it 
occurred, i.e., it does not include an adverse drug experience that, had 
it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
    Unexpected adverse drug experience. Any adverse drug experience that 
is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event 
because of greater severity or specificity. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the labeling only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the labeling 
only listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (c) Reporting requirements. Each person identified in paragraph 
(c)(1)(i) of this section shall report to FDA adverse drug experience 
information as described in this section and shall submit one copy of 
each report to the Division of Pharmacovigilance and Epidemiology (HFD-
730), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (1) Postmarketing 15-day ``Alert reports''. (i) Any person whose 
name appears on the label of a marketed prescription drug product as its 
manufacturer, packer, or distributor shall report to FDA each adverse 
drug experience received or otherwise obtained that is both serious and 
unexpected as soon as possible, but in no case later than 15 calendar 
days of initial receipt of the information by the person whose name 
appears on the label. Each report shall be accompanied by a copy of the 
current labeling for the drug product.
    (ii) A person identified in paragraph (c)(1)(i) of this section is 
not required to submit a 15-day ``Alert report'' for an adverse drug 
experience obtained from a postmarketing study (whether or not conducted 
under an investigational new drug application) unless the applicant 
concludes that there is a reasonable possibility that the drug caused 
the adverse experience.
    (2) Postmarketing 15-day ``Alert reports''--followup. Each person 
identified in paragraph (c)(1)(i) of this section shall promptly 
investigate all serious, unexpected adverse drug experiences

[[Page 20]]

that are the subject of these postmarketing 15-day Alert reports and 
shall submit followup reports within 15 calendar days of receipt of new 
information or as requested by FDA. If additional information is not 
obtainable, records should be maintained of the unsuccessful steps taken 
to seek additional information. Postmarketing 15-day Alert reports and 
followups to them shall be submitted under separate cover.
    (3) Submission of reports. To avoid unnecessary duplication in the 
submission of, and followup to, reports required in this section, a 
packer's or distributor's obligations may be met by submission of all 
reports of serious adverse drug experiences to the manufacturer of the 
drug product. If a packer or distributor elects to submit these adverse 
drug experience reports to the manufacturer rather than to FDA, it shall 
submit each report to the manufacturer within 5 calendar days of its 
receipt by the packer or distributor, and the manufacturer shall then 
comply with the requirements of this section even if its name does not 
appear on the label of the drug product. Under this circumstance, the 
packer or distributor shall maintain a record of this action which shall 
include:
    (i) A copy of each adverse drug experience report;
    (ii) The date the report was received by the packer or distributor;
    (iii) The date the report was submitted to the manufacturer; and
    (iv) The name and address of the manufacturer.
    (4) Each report submitted to FDA under this section shall bear 
prominent identification as to its contents, i.e., ``15-day Alert 
report,'' or ``15-day Alert report-followup.''
    (5) A person identified in paragraph (c)(1)(i) of this section is 
not required to resubmit to FDA adverse drug experience reports 
forwarded to that person by FDA; however, the person must submit all 
followup information on such reports to FDA.
    (d) Reporting form. (1) Except as provided in paragraph (d)(3) of 
this section, each person identified in paragraph (c)(1)(i) of this 
section shall submit each report of a serious and unexpected adverse 
drug experience on an FDA Form 3500A (foreign events may be submitted 
either on an FDA Form 3500A or, if preferred, on a CIOMS I form).
    (2) Each completed FDA Form 3500A should pertain only to an 
individual patient.
    (3) Instead of using Form FDA Form 3500A, a manufacturer, packer, or 
distributor may use a computer-generated FDA Form 3500A or other 
alternative format (e.g., a computer-generated tape or tabular listing) 
provided that:
    (i) The content of the alternative format is equivalent in all 
elements of information to those specified in FDA Form 3500A, and
    (ii) The format is agreed to in advance by MedWatch: The FDA Medical 
Products Reporting Program.
    (4) Ten copies or fewer of FDA Form 3500A and/or a copy of the 
instructions for completing the form may be obtained from the Division 
of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857. More than 10 copies of the form may be 
obtained by writing to the Consolidated Forms and Publications 
Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., 
Landover, MD 20785.
    (e) Patient privacy. Manufacturers, packers, and distributors should 
not include in reports under this section the names and addresses of 
individual patients; instead, the manufacturer, packer, and distributor 
should assign a unique code number to each report, preferably not more 
than eight characters in length. The manufacturer, packer, and 
distributor should include the name of the reporter from whom the 
information was received. Names of patients, individual reporters, 
health care professionals, hospitals, and geographical identifiers in 
adverse drug experience reports are not releasable to the public under 
FDA's public information regulations in part 20 of this chapter.
    (f) Recordkeeping. (1) Each manufacturer, packer, and distributor 
shall maintain for a period of 10 years records of all adverse drug 
experiences

[[Page 21]]

required under this section to be reported, including raw data and any 
correspondence relating to the adverse drug experiences, and the records 
required to be maintained under paragraph (c)(4) of this section.
    (2) Manufacturers and packers may retain the records required in 
paragraph (f)(1) of this section as part of its complaint files 
maintained under Sec. 211.198 of this chapter.
    (3) Manufacturers, packers, and distributors shall permit any 
authorized FDA employee, at all reasonable times, to have access to and 
copy and verify the records established and maintained under this 
section.
    (g) Disclaimer. A report or information submitted by a manufacturer, 
packer, or distributor under this section (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by 
the manufacturer, packer, or distributor, or by FDA, that the report or 
information constitutes an admission that the drug caused or contributed 
to an adverse effect. The manufacturer, packer, or distributor need not 
admit, and may deny, that the report or information submitted under this 
section constitutes an admission that the drug caused or contributed to 
an adverse effect.

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



        Subpart E--Requirements for Specific New Drugs or Devices



Sec. 310.500  Digoxin products for oral use; conditions for marketing.

    (a) Studies have shown evidence of clinically significant 
differences in bio-availability in different batches of certain marketed 
digoxin products for oral use from single manufacturers as well as in 
batches of these products produced by different manufacturers. These 
differences were observed despite the fact that the products met 
compendial specifications. Other studies have shown that there is a 
sufficient correlation between bioavailability in vivo and the 
dissolution rate of digoxin tablets in vitro to make the dissolution 
test an important addition to the compendial standards. Because of the 
potential for serious risk to cardiac patients using digoxin products 
which may vary in bioavailability, the Commissioner of Food and Drugs 
has determined that immediate action must be taken to assure the 
uniformity of all digoxin products for oral use. The Commissioner is of 
the opinion that digoxin products for oral use are new drugs within the 
meaning of section 201(p) of the Federal Food, Drug, and Cosmetic Act 
for which approved new drug applications are required. The Commissioner 
has determined that, because of questions raised regarding the 
bioavailability of digoxin products for oral use, there is sufficient 
evidence to invoke the authority under section 505(j) of the act to 
fully investigate this question and to facilitate a determination of 
whether there is a ground for withdrawal of approval of the drug product 
under section 505(e) of the act. Marketing of these products may be 
continued only under the following conditions:
    (1) Digoxin products for oral use, other than tablets: Any person 
marketing digoxin products for oral use, other than tablets, shall 
submit to the Food and Drug Administration on or before February 21, 
1974, an abbreviated new drug application for these products. Any such 
drug product then on the market which is not the subject of an 
application submitted for the drug product shall be subject to 
regulatory procedures under section 505 of the act. In addition to the 
information specified in Sec. 314.50 of this chapter, the application 
shall contain:
    (i) A full list of the articles used as components of the digoxin 
product, specifications for components, detailed identification and 
analytical procedures used to assure that the components meet 
established specifications of identity, strength, quality, and purity 
and a complete description of the manufacturing process.
    (ii) The source of the digoxin used in the formulation including the 
name and address of the supplier.
    (iii) A statement that stability studies will be conducted to 
establish a suitable expiration date for the digoxin

[[Page 22]]

product in the form in which it is distributed.
    (iv) A statement that the product label will contain a suitable 
expiration date. In the absence of any stability test data, this 
expiration date shall be no longer than one year after the batch is 
manufactured. If the expiration date is greater than one year, 
supporting stability data shall be included in the application.
    (v) Labeling that is in compliance with all requirements of the act 
and regulations promulgated thereunder, the pertinent parts of which are 
as indicated in paragraph (e) of this section.
    (vi) A statement that the applicant will initiate recall of all 
stocks of the drug product outstanding when so requested by the Food and 
Drug Administration.
    (vii) A statement that the applicant intends to conduct in vivo 
bioavailability tests and that the applicant, under the records and 
reports provisions of section 505(k) of the act, will:
    (a) Within 30 days after the submission of the application, submit 
to the Food and Drug Administration the protocol which the applicant 
proposes to follow in conducting these in vivo bioavailability tests. 
The protocol shall contain all of the essential elements set forth in 
paragraph (d) of this section. The tests shall not be initiated prior to 
receiving notification from the Food and Drug Administration that the 
bioavailability protocol has been reviewed and either approved or its 
deficiencies delineated.
    (b) Within 180 days after receiving notification from the Food and 
Drug Administration that the bioavailability protocol has been reviewed, 
submit to the Food and Drug Administration the results of the in vivo 
bioavailability tests.
    (2) Digoxin tablets: Any person marketing digoxin tablets, in 
addition to complying with all of the requirements of paragraph (a)(1) 
of this section, shall include in their abbreviated new drug 
application:
    (i) A statement that the applicant will establish procedures to test 
each lot of digoxin tablets prior to releasing the batch for 
distribution to assure that the batch meets all of The United States 
Pharmacopeia (USP XVIII) requirements for digoxin tablets including, but 
not limited to, potency, content uniformity, and dissolution and either 
(a) that the quantity of digoxin dissolved at one hour is not more than 
95 percent of the assayed amount of digoxin or (b) that the quantity of 
digoxin dissolved at 15 minutes is not more than 90 percent of the 
assayed amount of digoxin.
    (ii) A statement that finished product specifications shall be 
established to include provisions to assure that the range of average 
one-hour dissolution values among batches of digoxin tablets does not 
exceed 20 percent.
    (3) Before releasing for distribution any batch of digoxin tablets 
manufactured after January 22, 1974, the manufacturer shall:
    (i) Test a sample of the batch to assure that the batch meets all of 
the requirements of The United States Pharmacopeia (USP XVIII) including 
but not limited to, potency, content uniformity, and dissolution and 
either (a) that the quantity of digoxin dissolved at one hour is not 
more than 95 percent of the assayed amount of digoxin or (b) that the 
quantity of digoxin dissolved at 15 minutes is not more than 90 percent 
of the assayed amount of digoxin.
    (ii) Submit a sample of the batch to the Food and Drug 
Administration according to the procedures set forth in paragraph (g) of 
this section. Results of tests conducted on the batch by or for the 
manufacturer and the batch production record shall accompany the sample.
    (iii) Withhold the batch from distribution until he is notified by 
the Food and Drug Administration that the sample was tested and found to 
meet all of the requirements in The United States Pharmacopeia (USP 
XVIII) for potency, content uniformity, and dissolution and either (a) 
that the quantity of digoxin dissolved at one hour is not more than 95 
percent of the assayed amount of digoxin or (b) that the quantity of 
digoxin dissolved at 15 minutes is not more than 90 percent of the 
assayed amount of digoxin.
    (iv) Submit a sample of each batch of digoxin tablets as provided 
for in paragraph (a)(3)(ii) of this section until he

[[Page 23]]

is notified by the Food and Drug Administration that he is released from 
the certification program. This notification will be made on the basis 
of sample test results, inspectional findings regarding compliance with 
current good manufacturing practice, and compliance with all other 
requirements of this section and any other directives issued by the Food 
and Drug Administration as a condition for release from the 
certification program.
    (4) Any manufacturer who has distributed any batch of digoxin 
tablets which does not meet the compendial requirement for dissolution, 
when tested by the method in The United States Pharmacopeia (USP XVIII), 
shall initiate recall of the subject batch when so requested by the Food 
and Drug Administration.
    (b) Failure of an applicant to submit the protocol and/or the 
results of the in vivo bioavailability tests showing adequate evidence 
of the product's bioavailability within the times specified in paragraph 
(a)(1)(vii) of this section and/or to comply with all of the 
certification requirements of paragraph (a)(3) of this section shall be 
justification for withdrawal of approval of the application under 
section 505(e) of the act.
    (c) Any product reformulation or change in manufacturing process 
will require the submission of a supplement to the approved abbreviated 
new drug application containing adequate data to demonstrate the 
bioavailability of the reformulated product. Food and Drug 
Administration approval of the supplement is required before the 
reformulated product is marketed. The Food and Drug Administration 
recommends that, where digoxin tablets are reformulated, manufacturers 
reformulate their product to achieve dissolution of 70 to 90 percent at 
one hour when tested by all three methods (i.e., the USP method, and the 
``paddle-water'' and ``paddle-acid'' methods) described in paragraph (h) 
of this section.
    (d) The protocol for the in vivo bioavailability tests required in 
paragraphs (a) and (c) of this section shall employ a three-way 
crossover design using the digoxin test product; a reference digoxin 
tablet supplied, on request, by the Food and Drug Administration; and 
bulk digoxin USP in an oral solution. Appropriate venous blood and 
urinary samples are to be collected and analyzed. The method shall be 
capable of detecting the difference between the reference tablet and the 
reference oral solution. Bioavailability of the test product shall be 
demonstrated if a mean absorption of at least 75 percent of the combined 
mean of the two reference standards is observed. Assistance in 
developing a protocol for a particular dosage formulation may be 
obtained by contacting the Food and Drug Administration, Center for Drug 
Evaluation and Research (HFD-420), 5600 Fishers Lane, Rockville, MD 
20857.
    (e) Parts of the digoxin product labeling indicated below shall be 
as follows:

                        Digoxin Labeling Guidance

                          (adult and pediatric)

                               description

    Digoxin is one of the cardiac (or digitalis) glycosides, a closely 
related group of drugs having in common specific and powerful effects on 
the myocardium. These drugs are found in a number of plants. The term 
``digitalis'' is used to designate the whole group. Typically, the 
glycosides are composed of three portions: a steroid nucleus, a lactone 
ring, and a sugar (hence ``glycosides'').
    (This section should include a chemical and physical description of 
digoxin and the same quantitative ingredient information as that 
required on the label.)

                                 Action

    The digitalis glycosides have qualitatively the same therapeutic 
effects on the heart. They (1) increase the force of myocardial 
contraction, (2) increase the refractory period of the atrioventricular 
(A-V) node, and (3) to a lesser degree, affect the sinoatrial (S-A) node 
and conduction system via the parasympathetic and sympathetic nervous 
systems.
    Gastrointestinal absorption of digoxin is a passive process. About 
50-75 percent of digoxin in tablet form is absorbed. Digoxin is only 20-
25 percent bound to plasma proteins and is predominantly excreted by the 
kidneys unmetabolized unless there is significant renal failure. Renal 
excretion of digoxin is proportional to glomerular filtration rate and 
is largely independent of urine flow. Digoxin is not effectively removed 
from the body by dialysis, exchange transfusion, or during 
cardiopulmonary bypass, presumably because of tissue binding. In 
subjects with normal renal function, digoxin is excreted exponentially 
with an average half-life of 36

[[Page 24]]

hours, resulting in the loss of 35-40 percent of the body stores daily.
    Serum levels and pharmacokinetics are essentially unchanged by 
massive weight loss, suggesting that lean body mass should be used in 
dosage calculations. The peak blood level from oral dosing with tablets 
occurs 1-3 hours after administration. The onset of therapeutic action 
of digoxin after oral tablets is 1-2 hours, with the peak therapeutic 
effect occurring 6-8 hours after dosing.

                               indications

    1. Congestive heart failure, all degrees, is the primary indication. 
The increased cardiac output due to digoxin results in diuresis and 
general amelioration of the disturbances characteristic of right (venous 
congestion, edema) and left (dyspnea, orthopnea, cardiac asthma) heart 
failure.
    Digoxin, generally, is most effective in ``low output'' failure and 
less effective in ``high output'' (bronchopulmonary insufficiency, 
infection, hyperthyroidism) heart failure.
    Digoxin should be continued after heart failure is abolished unless 
some known precipitating factor is corrected.
    2. Atrial fibrillation, especially when the ventricular rate is 
elevated. Digoxin rapidly reduces ventricular rates and eliminates the 
pulse deficit. Palpitation, precordial distress or weakness are relieved 
and any concomitant congestive failure ameliorated.
    Digoxin should be continued in doses necessary to maintain the 
desired ventricular rate and other clinical effects.
    3. Atrial flutter. Digoxin slows the heart and regular sinus rhythm 
may appear. Frequently the flutter is converted to atrial fibrillation 
with a slow ventricular rate. Stopping digoxin at this point may be 
followed by restoration of sinus rhythm, especially if the flutter was 
of the paroxysmal type. It is preferable, however, to continue digoxin 
if failure ensues or if atrial flutter is a frequent occurrence.
    4. Paroxysmal atrial tachycardia. Oral digoxin may be used, 
especially if the condition is resistant to lesser measures. Depending 
on the urgency, a more rapid acting parenteral preparation may be 
preferable to initiate digitalization, although if heart failure has 
ensued or paroxysms recur frequently, digoxin should be maintained by 
oral administration.
    Digoxin is not indicated in sinus tachycardia unless due to heart 
failure.
    5. Cardiogenic shock. The drug is often employed, especially when 
the condition is accompanied by pulmonary edema. Digoxin seems to affect 
adversely shock due to septicemia from gram negative bacteria.

                            contraindications

    The presence of toxic effects (See ADVERSE REACTIONS section) 
induced by any digitalis preparation is a contraindication to all of the 
gylcosides.
    Allergy, though rare, does occur. It may not extend to all 
preparations, and another may be tried.
    Ventricular fibrillation.

                                Warnings

Digitalis alone or with other drugs has been promoted for use in the 
treatment of obesity. This use of digoxin or other digitalis glycosides 
is unwarranted. Moreover, since they may cause potentially fatal 
arrhythmias or other adverse effects, the use of these drugs in the 
treatment of obesity is dangerous.

    Many of the arrhythmias for which digoxin is advised closely 
resemble those reflecting digoxin intoxication. If the possibility of 
digoxin intoxication cannot be excluded, cardiac glycosides should be 
temporarily withheld if permitted by the clinical situation.
    The patient with congestive heart failure may complain of nausea and 
vomiting. These symptoms may also be indications on digoxin 
intoxication. A clinical determination of the cause of these symptoms 
must be attempted before further drug administration.
    Patients with renal insufficiency require smaller than usual doses 
of digoxin. See ACTION section for mechanism.

                               precautions

    Atrial arrhythmias associated with hypermetabolic states are 
particularly resistant to digoxin treatment. Care must be taken to avoid 
digoxin toxicity if digoxin is used to help the arrhythmia.
    Digoxin is not indicated for the treatment of ventricular 
tachycardia unless congestive heart failure supervenes after a 
protracted episode not itself due to digoxin.
    Potassium depletion sensitizes the myocardium to digoxin, and 
toxicity may develop even with the usual dosage. Hypokalemia may also 
alter the rate of onset and intensity of the positive inotropic effect 
of digoxin. Therefore, it is desirable to maintain normal serum 
potassium levels in patients being treated with digoxin.
    Potassium wastage may result from diuretic or corticosteriod 
therapy, hemodialysis, and from suction of gastrointestinal secretions. 
It may accompany malnutrition, diarrhea, prolonged vomiting, old age, 
and long-standing congestive heart failure. In general, rapid changes in 
serum potassium or other electrolytes are to be avoided, and intravenous 
treatment with potassium should be reserved only for special 
circumstances as

[[Page 25]]

described below (see TREATMENT OF ARRHYTHMIAS PRODUCED BY OVERDOSAGES 
section).
    Patients with acute myocardial infarction, severe pulmonary disease, 
or far advanced heart failure may be more sensitive to digoxin and more 
prone to disturbances of rhythm.
    Calcium affects contractility and excitability of the heart in a 
manner similar to that of digoxin. Calcium may produce serious 
arrhythmias in digitalized patients.
    In myxedema the digoxin requirements are less because excretion rate 
is decreased and blood levels are significantly higher.
    In incomplete A-V block, especially in patients subject to Stokes-
Adams attacks, advanced or complete heart block may develop if digoxin 
is given. Heart failure in these patients can usually be controlled by 
other measures and by increasing the heart rate.
    Patients with chronic constructive pericarditis may respond 
unfavorably to digoxin.
    Patients with idiopathic hypertrophic subaortic stenosis must be 
managed extremely carefully. Unless cardiac failure is severe, it is 
doubtful whether digoxin should be employed.
    Renal insufficiency delays the excretion of digoxin, and dosage must 
be adjusted accordingly in patients with renal disease. Note: This 
applies also to potassium administration should it become necessary.
    Electrical conversion of arrhythmias may require reduction of 
digoxin dosage.

                            adverse reactions

    Gynecomastia, uncommon.
    Overdosage or toxic effects.
    Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most 
common early symptoms of overdosages in the adult (but rarely 
conspicuous in infants). Uncontrolled heart failure may also produce 
such symptoms.
    Central nervous system: Visual disturbances (blurred vision, yellow 
vision), headache, weakness, apathy.
    Cardiac disturbances (arrhythmias): Ventricular premature beats are 
the most common, except in infants and young children. Paroxysmal and 
nonparoxysmal nodal rhythms, atrioventricular (interference) 
disassociation and paroxysmal atrial tachycardia (PAT) with block are 
also common arrhythmias due to digoxin overdosage. Conduction 
disturbances: Excessive slowing of the pulse is a clinical sign of 
digoxin overdosage. Atrioventricular block of increasing degree may 
proceed to complete heart block. Note: The electrocardiogram is 
fundamental in determining the presence and nature of these cardiac 
toxic disturbances. Digoxin may also induce other changes (as of the ST 
segment), but these provide no measure of the degree of digitalization.

            treatment of arrhythmias produced by overdosages

    Digoxin should be discontinued until all signs of toxicity are 
abolished. Discontinuation may be all that is necessary if toxic 
manifestations are not severe and appear after the time for peak effect 
of the drug.
    Potassium salts are commonly used. Potassium chloride in divided 
oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION 
section for pediatric dosage) may be given provided renal function is 
adequate.
    When correction of the arrhythmia is urgent and the serum potassium 
level is low or normal, potassium should be administered intravenously 
in a solution of 5 percent dextrose in water. A total of 40-100 
milliequivalents (30 milliequivalents per 500 milliliters) is given at 
the rate of 20 milliequivalents per hour unless limited by pain due to 
local irritation.
    Additional amounts may be given if the arrhythmia is uncontrolled 
and the potassium well tolerated.
    Continuous electrocardiographic monitoring should be performed to 
watch for any evidence of potassium toxicity, e.g., peaking of T waves, 
and to observe the effect on the arrhythmia so that the infusion may be 
promptly stopped when the desired effect is achieved.
    Caution: Potassium should not be used and may be dangerous for 
severe or complete heart block due to digoxin and not related to any 
tachycardia.
    Other agents that have been approved for the treatment of digoxin 
intoxication include procainamide, lidocaine, and propranolol.

                        dosage and administration

    Oral digoxin is administered slowly or rapidly as required until the 
desired therapeutic effect is obtained without symptoms of overdosage. 
The amount can be predicted approximately from the lean body mass of the 
patient with allowances made for excretion during the time taken to 
induce digitalization.
    Subsequent maintenance dosage is also determined tentatively by the 
amount necessary to sustain the desired therapeutic effect.
    Recommended dosages are practical average figures that may require 
considerable modification as dictated by individual sensitivity or 
associated conditions. Diminished renal function is the most important 
factor requiring modification of recommended or average doses. (See 
WARNINGS and PRECAUTIONS sections.)
    The average amount of digoxin that patients must accumulate to be 
digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization 
may be accomplished by any

[[Page 26]]

of several approaches that vary in dosage and frequency of 
administration, but reach the same endpoint in terms of total amount 
accumulated.
    In previously undigitalized patients, a single loading dose of 0.5-
0.75 milligram orally usually produces a detectable effect in 1-2 hours 
that becomes maximal in 6-8 hours. Additional doses of 0.25-0.5 
milligram may be given cautiously at 6-8 hour intervals to full 
digitalization.
    In previously undigitalized patients, institution of daily 
maintenance therapy (0.125-0.5 milligram, see next paragraph) without a 
loading dose results in development of a steady-state plateau 
concentrations in about 7 days in patients with normal renal function.
    The average daily oral maintenance dose is 0.125-0.5 milligram, 
usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram 
should be considered the average maintenance dose.
    In patients with renal impairment, digoxin excretion is impaired and 
serum half-life is prolonged (see ACTION section). Digitalizing and 
maintenance doses are lower than those recommended for patients with 
normal renal functions. Signs of digoxin toxicity develop sooner in 
patients with renal impairment, and it takes longer for toxic signs and 
symptoms to disappear. Because of the prolonged half-life, a longer 
period of time is required to achieve an initial or new steady-state 
plateau in patients with renal impairment than in patients with normal 
renal function.
    It cannot be overemphasized that the values given are averages and 
substantial individual variation can be expected.
    (If pediatric dosage is available, the labeling sections above 
should be expanded to include the following information.)

                          pediatric information

                                warnings

    Newborn infants display considerable variability in their tolerance 
to digoxin, depending on their degree of maturity.
    Premature and immature infants are particularly sensitive, and 
dosage must be reduced and digitalization should be even more 
individualized and cautiously approached than in more mature infants. 
Impaired renal function must also be carefully taken into consideration.
    Congestive heart failure accompanying acute glomerulonephritis 
requires extreme care in digitalization. A relatively low total dose 
administered in divided doses and concomitant use of antihypertensive 
drugs has been recommended. ECG monitoring is essential. Digoxin should 
be discontinued as soon as possible.
    Patients with idiopathic hypertrophic subaortic stenosis must be 
managed extremely carefully. Unless cardiac failure is severe, it is 
doubtful whether digoxin should be employed.
    Patients with rheumatic carditis, especially when severe, are 
unusually sensitive to digoxin and prone to disturbances of rhythm. If 
heart failure develops, digitalization may be initiated with relatively 
low doses; then it can be cautiously increased until a beneficial effect 
is obtained. If a therapeutic trial does not result in improvement, the 
drug should be considered ineffective and be discontinued.
    Note: Digitalis glycosides are an important cause of accidental 
poisoning in children.

                               precautions

    Dosage must be carefully titrated and differences in the 
bioavailability of parenteral preparations, elixirs, and tablets should 
be taken into account when switching patients from one preparation to 
another.
    Electrocardiographic monitoring may be necessary to avoid 
intoxication.
    Premonitory signs of toxicity in the newborn are undue slowing of 
the sinus rate, sinoatrial arrest, and prolongation of PR interval.

                            adverse reactions

    Toxic signs differ from the adult in a number of respects. Cardiac 
arrhythmias are the more reliable and frequent signs of toxicity.
    Vomiting and diarrhea, neurologic and visual disturbances are rare 
as initial signs.
    Premature ventricular systoles are rarely seen; nodal and atrial 
systoles are more frequent.
    Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial 
tachycardia with A-V block particularly are more common manifestations 
of toxicity in children. Ventricular arrhythmias are rare.

            treatment of arrhythmias produced by overdosages

    (See adult section for other recommendations for the treatment of 
arrhythmias produced by overdosages and for additional recommendations 
and cautions regarding the use of potassium.) Potassium preparations may 
be given orally in divided doses totaling 1-1.5 milliequivalents/
kilogram (1 gram K contains 13.4 milliequivalents). When correction of 
the arrhythmia is urgent, approximately 0.5 milliequivalents/kilogram of 
potassium per hour may be given, with careful electrocardiographic 
monitoring, as a solution of 20 milliequivalents or less per 500 
milliliters in 5 percent dextrose in water. The total dose should 
generally not exceed 2 milliequivalents of potassium/kilogram.

                        dosage and administration

    Digitalization must be individualized. Generally, premature and 
immature infants are

[[Page 27]]

particularly sensitive, requiring reduced dosage that must be determined 
by careful titration.
    Oral Dosage. Beyond the immediate newborn period, children require 
proportionally greater doses than adults on the basis of body weight or 
surface area. The recommended oral digitalizing dosages in children with 
normal renal function are:
    Newborn infants (normal), up to 1 month, require 40-60 micrograms/
kilogram.
    Infants, 1 month to 2 years, require approximately 60-80 micrograms/
kilogram.
    Children 2 years to 10 years, require 40-60 micrograms/kilogram.
    Children, over 10 years of age, require adult dosages in proportion 
to their body weight.
    Maintenance therapy is 20-30 percent of the digitalizing dose 
administered each day.
    Long term use of digoxin is indicated in almost all infants who have 
been digitalized for acute congestive heart failure unless the cause is 
transient. Many favor maintaining digoxin until at least 2 years of age 
in all infants with paroxysmal atrial tachycardia or in those who show 
either definite or latent failure.
    Many children with severe inoperable congenital defects need digoxin 
throughout childhood and often for life.

    (f) Abbreviated new drug applications shall be submitted to the Food 
and Drug Administration, Center for Drug Evaluation and Research, Office 
of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.
    (g) All samples of digoxin tablets required by paragraph (a)(3) of 
this section to be submitted to the Food and Drug Administration shall 
be handled as follows:
    (1) The sample shall consist of 6 subsamples of 1000 tablets each 
collected at random from throughout the manufacturing run. Each of the 6 
subsamples shall be identified with the name of the product, the labeled 
potency, the date of manufacture, the batch number, and the name and 
address of the manufacturer.
    (2) The sample together with the batch production record and results 
of all tests conducted by or for the manufacturer to determine the 
product's identity, strength, quality, and purity, content uniformity 
and dissolution shall be submitted to the Department of Health and Human 
Services, Public Health Service, FDA National Center for Drug Analysis, 
1114 Market St., St. Louis, MO 63101. The outer wrapper shall be 
identified ``SAMPLE--DIGOXIN CERTIFICATION.''
    (h) The Food and Drug Administration is aware of data with two in 
vitro methods, in addition to that described in The United States 
Pharmacopeia (USP XVIII), developed to measure digoxin tablets 
dissolution. These two methods, the so-called ``paddle-water'' and 
``paddle-acid'' methods, are described below and are identical with the 
exception of the nature of the dissolution medium used in the procedures 
(i.e., distilled or deionized water vs. dilute hydrochloric acid (0.6 
percent volume/volume)). The dissolution apparatus used in these two 
methods differs significantly from the apparatus described in the method 
in the compendium. The Food and Drug Administration is aware that the 
three methods (i.e., USP, ``paddle-water,'' and ``paddle-acid'') show 
significant differences in dissolution in comparative tests on some 
formulations. Definitive bioavailability data to compare the relative 
value of each of these methods to predict bioavailability of the few 
formulations where the methods show significant differences in 
dissolution rate are not now available. Manufacturers who conduct 
research utilizing the ``paddle-water'' and ``paddle-acid'' methods, 
particularly in comparison with the method in The United States 
Pharmacopeia, shall submit any data obtained using these methods to the 
Food and Drug Administration pursuant to section 505(k) of the act.
    (1) Dissolution apparatus.

    (Note: Throughout this procedure use scrupulously clean glassware, 
which previously has been rinsed with dilute hydrochloric acid, 
distilled or deionized water, then with alcohol, and carefully dried. 
Take precautions to prevent contamination from airborne, fluorescent 
particles and from metal and rubber surfaces.) The apparatus consists of 
a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No. 
26220 or equivalent), a motor, and a polytetrafluoroethylene stirring 
blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a glass 
stirring shaft (Sargent 5-76636, 14.5 inch length; or equivalent). The 
water bath may be of any convenient size that permits keeping the water 
temperature uniformly at 37 deg. C. 0.5 deg. C. throughout 
the test. The vessel is spherical, and is provided with three ports at 
the top, one of which is centered. The lower half of the vessel is 65 
millimeters in inside

[[Page 28]]

radius and the vessel's nominal capacity is 1000 milliliters. The glass 
stirring shaft from the motor is placed in the center port, and one of 
the outer ports may be used for insertion of a thermometer. Samples may 
be removed for analysis through the other port. The motor is fitted with 
a speed-regulating device that allows the motor speed to be held at 50 
rpm 2 rpm. The motor is suspended above the vessel in such a 
way that it may be raised or lowered to position the stirring blade. The 
glass stirring shaft is 10 millimeters in diameter and about 37 
centimeters in length. It must run true on the motor axis without 
perceptible wobble. The polytetrafluoroethylene stirring blade is 4 
millimeters thick and forms a section of a circle, whose diameter is 83 
millimeters and which is subtended by parallel chords of 42 and 77 
millimeters. The blade is positioned horizontally, with the 42-
millimeter edge down, 2.5 centimeters 0.2 centimeter above 
the lowest inner surface of the vessel.

    (2) Reagents--(i) Dissolution medium. For ``paddle-water,'' use 
distilled or deionized water. For ``paddle-acid,'' use dilute 
hydrochloric acid (0.6 percent volume/volume). Use the same batch of 
dissolution medium throughout the test.
    (ii) Standard solutions. Accurately weigh approximately 25 
milligrams of The United States Pharmacopeia Digoxin Reference Standard, 
dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter 
volumetric flask and add 95 percent ethanol to volume and mix. Dilute 
10.0 milliliters of this first solution to 100.0 milliliters with 95 
percent ethanol and mix for the second solution. Just prior to use, 
individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of 
the second solution with dissolution medium to 50.0 milliliters. These 
solutions are equivalent to 20, 40, 60, 80, and 100 percent of 
dissolution, respectively, for a 0.25 milligram digoxin tablet.
    (iii) Extraction solvent. Prepare a solvent containing 6 volumes of 
chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol, 
analytical reagent grade.
    (iv) Ascorbic acid-methanol solution. Prepare a solution containing 
2 milligrams of ascorbic acid, analytical reagent grade, per 1 
milliliter of methanol, absolute, analytical reagent grade.
    (v) Hydrochloric acid, concentrated reagent grade.
    (vi) Hydrogen peroxide-methanol solution. On the day of use, dilute 
2.0 milliliters of recently assayed 30 percent hydrogen peroxide, 
reagent grade, with methanol, absolute, analytical reagent grade to 
100.0 milliliters. Store in a refrigerator. Just prior to use, dilute 
2.0 milliliters of this solution with methanol to 100.0 milliliters.
    (3) Procedure--(i) Dissolution. Place 500 milliliters of dissolution 
medium in the vessel, immerse it in the constant-temperature bath set at 
37 deg.C.0.5 deg.C., and allow the dissolution medium to 
assume the temperature of the bath. Position the shaft so that there is 
a distance of 2.5 centimeters 0.2 centimeter between the 
midpoint of the bottom of the blade and the bottom of the vessel. With 
the stirrer operating at a speed of 50 rpm2 rpm, place 1 
tablet into the flask. After 60 minutes, accurately timed, withdraw 25 
milliliters, using a glass syringe connected to a glass sampling tube, 
of solution from a point midway between the stirring shaft and the wall 
of the vessel, and approximately midway in depth. Filter the solution 
promptly after withdrawal, using a suitable membrane filter of not 
greater than 0.8 micron porosity (Millipore AAWP 025 00, or equivalent), 
mounted in a suitable holder (Millipore Swinnex SX00 025 00, or 
equivalent), discarding the first 100 milliliters of filtrate. This is 
the test solution. Repeat the dissolution procedure on 5 additional 
tablets.
    (ii) Extraction. Transfer 10.0 milliliters of each of the six 
filtrates, 10.0 milliliters of each of the five standard solutions, and 
10.0 milliliters of dissolution medium, to provide a blank, in separate 
60-milliliter separators. Extract each solution with two 10-milliliter 
portions of extraction solvent. Combine the extracts of each solution in 
separate, glass-stoppered, 50-milliliter conical flasks, and evaporate 
on a steam bath with the aid of a stream of nitrogen to dryness, rinsing 
the sides of the flasks with extraction solvent. Take care to ensure 
that all traces of solvent are removed, but avoid prolonged heating. For 
convenience the residues may be stored in a vacuum desiccator overnight.
    (iii) Measurement of fluorescence. Begin with the standard 
solutions, and

[[Page 29]]

keep all flasks in the same sequence throughout, so that the elapsed 
time from addition of reagents to reading of fluorescence is the same 
for each. Carry the test solutions, standard solutions, and the blank 
through the determination in one group. Add the following three reagents 
in as rapid a sequence as possible, swirling after each addition, 
treating 1 flask at a time, in the order named: 1.0 milliliter of 
ascorbic acid-methanol solution, 3.0 milliliters of concentrated 
hydrochloric acid, and 1.0 milliliter of hydrogen peroxide-methanol 
solution. Insert the stoppers in the flasks, and after 2 hours, measure 
the fluorescence at about 485 millimicrons, using excitation at about 
372 millimicrons. In order to provide a check on the stability of the 
fluorometer, reread one or more standard solutions. Correct each reading 
for the blank and plot a standard curve of fluorescence versus 
precentage dissolution. Determine the percentage dissolution of digoxin 
in the test solutions by reading from the standard graph.
    (iv) Digoxin tablets formulated so that the quantity of digoxin 
dissolved at one hour, when tested by the method in The United States 
Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed 
amount of digoxin and so that the quantity of digoxin dissolved at 15 
minutes is greater than 90 percent of the assayed amount of digoxin are 
new drugs which may be marketed only with an approved full new drug 
application as provided for in Sec. 314.50 of this chapter. The 
application shall include, but not be limited to, clinical studies 
establishing significantly greater bioavailability than digoxin tablets 
meeting compendial requirements and dosage recommendations based on 
clinical studies establishing the safe and effective use of the 
bioavailable digoxin product. Marketing of these digoxin products will 
be allowed only under a proprietary or trade name, established name, and 
labeling which differs from that used for digoxin tablets that meet all 
of the requirements in The United States Pharmacopeia (USP XVIII) and 
that are formulated so that either (a) the quantity of digoxin dissolved 
at one hour is not more than 95 percent of the assayed amount of digoxin 
or (b) the quantity of digoxin dissolved at 15 minutes is not more than 
90 percent of the assayed amount of digoxin. New drug applications for 
these digoxin products shall be submitted to the Food and Drug 
Administration, Center for Drug Evaluation and Research, Office of Drug 
Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30, 1976; 
41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 
29, 1990; 65 FR 56479, Sept. 19, 2000]



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.
    (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.

[[Page 30]]

    (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 Research, Division of Metabolism and 
Endocrine Drug Products (HFD-510), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857.
    (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]

[[Page 31]]



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.
 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.

[[Page 32]]

 
 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.Starttime
  Tuesday, April 20, 1999 16:55:11

    (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 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

[[Page 33]]

on November 20, 1976, whichever occurs first.
    (e) No exemption from section 505 of the act or from part 312 of 
this chapter is in effect or has been in effect for radioactive drugs 
prepared from accelerator-produced radioisotopes, naturally occurring 
isotopes, or nonradioactive substances used in conjunction with 
isotopes.
    (f)(1) Based on its experience in regulating investigational 
radioactive pharmaceuticals, the Nuclear Regulatory Commission has 
compiled a list of reactor-produced isotopes for which it considers that 
applicants may reasonably be expected to submit adequate evidence of 
safety and effectiveness for use as recommended in appropriate labeling; 
such use may include, among others, the uses in this tabulation:

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

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

[[Page 34]]

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

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



Sec. 310.509  Parenteral drug products in plastic containers.

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

[[Page 35]]

    (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 
Metabolism and Endocrine Drug Products (HFD-510), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (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]



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:

[[Page 36]]

      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) Packaging. If the product contains 30 milligrams or more of iron 
per dosage unit, it shall be packaged in unit-dose packaging. ``Unit-
dose packaging'' means a method of packaging a product into a 
nonreusable container designed to hold a single dosage unit intended for 
administration directly from that container, irrespective of whether the 
recommended dose is one or more than one of these units. The term 
``dosage unit'' means the individual physical unit of the product, e.g., 
tablet or capsule. Iron-containing drugs that are subject to this 
regulation are also subject to child-resistant special packaging 
requirements in 16 CFR parts 1700, 1701, and 1702.
    (b) Temporary exemption. (1) Drug products offered in solid oral 
dosage form (e.g., tablets or capsules), and containing 30 milligrams or 
more of iron per dosage unit, are exempt from the provisions of 
paragraph (a) of this section until January 15, 1998, if the sole source 
of iron in the drug product is carbonyl iron that meets the 
specifications of Sec. 184.1375 of this chapter.
    (2) If this temporary exemption is not extended or made permanent, 
such drug products shall be in compliance with the provisions of 
paragraph (a) of this section on or before July 15, 1998.
    (c) 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 of 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 (c)(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 (c)(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 (c)(1) of this section shall 
also appear prominently and conspicuously on the information panel of 
the retail package label.

[[Page 37]]

    (4) The warning statement shall appear on any labeling that contains 
warnings.
    (5) The warning statement required by paragraph (c)(1) of this 
section shall be set off in a box by use of hairlines.
    (d) The iron-containing inert tablets supplied in monthly packages 
of oral contraceptives are categorically exempt from the requirements of 
paragraphs (a) and (c) of this section.

[62 FR 2250, Jan. 15, 1997; 62 FR 15111, Mar. 31, 1997]



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.

[[Page 38]]

    (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 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,

[[Page 39]]

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 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

[[Page 40]]

for OTC topical use in accordance with part 348 of this chapter.

[58 FR 47610, Sept. 9, 1993]



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

[[Page 41]]

of benign prostatic hypertrophy cannot be generally recognized as safe 
and effective.
    (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

[[Page 42]]

chlorophyllins, and hydrogen peroxide in aqueous solution have been 
present in oral mucosal injury drug products 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

[[Page 43]]

of fever blisters and cold sores. Based on evidence currently available, 
any 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, sodium sulfide, 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.

[58 FR 47605, Sept. 9, 1993]



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 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

[[Page 44]]

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 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]

[[Page 45]]



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 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

[[Page 46]]

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 acid1
Sodium dihydrogen phosphate
Sodium dihydrogen phosphate monohydrate
Sodium phosphate, dibasic anhydrous reagent1

    (3) Antidiarrheal drug products.

Aluminum hydroxide
Atropine sulfate
Calcium carbonate
Carboxymethylcellulose sodium
Glycine
Homatropine methylbromide
Hyoscyamine sulfate
Lactobacillus acidophilus
Lactobacillus bulgaricus
Opium, powdered
Opium tincture
Paregoric
Phenyl salicylate
Scopolamine hydrobromide
Zinc phenolsulfonate

    (4) Antiperspirant drug products.


[[Page 47]]


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

    (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)

    (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 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) oranalgesic-antipyretic(s), anticholinergic, 
antihistamine, oralantitussive, 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

[[Page 48]]

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
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

[[Page 49]]

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
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) Bulk laxatives.

Agar
Carrageenan (degraded)
Carrageenan (native)
Guar gun

    (ii) Saline laxative.

Tartaric acid

    (iii) Stool softener.

Poloxamer 188

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

Aloin
Bile salts/acids

[[Page 50]]

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

    (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 for the prevention of swimmer's ear 
and for the drying of water-clogged ears--(i) Approved as of May 7, 
1991.

Acetic acid

    (ii) 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) Ingredients.

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

    (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
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

[[Page 51]]

Trolamine
Zinc sulfate

    (v) Insect bite and sting drug products.

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

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

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

    (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

[[Page 52]]

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
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

[[Page 53]]

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.

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 druq 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)

[[Page 54]]

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 druq products.

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

    (viii) Protectant druq products.

Bismuth oxide
Bismuth subcarbonate
Bismuth subgallate
Bismuth subnitrate
Lanolin alcohols

    (ix) Vasoconstrictor druq products.

Epinephrine undecylenate

    (x) Wound healinq druq products.

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

    (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.

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

    (29) Sunscreen drug products.

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

    (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 initiallyintroduced or initially 
delivered for introduction intointerstate commerce after the dates 
specified in paragraphs(d)(1) through (d)(33) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3) through (a)(4), (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) through (a)(12)(iv)(A), 
(a)(14) through (a)(15)(i), and (a)(16) through (a)(18) of this section.

[[Page 55]]

    (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.
    (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) through (a)(18)(vi), 
(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 paragraphs (a)(26) of 
this section, except for those that contain live yeast cell derivative.
    (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) [Reserved]
    (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) of this section.
    (29) January 29, 1999, for products subject to paragraph 
(a)(12)(iv)(B) of this section.
    (30) [Reserved]
    (31) May 21, 2001 for products subject to paragraph (a)(29) of this 
section.-
    (32) [Reserved]
    (33) October 29, 2001, for products subject to paragraph 
(a)(6)(iv)(D) of this section.

[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 on GPO Access.

    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 64 FR 27687, May 21, 1999, in Sec. 310.545 paragraph (a)(29) 
was added, (d) introductory text was revised, paragraph (d)(30) was 
added and reserved, and paragraph (d)(31) was added, effective May 21, 
2001. At 65 FR 36319, 36324, June 8, 2000, the effective date was 
delayed through Dec. 31, 2002, and paragraph (d)(31) was revised. For 
the convenience of the user, the revised text is set forth as follows:

[[Page 56]]

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

    (a) * * *

                                * * * * *

    (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)(29) of this section.

                                * * * * *

    (31) December 31, 2002, for products subject to paragraph (a)(29) 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 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.

[[Page 57]]

    (b) Any OTC drug product containing quinine or quinine salts that is 
labeled, represented, or promoted for the treatment and/or prevention of 
malaria is regarded as a new drug within the meaning of section 201(p) 
of the act, for which an approved application or abbreviated application 
under section 505 of the act and part 314 of this chapter is required 
for marketing. In the absence of an approved new drug application or 
abbreviated new drug application, such product is also misbranded under 
section 502 of the act.
    (c) Clinical investigations designed to obtain evidence that any 
drug product labeled, represented, or promoted for OTC use for the 
treatment and/or prevention of malaria is safe and effective for the 
purpose intended must comply with the requirements and procedures 
governing the use of investigational new drugs set forth in part 312 of 
this chapter.
    (d) After April 20, 1998, any such OTC drug product initially 
introduced or initially delivered for introduction into interstate 
commerce that is not in compliance with this section is subject to 
regulatory action.

[63 FR 13528, Mar. 20, 1998]



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

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

[[Page 58]]

312.35 Submissions for treatment use.
312.36 Emergency use of an investigational new drug.
312.38 Withdrawal of an IND.

                    Subpart C--Administrative Actions

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

        Subpart D--Responsibilities of Sponsors and Investigators

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

    Subpart E--Drugs Intended to Treat Life-threatening and Severely-
                         debilitating Illnesses

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

                        Subpart F--Miscellaneous

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

Subpart G--Drugs for Investigational Use in Laboratory Research Animals 
                            or in Vitro Tests

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

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

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



                      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

[[Page 59]]

to support any other significant change in the labeling for the drug;
    (ii) If the drug that is undergoing investigation is lawfully 
marketed as a prescription drug product, the investigation is not 
intended to support a significant change in the advertising for the 
product;
    (iii) The investigation does not involve a route of administration 
or dosage level or use in a patient population or other factor that 
significantly increases the risks (or decreases the acceptability of the 
risks) associated with the use of the drug product;
    (iv) The investigation is conducted in compliance with the 
requirements for institutional review set forth in part 56 and with the 
requirements for informed consent set forth in part 50; and
    (v) The investigation is conducted in compliance with the 
requirements of Sec. 312.7.
    (2)(i) A clinical investigation involving an in vitro diagnostic 
biological product listed in paragraph (b)(2)(ii) of this section is 
exempt from the requirements of this part if (a) it is intended to be 
used in a diagnostic procedure that confirms the diagnosis made by 
another, medically established, diagnostic product or procedure and (b) 
it is shipped in compliance with Sec. 312.160.
    (ii) In accordance with paragraph (b)(2)(i) of this section, the 
following products are exempt from the requirements of this part: (a) 
blood grouping serum; (b) reagent red blood cells; and (c) anti-human 
globulin.
    (3) A drug intended solely for tests in vitro or in laboratory 
research animals is exempt from the requirements of this part if shipped 
in accordance with Sec. 312.160.
    (4) FDA will not accept an application for an investigation that is 
exempt under the provisions of paragraph (b)(1) of this section.
    (5) A clinical investigation involving use of a placebo is exempt 
from the requirements of this part if the investigation does not 
otherwise require submission of an IND.
    (6) A clinical investigation involving an exception from informed 
consent under Sec. 50.24 of this chapter is not exempt from the 
requirements of this part.
    (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.''
    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

[[Page 60]]

used in vitro for diagnostic purposes. The terms ``investigational 
drug'' and ``investigational new drug'' are deemed to be synonymous for 
purposes of this part.
    Investigator means an individual who actually conducts a clinical 
investigation (i.e., under whose immediate direction the drug is 
administered or dispensed to a subject). In the event an investigation 
is conducted by a team of individuals, the investigator is the 
responsible leader of the team. ``Subinvestigator'' includes any other 
individual member of that team.
    Marketing application means an application for a new drug submitted 
under section 505(b) of the act or a biologics license application for a 
biological product submitted under the Public Health Service Act.
    Sponsor means a person who takes responsibility for and initiates a 
clinical investigation. The sponsor may be an individual or 
pharmaceutical company, governmental agency, academic institution, 
private organization, or other organization. The sponsor does not 
actually conduct the investigation unless the sponsor is a sponsor-
investigator. A person other than an individual that uses one or more of 
its own employees to conduct an investigation that it has initiated is a 
sponsor, not a sponsor-investigator, and the employees are 
investigators.
    Sponsor-Investigator means an individual who both initiates and 
conducts an investigation, and under whose immediate direction the 
investigational drug is administered or dispensed. The term does not 
include any person other than an individual. The requirements applicable 
to a sponsor-investigator under this part include both those applicable 
to an investigator and a sponsor.
    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]



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.



Sec. 312.7  Promotion and charging for 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.
    (d) Charging for and commercialization of investigational drugs--(1) 
Clinical trials under an IND. Charging for an investigational drug in a 
clinical trial under an IND is not permitted without the prior written 
approval of FDA. In requesting such approval, the sponsor shall provide 
a full written explanation of why charging is necessary in order

[[Page 61]]

for the sponsor to undertake or continue the clinical trial, e.g., why 
distribution of the drug to test subjects should not be considered part 
of the normal cost of doing business.
    (2) Treatment protocol or treatment IND. A sponsor or investigator 
may charge for an investigational drug for a treatment use under a 
treatment protocol or treatment IND provided: (i) There is adequate 
enrollment in the ongoing clinical investigations under the authorized 
IND; (ii) charging does not constitute commercial marketing of a new 
drug for which a marketing application has not been approved; (iii) the 
drug is not being commercially promoted or advertised; and (iv) the 
sponsor of the drug is actively pursuing marketing approval with due 
diligence. FDA must be notified in writing in advance of commencing any 
such charges, in an information amendment submitted under Sec. 312.31. 
Authorization for charging goes into effect automatically 30 days after 
receipt by FDA of the information amendment, unless the sponsor is 
notified to the contrary.
    (3) Noncommercialization of investigational drug. Under this 
section, the sponsor may not commercialize an investigational drug by 
charging a price larger than that necessary to recover costs of 
manufacture, research, development, and handling of the investigational 
drug.
    (4) Withdrawal of authorization. Authorization to charge for an 
investigational drug under this section may be withdrawn by FDA if the 
agency finds that the conditions underlying the authorization are no 
longer satisfied.

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



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

[[Page 62]]

clinical investigation of a previously untested drug is generally 
divided into three phases. Although in general the phases are conducted 
sequentially, they may overlap. These three phases of an investigation 
are a follows:
    (a) Phase 1. (1) Phase 1 includes the initial introduction of an 
investigational new drug into humans. Phase 1 studies are typically 
closely monitored and may be conducted in patients or normal volunteer 
subjects. These studies are designed to determine the metabolism and 
pharmacologic actions of the drug in humans, the side effects associated 
with increasing doses, and, if possible, to gain early evidence on 
effectiveness. During Phase 1, sufficient information about the drug's 
pharmacokinetics and pharmacological effects should be obtained to 
permit the design of well-controlled, scientifically valid, Phase 2 
studies. The total number of subjects and patients included in Phase 1 
studies varies with the drug, but is generally in the range of 20 to 80.
    (2) Phase 1 studies also include studies of drug metabolism, 
structure-activity relationships, and mechanism of action in humans, as 
well as studies in which investigational drugs are used as research 
tools to explore biological phenomena or disease processes.
    (b) Phase 2. Phase 2 includes the controlled clinical studies 
conducted to evaluate the effectiveness of the drug for a particular 
indication or indications in patients with the disease or condition 
under study and to determine the common short-term side effects and 
risks associated with the drug. Phase 2 studies are typically well 
controlled, closely monitored, and conducted in a relatively small 
number of 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 63]]

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 64]]

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 65]]

    (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 66]]

    (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 durg 
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 67]]

    (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 68]]

    (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. 312.34. 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 69]]

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]



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 reports.

    (a) Definitions. The following definitions of terms apply to this 
section:-
    Associated with the use of the drug. There is a reasonable 
possibility that the experience may have been caused by the drug.
    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 or subject, in the view of the 
investigator, at immediate risk of death from the reaction as it 
occurred, i.e., it does not include a reaction that, had it occurred in 
a more severe form, might have caused death.
    Serious adverse drug experience: Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
    Unexpected adverse drug experience: Any adverse drug experience, the 
specificity or severity of which is not consistent with the current 
investigator brochure; or, if an investigator brochure is not required 
or available, the specificity or severity of which 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 only referred to elevated 
hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the investigator brochure only listed cerebral vascular 
accidents. ``Unexpected,'' as used in this definition, refers to an

[[Page 70]]

adverse drug experience that has not been previously observed (e.g., 
included in the investigator brochure) rather than from the perspective 
of such experience not being anticipated from the pharmacological 
properties of the pharmaceutical product.
    (b) Review of safety information. The sponsor shall promptly review 
all information relevant to the safety of the drug obtained or otherwise 
received by the sponsor from any source, foreign or domestic, including 
information derived from any clinical or epidemiological investigations, 
animal investigations, commercial marketing experience, reports in the 
scientific literature, and unpublished scientific papers, as well as 
reports from foreign regulatory authorities that have not already been 
previously reported to the agency by the sponsor.
    (c) IND safety reports. (1) Written reports--(i) The sponsor shall 
notify FDA and all participating investigators in a written IND safety 
report of:
    (A) Any adverse experience associated with the use of the drug that 
is both serious and unexpected; or
    (B) Any finding from tests in laboratory animals that suggests a 
significant risk for human subjects including reports of mutagenicity, 
teratogenicity, or carcinogenicity. Each notification shall be made as 
soon as possible and in no event later than 15 calendar days after the 
sponsor's initial receipt of the information. Each written notification 
may be submitted on FDA Form 3500A or in a narrative format (foreign 
events may be submitted either on an FDA Form 3500A or, if preferred, on 
a CIOMS I form; reports from animal or epidemiological studies shall be 
submitted in a narrative format) and shall bear prominent identification 
of its contents, i.e., ``IND Safety Report.'' Each written notification 
to FDA shall be transmitted to the FDA new drug review division in the 
Center for Drug Evaluation and Research or the product review division 
in the Center for Biologics Evaluation and Research that has 
responsibility for review of the IND. If FDA determines that additional 
data are needed, the agency may require further data to be submitted.
    (ii) In each written IND safety report, the sponsor shall identify 
all safety reports previously filed with the IND concerning a similar 
adverse experience, and shall analyze the significance of the adverse 
experience in light of the previouos, similar reports.
    (2) Telephone and facsimile transmission safety reports. The sponsor 
shall also notify FDA by telephone or by facsimile transmission of any 
unexpected fatal or life-threatening experience associated with the use 
of the drug as soon as possible but in no event later than 7 calendar 
days after the sponsor's initial receipt of the information. Each 
telephone call or facsimile transmission to FDA shall be transmitted to 
the FDA new drug review division in the Center for Drug Evaluation and 
Research or the product review division in the Center for Biologics 
Evaluation and Research that has responsibility for review of the IND.
    (3) Reporting format or frequency. FDA may request 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 new drug review division in the 
Center for Drug Evaluation and Research or the director of the products 
review division in the Center for Biologics Evaluation and Research 
which is responsible for review of the IND.
    (4) A sponsor of a clinical study of a marketed drug is not required 
to make a safety report for any adverse experience associated with use 
of the drug that is not from the clinical study itself.
    (d) Followup. (1) The sponsor shall promptly investigate all safety 
information received by it.
    (2) Followup information to a safety report shall be submitted as 
soon as the relevant information is available.
    (3) If the results of a sponsor's investigation show that an adverse 
drug experience not initially determined to be reportable under 
paragraph (c) of this section is so reportable, the sponsor shall report 
such experience in a written safety report as soon as possible,

[[Page 71]]

but in no event later than 15 calendar days after the determination is 
made.
    (4) Results of a sponsor's investigation of other safety information 
shall be submitted, as appropriate, in an information amendment or 
annual report.
    (e) Disclaimer. A safety report or other information submitted by a 
sponsor under this part (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the sponsor or 
FDA that the report or information constitutes an admission that the 
drug caused or contributed to an adverse experience. 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 experience.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 
FR 11579, Mar. 29, 1990; 62 FR 52250, Oct. 7, 1997; 67 FR 9585, Mar. 4, 
2002]



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 
trails, 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]

[[Page 72]]



Sec. 312.34  Treatment use of an investigational new drug.

    (a) General. A drug that is not approved for marketing may be under 
clinical investigation for a serious or immediately life-threatening 
disease condition in patients for whom no comparable or satisfactory 
alternative drug or other therapy is available. During the clinical 
investigation of the drug, it may be appropriate to use the drug in the 
treatment of patients not in the clinical trials, in accordance with a 
treatment protocol or treatment IND. The purpose of this section is to 
facilitate the availability of promising new drugs to desperately ill 
patients as early in the drug development process as possible, before 
general marketing begins, and to obtain additional data on the drug's 
safety and effectiveness. In the case of a serious disease, a drug 
ordinarily may be made available for treatment use under this section 
during Phase 3 investigations or after all clinical trials have been 
completed; however, in appropriate circumstances, a drug may be made 
available for treatment use during Phase 2. In the case of an 
immediately life-threatening disease, a drug may be made available for 
treatment use under this section earlier than Phase 3, but ordinarily 
not earlier than Phase 2. For purposes of this section, the ``treatment 
use'' of a drug includes the use of a drug for diagnostic purposes. If a 
protocol for an investigational drug meets the criteria of this section, 
the protocol is to be submitted as a treatment protocol under the 
provisions of this section.
    (b) Criteria. (1) FDA shall permit an investigational drug to be 
used for a treatment use under a treatment protocol or treatment IND if:
    (i) The drug is intended to treat a serious or immediately life-
threatening disease;
    (ii) There is no comparable or satisfactory alternative drug or 
other therapy available to treat that stage of the disease in the 
intended patient population;
    (iii) The drug is under investigation in a controlled clinical trial 
under an IND in effect for the trial, or all clinical trials have been 
completed; and
    (iv) The sponsor of the controlled clinical trial is actively 
pursuing marketing approval of the investigational drug with due 
diligence.
    (2) Serious disease. For a drug intended to treat a serious disease, 
the Commissioner may deny a request for treatment use under a treatment 
protocol or treatment IND if there is insufficient evidence of safety 
and effectiveness to support such use.
    (3) Immediately life-threatening disease. (i) For a drug intended to 
treat an immediately life-threatening disease, the Commissioner may deny 
a request for treatment use of an investigational drug under a treatment 
protocol or treatment IND if the available scientific evidence, taken as 
a whole, fails to provide a reasonable basis for concluding that the 
drug:
    (A) May be effective for its intended use in its intended patient 
population; or
    (B) Would not expose the patients to whom the drug is to be 
administered to an unreasonable and significant additional risk of 
illness or injury.
    (ii) For the purpose of this section, an ``immediately life-
threatening'' disease means a stage of a disease in which there is a 
reasonable likelihood that death will occur within a matter of months or 
in which premature death is likely without early treatment.
    (c) Safeguards. Treatment use of an investigational drug is 
conditioned on the sponsor and investigators complying with the 
safeguards of the IND process, including the regulations governing 
informed consent (21 CFR part 50) and institutional review boards (21 
CFR part 56) and the applicable provisions of part 312, including 
distribution of the drug through qualified experts, maintenance of 
adequate manufacturing facilities, and submission of IND safety reports.
    (d) Clinical hold. FDA may place on clinical hold a proposed or 
ongoing treatment protocol or treatment IND in accordance with 
Sec. 312.42.

[52 FR 19476, May 22, 1987, as amended at 57 FR 13248, Apr. 15, 1992]



Sec. 312.35  Submissions for treatment use.

    (a) Treatment protocol submitted by IND sponsor. Any sponsor of a 
clinical

[[Page 73]]

investigation of a drug who intends to sponsor a treatment use for the 
drug shall submit to FDA a treatment protocol under Sec. 312.34 if the 
sponsor believes the criteria of Sec. 312.34 are satisfied. If a 
protocol is not submitted under Sec. 312.34, but FDA believes that the 
protocol should have been submitted under this section, FDA may deem the 
protocol to be submitted under Sec. 312.34. A treatment use under a 
treatment protocol may begin 30 days after FDA receives the protocol or 
on earlier notification by FDA that the treatment use described in the 
protocol may begin.
    (1) A treatment protocol is required to contain the following:
    (i) The intended use of the drug.
    (ii) An explanation of the rationale for use of the drug, including, 
as appropriate, either a list of what available regimens ordinarily 
should be tried before using the investigational drug or an explanation 
of why the use of the investigational drug is preferable to the use of 
available marketed treatments.
    (iii) A brief description of the criteria for patient selection.
    (iv) The method of administration of the drug and the dosages.
    (v) A description of clinical procedures, laboratory tests, or other 
measures to monitor the effects of the drug and to minimize risk.
    (2) A treatment protocol is to be supported by the following:
    (i) Informational brochure for supplying to each treating physician.
    (ii) The technical information that is relevant to safety and 
effectiveness of the drug for the intended treatment purpose. 
Information contained in the sponsor's IND may be incorporated by 
reference.
    (iii) A commitment by the sponsor to assure compliance of all 
participating investigators with the informed consent requirements of 21 
CFR part 50.
    (3) A licensed practioner who receives an investigational drug for 
treatment use under a treatment protocol is an ``investigator'' under 
the protocol and is responsible for meeting all applicable investigator 
responsibilities under this part and 21 CFR parts 50 and 56.
    (b) Treatment IND submitted by licensed practitioner. (1) If a 
licensed medical practitioner wants to obtain an investigational drug 
subject to a controlled clinical trial for a treatment use, the 
practitioner should first attempt to obtain the drug from the sponsor of 
the controlled trial under a treatment protocol. If the sponsor of the 
controlled clinical investigation of the drug will not establish a 
treatment protocol for the drug under paragraph (a) of this section, the 
licensed medical practitioner may seek to obtain the drug from the 
sponsor and submit a treatment IND to FDA requesting authorization to 
use the investigational drug for treatment use. A treatment use under a 
treatment IND may begin 30 days after FDA receives the IND or on earlier 
notification by FDA that the treatment use under the IND may begin. A 
treatment IND is required to contain the following:
    (i) A cover sheet (Form FDA 1571) meeting Sec. 312.23(g)(1).
    (ii) Information (when not provided by the sponsor) on the drug's 
chemistry, manufacturing, and controls, and prior clinical and 
nonclinical experience with the drug submitted in accordance with 
Sec. 312.23. A sponsor of a clinical investigation subject to an IND who 
supplies an investigational drug to a licensed medical practitioner for 
purposes of a separate treatment clinical investigation shall be deemed 
to authorize the incorporation-by-reference of the technical information 
contained in the sponsor's IND into the medical practitioner's treatment 
IND.
    (iii) A statement of the steps taken by the practitioner to obtain 
the drug under a treatment protocol from the drug sponsor.
    (iv) A treatment protocol containing the same information listed in 
paragraph (a)(1) of this section.
    (v) A statement of the practitioner's qualifications to use the 
investigational drug for the intended treatment use.
    (vi) The practitioner's statement of familiarity with information on 
the drug's safety and effectiveness derived from previous clinical and 
nonclinical experience with the drug.
    (vii) Agreement to report to FDA safety information in accordance 
with Sec. 312.32.

[[Page 74]]

    (2) A licensed practitioner who submits a treatment IND under this 
section is the sponsor-investigator for such IND and is responsible for 
meeting all applicable sponsor and investigator responsibilities under 
this part and 21 CFR parts 50 and 56.

[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr. 15, 1992; 67 
FR 9585, Mar. 4, 2002]



Sec. 312.36  Emergency use of an investigational new drug.

    Need for an investigational drug may arise in an emergency situation 
that does not allow time for submission of an IND in accordance with 
Sec. 312.23 or Sec. 312.34. In such a case, FDA may authorize shipment 
of the drug for a specified use in advance of submission of an IND. A 
request for such authorization may be transmitted to FDA by telephone or 
other rapid communication means. For investigational biological drugs, 
the request should be directed to the Division of Biological 
Investigational New Drugs (HFB-230), Center for Biologics Evaluation and 
Research, 8800 Rockville Pike, Bethesda, MD 20892, 301-443-4864. For all 
other investigational drugs, the request for authorization should be 
directed to the Document Management and Reporting Branch (HFD-53), 
Center for Drug Evaluation and Research, 5600 Fishers Lane, Rockville, 
MD 20857, 301-443-4320. After normal working hours, eastern standard 
time, the request should be directed to the FDA Division of Emergency 
and Epidemiological Operations, 202-857-8400. Except in extraordinary 
circumstances, such authorization will be conditioned on the sponsor 
making an appropriate IND submission as soon as practicable after 
receiving the authorization.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55 
FR 11579, Mar. 29, 1990; 67 FR 9585, Mar. 4, 2002]



Sec. 312.38  Withdrawal of an IND.

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

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



                    Subpart C--Administrative Actions



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

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

[[Page 75]]



Sec. 312.41  Comment and advice on an IND.

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

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



Sec. 312.42  Clinical holds and requests for modification.

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

[[Page 76]]

    (ii) The plan or protocol for the investigation is clearly deficient 
in design to meet its stated objectives.
    (3) Clinical hold of a treatment IND or treatment protocol.
    (i) Proposed use. FDA may place a proposed treatment IND or 
treatment protocol on clinical hold if it is determined that:
    (A) The pertinent criteria in Sec. 312.34(b) for permitting the 
treatment use to begin are not satisfied; or
    (B) The treatment protocol or treatment IND does not contain the 
information required under Sec. 312.35 (a) or (b) to make the specified 
determination under Sec. 312.34(b).
    (ii) Ongoing use. FDA may place an ongoing treatment protocol or 
treatment IND on clinical hold if it is determined that:
    (A) There becomes available a comparable or satisfactory alternative 
drug or other therapy to treat that stage of the disease in the intended 
patient population for which the investigational drug is being used;
    (B) The investigational drug is not under investigation in a 
controlled clinical trial under an IND in effect for the trial and not 
all controlled clinical trials necessary to support a marketing 
application have been completed, or a clinical study under the IND has 
been placed on clinical hold:
    (C) The sponsor of the controlled clinical trial is not pursuing 
marketing approval with due diligence;
    (D) If the treatment IND or treatment protocol is intended for a 
serious disease, there is insufficient evidence of safety and 
effectiveness to support such use; or
    (E) If the treatment protocol or treatment IND was based on an 
immediately life-threatening disease, the available scientific evidence, 
taken as a whole, fails to provide a reasonable basis for concluding 
that the drug:
    (1) May be effective for its intended use in its intended 
population; or
    (2) Would not expose the patients to whom the drug is to be 
administered to an unreasonable and significant additional risk of 
illness or injury.
    (iii) FDA may place a proposed or ongoing treatment IND or treatment 
protocol on clinical hold if it finds that any of the conditions in 
paragraph (b)(4)(i) through (b)(4)(viii) of this section apply.
    (4) Clinical hold of any study that is not designed to be adequate 
and well-controlled. FDA may place a proposed or ongoing investigation 
that is not designed to be adequate and well-controlled on clinical hold 
if it finds that:
    (i) Any of the conditions in paragraph (b)(1) or (b)(2) of this 
section apply; or
    (ii) There is reasonable evidence the investigation that is not 
designed to be adequate and well-controlled is impeding enrollment in, 
or otherwise interfering with the conduct or completion of, a study that 
is designed to be an adequate and well-controlled investigation of the 
same or another investigational drug; or
    (iii) Insufficient quantities of the investigational drug exist to 
adequately conduct both the investigation that is not designed to be 
adequate and well-controlled and the investigations that are designed to 
be adequate and well-controlled; or
    (iv) The drug has been studied in one or more adequate and well-
controlled investigations that strongly suggest lack of effectiveness; 
or
    (v) Another drug under investigation or approved for the same 
indication and available to the same patient population has demonstrated 
a better potential benefit/risk balance; or
    (vi) The drug has received marketing approval for the same 
indication in the same patient population; or
    (vii) The sponsor of the study that is designed to be an adequate 
and well-controlled investigation is not actively pursuing marketing 
approval of the investigational drug with due diligence; or
    (viii) The Commissioner determines that it would not be in the 
public interest for the study to be conducted or continued. FDA 
ordinarily intends that clinical holds under paragraphs (b)(4)(ii), 
(b)(4)(iii) and (b)(4)(v) of this section would only apply to additional 
enrollment in nonconcurrently controlled trials rather than eliminating 
continued access to individuals already receiving the investigational 
drug.
    (5) Clinical hold of any investigation involving an exception from 
informed consent under Sec. 50.24 of this chapter. FDA

[[Page 77]]

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 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]



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

[[Page 78]]

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 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

[[Page 79]]

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 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

[[Page 80]]

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 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.

[[Page 81]]

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



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

    (a) A sponsor may transfer responsibility for any or all of the 
obligations

[[Page 82]]

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 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,

[[Page 83]]

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 Dockets Management Branch (HFA-305), 
Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, 
MD 20857, 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]



Sec. 312.55  Informing investigators.

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

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

[[Page 84]]

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 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

[[Page 85]]

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 Secs. 50.23 or 50.24 of this chapter. Additional 
specific responsibilities of clinical investigators are set forth in 
this part and in parts 50 and 56 of this chapter.

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



Sec. 312.61  Control of the investigational drug.

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



Sec. 312.62  Investigator recordkeeping and record retention.

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

[[Page 86]]

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 shall promptly report to the 
sponsor any adverse effect that may reasonably be regarded as caused by, 
or probably caused by, the drug. If the adverse effect is alarming, the 
investigator shall report the adverse effect immediately.
    (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]



Sec. 312.66  Assurance of IRB review.

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

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



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

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



Sec. 312.69  Handling of controlled substances.

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



Sec. 312.70  Disqualification of a clinical investigator.

    (a) If FDA has information indicating that an investigator 
(including a sponsor-investigator) has repeatedly or deliberately failed 
to comply with the requirements of this part, part 50, or part 56 of 
this chapter, or has submitted to FDA or to the sponsor false 
information in any required report, the Center for Drug Evaluation and 
Research or the Center for Biologics Evaluation and Research will 
furnish the investigator written notice of the matter complained of and 
offer the investigator an opportunity to explain the matter in writing, 
or, at the option of the investigator, in an informal conference. If an 
explanation is offered but not accepted by the Center for Drug 
Evaluation and Research or the Center for Biologics Evaluation and 
Research,

[[Page 87]]

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

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



    Subpart E--Drugs Intended to Treat Life-threatening and Severely-
                         debilitating Illnesses

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

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



Sec. 312.80  Purpose.

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

[[Page 88]]

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 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 Secs. 312.34 and 
312.35. 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)).



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

[[Page 89]]

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 (for a drug) a not approvable letter 
pursuant to Sec. 314.120 of this chapter, or (for a biologic) a 
deficiencies letter consistent with 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.



Sec. 312.85  Phase 4 studies.

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



Sec. 312.86  Focused FDA regulatory research.

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



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

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



Sec. 312.88  Safeguards for patient safety.

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



                        Subpart F--Miscellaneous



Sec. 312.110  Import and export requirements.

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

[[Page 90]]

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 intended for export from 
the United States complies with the requirements of this part as 
follows:
    (1) If an IND is in effect for the drug under Sec. 312.40 and each 
person who receives the drug is an investigator named in the 
application; or
    (2) If FDA authorizes shipment of the drug for use in a clinical 
investigation. Authorization may be obtained as follows:
    (i) Through submission to the International Affairs Staff (HFY-50), 
Associate Commissioner for Health Affairs, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, of a written request from the 
person that seeks to export the drug. A request must provide adequate 
information about the drug to satisfy FDA that the drug is appropriate 
for the proposed investigational use in humans, that the drug will be 
used for investigational purposes only, and that the drug may be legally 
used by that consignee in the importing country for the proposed 
investigational use. The request shall specify the quantity of the drug 
to be shipped per shipment and the frequency of expected shipments. If 
FDA authorizes exportation under this paragraph, the agency shall 
concurrently notify the government of the importing country of such 
authorization.
    (ii) Through submission to the International Affairs Staff (HFY-50), 
Associate Commissioner for Health Affairs, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, of a formal request from an 
authorized official of the government of the country to which the drug 
is proposed to be shipped. A request must specify that the foreign 
government has adequate information about the drug and the proposed 
investigational use, that the drug will be used for investigational 
purposes only, and that the foreign government is satisfied that the 
drug may legally be used by the intended consignee in that country. Such 
a request shall specify the quantity of drug to be shipped per shipment 
and the frequency of expected shipments.
    (iii) Authorization to export an investigational drug under 
paragraph (b)(2)(i) or (ii) of this section may be revoked by FDA if the 
agency finds that the conditions underlying its authorization are not 
longer met.
    (3) This paragraph applies only where the drug is to be used for the 
purpose of clinical investigation.
    (4) This paragraph does not apply to the export of new drugs 
(including biological products, antibiotic drugs, and insulin) approved 
or authorized for export under section 802 of the act (21 U.S.C. 382) or 
section 351(h)(1)(A) of the Public Health Service Act (42 U.S.C. 
262(h)(1)(A)).

[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]



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

    (a) Introduction. This section describes the criteria for acceptance 
by FDA of foreign clinical studies not conducted under an IND. In 
general, FDA accepts such studies provided they are well designed, well 
conducted, performed by qualified investigators, and conducted in 
accordance with ethical principles acceptable to the world community. 
Studies meeting these criteria may be utilized to support clinical 
investigations in the United States and/or marketing approval. Marketing 
approval of a new drug based solely on foreign clinical data is governed 
by Sec. 314.106.
    (b) Data submissions. A sponsor who wishes to rely on a foreign 
clinical study to support an IND or to support an application for 
marketing approval shall submit to FDA the following information:
    (1) A description of 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;

[[Page 91]]

    (4) A description of the drug substance and drug product used in the 
study, including a description of components, formulation, 
specifications, and bioavailability of the specific drug product used in 
the clinical study, if available; and
    (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.
    (c) Conformance with ethical principles. (1) Foreign clinical 
research is required to have been conducted in accordance with the 
ethical principles stated in the ``Declaration of Helsinki'' (see 
paragraph (c)(4) of this section) or the laws and regulations of the 
country in which the research was conducted, whichever represents the 
greater protection of the individual.
    (2) For each foreign clinical study submitted under this section, 
the sponsor shall explain how the research conformed to the ethical 
principles contained in the ``Declaration of Helsinki'' or the foreign 
country's standards, whichever were used. If the foreign country's 
standards were used, the sponsor shall explain in detail how those 
standards differ from the ``Declaration of Helsinki'' and how they offer 
greater protection.
    (3) When the research has been approved by an independent review 
committee, the sponsor shall submit to FDA documentation of such review 
and approval, including the names and qualifications of the members of 
the committee. In this regard, a ``review committee'' means a committee 
composed of scientists and, where practicable, individuals who are 
otherwise qualified (e.g., other health professionals or laymen). The 
investigator may not vote on any aspect of the review of his or her 
protocol by a review committee.
    (4) The ``Declaration of Helsinki'' states as follows:

  Recommendations Guiding Physicians in Biomedical Research Involving 
                             Human Subjects

                              Introduction

    It is the mission of the physician to safeguard the health of the 
people. His or her knowledge and conscience are dedicated to the 
fulfillment of this mission.
    The Declaration of Geneva of the World Medical Association binds the 
physician with the words, ``The health of my patient will be my first 
consideration,'' and the International Code of Medical Ethics declares 
that, ``A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the 
physical and mental condition of the patient.''
    The purpose of biomedical research involving human subjects must be 
to improve diagnostic, therapeutic and prophylactic procedures and the 
understanding of the aetiology and pathogenesis of disease.
    In current medical practice most diagnostic, therapeutic or 
prophylactic procedures involve hazards. This applies especially to 
biomedical research.
    Medical progress is based on research which ultimately must rest in 
part on experimentation involving human subjects.
    In the field of biomedical research a fundamental distinction must 
be recognized between medical research in which the aim is essentially 
diagnostic or therapeutic for a patient, and medical research, the 
essential object of which is purely scientific and without implying 
direct diagnostic or therapeutic value to the person subjected to the 
research.
    Special caution must be exercised in the conduct of research which 
may affect the environment, and the welfare of animals used for research 
must be respected.
    Because it is essential that the results of laboratory experiments 
be applied to human beings to further scientific knowledge and to help 
suffering humanity, the World Medical Association has prepared the 
following recommendations as a guide to every physician in biomedical 
research involving human subjects. They should be kept under review in 
the future. It must be stressed that the standards as drafted are only a 
guide to physicians all over the world. Physicians are not relieved from 
criminal, civil and ethical responsibilities under the laws of their own 
countries.

                           I. Basic Principles

    1. Biomedical research involving human subjects must conform to 
generally accepted scientific principles and should be based on 
adequately performed laboratory and animal experimentation and on a 
thorough knowledge of the scientific literature.
    2. The design and performance of each experimental procedure 
involving human subjects should be clearly formulated in an experimental 
protocol which should be transmitted for consideration, comment and 
guidance to a specially appointed committee independent of the 
investigator and the

[[Page 92]]

sponsor provided that this independent committee is in conformity with 
the laws and regulations of the country in which the research experiment 
is performed.
    3. Biomedical research involving human subjects should be conducted 
only by scientifically qualified persons and under the supervision of a 
clinically competent medical person. The responsibility for the human 
subject must always rest with a medically qualified person and never 
rest on the subject of the research, even though the subject has given 
his or her consent.
    4. Biomedical research involving human subjects cannot legitimately 
be carried out unless the importance of the objective is in proportion 
to the inherent risk to the subject.
    5. Every biomedical research project involving human subjects should 
be preceded by careful assessment of predictable risks in comparison 
with foreseeable benefits to the subject or to others. Concern for the 
interests of the subject must always prevail over the interests of 
science and society.
    6. The right of the research subject to safeguard his or her 
integrity must always be respected. Every precaution should be taken to 
respect the privacy of the subject and to minimize the impact of the 
study on the subject's physical and mental integrity and on the 
personality of the subject.
    7. Physicians should abstain from engaging in research projects 
involving human subjects unless they are satisfied that the hazards 
involved are believed to be predictable. Physicians should cease any 
investigation if the hazards are found to outweigh the potential 
benefits.
    8. In publication of the results of his or her research, the 
physician is obliged to preserve the accuracy of the results. Reports of 
experimentation not in accordance with the principles laid down in this 
Declaration should not be accepted for publication.
    9. In any research on human beings, each potential subject must be 
adequately informed of the aims, methods, anticipated benefits and 
potential hazards of the study and the discomfort it may entail. He or 
she should be informed that he or she is at liberty to abstain from 
participation in the study and that he or she is free to withdraw his or 
her consent to participation at any time. The physician should then 
obtain the subject's freely-given informed consent, preferably in 
writing.
    10. When obtaining informed consent for the research project the 
physician should be particularly cautious if the subject is in a 
dependent relationship to him or her or may consent under duress. In 
that case the informed consent should be obtained by a physician who is 
not engaged in the investigation and who is completely independent of 
this official relationship.
    11. In case of legal incompetence, informed consent should be 
obtained from the legal guardian in accordance with national 
legislation. Where physical or mental incapacity makes it impossible to 
obtain informed consent, or when the subject is a minor, permission from 
the responsible relative replaces that of the subject in accordance with 
national legislation.
    Whenever the minor child is in fact able to give a consent, the 
minor's consent must be obtained in addition to the consent of the 
minor's legal guardian.
    12. The research protocol should always contain a statement of the 
ethical considerations involved and should indicate that the principles 
enunciated in the present Declaration are complied with.

II. Medical Research Combined with Professional Care (Clinical Research)

    1. In the treatment of the sick person, the physician must be free 
to use a new diagnostic and therapeutic measure, if in his or her 
judgment it offers hope of saving life, reestablishing health or 
alleviating suffering.
    2. The potential benefits, hazards and discomfort of a new method 
should be weighed against the advantages of the best current diagnostic 
and therapeutic methods.
    3. In any medical study, every patient--including those of a control 
group, if any--should be assured of the best proven diagnostic and 
therapeutic method.
    4. The refusal of the patient to participate in a study must never 
interfere with the physician-patient relationship.
    5. If the physician considers it essential not to obtain informed 
consent, the specific reasons for this proposal should be stated in the 
experimental protocol for transmission to the independent committee (I, 
2).
    6. The physician can combine medical research with professional 
care, the objective being the acquisition of new medical knowledge, only 
to the extent that medical research is justified by its potential 
diagnostic or therapeutic value for the patient.

 III. Non-Therapeutic Biomedical Research Involving Human Subjects (Non-
                      Clinical Biomedical Research)

    1. In the purely scientific application of medical research carried 
out on a human being, it is the duty of the physician to remain the 
protector of the life and health of that person on whom biomedical 
research is being carried out.
    2. The subjects should be volunteers--either healthy persons or 
patients for whom the experimental design is not related to the 
patient's illness.
    3. The investigator or the investigating team should discontinue the 
research if in his/her or their judgment it may, if continued, be 
harmful to the individual.

[[Page 93]]

    4. In research on man, the interest of science and society should 
never take precedence over considerations related to the well-being of 
the subject.

[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 56 
FR 22113, May 14, 1991; 64 FR 401, Jan. 5, 1999; 67 FR 9586, Mar. 4, 
2002]



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 Secs. 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 
Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857, 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]



Sec. 312.140  Address for correspondence.

    (a) Except as provided in paragraph (b) of this section, a sponsor 
shall send an initial IND submission to the Central Document Room, 
Center for Drug Evaluation and Research, Food and Drug Administration, 
Park Bldg., Rm. 214, 12420 Parklawn Dr., Rockville, MD 20852. On 
receiving the IND, FDA will inform the sponsor which one of the 
divisions in the Center for Drug Evaluation and Research or the Center 
for Biologics Evaluation and Research is responsible for the IND. 
Amendments, reports, and other correspondence relating to matters 
covered by the IND should be directed to the appropriate division. The 
outside wrapper of each submission shall state what is contained in the 
submission, for example, ``IND Application'', ``Protocol Amendment'', 
etc.
    (b) Applications for the products listed below should be submitted 
to the Division of Biological Investigational New Drugs (HFB-230), 
Center for Biologics Evaluation and Research, Food and Drug 
Administration, 8800 Rockville Pike, Bethesda, MD 20892. (1) Products 
subject to the licensing provisions of the Public Health Service Act of 
July 1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or 
subject to part 600; (2) ingredients packaged together with containers 
intended for the collection, processing, or storage of blood or blood 
components; (3) urokinase products; (4) plasma volume expanders and 
hydroxyethyl starch for leukapheresis; and (5) coupled antibodies, i.e., 
products that consist of an antibody component coupled with a drug or 
radionuclide component in which both components provide a 
pharmacological effect but the biological component determines the site 
of action.
    (c) All correspondence relating to biological products for human use 
which are also radioactive drugs shall be submitted to the Division of 
Oncology and Radiopharmaceutical Drug Products (HFD-150), Center for 
Drug Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857, except that applications for coupled 
antibodies shall be submitted in accordance with paragraph (b) of this 
section.
    (d) 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 94]]

Administration, 5600 Fishers Lane, Rockville, MD 20857.

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



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 Communications 
Management, Drug Information Branch (HFD-210), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857. A request for a copy of the CBER list should 
be directed to the Office of Communication, Training, and Manufacturers 
Assistance (HFM-40), Center for Biologics Evaluation and Research, Food 
and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448.

[65 FR 56479, Sept. 19, 2000]



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 95]]

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]



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




                      Subpart A--General Provisions

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

                         Subpart B--Applications

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

                   Subpart C--Abbreviated Applications

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

   Subpart D--FDA Action on Applications and Abbreviated Applications

314.100 Timeframes for reviewing applications and abbreviated 
          applications.
314.101 Filing an application and receiving an abbreviated new drug 
          application.
314.102 Communications between FDA and applicants.
314.103 Dispute resolution.
314.104 Drugs with potential for abuse.
314.105 Approval of an application and an abbreviated application.
314.106 Foreign data.
314.107 Effective date of approval of a 505(b)(2) application or 
          abbreviated new drug application under section 505(j) of the 
          act.
314.108 New drug product exclusivity.
314.110 Approvable letter to the applicant.
314.120 Not approvable letter to the applicant.
314.122 Submitting an abbreviated application for, or a 505(j)(2)(C) 
          petition that relies on, a listed drug that is no longer 
          marketed.
314.125 Refusal to approve an application.
314.126 Adequate and well-controlled studies.
314.127 Refusal to approve an abbreviated new drug application.
314.150 Withdrawal of approval of an application or abbreviated 
          application.
314.151 Withdrawal of approval of an abbreviated new drug application 
          under section 505(j)(5) of the act.
314.152 Notice of withdrawal of approval of an application or 
          abbreviated application for a new drug.
314.153 Suspension of approval of an abbreviated new drug application.
314.160 Approval of an application or abbreviated application for which 
          approval was previously refused, suspended, or withdrawn.
314.161 Determination of reasons for voluntary withdrawal of a listed 
          drug.
314.162 Removal of a drug product from the list.
314.170 Adulteration and misbranding of an approved drug.

               Subpart E--Hearing Procedures for New Drugs

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

[[Page 96]]

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.

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

    Effective Date Note: At 65 FR 64617, Oct. 30, 2001, the authority 
citation for 21 CFR part 314 was revised, effective Feb. 27, 2001. At 66 
FR 10815, Feb. 20, 2001, the effective date was delayed until Apr. 30, 
2001. 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, 355a, 356, 356a, 
356b, 356c, 371, 374, 379e.

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



                      Subpart A--General Provisions



Sec. 314.1  Scope of this part.

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

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



Sec. 314.2  Purpose.

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



Sec. 314.3  Definitions.

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

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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.
    Approvable letter means a written communication to an applicant from 
FDA stating that the agency will approve the application or abbreviated 
application if specific additional information or material is submitted 
or specific conditions are met. An approvable letter does not constitute 
approval of any part of an application or abbreviated application and 
does not permit marketing of the drug that is the subject of the 
application or abbreviated application.
    Approval letter means a written communication to an applicant from 
FDA approving an application or an abbreviated application.
    Drug product means a finished dosage form, for example, tablet, 
capsule, or solution, that contains a drug substance, generally, but not 
necessarily, in association with one or more other ingredients.
    Drug substance means an active ingredient that is intended to 
furnish pharmacological activity or other direct effect in the 
diagnosis, cure, mitigation, treatment, or prevention of disease or to 
affect the structure or any function of the human body, but does not 
include intermediates use in the synthesis of such ingredient.
    FDA means the Food and Drug Administration.
    Listed drug means a new drug product that has an effective approval 
under section 505(c) of the act for safety and effectiveness or under 
section 505(j) of the act, which has not been withdrawn or suspended 
under section 505(e)(1) through (e)(5) or (j)(5) of the act, and which 
has not been withdrawn from sale for what FDA has determined are reasons 
of safety or effectiveness. Listed drug status is evidenced by the drug 
product's identification as a drug with an effective approval in the 
current edition of FDA's ``Approved Drug Products with Therapeutic 
Equivalence Evaluations'' (the list) or any current supplement thereto, 
as a drug with an effective approval. A drug product is deemed to be a 
listed drug on the date of effective approval of the application or 
abbreviated application for that drug product.
    Not approvable letter means a written communication to an applicant 
from FDA stating that the agency does not consider the application or 
abbreviated application approvable because one or more deficiencies in 
the application or abbreviated application preclude the agency from 
approving it.
    Reference listed drug means the listed drug identified by FDA as the 
drug product upon which an applicant relies in seeking approval of its 
abbreviated application.
    Right of reference or use means the authority to rely upon, and 
otherwise use, an investigation for the purpose of obtaining approval of 
an application, including the ability to make available the underlying 
raw data from the investigation for FDA audit, if necessary.
    The list means the list of drug products with effective approvals 
published in the current edition of FDA's publication ``Approved Drug 
Products with Therapeutic Equivalence Evaluations'' and any current 
supplement to the publication.

[50 FR 7493, Feb. 22, 1985, as amended at 57 FR 17981, Apr. 28, 1992]



                         Subpart B--Applications



Sec. 314.50  Content and format of an application.

    Applications and supplements to approved applications are required 
to be submitted in the form and contain the information, as appropriate 
for the particular submission, required under this section. Three copies 
of the application are required: An archival copy, a review copy, and a 
field copy. An application for a new chemical entity will generally 
contain an application form, an index, a summary, five or six technical 
sections, case report tabulations of patient data, case report forms, 
drug samples, and labeling, including, if applicable, any Medication 
Guide required under part 208 of this chapter. Other applications will 
generally contain only some of those items, and information will be 
limited to that needed to support the particular submission. These 
include an application of the type described in section 505(b)(2)

[[Page 98]]

of the act, an amendment, and a supplement. The application is required 
to contain reports of all investigations of the drug product sponsored 
by the applicant, and all other information about the drug pertinent to 
an evaluation of the application that is received or otherwise obtained 
by the applicant from any source. FDA will maintain guidance documents 
on the format and content of applications to assist applicants in their 
preparation.
    (a) Application form. The applicant shall submit a completed and 
signed application form that contains the following:
    (1) The name and address of the applicant; the date of the 
application; the application number if previously issued (for example, 
if the application is a resubmission, an amendment, or a supplement); 
the name of the drug product, including its established, proprietary, 
code, and chemical names; the dosage form and strength; the route of 
administration; the identification numbers of all investigational new 
drug applications that are referenced in the application; the 
identification numbers of all drug master files and other applications 
under this part that are referenced in the application; and the drug 
product's proposed indications for use.
    (2) A statement whether the submission is an original submission, a 
505(b)(2) application, a resubmission, or a supplement to an application 
under Sec. 314.70.
    (3) A statement whether the applicant proposes to market the drug 
product as a prescription or an over-the-counter product.
    (4) A check-list identifying what enclosures required under this 
section the applicant is submitting.
    (5) The applicant, or the applicant's attorney, agent, or other 
authorized official shall sign the application. If the person signing 
the application does not reside or have a place of business within the 
United States, the application is required to contain the name and 
address of, and be countersigned by, an attorney, agent, or other 
authorized official who resides or maintains a place of business within 
the United States.
    (b) Index. The archival copy of the application is required to 
contain a comprehensive index by volume number and page number to the 
summary under paragraph (c) of this section, the technical sections 
under paragraph (d) of this section, and the supporting information 
under paragraph (f) of this section.
    (c) Summary. (1) An application is required to contain a summary of 
the application in enough detail that the reader may gain a good general 
understanding of the data and information in the application, including 
an understanding of the quantitative aspects of the data. The summary is 
not required for supplements under Sec. 314.70. Resubmissions of an 
application should contain an updated summary, as appropriate. The 
summary should discuss all aspects of the application, and synthesize 
the information into a well-structured and unified document. The summary 
should be written at approximately the level of detail required for 
publication in, and meet the editorial standards generally applied by, 
refereed scientific and medical journals. In addition to the agency 
personnel reviewing the summary in the context of their review of the 
application, FDA may furnish the summary to FDA advisory committee 
members and agency officials whose duties require an understanding of 
the application. To the extent possible, data in the summary should be 
presented in tabular and graphic forms. FDA has prepared a guideline 
under Sec. 10.90(b) that provides information about how to prepare a 
summary. The summary required under this paragraph may be used by FDA or 
the applicant to prepare the Summary Basis of Approval document for 
public disclosure (under Sec. 314.430(e)(2)(ii)) when the application is 
approved.
    (2) The summary is required to contain the following information:
    (i) The proposed text of the labeling, including, if applicable, any 
Medication Guide required under part 208 of this chapter, for the drug, 
with annotations to the information in the summary and technical 
sections of the application that support the inclusion of each statement 
in the labeling, and, if the application is for a prescription

[[Page 99]]

drug, statements describing the reasons for omitting a section or 
subsection of the labeling format in Sec. 201.57 of this chapter.
    (ii) A statement identifying the pharmacologic class of the drug and 
a discussion of the scientific rationale for the drug, its intended use, 
and the potential clinical benefits of the drug product.
    (iii) A brief description of the marketing history, if any, of the 
drug outside the United States, including a list of the countries in 
which the drug has been marketed, a list of any countries in which the 
drug has been withdrawn from marketing for any reason related to safety 
or effectiveness, and a list of countries in which applications for 
marketing are pending. The description is required to describe both 
marketing by the applicant and, if known, the marketing history of other 
persons.
    (iv) A summary of the chemistry, manufacturing, and controls section 
of the application.
    (v) A summary of the nonclinical pharmacology and toxicology section 
of the application.
    (vi) A summary of the human pharmacokinetics and bioavailability 
section of the application.
    (vii) A summary of the microbiology section of the application (for 
anti-infective drugs only).
    (viii) A summary of the clinical data section of the application, 
including the results of statistical analyses of the clinical trials.
    (ix) A concluding discussion that presents the benefit and risk 
considerations related to the drug, including a discussion of any 
proposed additional studies or surveillance the applicant intends to 
conduct postmarketing.
    (d) Technical sections. The application is required to contain the 
technical sections described below. Each technical section is required 
to contain data and information in sufficient detail to permit the 
agency to make a knowledgeable judgment about whether to approve the 
application or whether grounds exist under section 505(d) of the act to 
refuse to approve the application. The required technical sections are 
as follows:
    (1) Chemistry, manufacturing, and controls section. A section 
describing the composition, manufacture, and specification of the drug 
substance and the drug product, including the following:
    (i) Drug substance. A full description of the drug substance 
including its physical and chemical characteristics and stability; the 
name and address of its manufacturer; the method of synthesis (or 
isolation) and purification of the drug substance; the process controls 
used during manufacture and packaging; and such specifications and 
analytical methods as are necessary to assure the identity, strength, 
quality, and purity of the drug substance and the bioavailability of the 
drug products made from the substance, including, for example, 
specifications relating to stability, sterility, particle size, and 
crystalline form. The application may provide additionally for the use 
of alternatives to meet any of these requirements, including alternative 
sources, process controls, methods, and specifications. 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; a statement of the specifications and analytical methods for 
each component; the name and address of each manufacturer the drug 
product; 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, for 
example, specifications relating to sterility, dissolution rate, 
containers and closure systems; and stability data with proposed 
expiration dating. The application may provide additionally for the use 
of alternatives to meet any of these requirements, including alternative 
components, manufacturing and packaging procedures, in-process controls, 
methods, and specifications. Reference to the current edition of the 
U.S. Pharmacopeia and the National Formulary may satisfy

[[Page 100]]

relevant requirements in this paragraph.
    (b) Unless provided by paragraph (d)(1)(ii)(a) of this section, for 
each batch of the drug product used to conduct a bioavailability or 
bioequivalence study described in Sec. 320.38 or Sec. 320.63 of this 
chapter or used to conduct a primary stability study: The batch 
production record; the specifications and test procedures 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 application is required to contain 
either a claim for categorical exclusion under Sec. 25.30 or 25.31 of 
this chapter or an environmental assessment under Sec. 25.40 of this 
chapter.
    (iv) The applicant may, at its option, submit a complete chemistry, 
manufacturing, and controls section 90 to 120 days before the 
anticipated submission of the remainder of the application. FDA will 
review such early submissions as resources permit.
    (v) Except for a foreign applicant, the applicant shall include a 
statement certifying that the field copy of the application has been 
provided to the applicant's home FDA district office.
    (2) Nonclinical pharmacology and toxicology section. A section 
describing, with the aid of graphs and tables, animal and in vitro 
studies with drug, including the following:
    (i) Studies of the pharmacological actions of the drug in relation 
to its proposed therapeutic indication and studies that otherwise define 
the pharmacologic properties of the drug or are pertinent to possible 
adverse effects.
    (ii) Studies of the toxicological effects of the drug as they relate 
to the drug's intended clinical uses, including, as appropriate, studies 
assessing the drug's acute, subacute, and chronic toxicity; 
carcinogenicity; and studies of toxicities related to the drug's 
particular mode of administration or conditions of use.
    (iii) Studies, as appropriate, of the effects of the drug on 
reproduction and on the developing fetus.
    (iv) Any studies of the absorption, distribution, metabolism, and 
excretion of the drug in animals.
    (v) For each nonclinical laboratory study subject to the good 
laboratory practice regulations under part 58 a statement that it was 
conducted in compliance with the good laboratory practice regulations in 
part 58, or, if the study was not conducted in compliance with those 
regulations, a brief statement of the reason for the noncompliance.
    (3) Human pharmacokinetics and bioavailability section. A section 
describing the human pharmacokinetic data and human bioavailability 
data, or information supporting a waiver of the submission of in vivo 
bioavailability data under subpart B of part 320, including the 
following:
    (i) A description of each of the bioavailability and pharmacokinetic 
studies of the drug in humans performed by or on behalf of the applicant 
that includes a description of the analytical and statistical methods 
used in each study and a statement with respect to each study that it 
either was conducted in compliance with the institutional review board 
regulations in part 56, or was not subject to the regulations under 
Sec. 56.104 or Sec. 56.105, and that it was conducted in compliance with 
the informed consent regulations in part 50.
    (ii) If the application describes in the chemistry, manufacturing, 
and controls section specifications or analytical methods needed to 
assure the bioavailability of the drug product or drug

[[Page 101]]

substance, or both, a statement in this section of the rationale for 
establishing the specification or analytical methods, including data and 
information supporting the rationale.
    (iii) A summarizing discussion and analysis of the pharmacokinetics 
and metabolism of the active ingredients and the bioavailability or 
bioequivalence, or both, of the drug product.
    (4) Microbiology section. If the drug is an anti-infective drug, a 
section describing the microbiology data, including the following:
    (i) A description of the biochemical basis of the drug's action on 
microbial physiology.
    (ii) A description of the antimicrobial spectra of the drug, 
including results of in vitro preclinical studies to demonstrate 
concentrations of the drug required for effective use.
    (iii) A description of any known mechanisms of resistance to the 
drug, including results of any known epidemiologic studies to 
demonstrate prevalence of resistance factors.
    (iv) A description of clinical microbiology laboratory methods (for 
example, in vitro sensitivity discs) needed for effective use of the 
drug.
    (5) Clinical data section. A section describing the clinical 
investigations of the drug, including the following:
    (i) A description and analysis of each clinical pharmacology study 
of the drug, including a brief comparison of the results of the human 
studies with the animal pharmacology and toxicology data.
    (ii) A description and analysis of each controlled clinical study 
pertinent to a proposed use of the drug, including the protocol and a 
description of the statistical analyses used to evaluate the study. If 
the study report is an interim analysis, this is to be noted and a 
projected completion date provided. Controlled clinical studies that 
have not been analyzed in detail for any reason (e.g., because they have 
been discontinued or are incomplete) are to be included in this section, 
including a copy of the protocol and a brief description of the results 
and status of the study.
    (iii) A description of each uncontrolled clinical study, a summary 
of the results, and a brief statement explaining why the study is 
classified as uncontrolled.
    (iv) A description and analysis of any other data or information 
relevant to an evaluation of the safety and effectiveness of the drug 
product obtained or otherwise received by the applicant from any source, 
foreign or domestic, including information derived from clinical 
investigations, including controlled and uncontrolled studies of uses of 
the drug other than those proposed in the application, commercial 
marketing experience, reports in the scientific literature, and 
unpublished scientific papers.
    (v) An integrated summary of the data demonstrating substantial 
evidence of effectiveness for the claimed indications. Evidence is also 
required to support the dosage and administration section of the 
labeling, including support for the dosage and dose interval 
recommended. The effectiveness data shall be presented by gender, age, 
and racial subgroups and shall identify any modifications of dose or 
dose interval needed for specific subgroups. Effectiveness data from 
other subgroups of the population of patients treated, when appropriate, 
such as patients with renal failure or patients with different levels of 
severity of the disease, also shall be presented.
    (vi) A summary and updates of safety information, as follows:
    (a) The applicant shall submit an integrated summary of all 
available information about the safety of the drug product, including 
pertinent animal data, demonstrated or potential adverse effects of the 
drug, clinically significant drug/drug interactions, and other safety 
considerations, such as data from epidemiological studies of related 
drugs. The safety data shall be presented by gender, age, and racial 
subgroups. When appropriate, safety data from other subgroups of the 
population of patients treated also shall be presented, such as for 
patients with renal failure or patients with different levels of 
severity of the disease. A description of any statistical analyses 
performed in analyzing safety data should also be included, unless 
already included under paragraph (d)(5)(ii) of this section.

[[Page 102]]

    (b) The applicant shall, under section 505(i) of the act, update 
periodically its pending application with new safety information learned 
about the drug that may reasonably affect the statement of 
contraindications, warnings, precautions, and adverse reactions in the 
draft labeling and, if applicable, any Medication Guide required under 
part 208 of this chapter. These ``safety update reports'' are required 
to include the same kinds of information (from clinical studies, animal 
studies, and other sources) and are required to be submitted in the same 
format as the integrated summary in paragraph (d)(5)(vi)(a) of this 
section. In addition, the reports are required to include the case 
report forms for each patient who died during a clinical study or who 
did not complete the study because of an adverse event (unless this 
requirement is waived). The applicant shall submit these reports (1) 4 
months after the initial submission; (2) following receipt of an 
approvable letter; and (3) at other times as requested by FDA. Prior to 
the submission of 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 
shall submit the samples described below to the places identified in the 
agency's request. FDA will generally ask applicants to submit samples 
directly to two or more agency laboratories that will perform all 
necessary tests on the

[[Page 103]]

samples and validate the applicant's analytical methods.
    (i) Four representative samples of the following, each sample in 
sufficient quantity to permit FDA to perform three times each test 
described in the application to determine whether the drug substance and 
the drug product meet the specifications given in the application:
    (a) The drug product proposed for marketing;
    (b) The drug substance used in the drug product from which the 
samples of the drug product were taken; and
    (c) Reference standards and blanks (except that reference standards 
recognized in an official compendium need not be submitted).
    (ii) Samples of the finished market package, if requested by FDA.
    (2) The applicant shall submit the following in the archival copy of 
the application:
    (i) Three copies of the analytical methods 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 methods. The related descriptive information 
includes a description of each sample; the proposed regulatory 
specifications for the drug; a detailed description of the methods of 
analysis; supporting data for accuracy, specificity, precision and 
ruggedness; and complete results of the applicant's tests on each 
sample.
    (ii) Copies of the label and all labeling for the drug product 
(including, if applicable, any Medication Guide required under part 208 
of this chapter) for the drug product (4 copies of draft labeling or 12 
copies of final printed labeling).
    (f) Case report forms and tabulations. The archival copy of the 
application is required to contain the following case report tabulations 
and case report forms:
    (1) Case report tabulations. The application is required to contain 
tabulations of the data from each adequate and well-controlled study 
under Sec. 314.126 (Phase 2 and Phase 3 studies as described in 
Secs. 312.21 (b) and (c) of this chapter), tabulations of the data from 
the earliest clinical pharmacology studies (Phase 1 studies as described 
in Sec. 312.21(a) of this chapter), and tabulations of the safety data 
from other clinical studies. Routine submission of other patient data 
from uncontrolled studies is not required. The tabulations are required 
to include the data on each patient in each study, except that the 
applicant may delete those tabulations which the agency agrees, in 
advance, are not pertinent to a review of the drug's safety or 
effectiveness. Upon request, FDA will discuss with the applicant in a 
``pre-NDA'' conference those tabulations that may be appropriate for 
such deletion. Barring unforeseen circumstances, tabulations agreed to 
be deleted at such a conference will not be requested during the conduct 
of FDA's review of the application. If such unforeseen circumstances do 
occur, any request for deleted tabulations will be made by the director 
of the FDA division responsible for reviewing the application, in 
accordance with paragraph (f)(3) of this section.
    (2) Case report forms. The application is required to contain copies 
of individual case report forms for each patient who died during a 
clinical study or who did not complete the study because of an adverse 
event, whether believed to be drug related or not, including patients 
receiving reference drugs or placebo. This requirement may be waived by 
FDA for specific studies if the case report forms are unnecessary for a 
proper review of the study.
    (3) Additional data. The applicant shall submit to FDA additional 
case report forms and tabulations needed to conduct a proper review of 
the application, as requested by the director of the FDA division 
responsible for reviewing the application. The applicant's failure to 
submit information requested by FDA within 30 days after receipt of the 
request may result in the agency viewing any eventual submission as a 
major amendment under Sec. 314.60 and extending the review period as 
necessary. If desired by the applicant, the FDA division director will 
verify in writing any request for additional data that was made orally.

[[Page 104]]

    (4) Applicants are invited to meet with FDA before submitting an 
application to discuss the presentation and format of supporting 
information. If the applicant and FDA agree, the applicant may submit 
tabulations of patient data and case report forms in a form other than 
hard copy, for example, on microfiche or computer tapes.
    (g) Other. The following general requirements apply to the 
submission of information within the summary under paragraph (c) of this 
section and within the technical sections under paragraph (d) of this 
section.
    (1) The applicant ordinarily is not required to resubmit information 
previously submitted, but may incorporate the information by reference. 
A reference to information submitted previously is required to identify 
the file by name, reference number, volume, and page number in the 
agency's records where the information can be found. A reference to 
information submitted to the agency by a person other than the applicant 
is required to contain a written statement that authorizes the reference 
and that is signed by the person who submitted the information.
    (2) The applicant shall submit an accurate and complete English 
translation of each part of the application that is not in English. The 
applicant shall submit a copy of each original literature publication 
for which an English translation is submitted.
    (3) If an applicant who submits a new drug application under section 
505(b) of the act obtains a ``right of reference or use,'' as defined 
under Sec. 314.3(b), to an investigation described in clause (A) of 
section 505(b)(1) of the act, the applicant shall include in its 
application a written statement signed by the owner of the data from 
each such investigation that the applicant may rely on in support of the 
approval of its application, and provide FDA access to, the underlying 
raw data that provide the basis for the report of the investigation 
submitted in its application.
    (h) Patent information. The application is required to contain the 
patent information described under Sec. 314.53.
    (i) Patent certification--(1) Contents. A 505(b)(2) application is 
required to contain the following:
    (i) Patents claiming drug, drug product, or method of use. (A) 
Except as provided in paragraph (i)(2) of this section, a certification 
with respect to each patent issued by the United States Patent and 
Trademark Office that, in the opinion of the applicant and to the best 
of its knowledge, claims a drug (the drug product or drug substance that 
is a component of the drug product) on which investigations that are 
relied upon by the applicant for approval of its application were 
conducted or that claims an approved use for such drug and for which 
information is required to be filed under section 505(b) and (c) of the 
act and Sec. 314.53. For each such patent, the applicant shall provide 
the patent number and certify, in its opinion and to the best of its 
knowledge, one of the following circumstances:
    (1) That the patent information has not been submitted to FDA. The 
applicant shall entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant shall entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant shall 
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the application is submitted. The applicant shall entitle such a 
certification ``Paragraph IV Certification''. This certification shall 
be submitted in the following form:

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


The certification shall be accompanied by a statement that the applicant 
will comply with the requirements under Sec. 314.52(a) with respect to 
providing a notice to each owner of the patent or their representatives 
and to the holder of the approved application for the drug product which 
is claimed by the patent or a use of which is claimed by the patent and 
with the requirements under Sec. 314.52(c) with respect to the content 
of the notice.

[[Page 105]]

    (B) If the drug on which investigations that are relied upon by the 
applicant were conducted is itself a licensed generic drug of a patented 
drug first approved under section 505(b) of the act, the appropriate 
patent certification under this section with respect to each patent that 
claims the first-approved patented drug or that claims an approved use 
for such a drug.
    (ii) No relevant patents. If, in the opinion of the applicant and to 
the best of its knowledge, there are no patents described in paragraph 
(i)(1)(i) of this section, a certification in the following form:

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

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

[[Page 106]]

longer be considered to be one containing the prior certification.
    (i) After finding of infringement. An applicant who has submitted a 
certification under paragraph (i)(1)(i)(A)(4) of this section and is 
sued for patent infringement within 45 days of the receipt of notice 
sent under Sec. 314.52 shall amend the certification if a final judgment 
in the action is entered finding the patent to be infringed unless the 
final judgment also finds the patent to be invalid. In the amended 
certification, the applicant shall certify under paragraph 
(i)(1)(i)(A)(3) of this section that the patent will expire on a 
specific date.
    (ii) After removal of a patent from the list. If a patent is removed 
from the list, any applicant with a pending application (including a 
tentatively approved application with a delayed effective date) who has 
made a certification with respect to such patent shall amend its 
certification. The applicant shall certify under paragraph (i)(1)(ii) of 
this section that no patents described in paragraph (i)(1)(i) of this 
section claim the drug or, if other relevant patents claim the drug, 
shall amend the certification to refer only to those relevant patents. 
In the amendment, the applicant shall state the reason for the change in 
certification (that the patent is or has been removed from the list). A 
patent that is the subject of a lawsuit under Sec. 314.107(c) shall not 
be removed from the list until FDA determines either that no delay in 
effective dates of approval is required under that section as a result 
of the lawsuit, that the patent has expired, or that any such period of 
delay in effective dates of approval is ended. An applicant shall submit 
an amended certification as an amendment to a pending application. Once 
an amendment for the change has been submitted, the application will no 
longer be considered to be one containing a certification under 
paragraph (i)(1)(i)(A)(4) of this section.
    (iii) Other amendments. (A) Except as provided in paragraphs (i)(4) 
and (i)(6)(iii)(B) of this section, an applicant shall amend a submitted 
certification if, at any time before the effective date of the approval 
of the application, the applicant learns that the submitted 
certification is no longer accurate.
    (B) An applicant is not required to amend a submitted certification 
when information on an otherwise applicable patent is submitted after 
the effective date of approval for the 505(b)(2) application.
    (j) Claimed exclusivity. A new drug product, upon approval, may be 
entitled to a period of marketing exclusivity under the provisions of 
Sec. 314.108. If an applicant believes its drug product is entitled to a 
period of exclusivity, it shall submit with the new drug application 
prior to approval the following information:
    (1) A statement that the applicant is claiming exclusivity.
    (2) A reference to the appropriate paragraph under Sec. 314.108 that 
supports its claim.
    (3) If the applicant claims exclusivity under Sec. 314.108(b)(2), 
information to show that, to the best of its knowledge or belief, a drug 
has not previously been approved under section 505(b) of the act 
containing any active moiety in the drug for which the applicant is 
seeking approval.
    (4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or 
(b)(5), the following information to show that the application contains 
``new clinical investigations'' that are ``essential to approval of the 
application or supplement'' and were ``conducted or sponsored by the 
applicant:''
    (i) ``New clinical investigations.'' A certification that to the 
best of the applicant's knowledge each of the clinical investigations 
included in the application meets the definition of ``new clinical 
investigation'' set forth in Sec. 314.108(a).
    (ii) ``Essential to approval.'' A list of all published studies or 
publicly available reports of clinical investigations known to the 
applicant through a literature search that are relevant to the 
conditions for which the applicant is seeking approval, a certification 
that the applicant has thoroughly searched the scientific literature 
and, to the best of the applicant's knowledge, the list is complete and 
accurate and, in the applicant's opinion, such published studies or 
publicly available reports do not provide a sufficient basis for the

[[Page 107]]

approval of the conditions for which the applicant is seeking approval 
without reference to the new clinical investigation(s) in the 
application, and an explanation as to why the studies or reports are 
insufficient.
    (iii) ``Conducted or sponsored by.'' If the applicant was the 
sponsor named in the Form FDA-1571 for an investigational new drug 
application (IND) under which the new clinical investigation(s) that is 
essential to the approval of its application was conducted, 
identification of the IND by number. If the applicant was not the 
sponsor of the IND under which the clinical investigation(s) was 
conducted, a certification that the applicant or its predecessor in 
interest provided substantial support for the clinical investigation(s) 
that is essential to the approval of its application, and information 
supporting the certification. To demonstrate ``substantial support,'' an 
applicant must either provide a certified statement from a certified 
public accountant that the applicant provided 50 percent or more of the 
cost of conducting the study or provide an explanation of why FDA should 
consider the applicant to have conducted or sponsored the study if the 
applicant's financial contribution to the study is less than 50 percent 
or the applicant did not sponsor the investigational new drug. A 
predecessor in interest is an entity, e.g., a corporation, that the 
applicant has taken over, merged with, or purchased, or from which the 
applicant has purchased all rights to the drug. Purchase of nonexclusive 
rights to a clinical investigation after it is completed is not 
sufficient to satisfy this definition.
    (k) Financial certification or disclosure statement. The application 
shall contain a financial certification or disclosure statement or both 
as required by part 54 of this chapter.
    (l) Format of an original application. (1) The applicant shall 
submit a complete archival copy of the application that contains the 
information required under paragraphs (a) through (f) of this section. 
FDA will maintain the archival copy during the review of the application 
to permit individual reviewers to refer to information that is not 
contained in their particular technical sections of the application, to 
give other agency personnel access to the application for official 
business, and to maintain in one place a complete copy of the 
application. An applicant may submit on microfiche the portions of the 
archival copy of the application described in paragraphs (b) through (d) 
of this section. Information relating to samples and labeling 
(including, if applicable, any Medication Guide required under part 208 
of this chapter), described in paragraph (e) of this section, is 
required to be submitted in hard copy. Tabulations of patient data and 
case report forms, described in paragraph (f) of this section, may be 
submitted on microfiche only if the applicant and FDA agree. If FDA 
agrees, the applicant may use another suitable microform system.
    (2) The applicant shall submit a review copy of the application. 
Each of the technical sections, described in paragraphs (d)(1) through 
(d)(6) of this section, in the review copy is required to be separately 
bound with a copy of the application form required under paragraph (a) 
of this section and a copy of the summary required under paragraph (c) 
of this section.
    (3) The applicant shall submit a field copy of the application that 
contains the technical section described in paragraph (d)(1) of this 
section, a copy of the application form required under paragraph (a) of 
this section, a copy of the summary required under paragraph (c) of this 
section, and a certification that the field copy is a true copy of the 
technical section described in paragraph (d)(1) of this section 
contained in the archival and review copies of the application.
    (4) The applicant may obtain from FDA sufficient folders to bind the 
archival, the review, and the field copies of the application.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 16668, Apr. 26, 1985; 50 FR 21238, May 23, 1985; 52 FR 8847, Mar. 19, 
1987; 55 FR 11580, Mar. 29, 1990; 57 FR 17982, Apr. 28, 1992; 58 FR 
47351, Sept. 8, 1993; 59 FR 13200, Mar. 21, 1994; 59 FR 50361, Oct. 3, 
1994; 59 FR 60051, Nov. 21, 1994; 62 FR 40599, July 29, 1997; 63 FR 
5252, Feb. 2, 1998; 63 FR 6862, Feb. 11, 1998; 63 FR 66398, Dec. 1, 
1998; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 56479, 
Sept. 19, 2000; 67 FR 9586, Mar. 4, 2002]

[[Page 108]]



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

    (a) Notice of certification. For each patent which claims the drug 
or drugs on which investigations that are relied upon by the applicant 
for approval of its application were conducted or which claims a use for 
such drug or drugs and which the applicant certifies under 
Sec. 314.50(i)(1)(i)(A)(4) that a patent is invalid, unenforceable, or 
will not be infringed, the applicant shall send notice of such 
certification by registered or certified mail, return receipt requested 
to each of the following persons:
    (1) Each owner of the patent that is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the United States Patent and 
Trademark Office; and
    (2) The holder of the approved application under section 505(b) of 
the act for each drug product which is claimed by the patent or a use of 
which is claimed by the patent and for which the applicant is seeking 
approval, or, if the application holder does not reside or maintain a 
place of business within the United States, the application holder's 
attorney, agent, or other authorized official. The name and address of 
the application holder or its attorney, agent, or authorized official 
may be obtained from the Division of Drug Information Resources (HFD-
80), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (3) This paragraph does not apply to a use patent that claims no 
uses for which the applicant is seeking approval.
    (b) Sending the notice. The applicant shall send the notice required 
by paragraph (a) of this section when it receives from FDA an 
acknowledgment letter stating that its application has been filed. At 
the same time, the applicant shall amend its application to include a 
statement certifying that the notice has been provided to each person 
identified under paragraph (a) of this section and that the notice met 
the content requirement under paragraph (c) of this section.
    (c) Content of a notice. In the notice, the applicant shall cite 
section 505(b)(3)(B) of the act and shall include, but not be limited 
to, the following information:
    (1) A statement that a 505(b)(2) application submitted by the 
applicant has been filed by FDA.
    (2) The application number.
    (3) The established name, if any, as defined in section 502(e)(3) of 
the act, of the proposed drug product.
    (4) The active ingredient, strength, and dosage form of the proposed 
drug product.
    (5) The patent number and expiration date, as submitted to the 
agency or as known to the applicant, of each patent alleged to be 
invalid, unenforceable, or not infringed.
    (6) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or will 
not be infringed. The applicant shall include in the detailed statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds supporting 
the allegation.
    (7) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United States 
authorized to accept service of process for the applicant.
    (d) Amendment to an application. If an application is amended to 
include the certification described in Sec. 314.50(i), the applicant 
shall send the notice required by paragraph (a) of this section at the 
same time that the amendment to the application is submitted to FDA.
    (e) Documentation of receipt of notice. The applicant shall amend 
its application to document receipt of the notice required under 
paragraph (a) of this section by each person provided the notice. The 
applicant shall include a copy of the return receipt or other similar 
evidence of the date the notification

[[Page 109]]

was received. FDA will accept as adequate documentation of the date of 
receipt a return receipt or a letter acknowledging receipt by the person 
provided the notice. An applicant may rely on another form of 
documentation only if FDA has agreed to such documentation in advance. A 
copy of the notice itself need not be submitted to the agency.
    (f) Approval. If the requirements of this section are met, the 
agency will presume the notice to be complete and sufficient, and it 
will count the day following the date of receipt of the notice by the 
patent owner or its representative and by the approved application 
holder as the first day of the 45-day period provided for in section 
505(c)(3)(C) of the act. FDA may, if the applicant amends its 
application with a written statement that a later date should be used, 
count from such later date.

[59 FR 50362, Oct. 3, 1994]



Sec. 314.53  Submission of patent information.

    (a) Who must submit patent information. This section applies to any 
applicant who submits to FDA a new drug application or an amendment to 
it under section 505(b) of the act and Sec. 314.50 or a supplement to an 
approved application under Sec. 314.70, except as provided in paragraph 
(d)(2) of this section.
    (b) Patents for which information must be submitted. An applicant 
described in paragraph (a) of this section shall submit information on 
each patent that claims the drug or a method of using the drug that is 
the subject of the new drug application or amendment or supplement to it 
and with respect to which a claim of patent infringement could 
reasonably be asserted if a person not licensed by the owner of the 
patent engaged in the manufacture, use, or sale of the drug product. For 
purposes of this part, such patents consist of drug substance 
(ingredient) patents, drug product (formulation and composition) 
patents, and method of use patents. Process patents are not covered by 
this section and information on process patents may not be submitted to 
FDA. For patents that claim a drug substance or drug product, the 
applicant shall submit information only on those patents that claim a 
drug product that is the subject of a pending or approved application, 
or that claim a drug substance that is a component of such a product. 
For patents that claim a method of use, the applicant shall submit 
information only on those patents that claim indications or other 
conditions of use of a pending or approved application.
    (c) Reporting requirements--(1) General requirements. An applicant 
described in paragraph (a) of this section shall submit the following 
information for each patent described in paragraph (b) of this section:
    (i) Patent number and the date on which the patent will expire.
    (ii) Type of patent, i.e., drug, drug product, or method of use.
    (iii) Name of the patent owner.
    (iv) If the patent owner or applicant does not reside or have a 
place of business within the United States, the name of an agent 
(representative) of the patent owner or applicant 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 act and Secs. 314.52 and 314.95.
    (2) Formulation, composition, or method of use patents--(i) Original 
declaration. For each formulation, composition, or method of use patent, 
in addition to the patent information described in paragraph (c)(1) of 
this section the applicant shall submit the following declaration:

    The undersigned declares that Patent No. -------- covers the 
formulation, composition, and/or method of use of (name of drug 
product). This product is (currently approved under section 505 of the 
Federal Food, Drug, and Cosmetic Act) [or] (the subject of this 
application for which approval is being sought):
_______________________________________________________________________

    (ii) Amendment of patent information upon approval. Within 30 days 
after the date of approval of its application, if the application 
contained a declaration required under paragraph (c)(2)(i) of this 
section, the applicant shall by letter amend the declaration to identify 
each patent that claims the formulation, composition, or the specific 
indications or other conditions of use that have been approved.

[[Page 110]]

    (3) No relevant patents. If the applicant believes that there are no 
patents which claim the drug or the drug product or which claim a method 
of using the drug product 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, it shall so declare.
    (4) Authorized signature. The declarations required by this section 
shall be signed by the applicant or patent owner, or the applicant's or 
patent owner's attorney, agent (representative), or other authorized 
official.
    (d) When and where to submit patent information--(1) Original 
application. An applicant shall submit with its original application 
submitted under this part, including an application described in section 
505(b)(2) of the act, the information described in paragraph (c) of this 
section on each drug (ingredient), drug product (formulation and 
composition), and method of use patent issued before the application is 
filed with FDA and for which patent information is required to be 
submitted under this section. If a patent is issued after the 
application is filed with FDA but before the application is approved, 
the applicant shall, within 30 days of the date of issuance of the 
patent, submit the required patent information in an amendment to the 
application under Sec. 314.60.
    (2) Supplements. (i) An applicant shall submit patent information 
required under paragraph (c) of this section for a patent that claims 
the drug, drug product, or method of use for which approval is sought in 
any of the following supplements:
    (A) To change the formulation;
    (B) To add a new indication or other condition of use, including a 
change in route of administration;
    (C) To change the strength;
    (D) To make any other patented change regarding the drug, drug 
product, or any method of use.
    (ii) If the applicant submits a supplement for one of the changes 
listed under paragraph (d)(2)(i) of this section and existing patents 
for which information has already been submitted to FDA claim the 
changed product, the applicant shall submit a certification with the 
supplement identifying the patents that claim the changed product.
    (iii) If the applicant submits a supplement for one of the changes 
listed under paragraph (d)(2)(i) of this section and no patents, 
including previously submitted patents, claim the changed product, it 
shall so certify.
    (iv) The applicant shall comply with the requirements for amendment 
of formulation or composition and method of use patent information under 
paragraphs (c)(2)(ii) and (d)(3) of this section.
    (3) Patent information deadline. If a patent is issued for a drug, 
drug product, or method of use after an application is approved, the 
applicant shall submit to FDA the required patent information within 30 
days of the date of issuance of the patent.
    (4) Copies. The applicant shall submit two copies of each submission 
of patent information, an archival copy and a copy for the chemistry, 
manufacturing, and controls section of the review copy, to the Central 
Document Room, Center for Drug Evaluation and Research, Food and Drug 
Administration, Park Bldg., rm. 2-14, 12420 Parklawn Dr., Rockville, MD 
20857. The applicant shall submit the patent information by letter 
separate from, but at the same time as, submission of the supplement.
    (5) Submission date. Patent information shall be considered to be 
submitted to FDA as of the date the information is received by the 
Central Document Room.
    (6) Identification. Each submission of patent information, except 
information submitted with an original application, and its mailing 
cover shall bear prominent identification as to its contents, i.e., 
``Patent Information,'' or, if submitted after approval of an 
application, ``Time Sensitive Patent Information.''
    (e) Public disclosure of patent information. FDA will publish in the 
list the patent number and expiration date of each patent that is 
required to be, and is, submitted to FDA by an applicant, and for each 
use patent, the approved indications or other conditions of use covered 
by a patent. FDA will publish such patent information upon approval

[[Page 111]]

of the application, or, if the patent information is submitted by the 
applicant after approval of an application as provided under paragraph 
(d)(2) of this section, as soon as possible after the submission to the 
agency of the patent information. Patent information submitted by the 
last working day of a month will be published in that month's supplement 
to the list. Patent information received by the agency between monthly 
publication of supplements to the list will be placed on public display 
in FDA's Freedom of Information Staff. A request for copies of the file 
shall be sent in writing to the Freedom of Information Staff (HFI-35), 
Food and Drug Administration, rm. 12A-16, 5600 Fishers Lane, Rockville, 
MD 20857.
    (f) Correction of patent information errors. If any person disputes 
the accuracy or relevance of patent information submitted to the agency 
under this section and published by FDA in the list, or believes that an 
applicant has failed to submit required patent information, that person 
must first notify the agency in writing stating the grounds for 
disagreement. Such notification should be directed to the Drug 
Information Services Branch (HFD-84), Center for Drug Evaluation and 
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857. The agency will then request of the applicable new drug 
application holder that the correctness of the patent information or 
omission of patent information be confirmed. Unless the application 
holder withdraws or amends its patent information in response to FDA's 
request, the agency will not change the patent information in the list. 
If the new drug application holder does not change the patent 
information submitted to FDA, a 505(b)(2) application or an abbreviated 
new drug application under section 505(j) of the act submitted for a 
drug that is claimed by a patent for which information has been 
submitted must, despite any disagreement as to the correctness of the 
patent information, contain an appropriate certification for each listed 
patent.

[59 FR 50363, Oct. 3, 1994]



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

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

[[Page 112]]

drug for which approval is sought or a method of using such drug and to 
which a claim of patent infringement could reasonably be asserted if a 
person not licensed by the owner of the patent engaged in the 
manufacture, use, or sale of the drug product.
    (vi) Any patent certification or statement required under section 
505(b)(2) of the act with respect to any relevant patents that claim the 
listed drug or that claim any other drugs on which investigations relied 
on by the applicant for approval of the application were conducted, or 
that claim a use for the listed or other drug.
    (vii) If the applicant believes the change for which it is seeking 
approval is entitled to a period of exclusivity, the information 
required under Sec. 314.50(j).
    (2) The applicant shall submit a review copy that contains the 
technical sections described in Sec. 314.50(d)(1), except that 
Sec. 314.50(d)(1)(ii)(c) shall contain the proposed or actual master 
production record, including a description of the equipment, to be used 
for the manufacture of a commercial lot of the drug product, and 
paragraph (d)(3), and the technical sections described in paragraphs 
(d)(2), (d)(4), (d)(5), (d)(6), and (f) when needed to support the 
modification. Each of the technical sections in the review copy is 
required to be separately bound with a copy of the information required 
under Sec. 314.50 (a), (b), and (c) and a copy of the proposed labeling.
    (3) The information required by Sec. 314.50 (d)(2), (d)(4) (if an 
anti-infective drug), (d)(5), (d)(6), and (f) for the listed drug on 
which the applicant relies shall be satisfied by reference to the listed 
drug under paragraph (a)(1)(iii) of this section.
    (4) The applicant shall submit a field copy of the application that 
contains the technical section described in Sec. 314.50(d)(1), a copy of 
the information required under Sec. 314.50(a) and (c), and certification 
that the field copy is a true copy of the technical section described in 
Sec. 314.50(d)(1) contained in the archival and review copies of the 
application.
    (b) An application may not be submitted under this section for a 
drug product whose only difference from the reference listed drug is 
that:
    (1) The extent to which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is less than that of the 
reference listed drug; or
    (2) The rate at which its active ingredient(s) is absorbed or 
otherwise made available to the site of action is unintentionally less 
than that of the reference listed drug.

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



Sec. 314.55  Pediatric use information.

    (a) Required assessment. Except as provided in paragraphs (b), (c), 
and (d) of this section, each application for a new active ingredient, 
new indication, new dosage form, new dosing regimen, or new route of 
administration shall contain data that are adequate to assess the safety 
and effectiveness of the drug product for the claimed indications in all 
relevant pediatric subpopulations, and to support dosing and 
administration for each pediatric subpopulation for which the drug is 
safe and effective. Where the course of the disease and the effects of 
the drug are sufficiently similar in adults and pediatric patients, FDA 
may conclude that pediatric effectiveness can be extrapolated from 
adequate and well-controlled studies in adults usually supplemented with 
other information obtained in pediatric patients, such as 
pharmacokinetic studies. Studies may not be needed in each pediatric age 
group, if data from one age group can be extrapolated to another. 
Assessments of safety and effectiveness required under this section for 
a drug product that represents a meaningful therapeutic benefit over 
existing treatments for pediatric patients must be carried out using 
appropriate formulations for each age group(s) for which the assessment 
is required.
    (b) Deferred submission. (1) FDA may, on its own initiative or at 
the request of an applicant, defer submission of some or all assessments 
of safety and effectiveness described in paragraph (a) of this section 
until after approval of the drug product for use in adults. Deferral may 
be granted if, among other

[[Page 113]]

reasons, the drug is ready for approval in adults before studies in 
pediatric patients are complete, or pediatric studies should be delayed 
until additional safety or effectiveness data have been collected. If an 
applicant requests deferred submission, the request must provide a 
certification from the applicant of the grounds for delaying pediatric 
studies, a description of the planned or ongoing studies, and evidence 
that the studies are being or will be conducted with due diligence and 
at the earliest possible time.
    (2) If FDA determines that there is an adequate justification for 
temporarily delaying the submission of assessments of pediatric safety 
and effectiveness, the drug product may be approved for use in adults 
subject to the requirement that the applicant submit the required 
assessments within a specified time.
    (c) Waivers--(1) General. FDA may grant a full or partial waiver of 
the requirements of paragraph (a) of this section on its own initiative 
or at the request of an applicant. A request for a waiver must provide 
an adequate justification.
    (2) Full waiver. An applicant may request a waiver of the 
requirements of paragraph (a) of this section if the applicant certifies 
that:
    (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

[[Page 114]]

under part 316, subpart C, of this chapter.

[63 FR 66670, Dec. 2, 1998]



Sec. 314.60  Amendments to an unapproved application.

    (a) Except as provided in paragraph (b) of this section, the 
applicant may submit an amendment to an application that is filed under 
Sec. 314.100, but not yet approved. The submission of a major amendment 
(for example, an amendment that contains significant new data from a 
previously unreported study or detailed newnalyses of previously 
submitted data), whether on the applicant's own initiative or at the 
invitation of the agency, constitutes an agreement by the applicant 
under section 505(c) of the act to extend the date by which the agency 
is required to reach a decision on the application. Ordinarily, the 
agency will extend the review period for a major amendment but only for 
the time necessary to review the new information. However, the agency 
may not extend the review period more than 180 days. If the agency 
extends the review period for the application, the director of the 
division responsible for reviewing the application will notify the 
applicant of the length of the extension. The submission of an amendment 
that is not a major amendment will not extend the review period. An 
amendment that contains new clinical data from a previously unreported 
study shall contain a financial certification or disclosure statement or 
both as required by part 54 of this chapter, or FDA may refuse to accept 
any such amendment.
    (b)(1) An unapproved application may not be amended if all of the 
following conditions apply:
    (i) The unapproved application is for a drug for which a previous 
application has been approved and granted a period of exclusivity in 
accordance with section 505(c)(3)(D)(ii) of the act that has not 
expired;
    (ii) The applicant seeks to amend the unapproved application to 
include a published report of an investigation that was conducted or 
sponsored by the applicant entitled to exclusivity for the drug;
    (iii) The applicant has not obtained a right of reference to the 
investigation described in paragraph (b)(1)(ii) of this section; and
    (iv) The report of the investigation described in paragraph 
(b)(1)(ii) of this section would be essential to the approval of the 
unapproved application.
    (2) The submission of an amendment described in paragraph (b)(1) of 
this section will cause the unapproved application to be deemed to be 
withdrawn by the applicant under Sec. 314.65 on the date of receipt by 
FDA of the amendment. The amendment will be considered a resubmission of 
the application, which may not be accepted except as provided in 
accordance with section 505(c)(3)(D)(ii) of the act.
    (c) The applicant shall submit a field copy of each amendment to 
Sec. 314.50(d)(1). The applicant, other than a foreign applicant, shall 
include in its submission of each such amendment to FDA a statement 
certifying that a field copy of the amendment has been sent to the 
applicant's home FDA district office.

[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]



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. The 
agency will consider an applicant's failure to respond within 10 days to 
an approvable letter under Sec. 314.110 or a not approvable letter under 
Sec. 314.120 to be a request by the applicant to withdraw the 
application. 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. 20.42 of 
FDA's public information regulations.



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

    (a) Changes to an approved application. The applicant shall notify 
FDA about each change in each condition established in an approved 
application beyond the variations already provided

[[Page 115]]

for in the application. The notice is required to describe the change 
fully. Depending on the type of change, the applicant shall notify FDA 
about it in a supplemental application under paragraph (b) or (c) of 
this section or by inclusion of the information in the annual report to 
the application under paragraph (d) of this section. Notwithstanding the 
requirements of paragraphs (b) and (c) of this section, an applicant 
shall make a change provided for in those paragraphs (for example, the 
deletion of an ingredient common to many drug products) in accordance 
with a notice, or regulation published in the Federal Register that 
provides for a less burdensome notification of the change (for example, 
by notification at the time a supplement is submitted or in the next 
annual report). Except for a supplemental application providing for a 
change in the labeling, the applicant, other than a foreign applicant, 
shall include in each supplemental application providing for a change 
under paragraph (b) or (c) of this section a statement certifying that a 
field copy of the supplement has been provided to the applicant's home 
FDA district office.
    (b) Supplements requiring FDA approval before the change is made. An 
applicant shall submit a supplement, and obtain FDA approval of it, 
before making the changes listed below in the conditions in an approved 
application, unless the change is made to comply with an official 
compendium. An applicant may ask FDA to expedite its review of a 
supplement if a delay in making the change described in it would impose 
an extraordinary hardship on the applicant. Such a supplement and its 
mailing cover should be plainly marked: ``Supplement--Expedited Review 
Requested.''
    (1) Drug substance. A change affecting the drug substance to 
accomplish any of the following:
    (i) To relax the limits for a specification;
    (ii) To establish a new regulatory analytical method;
    (iii) To delete a specification or regulatory analytical method;
    (iv) To change the synthesis of the drug substance, including a 
change in solvents and a change in the route of synthesis.
    (v) To use a different facility or establishment to manufacture the 
drug substance, where: (a) the manufacturing process in the new facility 
or establishment differs materially from that in the former facility or 
establishment, or (b) the new facility or establishment has not received 
a satisfactory current good manufacturing practice (CGMP) inspection 
within the previous 2 years covering that manufacturing process.
    (2) Drug product. A change affecting the drug product to accomplish 
any of the following:
    (i) To add or delete an ingredient, or otherwise to change the 
composition of the drug product, other than deletion of an ingredient 
intended only to affect the color of the drug product;
    (ii) To relax the limits for a specification;
    (iii) To establish a new regulatory analytical method;
    (iv) To delete a specification or regulatory analytical method;
    (v) To change the method of manufacture of the drug product, 
including changing or relaxing an in-process control;
    (vi) To use a different facility or establishment, including a 
different contract laboratory or labeler, to manufacture, process, or 
pack the drug product;
    (vii) To change the container and closure system for the drug 
product (for example, glass to high density polyethylene (HDPE), or HDPE 
to polyvinyl chloride) or change a specification or regulatory 
analytical method for the container and closure system;
    (viii) To change the size of the container, except for solid dosage 
forms, without a change in the container and closure system.
    (ix) To extend the expiration date of the drug product based on data 
obtained under a new or revised stability testing protocol that has not 
been approved in the application.
    (x) To establish a new procedure for reprocessing a batch of the 
drug product that fails to meet specifications.
    (xi) To add a code imprint by printing with ink on a solid oral 
dosage form drug product.

[[Page 116]]

    (xii) To add a code imprint by embossing, debossing, or engraving on 
a modified release solid oral dosage form drug product.
    (3) Labeling. (i) Any change in labeling, except one described in 
paragraphs (c)(2) or (d) of this section.
    (ii) 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).
    (c) Supplements for changes that may be made before FDA approval. An 
applicant shall submit a supplement at the time the applicant makes any 
kind of change listed below in the conditions in an approved 
application, unless the change is made to comply with an official 
compendium. A supplement under this paragraph is required to give a full 
explanation of the basis for the change, identify the date on which the 
change is made, and, if the change concerns labeling, include 12 copies 
of final printed labeling. The applicant shall promptly revise all 
promotional labeling and drug advertising to make it consistent with any 
change in the labeling. The supplement and its mailing cover should be 
plainly marked: ``Special Supplement--Changes Being Effected.''
    (1) Adds a new specification or test method or changes in the 
methods, facilities (except a change to a new facility), or controls to 
provide increased assurance that the drug will have the characteristics 
of identity, strength, quality, and purity which it purports or is 
represented to possess;
    (2) Changes labeling to accomplish any of the following:
    (i) To add or strengthen a contraindication, warning, precaution, or 
adverse reaction;
    (ii) To add or strengthen a statement about drug abuse, dependence, 
or overdosage; or
    (iii) To add or strengthen an instruction about dosage and 
administration that is intended to increase the safe use of the product.
    (iv) To delete false, misleading, or unsupported indications for use 
or claims for effectiveness.
    (3) To use a different facility or establishment to manufacture the 
drug substance, where: (i) The manufacturing process in the new facility 
or establishment does not differ materially from that in the former 
facility or establishment, and (ii) the new facility or establishment 
has received a satisfactory current good manufacturing practice (CGMP) 
inspection within the previous 2 years covering that manufacturing 
process.
    (d) Changes described in the annual report. An applicant shall not 
submit a supplement to make any change in the conditions in an approved 
application, unless otherwise required under paragraph (b) or (c) of 
this section, but shall describe the change in the next annual report 
required under Sec. 314.81. Some examples of changes that can be 
described in the annual report are the following:
    (1) Any change made to comply with an official compendium.
    (2) 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.
    (3) An editorial or similar minor change in labeling.
    (4) The deletion of an ingredient intended only to affect the color 
of the drug product.
    (5) An extension of the expiration date based upon full shelf-life 
data obtained from a protocol approved in the application.
    (6) A change within the container and closure system for the drug 
product (for example, a change from one high density polyethylene (HDPE) 
to another HDPE), except a change in container size for nonsolid dosage 
forms, based upon a showing of equivalency to the approved system under 
a protocol approved in the application or published in an official 
compendium.
    (7) The addition or deletion of an alternate analytical method.
    (8) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another.
    (9) 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.

[[Page 117]]

    (e) Patent information. The applicant shall comply with the patent 
information requirements under section 505(c)(2) of the act.
    (f) Claimed exclusivity. If an applicant claims exclusivity under 
Sec. 314.108 upon approval of a supplemental application for a change to 
its previously approved drug product, the applicant shall include with 
its supplemental application the information required under 
Sec. 314.50(j).
    (g) Exception. An applicant proposing to make a change of a type 
described in paragraphs (a), (b)(1), (b)(2), (c)(1), (c)(3), (d)(1), and 
(d)(4) through (d)(9) of this section affecting a recombinant DNA-
derived protein/polypeptide product or a complex or conjugate of a drug 
with a monoclonal antibody regulated under the Federal Food, Drug, and 
Cosmetic Act shall comply with the following:
    (1) Changes requiring supplement submission and approval prior to 
distribution of the product made using the change (major changes). (i) A 
supplement shall be submitted for any change in the 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 product as they may relate 
to the safety or effectiveness of the product.
    (ii) These changes include, but are not limited to:
    (A) Changes in the qualitative or quantitative formulation or other 
specifications as provided in the approved application or in the 
regulations;
    (B) Changes requiring completion of an appropriate human study to 
demonstrate the equivalence of the identity, strength, quality, purity, 
or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (C) Changes in the virus or adventitious agent removal or 
inactivation method(s);
    (D) Changes in the source material or cell line;
    (E) Establishment of a new master cell bank or seed; and
    (F) Changes which may affect product sterility assurance, such as 
changes in product or component sterilization method(s) or an addition, 
deletion, or substitution of steps in an aseptic processing operation.
    (iii) The applicant must obtain approval of the supplement from FDA 
prior to distribution of the product made using the change. Except for 
submissions under paragraph (g)(4) of this section, the following shall 
be contained in the supplement:
    (A) A detailed description of the proposed change;
    (B) The product(s) involved;
    (C) The manufacturing site(s) or area(s) affected;
    (D) A description of the methods used and studies performed to 
evaluate the effect of the change on the identity, strength, quality, 
purity, or potency of the product as they may relate to the safety or 
effectiveness of the product;
    (E) The data derived from such studies;
    (F) Relevant validation protocols and data; and
    (G) A reference list of relevant standard operating procedures 
(SOP's).
    (2) Changes requiring supplement submission at least 30 days prior 
to distribution of the product made using the change. (i) A supplement 
shall be submitted for any change in the 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 product as they may relate to the safety or effectiveness 
of the product. The supplement shall be labeled ``Supplement--Changes 
Being Effected in 30 Days'' or, if applicable under paragraph (g)(2)(v) 
of this section, ``Supplement--Changes Being Effected.''
    (ii) These changes include, but are not limited to:
    (A) Change in the site of testing from one facility to another;
    (B) An increase or decrease in production scale during finishing 
steps that involves new or different equipment; and
    (C) Replacement of equipment with that of similar, but not 
identical, design and operating principle that does not affect the 
process methodology or process operating parameters.
    (iii) Pending approval of the supplement by FDA, and except as 
provided in paragraph (g)(2)(v) of this section,

[[Page 118]]

distribution of the product made using the change may begin not less 
than 30 days after receipt of the supplement by FDA. The information 
listed in paragraph (g)(1)(iii)(A) through (g)(1)(iii)(G) of this 
section shall be contained in the supplement.
    (iv) If within 30 days following FDA's receipt of the supplement, 
FDA informs the applicant that either:
    (A) The change requires approval prior to distribution of the 
product in accordance with paragraph (g)(1) of this section; or
    (B) Any of the information required under paragraph (g)(2)(iii) of 
this section is missing; the applicant shall not distribute the product 
made using the change until FDA determines that compliance with this 
section is achieved.
    (v) In certain circumstances, FDA may determine that, based on 
experience with a particular type of change, the supplement for such 
change is usually complete and provides the proper information, and on 
particular assurances that the proposed change has been appropriately 
submitted, the product made using the change may be distributed 
immediately upon receipt of the supplement by FDA. These circumstances 
may include substantial similarity with a type of change regularly 
involving a ``Supplement--Changes Being Effected'' supplement, or a 
situation in which the applicant presents evidence that the proposed 
change has been validated in accordance with an approved protocol for 
such change under paragraph (g)(4) of this section.
    (3) Changes to be described in an annual report (minor changes). (i) 
Changes in the 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 product as 
they may relate to the safety or effectiveness of the product shall be 
documented by the applicant in the next annual report in accordance with 
Sec. 314.81(b)(2)(iv).
    (ii) These changes include, but are not limited to:
    (A) Any change made to comply with an official compendium that is 
consistent with FDA requirements;
    (B) The deletion of an ingredient intended only to affect the color 
of the product;
    (C) An extension of an expiration date based upon full shelf life 
data obtained from a protocol approved in the application;
    (D) A change within the container and closure system for solid 
dosage forms, based upon a showing of equivalency to the approved system 
under a protocol approved in the application or published in an official 
compendium;
    (E) A change in the size of a container for a solid dosage form, 
without a change from one container and closure system to another;
    (F) The addition by embossing, debossing, or engraving of a code 
imprint to a solid dosage form drug product other than a modified 
release dosage form, or a minor change in an existing code imprint; and
    (G) The addition or deletion of an alternate analytical method.
    (4) An applicant may submit one or more protocols describing the 
specific tests and validation studies and acceptable limits to be 
achieved to demonstrate the lack of adverse effect for specified types 
of manufacturing changes on the identity, strength, quality, purity, or 
potency of the product as they may relate to the safety or effectiveness 
of the product. Any such protocols, or change to a protocol, shall be 
submitted as a supplement requiring approval from FDA prior to 
distribution of the product which, if approved, may 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.

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 57 FR 17983, Apr. 28, 1992; 58 FR 47352, Sept. 
8, 1993; 58 FR 47959, Sept. 13, 1993; 59 FR 50364, Oct. 3, 1994; 62 FR 
39900, July 24, 1997; 63 FR 66399, Dec. 1, 1998; 65 FR 56479, Sept. 19, 
2000; 67 FR 9586, Mar. 4, 2002]



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

[[Page 119]]

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

[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]



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. 20.42 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]



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.
    Disability. A substantial disruption of a person's ability to 
conduct normal life functions.
    Life-threatening adverse drug experience. Any adverse drug 
experience that places the patient, in the view of the initial reporter, 
at immediate risk of death from the adverse drug experience as it 
occurred, i.e., it does not include an adverse drug experience that, had 
it occurred in a more severe form, might have caused death.
    Serious adverse drug experience. Any adverse drug experience 
occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a 
persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered 
a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed 
in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or

[[Page 120]]

the development of drug dependency or drug abuse.
    Unexpected adverse drug experience. Any adverse drug experience that 
is not listed in the current labeling for the drug product. This 
includes events that may be symptomatically and pathophysiologically 
related to an event listed in the labeling, but differ from the event 
because of greater severity or specificity. For example, under this 
definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the labeling only referred to elevated hepatic enzymes or 
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the labeling 
only listed cerebral vascular accidents. ``Unexpected,'' as used in this 
definition, refers to an adverse drug experience that has not been 
previously observed (i.e., included in the labeling) rather than from 
the perspective of such experience not being anticipated from the 
pharmacological properties of the pharmaceutical product.
    (b) Review of adverse drug experiences. Each applicant having an 
approved application under Sec. 314.50 or, in the case of a 505(b)(2) 
application, an effective approved application, shall promptly review 
all adverse drug experience information obtained or otherwise received 
by the applicant from any source, foreign or domestic, including 
information derived from commercial marketing experience, postmarketing 
clinical investigations, postmarketing epidemiological/surveillance 
studies, reports in the scientific literature, and unpublished 
scientific papers. Applicants are not required to resubmit to FDA 
adverse drug experience reports forwarded to the applicant by FDA; 
however, applicants must submit all followup information on such reports 
to FDA. Any person subject to the reporting requirements under paragraph 
(c) of this section shall also develop written procedures for the 
surveillance, receipt, evaluation, and reporting of postmarketing 
adverse drug experiences to FDA.
    (c) Reporting requirements. The applicant shall report to FDA 
adverse drug experience information, as described in this section. The 
applicant shall submit two copies of each report described in this 
section to the Central Document Room, 12229 Wilkins Ave., Rockville, MD 
20852. FDA may waive the requirement for the second copy in appropriate 
instances.
    (1)(i) Postmarketing 15-day ``Alert reports''. The applicant shall 
report each adverse drug experience that is both serious and unexpected, 
whether foreign or domestic, as soon as possible but in no case later 
than 15 calendar days of initial receipt of the information by the 
applicant.
    (ii) Postmarketing 15-day ``Alert reports''--followup. The applicant 
shall promptly investigate all adverse drug experiences that are the 
subject of these postmarketing 15-day Alert reports and shall submit 
followup reports within 15 calendar days of receipt of new information 
or as requested by FDA. If additional information is not obtainable, 
records should be maintained of the unsuccessful steps taken to seek 
additional information. Postmarketing 15-day Alert reports and followups 
to them shall be submitted under separate cover.
    (iii) Submission of reports. The requirements of paragraphs 
(c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of 
postmarketing 15-day Alert reports, shall also apply to any person other 
than the applicant (nonapplicant) whose name appears on the label of an 
approved drug product as a manufacturer, packer, or distributor. To 
avoid unnecessary duplication in the submission to FDA of reports 
required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, 
obligations of a nonapplicant may be met by submission of all reports of 
serious adverse drug experiences to the applicant. If a nonapplicant 
elects to submit adverse drug experience reports to the applicant rather 
than to FDA, the nonapplicant shall submit each report to the applicant 
within 5 calendar days of receipt of the report by the nonapplicant, and 
the applicant shall then comply with the requirements of this section. 
Under this circumstance, the nonapplicant shall maintain a record of 
this action which shall include:
    (A) A copy of each adverse drug experience report;

[[Page 121]]

    (B) The date the report was received by the nonapplicant;
    (C) The date the report was submitted to the applicant; and
    (D) The name and address of the applicant.
    (iv) Report identification. Each report submitted under this 
paragraph shall bear prominent identification as to its contents, i.e., 
``15-day Alert report,'' or ``15-day Alert report-followup.''
    (2) Periodic adverse drug experience reports. (i) The applicant 
shall report each adverse drug experience not reported under paragraph 
(c)(1)(i) of this section at quarterly intervals, for 3 years from the 
date of approval of the application, and then at annual intervals. The 
applicant shall submit each quarterly report within 30 days of the close 
of the quarter (the first quarter beginning on the date of approval of 
the application) and each annual report within 60 days of the 
anniversary date of approval of the application. Upon written notice, 
FDA may extend or reestablish the requirement that an applicant submit 
quarterly reports, or require that the applicant submit reports under 
this section at different times than those stated. For example, the 
agency may reestablish a quarterly reporting requirement following the 
approval of a major supplement. Followup information to adverse drug 
experiences submitted in a periodic report may be submitted in the next 
periodic report.
    (ii) Each periodic report is required to contain: (a) a narrative 
summary and analysis of the information in the report and an analysis of 
the 15-day Alert reports submitted during the reporting interval (all 
15-day Alert reports being appropriately referenced by the applicant's 
patient identification number, adverse reaction term(s), and date of 
submission to FDA); (b) a FDA Form 3500A (Adverse Reaction Report) for 
each adverse drug experience not reported under paragraph (c)(1)(i) of 
this section (with an index consisting of a line listing of the 
applicant's patient identification number and adverse reaction term(s)); 
and (c) a history of actions taken since the last report because of 
adverse drug experiences (for example, labeling changes or studies 
initiated).
    (iii) Periodic reporting, except for information regarding 15-day 
Alert reports, does not apply to adverse drug experience information 
obtained from postmarketing studies (whether or not conducted under an 
investigational new drug application), from reports in the scientific 
literature, and from foreign marketing experience.
    (d) Scientific literature. (1) A 15-day Alert report based on 
information from the scientific literature is required to be accompanied 
by a copy of the published article. The 15-day reporting requirements in 
paragraph (c)(1)(i) of this section (i.e., serious, unexpected adverse 
drug experiences) apply only to reports found in scientific and medical 
journals either as case reports or as the result of a formal clinical 
trial.
    (2) As with all reports submitted under paragraph (c)(1)(i) of this 
section, reports based on the scientific literature shall be submitted 
on FDA Form 3500A or comparable format as prescribed by paragraph (f) of 
this section. In cases where the applicant believes that preparing the 
FDA Form 3500A constitutes an undue hardship, the applicant may arrange 
with the Division of Pharmacovigilance and Epidemiology for an 
acceptable alternative reporting format.
    (e) Postmarketing studies. (1) An applicant is not required to 
submit a 15-day Alert report under paragraph (c) of this section for an 
adverse drug experience obtained from a postmarketing study (whether or 
not conducted under an investigational new drug application) unless the 
applicant concludes that there is a reasonable possibility that the drug 
caused the adverse experience.
    (2) The applicant shall separate and clearly mark reports of adverse 
drug experiences that occur during a postmarketing study as being 
distinct from those experiences that are being reported spontaneously to 
the applicant.
    (f) Reporting FDA Form 3500A. (1) Except as provided in paragraph 
(f)(3) of this section, the applicant shall complete FDA Form 3500A for 
each report of an adverse drug experience (foreign events may be 
submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I 
form).

[[Page 122]]

    (2) Each completed FDA Form 3500A should refer only to an individual 
patient or a single attached publication.
    (3) Instead of using FDA Form 3500A, an applicant may use a 
computer-generated FDA Form 3500A or other alternative format (e.g., a 
computer-generated tape or tabular listing) provided that: (i) The 
content of the alternative format is equivalent in all elements of 
information to those specified in FDA Form 3500A; and (ii) The format is 
agreed to in advance by MedWatch: The FDA Medical Products Reporting 
Program.
    (4) Ten copies or fewer of FDA Form 3500A and/or a copy of the 
instructions for completing the form may be obtained from the Division 
of Pharmacovigilance and Epidemiology (HFD-730), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857. More than 10 copies of the form may be 
obtained by writing to the Consolidated Forms and Publications 
Distribution Center, Washington Commerce Center, 3222 Hubbard Rd., 
Landover, MD 20785.
    (g) Multiple reports. An applicant should not include in reports 
under this section any adverse drug experiences that occurred in 
clinical trials if they were previously submitted as part of the 
approved application. If a report applies to a drug for which an 
applicant holds more than one approved application, the applicant should 
submit the report to the application that was first approved. If a 
report refers to more than one drug marketed by an applicant, the 
applicant should submit the report to the application for the drug 
listed first in the report.
    (h) Patient privacy. An applicant should not include in reports 
under this section the names and addresses of individual patients; 
instead, the applicant should assign a unique code number to each 
report, preferably not more than eight characters in length. The 
applicant should include the name of the reporter from whom the 
information was received. Names of patients, health care professionals, 
hospitals, and geographical identifiers in adverse drug experience 
reports are not releasable to the public under FDA's public information 
regulations in part 20.
    (i) Recordkeeping. The applicant shall maintain for a period of 10 
years records of all adverse drug experiences known to the applicant, 
including raw data and any correspondence relating to adverse drug 
experiences.
    (j) Withdrawal of approval. If an applicant fails to establish and 
maintain records and make reports required under this section, FDA may 
withdraw approval of the application and, thus, prohibit continued 
marketing of the drug product that is the subject of the application.
    (k) Disclaimer. A report or information submitted by an applicant 
under this section (and any release by FDA of that report or 
information) does not necessarily reflect a conclusion by the applicant 
or FDA that the report or information constitutes an admission that the 
drug caused or contributed to 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]



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,

[[Page 123]]

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 specifications 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) 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.
    (iii) Labeling. Currently used professional labeling, patient 
brochures or package inserts (if any), a representative sample of the 
package labels, and 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,

[[Page 124]]

epidemiologic studies or analyses of experience in a monitored series of 
patients) conducted by or otherwise obtained by the applicant. Review 
articles, papers describing the use of the drug product in medical 
practice, papers and abstracts in which the drug is used as a research 
tool, promotional articles, press clippings, and papers that do not 
contain tabulations or summaries of original data should not be 
reported.
    (b) Summaries of completed unpublished clinical trials, or 
prepublication manuscripts if available, conducted by, or otherwise 
obtained by, the applicant. Supporting information should not be 
reported. (A study is considered completed 1 year after it is 
concluded.)
    (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

[[Page 125]]

study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(2)(vii)(a)(8) of this 
section. If the study has been completed, include the date the study was 
completed and the date the final study report was submitted to FDA, as 
applicable. Provide a revised schedule, as well as the reason(s) for the 
revision, if the schedule under paragraph (b)(2)(vii)(a)(7) of this 
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 may 
be obtained from the PHS Forms and Publications Distribution Center, 
12100 Parklawn Dr., Rockville, MD 20857.
    (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) Withdrawal of approved drug product from sale. (a) The 
applicant shall submit on Form FDA 2657 (Drug Product Listing), within 
15 working days of the withdrawal from sale of a drug product, the 
following information:
    (1) The National Drug Code (NDC) number.
    (2) The identity of the drug product by established name and by 
proprietary name.
    (3) The new drug application or abbreviated application number.
    (4) The date of withdrawal from sale. It is requested but not 
required that the reason for withdrawal of the drug product from sale be 
included with the information.
    (b) The applicant shall submit each Form FDA-2657 to the Drug 
Listing Branch (HFD-334), Center for Drug Evaluation and Research, Food 
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (c) Reporting under paragraph (b)(3)(iii) of this section 
constitutes compliance with the requirements

[[Page 126]]

under Sec. 207.30(a) of this chapter to report ``at the discretion of 
the registrant when the change occurs.''
    (c) General requirements--(1) Multiple applications. For all reports 
required by this section, the applicant shall submit the information 
common to more than one application only to the application first 
approved, and shall not report separately on each application. The 
submission is required to identify all the applications to which the 
report applies.
    (2) Patient identification. Applicants should not include in reports 
under this section the names and addresses of individual patients; 
instead, the applicant should code the patient names whenever possible 
and retain the code in the applicant's files. The applicant shall 
maintain sufficient patient identification information to permit FDA, by 
using that information alone or along with records maintained by the 
investigator of a study, to identify the name and address of individual 
patients; this will ordinarily occur only when the agency needs to 
investigate the reports further or when there is reason to believe that 
the reports do not represent actual results obtained.
    (d) Withdrawal of approval. If an applicant fails to make reports 
required under this section, FDA may withdraw approval of the 
application and, thus, prohibit continued marketing of the drug product 
that is the subject of the application.

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

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17983, Apr. 
28, 1992; 63 FR 66670, Dec. 2, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 
64617, Oct. 30, 2000; 66 FR 10815, Feb. 20, 2001]

    Effective Date Note: At 65 FR 64617, Oct. 30, 2000, Sec. 314.81 was 
amended by revising the introductory text of paragraph (b)(2), by 
revising paragraph (b)(2)(vii), and by adding paragraphs (b)(2)(viii) 
and (b)(2)(ix), effective Feb. 27, 2001. At 66 FR 10815, Feb. 20, 2001, 
the effective date was delayed until Apr. 30, 2001. For the convenience 
of the user, the amended text is set forth as follows:

Sec. 314.81  Other postmarketing reports.

                                * * * * *

    (b) * * *
    (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:

                                * * * * *

    (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

[[Page 127]]

or initiation of an animal study, completion of the study, submission of 
the final study report to FDA, and any additional milestones or 
submissions for which projected dates were specified as part of the 
commitment. In addition, it should include a revised schedule, as 
appropriate. If the schedule has been previously revised, provide both 
the original schedule and the most recent, previously submitted 
revision.
    (8) Current status of the postmarketing study commitment. The status 
of each postmarketing study should be categorized using one of the 
following terms that describes the study's status on the anniversary 
date of U.S. approval of the application or other agreed upon date:
    (i) Pending. The study has not been initiated, but does not meet the 
criterion for delayed.
    (ii) Ongoing. The study is proceeding according to or ahead of the 
original schedule described under paragraph (b)(2)(vii)(a)(7) of this 
section.
    (iii) Delayed. The study is behind the original schedule described 
under paragraph (b)(2)(vii)(a)(7) of this section.
    (iv) Terminated. The study was ended before completion but a final 
study report has not been submitted to FDA.
    (v) Submitted. The study has been completed or terminated and a 
final study report has been submitted to FDA.
    (9) Explanation of the study's status. Provide a brief description 
of the status of the study, including the patient accrual rate 
(expressed by providing the number of patients or subjects enrolled to 
date, and the total planned enrollment), and an explanation of the 
study's status identified under paragraph (b)(2)(vii)(a)(8) of this 
section. If the study has been completed, include the date the study was 
completed and the date the final study report was submitted to FDA, as 
applicable. Provide a revised schedule, as well as the reason(s) for the 
revision, if the schedule under paragraph (b)(2)(vii)(a)(7) of this 
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).



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

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

[[Page 128]]



                   Subpart C--Abbreviated Applications

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



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

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

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



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

    (a) The only changes from a listed drug for which the agency will 
accept a petition under this section are those changes described in 
paragraph (b) of this section. Petitions to submit abbreviated new drug 
applications for other changes from a listed drug will not be approved.
    (b) A person who wants to submit an abbreviated new drug application 
for a drug product which is not identical to a listed drug in route of 
administration, dosage form, and strength, or in which one active 
ingredient is substituted for one of the active ingredients in a listed 
combination drug, must first obtain permission from FDA to submit such 
an abbreviated application.
    (c) To obtain permission to submit an abbreviated new drug 
application for a change described in paragraph (b) of this section, a 
person must submit and obtain approval of a petition requesting the 
change. A person seeking permission to request such a change from a 
reference listed drug shall submit a petition in accordance with 
Sec. 10.20 of this chapter and in the format specified in Sec. 10.30 of 
this chapter. The petition shall contain the information specified in 
Sec. 10.30 of this chapter and any additional information required by 
this section. If any provision of Sec. 10.20 or Sec. 10.30 of this 
chapter is inconsistent with any provision of this section, the 
provisions of this section apply.
    (d) The petitioner shall identify a listed drug and include a copy 
of the proposed labeling for the drug product that is the subject of the 
petition and a copy of the approved labeling for the listed drug. The 
petitioner may, under limited circumstances, identify more than one 
listed drug, for example, when the proposed drug product is a 
combination product that differs from the combination reference listed 
drug with regard to an active ingredient, and the different active 
ingredient is an active ingredient of a listed drug. The petitioner 
shall also include information to show that:
    (1) The active ingredients of the proposed drug product are of the 
same pharmacological or therapeutic class as those of the reference 
listed drug.
    (2) The drug product can be expected to have the same therapeutic 
effect as the reference listed drug when administered to patients for 
each condition of use in the reference listed drug's labeling for which 
the applicant seeks approval.
    (3) If the proposed drug product is a combination product with one 
different active ingredient, including a different ester or salt, from 
the reference listed

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



Sec. 314.94  Content and format of an abbreviated application.

    Abbreviated applications are required to be submitted in the form 
and contain the information required under this section. Three copies of 
the application are required, an archival copy, a review copy, and a 
field copy. FDA will maintain guidance documents on the format and 
content of applications to assist applicants in their preparation.
    (a) Abbreviated new drug applications. Except as provided in 
paragraph (b) of this section, the applicant shall submit a complete 
archival copy of the abbreviated new drug application that includes the 
following:
    (1) Application form. The applicant shall submit a completed and 
signed application form that contains the information described under 
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant shall state 
whether the submission is

[[Page 130]]

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

[[Page 131]]

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

[[Page 132]]

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)(4)(D) 
of the act.
    (9) Chemistry, manufacturing, and controls. (i) The information 
required under Sec. 314.50(d)(1), except that Sec. 314.50(d)(1)(ii)(c) 
shall contain the proposed or actual master production record, including 
a description of the equipment, to be used for the manufacture of a 
commercial lot of the drug product.
    (ii) Inactive ingredients. Unless otherwise stated in paragraphs 
(a)(9)(iii) through (a)(9)(v) of this section, an applicant shall 
identify and characterize the inactive ingredients in the proposed drug 
product and provide information demonstrating that such inactive 
ingredients do not affect the safety of the proposed drug product.
    (iii) Inactive ingredient changes permitted in drug products 
intended for parenteral use. Generally, a drug product intended for 
parenteral use shall contain the same inactive ingredients and in the 
same concentration as the reference listed drug identified by the 
applicant under paragraph (a)(3) of this section. However, an applicant 
may seek approval of a drug product that differs from the reference 
listed drug in preservative, buffer, or antioxidant provided that the 
applicant identifies and characterizes the differences and provides 
information demonstrating that the differences do not affect the safety 
of the proposed drug product.
    (iv) Inactive ingredient changes permitted in drug products intended 
for ophthalmic or otic use. Generally, a drug product intended for 
ophthalmic or otic use shall contain the same inactive ingredients and 
in the same concentration as the reference listed drug identified by the 
applicant under paragraph (a)(3) of this section. However, an applicant 
may seek approval of a drug product that differs from the reference 
listed drug in preservative, buffer, substance to adjust tonicity, or 
thickening agent provided that the applicant identifies and 
characterizes the differences and provides information demonstrating 
that the differences do not affect the safety of the proposed drug 
product, except that, in a product intended for ophthalmic use, an 
applicant may not change a buffer or substance to adjust tonicity for 
the purpose of claiming a therapeutic advantage over or difference from 
the listed drug, e.g., by using a balanced salt solution as a diluent as 
opposed to an isotonic saline solution, or by making a significant 
change in the pH or other change that may raise questions of 
irritability.
    (v) Inactive ingredient changes permitted in drug products intended 
for topical use. Generally, a drug product intended for topical use 
shall contain the same inactive ingredients 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 provided that the applicant identifies 
and characterizes the differences and provides information demonstrating 
that the differences do not affect the safety of the proposed drug 
product.
    (10) Samples. The information required under Sec. 314.50(e)(1) and 
(e)(2)(i). Samples need not be submitted until requested by FDA.
    (11) Other. The information required under Sec. 314.50(g).
    (12) Patent certification--(i) Patents claiming drug, drug product, 
or method of use. (A) Except as provided in paragraph (a)(12)(iv) of 
this section, a certification with respect to each patent issued by the 
United States Patent and Trademark Office that, in the opinion of the 
applicant and to the best of its knowledge, claims the reference listed 
drug or that claims a use of such listed drug for which the applicant is 
seeking approval under section 505(j) of the act and for which 
information is required to be filed under section 505(b) and (c) of the 
act and Sec. 314.53. For each such patent, the applicant shall provide 
the patent number and certify, in its opinion and to the best of its 
knowledge, one of the following circumstances:

[[Page 133]]

    (1) That the patent information has not been submitted to FDA. The 
applicant shall entitle such a certification ``Paragraph I 
Certification'';
    (2) That the patent has expired. The applicant shall entitle such a 
certification ``Paragraph II Certification'';
    (3) The date on which the patent will expire. The applicant shall 
entitle such a certification ``Paragraph III Certification''; or
    (4) That the patent is invalid, unenforceable, or will not be 
infringed by the manufacture, use, or sale of the drug product for which 
the abbreviated application is submitted. The applicant shall entitle 
such a certification ``Paragraph IV Certification''. This certification 
shall be submitted in the following form:

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


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

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

    (iii) Method of use patent. (A) If patent information is submitted 
under section 505(b) or (c) of the act and Sec. 314.53 for a patent 
claiming a method of using the listed drug, and the labeling for the 
drug product for which the applicant is seeking approval does not 
include any indications that are covered by the use patent, a statement 
explaining that the method of use patent does not claim any of the 
proposed indications.
    (B) If the labeling of the drug product for which the applicant is 
seeking approval includes an indication that, according to the patent 
information submitted under section 505(b) or (c) of the act and 
Sec. 314.53 or in the opinion of the applicant, is claimed by a use 
patent, an applicable certification under paragraph (a)(12)(i) of this 
section.
    (iv) Method of manufacturing patent. An applicant is not required to 
make a certification with respect to any patent that claims only a 
method of manufacturing the listed drug.
    (v) Licensing agreements. If the abbreviated new drug application is 
for a drug or method of using a drug claimed by a patent and the 
applicant has a licensing agreement with the patent owner, a 
certification under paragraph (a)(12)(i)(A)(4) of this section 
(``Paragraph IV Certification'') as to that patent and a statement that 
it has been granted a patent license.
    (vi) Late submission of patent information. If a patent on the 
listed drug is issued and the holder of the approved application for the 
listed drug does not submit the required information on the patent 
within 30 days of issuance of the patent, an applicant who submitted an 
abbreviated new drug application for that drug that contained an 
appropriate patent certification before the submission of the patent 
information is not required to submit an amended certification. An 
applicant whose abbreviated new drug application is submitted after a 
late submission of patent information, or whose pending abbreviated 
application was previously submitted but did not contain an appropriate 
patent certification at the time of the patent submission, shall submit 
a certification under paragraph (a)(12)(i) of this section or a 
statement under paragraph (a)(12)(iii) of this section as to that 
patent.

[[Page 134]]

    (vii) Disputed patent information. If an applicant disputes the 
accuracy or relevance of patent information submitted to FDA, the 
applicant may seek a confirmation of the correctness of the patent 
information in accordance with the procedures under Sec. 314.53(f). 
Unless the patent information is withdrawn or changed, the applicant 
shall submit an appropriate certification for each relevant patent.
    (viii) Amended certifications. A certification submitted under 
paragraphs (a)(12)(i) through (a)(12)(iii) of this section may be 
amended at any time before the effective date of the approval of the 
application. However, an applicant who has submitted a paragraph IV 
patent certification may not change it to a paragraph III certification 
if a patent infringement suit has been filed against another paragraph 
IV applicant unless the agency has determined that no applicant is 
entitled to 180-day exclusivity or the patent expires before the lawsuit 
is resolved or expires after the suit is resolved but before the end of 
the 180-day exclusivity period. If an applicant with a pending 
application voluntarily makes a patent certification for an untimely 
filed patent, the applicant may withdraw the patent certification for 
the untimely filed patent. An applicant shall submit an amended 
certification by letter or as an amendment to a pending application or 
by letter to an approved application. Once an amendment or letter is 
submitted, the application will no longer be considered to contain the 
prior certification.
    (A) After finding of infringement. An applicant who has submitted a 
certification under paragraph (a)(12)(i)(A)(4) of this section and is 
sued for patent infringement within 45 days of the receipt of notice 
sent under Sec. 314.95 shall amend the certification if a final judgment 
in the action against the applicant is entered finding the patent to be 
infringed. In the amended certification, the applicant shall certify 
under paragraph (a)(12)(i)(A)(3) of this section that the patent will 
expire on a specific date. Once an amendment or letter for the change 
has been submitted, the application will no longer be considered to be 
one containing a certification under paragraph (a)(12)(i)(A)(4) of this 
section. If a final judgment finds the patent to be invalid and 
infringed, an amended certification is not required.
    (B) After removal of a patent from the list. If a patent is removed 
from the list, any applicant with a pending application (including a 
tentatively approved application with a delayed effective date) who has 
made a certification with respect to such patent shall amend its 
certification. The applicant shall certify under paragraph (a)(12)(ii) 
of this section that no patents described in paragraph (a)(12)(i) of 
this section claim the drug or, if other relevant patents claim the 
drug, shall amend the certification to refer only to those relevant 
patents. In the amendment, the applicant shall state the reason for the 
change in certification (that the patent is or has been removed from the 
list). A patent that is the subject of a lawsuit under Sec. 314.107(c) 
shall not be removed from the list until FDA determines either that no 
delay in effective dates of approval is required under that section as a 
result of the lawsuit, that the patent has expired, or that any such 
period of delay in effective dates of approval is ended. An applicant 
shall submit an amended certification. Once an amendment or letter for 
the change has been submitted, the application will no longer be 
considered to be one containing a certification under paragraph 
(a)(12)(i)(A)(4) of this section.
    (C) Other amendments. (1) Except as provided in paragraphs 
(a)(12)(vi) and (a)(12)(viii)(C)(2) of this section, an applicant shall 
amend a submitted certification if, at any time before the effective 
date of the approval of the application, the applicant learns that the 
submitted certification is no longer accurate.
    (2) An applicant is not required to amend a submitted certification 
when information on a patent on the listed drug is submitted after the 
effective date of approval of the abbreviated application.
    (13) Financial certification or disclosure statement. An abbreviated 
application shall contain a financial certification or disclosure 
statement as required by part 54 of this chapter.

[[Page 135]]

    (b) Drug products subject to the Drug Efficacy Study Implementation 
(DESI) review. If the abbreviated new drug application is for a 
duplicate of a drug product that is subject to FDA's DESI review (a 
review of drug products approved as safe between 1938 and 1962) or other 
DESI-like review and the drug product evaluated in the review is a 
listed drug, the applicant shall comply with the provisions of paragraph 
(a) of this section.
    (c) [Reserved]
    (d) Format of an abbreviated application. (1) The applicant shall 
submit a complete archival copy of the abbreviated application as 
required under paragraphs (a) and (c) of this section. FDA will maintain 
the archival copy during the review of the application to permit 
individual reviewers to refer to information that is not contained in 
their particular technical sections of the application, to give other 
agency personnel access to the application for official business, and to 
maintain in one place a complete copy of the application. An applicant 
may submit all or portions of the archival copy of the abbreviated 
application in any form (e.g., microfiche, optical disc, and magnetic 
tape) that the applicant and FDA agree is acceptable.
    (2) For abbreviated new drug applications, the applicant shall 
submit a review copy of the abbreviated application that contains two 
separate sections. One section shall contain the information described 
under paragraphs (a)(2) through (a)(6), (a)(8), and (a)(9) of this 
section 505(j)(2)(A)(vii) of the act and one copy of the analytical 
methods 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 methods. The other section shall contain the 
information described under paragraphs (a)(3), (a)(7), and (a)(8) of 
this section. Each of the sections in the review copy is required to 
contain a copy of the application form described under Sec. 314.50(a).
    (3) [Reserved]
    (4) The applicant may obtain from FDA sufficient folders to bind the 
archival, the review, and the field copies of the abbreviated 
application.
    (5) The applicant shall submit a field copy of the abbreviated 
application that contains the technical section described in paragraph 
(a)(9) of this section, a copy of the application form required under 
paragraph (a)(1) of this section, and a certification that the field 
copy is a true copy of the technical section described in paragraph 
(a)(9) of this section contained in the archival and review copies of 
the abbreviated application.

[57 FR 17983, Apr. 28, 1992; 57 FR 29353, July 1, 1992, as amended at 58 
FR 47352, Sept. 8, 1993; 59 FR 50364, Oct. 3, 1994; 63 FR 5252, Feb. 2, 
1998; 63 FR 66399, Dec. 1, 1998; 64 FR 401, Jan. 5, 1999; 65 FR 56479, 
Sept. 19, 2000]



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

    (a) Notice of certification. For each patent that claims the listed 
drug or that claims a use for such listed drug for which the applicant 
is seeking approval and that the applicant certifies under 
Sec. 314.94(a)(12) is invalid, unenforceable, or will not be infringed, 
the applicant shall send notice of such certification by registered or 
certified mail, return receipt requested to each of the following 
persons:
    (1) Each owner of the patent which is the subject of the 
certification or the representative designated by the owner to receive 
the notice. The name and address of the patent owner or its 
representative may be obtained from the United States Patent and 
Trademark Office; and
    (2) The holder of the approved application under section 505(b) of 
the act for the listed drug that is claimed by the patent and for which 
the applicant is seeking approval, or, if the application holder does 
not reside or maintain a place of business within the United States, the 
application holder's attorney, agent, or other authorized official. The 
name and address of the application holder or its attorney, agent, or 
authorized official may be obtained from the Division of Drug 
Information Resources (HFD-80), Center for Drug Evaluation and Research, 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (3) This paragraph does not apply to a use patent that claims no 
uses for

[[Page 136]]

which the applicant is seeking approval.
    (b) Sending the notice. The applicant shall send the notice required 
by paragraph (a) of this section when it receives from FDA an 
acknowledgment letter stating that its abbreviated new drug application 
is sufficiently complete to permit a substantive review. At the same 
time, the applicant shall amend its abbreviated new drug application to 
include a statement certifying that the notice has been provided to each 
person identified under paragraph (a) of this section and that the 
notice met the content requirements under paragraph (c) of this section.
    (c) Contents of a notice. In the notice, the applicant shall cite 
section 505(j)(2)(B)(ii) of the act and shall include, but not be 
limited to, the following information:
    (1) A statement that FDA has received an abbreviated new drug 
application submitted by the applicant containing any required 
bioavailability or bioequivalence data or information.
    (2) The abbreviated application number.
    (3) The established name, if any, as defined in section 502(e)(3) of 
the act, of the proposed drug product.
    (4) The active ingredient, strength, and dosage form of the proposed 
drug product.
    (5) The patent number and expiration date, as submitted to the 
agency or as known to the applicant, of each patent alleged to be 
invalid, unenforceable, or not infringed.
    (6) A detailed statement of the factual and legal basis of the 
applicant's opinion that the patent is not valid, unenforceable, or will 
not be infringed. The applicant shall include in the detailed statement:
    (i) For each claim of a patent alleged not to be infringed, a full 
and detailed explanation of why the claim is not infringed.
    (ii) For each claim of a patent alleged to be invalid or 
unenforceable, a full and detailed explanation of the grounds supporting 
the allegation.
    (7) If the applicant does not reside or have a place of business in 
the United States, the name and address of an agent in the United States 
authorized to accept service of process for the applicant.
    (d) Amendment to an abbreviated application. If an abbreviated 
application is amended to include the certification described in 
Sec. 314.94(a)(12)(i)(A)(4), the applicant shall send the notice 
required by paragraph (a) of this section at the same time that the 
amendment to the abbreviated application is submitted to FDA.
    (e) Documentation of receipt of notice. The applicant shall amend 
its abbreviated application to document receipt of the notice required 
under paragraph (a) of this section by each person provided the notice. 
The applicant shall include a copy of the return receipt or other 
similar evidence of the date the notification was received. FDA will 
accept as adequate documentation of the date of receipt a return receipt 
or a letter acknowledging receipt by the person provided the notice. An 
applicant may rely on another form of documentation only if FDA has 
agreed to such documentation in advance. A copy of the notice itself 
need not be submitted to the agency.
    (f) Approval. If the requirements of this section are met, FDA will 
presume the notice to be complete and sufficient, and it will count the 
day following the date of receipt of the notice by the patent owner or 
its representative and by the approved application holder as the first 
day of the 45-day period provided for in section 505(j)(4)(B)(iii) of 
the act. FDA may, if the applicant provides a written statement to FDA 
that a later date should be used, count from such later date.

[59 FR 50366, Oct. 3, 1994]



Sec. 314.96  Amendments to an unapproved abbreviated application.

    (a) Abbreviated new drug application. (1) An applicant may amend an 
abbreviated new drug application that is submitted under Sec. 314.94, 
but not yet approved, to revise existing information or provide 
additional information.
    (2) Submission of an amendment containing significant data or 
information constitutes an agreement between FDA and the applicant to 
extend the review period only for the time necessary to review the 
significant data or information and for no more than 180 days.

[[Page 137]]

    (3) Submission of an amendment containing significant data or 
information to resolve deficiencies in the application as set forth in a 
not approvable letter issued under Sec. 314.120 constitutes an agreement 
between FDA and the applicant under section 505(j)(4)(A) of the act to 
extend the date by which the agency is required to reach a decision on 
the abbreviated new drug application only for the time necessary to 
review the significant data or information and for no more than 180 
days.
    (b) The applicant shall submit a field copy of each amendment to 
Sec. 314.94(a)(9). The applicant, other than a foreign applicant, shall 
include in its submission of each such amendment to FDA a statement 
certifying that a field copy of the amendment has been sent to the 
applicant's home FDA district office.

[57 FR 17983, Apr. 28, 1992, as amended at 58 FR 47352, Sept. 8, 1993; 
64 FR 401, Jan. 5, 1999]



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

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



Sec. 314.98  Postmarketing reports.

    (a) Except as provided in paragraph (b) of this section, each 
applicant having an approved abbreviated new drug application under 
Sec. 314.94 that is effective shall comply with the requirements of 
Sec. 314.80 regarding the reporting and recordkeeping of adverse drug 
experiences.
    (b) Each applicant shall submit one copy of each report required 
under Sec. 314.80 to the Division of Epidemiology and Surveillance (HFD-
730), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857.
    (c) Each applicant shall make the reports required under Sec. 314.81 
and section 505(k) of the act for each of its approved abbreviated 
applications.

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



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

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



   Subpart D--FDA Action on Applications and Abbreviated Applications

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



Sec. 314.100  Timeframes for reviewing applications and abbreviated applications.

    (a) Within 180 days of receipt of an application for a new drug 
under section 505(b) of the act, or of 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 an 
approvable letter under Sec. 314.110, or a not approvable letter under 
Sec. 314.120. This 180-day period is called the ``review clock.''
    (b) During the review period, an applicant may withdraw an 
application under Sec. 314.65 or an abbreviated application under 
Sec. 314.99 and later resubmit it. FDA will treat the resubmission as a 
new application or abbreviated application.
    (c) The review clock may be extended by mutual agreement between FDA 
and an applicant or as provided in Secs. 314.60 and 314.96, as the 
result of a major amendment.

[57 FR 17987, Apr. 28, 1992, as amended at 64 FR 402, Jan. 5, 1999]



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

    (a)(1) Within 60 days after FDA receives an application, the agency 
will

[[Page 138]]

determine whether the application may be filed. The filing of an 
application means that FDA has made a threshold determination that the 
application is sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for refusing to file the application apply, the agency 
will file the application and notify the applicant in writing. The date 
of filing will be the date 60 days after the date FDA received the 
application. The date of filing begins the 180-day period described in 
section 505(c) of the act. This 180-day period is called the ``filing 
clock.''
    (3) If FDA refuses to file the application, the agency will notify 
the applicant in writing and state the reason under paragraph (d) or (e) 
of this section for the refusal. If FDA refuses to file the application 
under paragraph (d) of this section, the applicant may request in 
writing within 30 days of the date of the agency's notification an 
informal conference with the agency about whether the agency should file 
the application. If, following the informal conference, the applicant 
requests that FDA file the application (with or without amendments to 
correct the deficiencies), the agency will file the application over 
protest under paragraph (a)(2) of this section, notify the applicant in 
writing, and review it as filed. If the application is filed over 
protest, the date of filing will be the date 60 days after the date the 
applicant requested the informal conference. The applicant need not 
resubmit a copy of an application that is filed over protest. If FDA 
refuses to file the application under paragraph (e) of this section, the 
applicant may amend the application and resubmit it, and the agency will 
make a determination under this section whether it may be filed.
    (b)(1) An abbreviated new drug application will be reviewed after it 
is submitted to determine whether the abbreviated application may be 
received. Receipt of an abbreviated new drug application means that FDA 
has made a threshold determination that the abbreviated application is 
sufficiently complete to permit a substantive review.
    (2) If FDA finds that none of the reasons in paragraphs (d) and (e) 
of this section for considering the abbreviated new drug application not 
to have been received applies, the agency will receive the abbreviated 
new drug application and notify the applicant in writing.
    (3) If FDA considers the abbreviated new drug application not to 
have been received under paragraph (d) or (e) of this section, FDA will 
notify the applicant, ordinarily by telephone. The applicant may then:
    (i) Withdraw the abbreviated new drug application under Sec. 314.99; 
or
    (ii) Amend the abbreviated new drug application to correct the 
deficiencies; or
    (iii) Take no action, in which case FDA will refuse to receive the 
abbreviated new drug application.
    (c) [Reserved]
    (d) FDA may refuse to file an application or may not consider an 
abbreviated new drug application to be received if any of the following 
applies:
    (1) The application does not contain a completed application form.
    (2) The application is not submitted in the form required under 
Sec. 314.50 or Sec. 314.94.
    (3) The application or abbreviated application is incomplete because 
it does not on its face contain information required under section 
505(b), section 505(j), or section 507 of the act and Sec. 314.50 or 
Sec. 314.94.
    (4) The applicant fails to submit a complete environmental 
assessment, which addresses each of the items specified in the 
applicable format under Sec. 25.40 of this chapter or fails to provide 
sufficient information to establish that the requested action is subject 
to categorical exclusion under Sec. 25.30 or Sec. 25.31 of this chapter.
    (5) The application or abbreviated application does not contain an 
accurate and complete English translation of each part of the 
application that is not in English.
    (6) The application does not contain a statement for each 
nonclinical laboratory study that it was conducted in compliance with 
the requirements set forth in part 58 of this chapter, or, for each 
study not conducted in compliance with part 58 of this chapter, a

[[Page 139]]

brief statement of the reason for the noncompliance.
    (7) The application does not contain a statement for each clinical 
study that it was conducted in compliance with the institutional review 
board regulations in part 56 of this chapter, or was not subject to 
those regulations, and that it was conducted in compliance with the 
informed consent regulations in part 50 of this chapter, or, if the 
study was subject to but was not conducted in compliance with those 
regulations, the application does not contain a brief statement of the 
reason for the noncompliance.
    (8) The drug product that is the subject of the submission is 
already covered by an approved application or abbreviated application 
and the applicant of the submission:
    (i) Has an approved application or abbreviated application for the 
same drug product; or
    (ii) Is merely a distributor and/or repackager of the already 
approved drug product.
    (9) The application is submitted as a 505(b)(2) application for a 
drug that is a duplicate of a listed drug and is eligible for approval 
under section 505(j) of the act.
    (e) The agency will refuse to file an application or will consider 
an abbreviated new drug application not to have been received if any of 
the following applies:
    (1) The drug product is subject to licensing by FDA under the Public 
Health Service Act (42 U.S.C. 201 et seq.) and subchapter F of this 
chapter.
    (2) In the case of a 505(b)(2) application or an abbreviated new 
drug application, the drug product contains the same active moiety as a 
drug that:
    (i) Was approved after September 24, 1984, in an application under 
section 505(b) of the act, and
    (ii) Is entitled to a 5-year period of exclusivity under section 
505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act and Sec. 314.108(b)(2), 
unless the 5-year exclusivity period has elapsed or unless 4 years of 
the 5-year period have elapsed and the application or abbreviated 
application contains a certification of patent invalidity or 
noninfringement described in Sec. 314.50(i)(1)(i)(A)(4) or 
Sec. 314.94(a)(12)(i)(A)(4).
    (f)(1) Within 180 days after the date of filing, plus the period of 
time the review period was extended (if any), FDA will either:
    (i) Approve the application; or
    (ii) Issue a notice of opportunity for hearing if the applicant 
asked FDA to provide it an opportunity for a hearing on an application 
in response to an approvable letter or a not approvable letter.
    (2) Within 180 days after the date of receipt, plus the period of 
time the review clock was extended (if any), FDA will either approve or 
disapprove the abbreviated new drug application. If FDA disapproves the 
abbreviated new drug application, FDA will issue a notice of opportunity 
for hearing if the applicant asked FDA to provide it an opportunity for 
a hearing on an abbreviated new drug application in response to a not 
approvable letter.
    (3) This paragraph does not apply to applications or abbreviated 
applications that have been withdrawn from FDA review by the applicant.

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



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

[[Page 140]]

correctable deficiencies found in an application or an abbreviated 
application when those deficiencies are discovered, particularly 
deficiencies concerning chemistry, manufacturing, and controls issues. 
The agency will also inform applicants promptly of its need for more 
data or information or for technical changes in the application or the 
abbreviated application needed to facilitate the agency's review. This 
early communication is intended to permit applicants to correct such 
readily identified deficiencies relatively early in the review process 
and to submit an amendment before the review period has elapsed. Such 
early communication would not ordinarily apply to major scientific 
issues, which require consideration of the entire pending application or 
abbreviated application by agency managers as well as reviewing staff. 
Instead, major scientific issues will ordinarily be addressed in an 
action 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 application or an abbreviated application as designated by the 
issuance of an approvable or not approvable letter, FDA will provide 
applicants 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 or abbreviated 
application can be approved. This meeting will be available on all 
applications or abbreviated applications, with priority given to 
applications for new chemical entities and major new indications for 
marketed drugs and for the first duplicates for such drugs. Requests for 
such meetings shall be directed to the director of the division 
responsible for reviewing the application or abbreviated 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]



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

[[Page 141]]

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 an approvable or not 
approvable letter pursuant to Sec. 314.110 or Sec. 314.120, 
respectively, the ``end-of-review conference'' described in 
Sec. 314.102(d) will provide a timely forum for discussing and 
resolving, if possible, scientific and medical issues on which the 
applicant disagrees with the agency. In addition, the ``ninety-day 
conference'' described in Sec. 314.102(c) will provide a timely forum 
for discussing and resolving, if possible, issues identified by that 
date.
    (2) When scientific or medical disputes arise at other times during 
the review process, applicants should discuss the matter directly with 
the responsible reviewing officials. If necessary, applicants may 
request a meeting with the appropriate reviewing officials and 
management representatives in order to seek a resolution. Ordinarily, 
such meetings would be held first with the Division Director, then with 
the Office Director, and finally with the Center Director if the matter 
is still unresolved. Requests for such meetings shall be directed to the 
director of the division responsible for reviewing the application or 
abrreviated application. FDA will make every attempt to grant requests 
for meetings that involve important issues and that can be scheduled at 
mutually convenient times.
    (3) In requesting a meeting designed to resolve a scientific or 
medical dispute, applicants may suggest that FDA seek the advice of 
outside experts, in which case FDA may, in its discretion, invite to the 
meeting one or more of its advisory committee members or other 
consultants, as designated by the agency. Applicants may also bring 
their own consultants. For major scientific 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]



Sec. 314.104  Drugs with potential for abuse.

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

[57 FR 17989, Apr. 28, 1992]



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

    (a) The Food and Drug Administration will approve an application and 
send the applicant an approval letter if none of the reasons in 
Sec. 314.125 for refusing to approve the application applies. An 
approval becomes effective on the date of the issuance of the approval 
letter, except with regard to an approval under section 505(b)(2) of the 
act with a delayed effective date. An approval with a delayed effective 
date is tentative and does not become final until the effective date. A 
new drug product or antibiotic approved under this paragraph may not be 
marketed until an approval is effective.
    (b) FDA will approve an application and issue the applicant an 
approval letter (rather than an approvable letter under Sec. 314.110) on 
the basis of draft labeling if the only deficiencies in the application 
concern editorial or similar minor deficiencies in the draft labeling. 
Such approval will be conditioned upon the applicant incorporating the 
specified labeling changes exactly as directed, and upon the applicant 
submitting to FDA a copy of the final printed labeling prior to 
marketing.
    (c) FDA will approve an application after it determines that the 
drug meets the statutory standards for safety and effectiveness, 
manufacturing and controls, and labeling, and an abbreviated application 
after it determines that the drug meets the statutory standards for 
manufacturing and controls, labeling, and, where applicable, 
bioequivalence. While the statutory standards apply to all drugs, the 
many kinds of drugs that are subject to the statutory standards and the 
wide range of uses for those drugs demand flexibility in applying the 
standards. Thus FDA is required to

[[Page 142]]

exercise its scientific judgment to determine the kind and quantity of 
data and information an applicant is required to provide for a 
particular drug to meet the statutory standards. FDA makes its views on 
drug products and classes of drugs available through guidance documents, 
recommendations, and other statements of policy.
    (d) FDA will approve an abbreviated new drug application and send 
the applicant an approval letter if none of the reasons in Sec. 314.127 
for refusing to approve the abbreviated new drug application applies. 
The approval becomes effective on the date of the issuance of the 
agency's approval letter unless the approval letter provides for a 
delayed effective date. An approval with a delayed effective date is 
tentative and does not become final until the effective date. A new drug 
product approved under this paragraph may not be introduced or delivered 
for introduction into interstate commerce until approval of the 
abbreviated new drug application is effective. Ordinarily, the effective 
date of approval will be stated in the approval letter.

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



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

    (a) General. A drug product may be introduced or delivered for 
introduction into interstate commerce when approval of the application 
or abbreviated application for the drug product becomes effective. 
Except as provided in this section, approval of an application or 
abbreviated application for a drug product becomes effective on the date 
FDA issues an approval letter under Sec. 314.105 for the application or 
abbreviated application.
    (b) Effect of patent on the listed drug. If approval of an 
abbreviated new drug application submitted under section 505(j) of the 
act or of a 505(b)(2) application is granted, that approval will become 
effective in accordance with the following:
    (1) Date of approval letter. Except as provided in paragraphs 
(b)(3), (b)(4), and (c) of this section, approval will become effective 
on the date FDA issues an approval letter under Sec. 314.105 if the 
applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that:
    (i) There are no relevant patents; or
    (ii) The applicant is aware of a relevant patent but the patent 
information required under section 505 (b) or (c) of the act has not 
been submitted to FDA; or
    (iii) The relevant patent has expired; or
    (iv) The relevant patent is invalid, unenforceable, or will not be 
infringed.
    (2) Patent expiration. If the applicant certifies under 
Sec. 314.50(i) or Sec. 314.94(a)(12) that the relevant patent will 
expire on a specified date, approval will become effective on the 
specified date.
    (3) Disposition of patent litigation. (i)(A) Except as provided in 
paragraphs (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this section, if 
the applicant certifies under

[[Page 143]]

Sec. 314.50(i) or Sec. 314.94(a)(12) that the relevant patent is 
invalid, unenforceable, or will not be infringed, and the patent owner 
or its representative or the exclusive patent licensee brings suit for 
patent infringement within 45 days of receipt by the patent owner of the 
notice of certification from the applicant under Sec. 314.52 or 
Sec. 314.95, approval may be made effective 30 months after the date of 
the receipt of the notice of certification by the patent owner or by the 
exclusive licensee (or their representatives) unless the court has 
extended or reduced the period because of a failure of either the 
plaintiff or defendant to cooperate reasonably in expediting the action; 
or
    (B) If the patented drug product qualifies for 5 years of exclusive 
marketing under Sec. 314.108(b)(2) and the patent owner or its 
representative or the exclusive patent licensee brings suit for patent 
infringement during the 1-year period beginning 4 years after the date 
the patented drug was approved and within 45 days of receipt by the 
patent owner of the notice of certification, the approval may be made 
effective at the expiration of the 7\1/2\ years from the date of 
approval of the application for the patented drug product.
    (ii) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court issues a final order that the patent 
is invalid, unenforceable, or not infringed, approval may be made 
effective on the date the court enters judgment;
    (iii) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court issues a final order or judgment that 
the patent has been infringed, approval may be made effective on the 
date the court determines that the patent will expire or otherwise 
orders; or
    (iv) If before the expiration of the 30-month period, or 7\1/2\ 
years where applicable, the court grants a preliminary injunction 
prohibiting the applicant from engaging in the commercial manufacture or 
sale of the drug product until the court decides the issues of patent 
validity and infringement, and if the court later decides that the 
patent is invalid, unenforceable, or not infringed, approval may be made 
effective on the date the court enters a final order or judgment that 
the patent is invalid, unenforceable, or not infringed.
    (v) In order for an approval to be made effective under paragraph 
(b)(3) of this section, the applicant must receive an approval letter 
from the agency indicating that the application has received final 
approval. Tentative approval of an application does not constitute 
``approval'' of an application and cannot, absent a final approval 
letter from the agency, result in an effective approval under paragraph 
(b)(3) of this section.
    (4) Multiple certifications. If the applicant has submitted 
certifications under Sec. 314.50(i) or Sec. 314.94(a)(12) for more than 
one patent, the date of approval will be calculated for each 
certification, and the approval will become effective on the last 
applicable date.
    (c) Subsequent abbreviated new drug application submission. (1) If 
an abbreviated new drug application contains a certification that a 
relevant patent is invalid, unenforceable, or will not be infringed and 
the application is for a generic copy of the same listed drug for which 
one or more substantially complete abbreviated new drug applications 
were previously submitted containing a certification that the same 
patent was invalid, unenforceable, or would not be infringed, approval 
of the subsequent abbreviated new drug application will be made 
effective no sooner than 180 days from whichever of the following dates 
is earlier:
    (i) The date the applicant submitting the first application first 
commences commercial marketing of its drug product; or
    (ii) The date of a decision of the court holding the relevant patent 
invalid, unenforceable, or not infringed.
    (2) For purposes of paragraph (c)(1) of this section, the 
``applicant submitting the first application'' is the applicant that 
submits an application that is both substantially complete and contains 
a certification that the patent was invalid, unenforceable, or not 
infringed prior to the submission of any other application for the same 
listed

[[Page 144]]

drug that is both substantially complete and contains the same 
certification. A ``substantially complete'' application must contain the 
results of any required bioequivalence studies, or, if applicable, a 
request for a waiver of such studies.
    (3) For purposes of paragraph (c)(1) of this section, if FDA 
concludes that the applicant submitting the first application is not 
actively pursuing approval of its abbreviated application, FDA will make 
the approval of subsequent abbreviated applications immediately 
effective if they are otherwise eligible for an immediately effective 
approval.
    (4) For purposes of paragraph (c)(1)(i) of this section, the 
applicant submitting the first application shall notify FDA of the date 
that it commences commercial marketing of its drug product. Commercial 
marketing commences with the first date of introduction or delivery for 
introduction into interstate commerce outside the control of the 
manufacturer of a drug product, except for investigational use under 
part 312 of this chapter, but does not include transfer of the drug 
product for reasons other than sale within the control of the 
manufacturer or application holder. If an applicant does not promptly 
notify FDA of such date, the effective date of approval shall be deemed 
to be the date of the commencement of first commercial marketing.
    (d) Delay due to exclusivity. The agency will also delay the 
effective date of the approval of an abbreviated new drug application 
under section 505(j) of the act or a 505(b)(2) application if delay is 
required by the exclusivity provisions in Sec. 314.108. When the 
effective date of an application is delayed under both this section and 
Sec. 314.108, the effective date will be the later of the 2 days 
specified under this section and Sec. 314.108.
    (e) Notification of court actions. The applicant shall submit a copy 
of the entry of the order or judgment to the Office of Generic Drugs 
(HFD-600), or to the appropriate division in the Office of Drug 
Evaluation I (HFD-100) or Office of Drug Evaluation II (HFD-500), 
whichever is applicable, within 10 working days of a final judgment.
    (f) Computation of 45-day time clock. (1) The 45-day clock described 
in paragraph (b)(3) of this section begins on the day after the date of 
receipt of the applicant's notice of certification by the patent owner 
or its representative, and by the approved application holder. When the 
45th day falls on Saturday, Sunday, or a Federal holiday, the 45th day 
will be the next day that is not a Saturday, Sunday, or a Federal 
holiday.
    (2) The abbreviated new drug applicant or the 505(b)(2) applicant 
shall notify FDA immediately of the filing of any legal action filed 
within 45 days of receipt of the notice of certification. If the 
applicant submitting the abbreviated new drug application or the 
505(b)(2) application or patent owner or its representative does not 
notify FDA in writing before the expiration of the 45-day time period or 
the completion of the agency's review of the application, whichever 
occurs later, that a legal action for patent infringement was filed 
within 45 days of receipt of the notice of certification, approval of 
the abbreviated new drug application or the 505(b)(2) application will 
be made effective immediately upon expiration of the 45 days or upon 
completion of the agency's review and approval of the application, 
whichever is later. The notification to FDA of the legal action shall 
include:
    (i) The abbreviated new drug application or 505(b)(2) application 
number.
    (ii) The name of the abbreviated new drug or 505(b)(2) application 
applicant.
    (iii) The established name of the drug product or, if no established 
name exists, the name(s) of the active ingredient(s), the drug product's 
strength, and dosage form.
    (iv) A certification that an action for patent infringement 
identified by number, has been filed in an appropriate court on a 
specified date.
    The applicant of an abbreviated new drug application shall send the 
notification to FDA's Office of Generic Drugs (HFD-600). A 505(b)(2) 
applicant shall send the notification to the appropriate division in the 
Center for Drug Evaluation and Research reviewing the application. A 
patent owner or its representative may also notify FDA

[[Page 145]]

of the filing of any legal action for patent infringement. The notice 
should contain the information and be sent to the offices or divisions 
described in this paragraph.
    (3) If the patent owner or approved application holder who is an 
exclusive patent licensee waives its opportunity to file a legal action 
for patent infringement within 45 days of a receipt of the notice of 
certification and the patent owner or approved application holder who is 
an exclusive patent licensee submits to FDA a valid waiver before the 45 
days elapse, approval of the abbreviated new drug application or the 
505(b)(2) application will be made effective upon completion of the 
agency's review and approval of the application. FDA will only accept a 
waiver in the following form:

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

[59 FR 50367, Oct. 3, 1994, as amended at 63 FR 59712, Nov. 5, 1998; 65 
FR 43235, July 13, 2000]



Sec. 314.108  New drug product exclusivity.

    (a) Definitions. The following definitions of terms apply to this 
section:
    Active moiety means the molecule or ion, excluding those appended 
portions of the molecule that cause the drug to be an ester, salt 
(including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological action of 
the drug substance.
    Approved under section 505(b) means an application submitted under 
section 505(b) and approved on or after October 10, 1962, or an 
application that was ``deemed approved'' under section 107(c)(2) of Pub. 
L. 87-781.
    Clinical investigation means any experiment other than a 
bioavailability study in which a drug is administered or dispensed to, 
or used on, human subjects.
    Conducted or sponsored by the applicant with regard to an 
investigation means that before or during the investigation, the 
applicant was named in Form FDA-1571 filed with FDA as the sponsor of 
the investigational new drug application under which the investigation 
was conducted, or the applicant or the applicant's predecessor in 
interest, provided substantial support for the investigation. To 
demonstrate ``substantial support,'' an applicant must either provide a 
certified statement from a certified public accountant that the 
applicant provided 50 percent or more of the cost of conducting the 
study or provide an explanation why FDA should consider the applicant to 
have conducted or sponsored the study if the applicant's financial 
contribution to the study is less than 50 percent or the applicant did 
not sponsor the investigational new drug. A predecessor in interest is 
an entity, e.g., a corporation, that the applicant has taken over, 
merged with, or purchased, or from which the applicant has purchased all 
rights to the drug. Purchase of nonexclusive rights to a clinical 
investigation after it is completed is not sufficient to satisfy this 
definition.
    Date of approval means the date on the letter from FDA stating that 
the new drug application is approved, whether or not final printed 
labeling or other materials must yet be submitted as long as approval of 
such labeling or materials is not expressly required. ``Date of 
approval'' refers only to a final approval and not to a tentative 
approval that may become effective at a later date.
    Essential to approval means, with regard to an investigation, that 
there are no other data available that could support approval of the 
application.
    FDA means the Food and Drug Administration.
    New chemical entity means a drug that contains no active moiety that 
has been approved by FDA in any other application submitted under 
section 505(b) of the act.

[[Page 146]]

    New clinical investigation means an investigation in humans the 
results of which have not been relied on by FDA to demonstrate 
substantial evidence of effectiveness of a previously approved drug 
product for any indication or of safety for a new patient population and 
do not duplicate the results of another investigation that was relied on 
by the agency to demonstrate the effectiveness or safety in a new 
patient population of a previously approved drug product. For purposes 
of this section, data from a clinical investigation previously submitted 
for use in the comprehensive evaluation of the safety of a drug product 
but not to support the effectiveness of the drug product would be 
considered new.
    (b) Submission of and effective date of approval of an abbreviated 
new drug application submitted under section 505(j) of the act or a 
505(b)(2) application. (1) [Reserved]
    (2) If a drug product that contains a new chemical entity was 
approved after September 24, 1984, in an application submitted under 
section 505(b) of the act, no person may submit a 505(b)(2) application 
or abbreviated new drug application under section 505(j) of the act for 
a drug product that contains the same active moiety as in the new 
chemical entity for a period of 5 years from the date of approval of the 
first approved new drug application, except that the 505(b)(2) 
application or abbreviated application may be submitted after 4 years if 
it contains a certification of patent invalidity or noninfringement 
described in Sec. 314.50(i)(1)(i)(A)(4) or Sec. 314.94(a)(12)(i)(A)(4).
    (3) The approval of a 505(b)(2) application or abbreviated 
application described in paragraph (b)(2) of this section will become 
effective as provided in Sec. 314.107(b)(1) or (b)(2), unless the owner 
of a patent that claims the drug, the patent owner's representative, or 
exclusive licensee brings suit for patent infringement against the 
applicant during the 1-year period beginning 48 months after the date of 
approval of the new drug application for the new chemical entity and 
within 45 days after receipt of the notice described at Sec. 314.52 or 
Sec. 314.95, in which case, approval of the 505(b)(2) application or 
abbreviated application will be made effective as provided in 
Sec. 314.107(b)(3).
    (4) If an application:
    (i) Was submitted under section 505(b) of the act;
    (ii) Was approved after September 24, 1984;
    (iii) Was for a drug product that contains an active moiety that has 
been previously approved in another application under section 505(b) of 
the act; and
    (iv) Contained reports of new clinical investigations (other than 
bioavailability studies) conducted or sponsored by the applicant that 
were essential to approval of the application, the agency will not make 
effective for a period of 3 years after the date of approval of the 
application the approval of a 505(b)(2) application or an abbreviated 
new drug application for the conditions of approval of the original 
application, or an abbreviated new drug application submitted pursuant 
to an approved petition under section 505(j)(2)(C) of the act that 
relies on the information supporting the conditions of approval of an 
original new drug application.
    (5) If a supplemental application:
    (i) Was approved after September 24, 1984; and
    (ii) Contained reports of new clinical investigations (other than 
bioavailability studies) that were conducted or sponsored by the 
applicant that were essential to approval of the supplemental 
application, the agency will not make effective for a period of 3 years 
after the date of approval of the supplemental application the approval 
of a 505(b)(2) application or an abbreviated new drug application for a 
change, or an abbreviated new drug application submitted pursuant to an 
approved petition under section 505(j)(2)(C) of the act that relies on 
the information supporting a change approved in the supplemental new 
drug application.

[59 FR 50368, Oct. 3, 1994]



Sec. 314.110  Approvable letter to the applicant.

    (a) In selected circumstances, it is useful at the end of the review 
period for the Food and Drug Administration to indicate to the applicant 
that the

[[Page 147]]

application or abbreviated application is basically approvable providing 
certain issues are resolved. An approvable letter may be issued in such 
circumstances. FDA will send the applicant an approvable letter if the 
application or abbreviated application substantially meets the 
requirements of this part and the agency believes that it can approve 
the application or abbreviated application if specific additional 
information or material is submitted or specific conditions (for 
example, certain changes in labeling) are agreed to by the applicant. 
The approvable letter will describe the information or material FDA 
requires or the conditions the applicant is asked to meet. As a 
practical matter, the approvable letter will serve in most instances as 
a mechanism for resolving outstanding issues on drugs that are about to 
be approved and marketed. For an application, the applicant shall, 
within 10 days after the date of the approvable letter:
    (1) Amend the application or notify FDA of an intent to file an 
amendment. The filing of an amendment or notice of intent to file an 
amendment constitutes an agreement by the applicant to extend the review 
period for 45 days after the date FDA receives the amendment. The 
extension is to permit the agency to review the amendment;
    (2) Withdraw the application. FDA will consider the applicant's 
failure to respond within 10 days to an approvable letter to be a 
request by the applicant to withdraw the application under Sec. 314.65. 
A decision to withdraw an application is without prejudice to a 
refiling;
    (3) For a new drug application, 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 under section 505(d) 
of the act. The applicant shall submit the request to the Associate 
Director for Policy (HFD-5), Center for Drug Evaluation and Research, 
Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857. 
Within 60 days of the date of the approvable letter, or within a 
different time period to which FDA and the applicant agree, the agency 
will either approve the application under Sec. 314.105 or refuse to 
approve the application under Sec. 314.125 and give the applicant 
written notice of an opportunity for a hearing under Sec. 314.200 and 
section 505(c)(2) of the act on the question of whether there are 
grounds for denying approval of the application under section 505(d) of 
the act;
    (4) [Reserved]
    (5) Notify FDA that the applicant agrees to an extension of the 
review period under section 505(c) of the act, so that the applicant can 
determine whether to respond further under paragraph (a)(1), (a)(2), or 
(a)(3) of this section. The applicant's notice is required to state the 
length of the extension. FDA will honor any reasonable request for such 
an extension. FDA will consider the applicant's failure to respond 
further within the extended review period to be a request to withdraw 
the application under Sec. 314.65. A decision to withdraw an application 
is without prejudice to a refiling.
    (b) FDA will send the applicant of an abbreviated new drug 
application an approvable letter only if the application substantially 
meets the requirements of this part and the agency believes that it can 
approve the abbreviated application if minor deficiencies (e.g., 
labeling deficiencies) are corrected. The approvable letter will 
describe the deficiencies and state a time period within which the 
applicant must respond. Unless the applicant corrects the deficiencies 
by amendment within the specified time period, FDA will refuse to 
approve the abbreviated application under Sec. 314.127. Within 10 days 
after the date of the approvable letter, the applicant may also 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 
abbreviated new drug application. Applicants who request a hearing shall 
submit the request to the Associate Director for Policy (HFD-5), Center 
for Drug Evaluation and Research, Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857.

[57 FR 17989, Apr. 28, 1992, as amended at 62 FR 43639, Aug. 15, 1997; 
64 FR 402, Jan. 5, 1999]

[[Page 148]]



Sec. 314.120  Not approvable letter to the applicant.

    (a) The Food and Drug Administration will send the applicant a not 
approvable letter if the agency believes that the application may not be 
approved for one of the reasons given in Sec. 314.125 or the abbreviated 
new drug application may not be approved for one of the reasons given in 
Sec. 314.127. The not approvable letter will describe the deficiencies 
in the application or abbreviated application. Except as provided in 
paragraph (b) of this section, within 10 days after the date of the not 
approvable letter, the applicant shall:
    (1) Amend the application or abbreviated application or notify FDA 
of an intent to file an amendment. The filing of an amendment or a 
notice of intent to file an amendment constitutes an agreement by the 
applicant to extend the review period under Sec. 314.60 or Sec. 314.96;
    (2) Withdraw the application or abbreviated application. Except as 
provided in paragraph (b) of this section, FDA will consider the 
applicant's failure to respond within 10 days to a not approvable letter 
to be a request by the applicant to withdraw the application under 
Sec. 314.65 or abbreviated application under Sec. 314.99. A decision to 
withdraw the application or abbreviated application is without prejudice 
to refiling;
    (3) For a new drug application or an abbreviated application, 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 under section 505(d) or (j)(3) of the act. The applicant 
shall submit the request to the Associate Director for Policy (HFD-5), 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857. Within 60 days of the date of 
the not approvable letter, 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 new drug 
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)(4)(C) of the act on the question of whether there are grounds for 
denying approval of the application under section 505(d) or (j)(3) of 
the act; or
    (4) [Reserved]
    (5) Notify FDA that the applicant agrees to an extension of the 
review period under section 505(c)(1) or (j)(4)(A) of the act, so that 
the applicant can determine whether to respond further under paragraph 
(a)(1), (a)(2), or (a)(3) of this section. The applicant's notice is 
required to state the length of the extension. FDA will honor any 
reasonable request for such an extension. FDA will consider the 
applicant's failure to respond further within the extended review period 
to be a request to withdraw the application under Sec. 314.65 or 
abbreviated application under Sec. 314.99. A decision to withdraw an 
application or abbreviated application is without prejudice to a 
refiling.
    (b) With the exception of a request for an opportunity for a hearing 
under paragraph (a)(3) of this section, the 10-day time period in this 
section for responding to a not approvable letter does not apply to 
abbreviated new drug applications. FDA may consider the applicant's 
failure to respond within 180 days to a not approvable letter to be a 
request by the applicant to withdraw the abbreviated new drug 
application under Sec. 314.99.

[57 FR 17990, Apr. 28, 1992, as amended at 62 FR 43639, Aug. 15, 1997; 
64 FR 402, Jan. 5, 1999]



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 
Secs. 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.

[[Page 149]]

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

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



Sec. 314.125  Refusal to approve an application.

    (a) The Food and Drug Administration will refuse to approve the 
application and for a new drug give the applicant written notice of an 
opportunity for a hearing under Sec. 314.200 on the question of whether 
there are grounds for denying approval of the application under section 
505(d) of the act, if:
    (1) FDA sends the applicant an approvable or a not approvable letter 
under Sec. 314.110 or Sec. 314.120;
    (2) The applicant requests an opportunity for hearing for a new drug 
on the question of whether the application is approvable; and
    (3) FDA finds that any of the reasons given in paragraph (b) of this 
section apply.
    (b) FDA may refuse to approve an application for any of the 
following reasons:
    (1) The methods to be used in, and the facilities and controls used 
for, the manufacture, processing, packing, or holding of the drug 
substance or the drug product are inadequate to preserve its identity, 
strength, quality, purity, stability, and bioavailability.
    (2) The investigations required under section 505(b) of the act do 
not include adequate tests by all methods reasonably applicable to show 
whether or not the drug is safe for use under the conditions prescribed, 
recommended, or suggested in its proposed labeling.
    (3) The results of the tests show that the drug is unsafe for use 
under the conditions prescribed, recommended, or suggested in its 
proposed labeling or the results do not show that the drug product is 
safe for use under those conditions.
    (4) There is insufficient information about the drug to determine 
whether the product is safe for use under the conditions prescribed, 
recommended, or suggested in its proposed labeling.
    (5) There is a lack of substantial evidence consisting of adequate 
and well-controlled investigations, as defined in Sec. 314.126, that the 
drug product will have the effect it purports or is represented to have 
under the conditions of use prescribed, recommended, or suggested in its 
proposed labeling.
    (6) The proposed labeling is false or misleading in any particular.
    (7) The application contains an untrue statement of a material fact.
    (8) The drug product's proposed labeling does not comply with the 
requirements for labels and labeling in part 201.
    (9) The application does not contain bioavailability or 
bioequivalence data required under part 320 of this chapter.
    (10) A reason given in a letter refusing to file the application 
under Sec. 314.101(d), if the deficiency is not corrected.

[[Page 150]]

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



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 151]]

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 152]]

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

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



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

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

[[Page 153]]

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

[[Page 154]]

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

[[Page 155]]

described in Sec. 320.63 of this chapter that is contained in the 
abbreviated new drug application refuses to permit an inspection of 
facilities or records relevant to the study by a properly authorized 
officer of employee of the Department of Health and Human Services or 
refuses to submit reserve samples of the drug products used in the study 
when requested by FDA.

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



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 Secs. 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

[[Page 156]]

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

[[Page 157]]

agency will not make a finding under paragraph (b) of this section, but 
will withdraw approval of the application or abbreviated application in 
a notice published in the Federal Register that contains a brief summary 
of the agency's and the applicant's views of the reasons for withdrawal.

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



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

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

[[Page 158]]

drug application whose holder submitted comments on the notice of 
opportunity for hearing shall be withdrawn upon the issuance of a final 
decision concluding that the listed drug should be withdrawn for grounds 
as described in Sec. 314.150(a). The final decision shall be in writing 
and shall constitute final agency action, reviewable in a judicial 
proceeding.
    (8) Documents in the record will be publicly available in accordance 
with Sec. 10.20(j) of this chapter. Documents available for examination 
or copying will be placed on public display in the Dockets Management 
Branch (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 Dockets Management Branch (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

[[Page 159]]

present, in writing, comments and information bearing on the initial 
decision. If no comments or information is received, the initial 
decision will become final at the expiration of 30 days.
    (3) Comments and information received within 30 days of the issuance 
of the initial decision will be considered by the agency and responded 
to in a final decision.
    (4) The agency may, in its discretion, hold a limited oral hearing 
to resolve dispositive factual issues that cannot be resolved on the 
basis of written submissions.
    (5) If the final decision affirms the agency's initial decision that 
the listed drug was withdrawn for reasons of safety or effectiveness, 
the decision will be published in the Federal Register in compliance 
with Sec. 314.152, and will, except as provided in paragraph (b)(6) of 
this section, suspend approval of all abbreviated new drug applications 
identified under paragraph (b)(1) of this section and remove from the 
list the listed drug and any drug whose approval was suspended under 
this paragraph. The notice will satisfy the requirement of 
Sec. 314.162(b). The agency's final decision and copies of materials on 
which it relies will also be filed with the Dockets Management Branch 
(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 Dockets Management 
Branch (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 
Secs. 10.25(a) and 10.30 of this chapter.
    (b) Any person may petition under Secs. 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

[[Page 160]]

act, FDA will initiate a proceeding in accordance with Sec. 314.153(b).
    (e) A drug that the agency determines is withdrawn for safety or 
effectiveness reasons will be removed from the list, under Sec. 314.162. 
The drug may be relisted if the agency has evidence that marketing of 
the drug has resumed or that the withdrawal is not for safety or 
effectiveness reasons. A determination that the drug is not withdrawn 
for safety or effectiveness reasons may be made at any time after its 
removal from the list, upon the agency's initiative, or upon the 
submission of a petition under Secs. 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).

[[Page 161]]

    (2) FDA will publish the notice in the Federal Register and will 
state that the applicant, and other persons subject to the notice under 
Sec. 310.6, who wishes to participate in a hearing, has 30 days after 
the date of publication of the notice to file a written notice of 
participation and request for hearing. The applicant, or other persons 
subject to the notice under Sec. 310.6, who fails to file a written 
notice of participation and request for hearing within 30 days, waives 
the opportunity for a hearing.
    (3) It is the responsibility of every manufacturer and distributor 
of a drug product to review every notice of opportunity for a hearing 
published in the Federal Register to determine whether it covers any 
drug product that person manufactures or distributes. Any person may 
request an opinion of the applicability of a notice to a specific 
product that may be identical, related, or similar to a product listed 
in a notice by writing to the Division of Drug Labeling Compliance (HFD-
310), Center for Drug Evaluation and Research, Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857. 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 Dockets Management Branch (HFA-305), Food 
and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 
20857, (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

[[Page 162]]

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

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

[[Page 163]]

clearly and a waiver obtained under Sec. 314.126 is required to be 
submitted.
    IV. A statement signed by the person responsible for such submission 
that it includes in full (or incorporates by reference as permitted in 
Sec. 314.200(c)(2)) all studies and information specified in 
Sec. 314.200(d).

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

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

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

[[Page 164]]

should be submitted to support the statement.
    III. Marketing.
    A. A copy of each pertinent document or record to establish the 
exact date the drug was initially marketed.
    B. A statement whether such marketing has at any subsequent time 
been discontinued. If such marketing has been discontinued, the exact 
date of each such discontinuance should be submitted, together with a 
copy of each pertinent document or record to establish each such date.
    IV. Verification.
    A statement signed by the person responsible for such submission, 
that all appropriate records have been searched and to the best of that 
person's knowledge and belief it includes a true and accurate 
presentation of the facts.

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

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

[[Page 165]]

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

[50 FR 7493, Feb. 22, 1985; 50 FR 14212, Apr. 11, 1985, as amended at 50 
FR 21238, May 23, 1985; 55 FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 
28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, Feb. 2, 1998; 67 FR 
9586, Mar. 4, 2002]



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

[[Page 166]]

certified by the Commissioner is required to include the requests for 
hearing together with the data and information submitted and the 
Commissioner's findings and conclusion.
    (b) A manufacturer or distributor of an identical, related, or 
similar drug product under Sec. 310.6 may seek judicial review of an 
order withdrawing approval of a new drug application, whether or not a 
hearing has been held, in a United States court of appeals under section 
505(h) of the act.

Subpart F [Reserved]



                   Subpart G--Miscellaneous Provisions

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



Sec. 314.410  Imports and exports of new drugs.

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

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



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, 
12229 Wilkins Ave., Rockville, MD 20852). FDA will then contact the 
person to discuss the proposed submission.

[[Page 167]]

    (b) An investigational new drug application or an application, 
abbreviated application, amendment, or supplement may incorporate by 
reference all or part of the contents of any drug master file in support 
of the submission if the holder authorizes the incorporation in writing. 
Each incorporation by reference is required to describe the incorporated 
material by name, reference number, volume, and page number of the drug 
master file.
    (c) A drug master file is required to be submitted in two copies. 
The agency has prepared guidance that provides information about how to 
prepare a well-organized drug master file. If the drug master file 
holder adds, changes, or deletes any information in the file, the holder 
shall notify in writing, each person authorized to reference that 
information. Any addition, change, or deletion of information in a drug 
master file (except the list required under paragraph (d) of this 
section) is required to be submitted in two copies and to describe by 
name, reference number, volume, and page number the information affected 
in the drug master file.
    (d) The drug master file is required to contain a complete list of 
each person currently authorized to incorporate by reference any 
information in the file, identifying by name, reference number, volume, 
and page number the information that each person is authorized to 
incorporate. If the holder restricts the authorization to particular 
drug products, the list is required to include the name of each drug 
product and the application number, if known, to which the authorization 
applies.
    (e) The public availability of data and information in a drug master 
file, including the availability of data and information in the file to 
a person authorized to reference the file, is determined under part 20 
and Sec. 314.430.

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



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 approvable letter is sent to the 
applicant under Sec. 314.110, unless the existence of the application or 
abbreviated application has been previously publicly disclosed or 
acknowledged. The Center for Drug Evaluation and Research will maintain 
and make available for public disclosure a list of applications or 
abbreviated applications for which the agency has sent an approvable 
letter to the applicant.
    (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

[[Page 168]]

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 Dockets Management Branch (HFA-305), Food 
and Drug Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 
20857, 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 method or other analytical method, 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

[[Page 169]]

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

[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55 
FR 11580, Mar. 29, 1990; 57 FR 17996, Apr. 28, 1992; 61 FR 51530, Oct. 
2, 1996; 64 FR 26698, May 13, 1998; 64 FR 402, Jan. 5, 1999; 66 FR 1832, 
Jan. 10, 2001]



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 
Center for Drug Evaluation and Research, Food and Drug Administration, 
5600 Fishers Lane, Rockville, MD 20857, and directed 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 Document and Records Section, 12420 Parklawn Dr., 
Rockville, MD 20852. Applicants may obtain folders for binding 
applications from the Consolidated Forms and Publications Distribution 
Center, Washington Commerce Center, 3222 Hubbard Rd., Landover, MD 
20785. 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 
directed to 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, 5600 Fishers Lane, Rockville, MD 20857. Items sent by 
parcel post or overnight courier service should be directed to the 
Office of Generic Drugs (HFD-600), Center for Drug Evaluation and 
Research, Food and Drug Administration, Metro Park North II, 7500 
Standish Place, rm. 150, Rockville, MD 20855. Correspondence not 
associated with an application should be addressed specifically to the 
intended office or division and to the

[[Page 170]]

person as follows: Center for Drug Evaluation and Research, Food and 
Drug Administration, Attn: [insert name of person], MPN II, HFD-[insert 
mail code of office or division], 5600 Fishers Lane, Rockville, MD 
20857. The mail code for the Office of Generic Drugs is HFD-600, the 
mail code for the Division of Chemistry is HFD-630, 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 or 
Sec. 314.120 on the question of whether there are grounds for denying 
approval of an application, except an application under paragraph (b) of 
this section, should be directed to the Associate Director for Policy 
(HFD-5).
    (4) The field copy of an application, an abbreviated application, 
amendments, supplements, resubmissions, requests for waivers, and other 
correspondence about an application and an abbreviated application shall 
be sent to the applicant's home FDA district office, except that a 
foreign applicant shall send the field copy to the appropriate address 
identified in paragraphs (a)(1) and (a)(2) of this section.
    (b) Applicants shall send applications and other correspondence 
relating to matters covered by this part for the drug products listed 
below to the Division of Product Certification (HFB-240), Center for 
Biologics Evaluation and Research, Food and Drug Administration, 8800 
Rockville Pike, Bethesda, MD 20892, except applicants shall send a 
request for an opportunity for a hearing under Sec. 314.110 or 
Sec. 314.120 on the question of whether there are grounds for denying 
approval of an application to the Director, Center for Biologics 
Evaluation and Research (HFB-1), at the same address.
    (1) Ingredients packaged together with containers intended for the 
collection, processing, or storage of blood and blood components.
    (2) Urokinase products.
    (3) Plasma volume expanders and hydroxyethyl starch for 
leukapheresis.

[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]



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 Communications 
Management, Drug Information Branch (HFD-210), Center for Drug 
Evaluation and Research, Food and Drug Administration, 5600 Fishers 
Lane, Rockville, MD 20857.

[65 FR 56480, Sept. 19, 2000]



    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

[[Page 171]]

subject to the requirement that the applicant study the drug further, to 
verify and describe its clinical benefit, where there is uncertainty as 
to the relation of the surrogate endpoint to clinical benefit, or of the 
observed clinical benefit to ultimate outcome. Postmarketing studies 
would usually be studies already underway. When required to be 
conducted, such studies must also be adequate and well-controlled. The 
applicant shall carry out any such studies with due diligence.



Sec. 314.520  Approval with restrictions to assure safe use.

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



Sec. 314.530  Withdrawal procedures.

    (a) For new drugs approved under Secs. 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 Secs. 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

[[Page 172]]

agency action from which the applicant may petition for judicial review. 
Before requesting an order from a court for a stay of action pending 
review, an applicant must first submit a petition for a stay of action 
under Sec. 10.35 of this chapter.

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



Sec. 314.540  Postmarketing safety reporting.

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



PART 315--DIAGNOSTIC RADIOPHARMACEUTICALS--Table of Contents




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

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

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



Sec. 315.1  Scope.

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



Sec. 315.2  Definition.

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



Sec. 315.3  General factors relevant to safety and effectiveness.

    FDA's determination of the safety and effectiveness of a diagnostic 
radiopharmaceutical includes consideration of the following:
    (a) The proposed use of the diagnostic radiopharmaceutical in the 
practice of medicine,

[[Page 173]]

    (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 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.

[[Page 174]]

    (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.
316.23 Timing of requests for orphan-drug designation; designation of 
          already approved drugs.
316.24 Granting orphan-drug designation.
316.25 Refusal to grant orphan-drug designation.
316.26 Amendment to orphan-drug designation.
316.27 Change in ownership of orphan-drug designation.
316.28 Publication of orphan-drug designations.
316.29 Revocation of orphan-drug designation.
316.30 Annual reports of holder of orphan-drug designation.

                Subpart D--Orphan-drug Exclusive Approval

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

              Subpart E--Open Protocols for Investigations

316.40 Treatment use of a designated orphan drug.

                 Subpart F--Availability of Information

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

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

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



                      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:

[[Page 175]]

    (i) Requests for recommendations for investigations of drugs for 
rare diseases or conditions;
    (ii) Requests for designation of a drug for a rare disease or 
condition; and
    (iii) Requests for gaining exclusive approval for a drug product for 
a rare disease or condition.
    (2) Allowing a sponsor to provide an investigational drug product 
under a treatment protocol to patients who need the drug for treatment 
of a rare disease or condition.
    (b) This part does not apply to food, medical devices, or drugs for 
veterinary use.
    (c) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21, unless otherwise 
noted.



Sec. 316.2  Purpose.

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



Sec. 316.3  Definitions.

    (a) The definitions and interpretations contained in section 201 of 
the act apply to those terms when used in this part.
    (b) The following definitions of terms apply to this part:
    (1) Act means the Federal Food, Drug, and Cosmetic Act as amended by 
section 2 of the Orphan Drug Act (sections 525-528 (21 U.S.C. 360aa-
360dd)).
    (2) Active moiety means the molecule or ion, excluding those 
appended portions of the molecule that cause the drug to be an ester, 
salt (including a salt with hydrogen or coordination bonds), or other 
noncovalent derivative (such as a complex, chelate, or clathrate) of the 
molecule, responsible for the physiological or pharmacological action of 
the drug substance.
    (3) Clinically superior means that a drug is shown to provide a 
significant therapeutic advantage over and above that provided by an 
approved orphan drug (that is otherwise the same drug) in one or more of 
the following ways:
    (i) Greater effectiveness than an approved orphan drug (as assessed 
by effect on a clinically meaningful endpoint in adequate and well 
controlled clinical trials). Generally, this would represent the same 
kind of evidence needed to support a comparative effectiveness claim for 
two different drugs; in most cases, direct comparative clinical trials 
would be necessary; or
    (ii) Greater safety in a substantial portion of the target 
populations, for example, by the elimination of an ingredient or 
contaminant that is associated with relatively frequent adverse effects. 
In some cases, direct comparative clinical trials will be necessary; or
    (iii) In unusual cases, where neither greater safety nor greater 
effectiveness has been shown, a demonstration that the drug otherwise 
makes a major contribution to patient care.
    (4) Director means the Director of FDA's Office of Orphan Products 
Development.
    (5) FDA means the Food and Drug Administration.
    (6) Holder means the sponsor in whose name an orphan drug is 
designated and approved.
    (7) IND means an investigational new drug application under part 312 
of this chapter.
    (8) Manufacturer means any person or agency engaged in the 
manufacture of a drug that is subject to investigation and approval 
under the act or the biologics provisions of the Public Health Service 
Act (42 U.S.C. 262-263).
    (9)  Marketing application means an application for approval of a 
new drug filed under section 505(b) of the act or an application for a 
biologics license submitted under section 351 of the Public Health 
Service Act (42 U.S.C. 262).
    (10) Orphan drug means a drug intended for use in a rare disease or 
condition as defined in section 526 of the act.
    (11) Orphan-drug designation means FDA's act of granting a request 
for designation under section 526 of the act.
    (12) Orphan-drug exclusive approval or exclusive approval means 
that, effective on the date of FDA approval as stated

[[Page 176]]

in the approval letter of a marketing application for a sponsor of a 
designated orphan drug, no approval will be given to a subsequent 
sponsor of the same drug product for the same indication for 7 years, 
except as otherwise provided by law or in this part.
    (13) Same drug means:
    (i) If it is a drug composed of small molecules, a drug that 
contains the same active moiety as a previously approved drug and is 
intended for the same use as the previously approved drug, even if the 
particular ester or salt (including a salt with hydrogen or coordination 
bonds) or other noncovalent derivative such as a complex, chelate or 
clathrate has not been previously approved, except that if the 
subsequent drug can be shown to be clinically superior to the first 
drug, it will not be considered to be the same drug.
    (ii) If it is a drug composed of large molecules (macromolecules), a 
drug that contains the same principal molecular structural features (but 
not necessarily all of the same structural features) and is intended for 
the same use as a previously approved drug, except that, if the 
subsequent drug can be shown to be clinically superior, it will not be 
considered to be the same drug. This criterion will be applied as 
follows to different kinds of macromolecules:
    (A) Two protein drugs would be considered the same if the only 
differences in structure between them were due to post-translational 
events or infidelity of translation or transcription or were minor 
differences in amino acid sequence; other potentially important 
differences, such as different glycosylation patterns or different 
tertiary structures, would not cause the drugs to be considered 
different unless the differences were shown to be clinically superior.
    (B) Two polysaccharide drugs would be considered the same if they 
had identical saccharide repeating units, even if the number of units 
were to vary and even if there were postpolymerization modifications, 
unless the subsequent drug could be shown to be clinically superior.
    (C) Two polynucleotide drugs consisting of two or more distinct 
nucleotides would be considered the same if they had an identical 
sequence of purine and pyrimidine bases (or their derivatives) bound to 
an identical sugar backbone (ribose, deoxyribose, or modifications of 
these sugars), unless the subsequent drug were shown to be clinically 
superior.
    (D) Closely related, complex partly definable drugs with similar 
therapeutic intent, such as two live viral vaccines for the same 
indication, would be considered the same unless the subsequent drug was 
shown to be clinically superior.
    (14) Sponsor means the entity that assumes responsibility for a 
clinical or nonclinical investigation of a drug, including the 
responsibility for compliance with applicable provisions of the act and 
regulations. A sponsor may be an individual, partnership, corporation, 
or Government agency and may be a manufacturer, scientific institution, 
or an investigator regularly and lawfully engaged in the investigation 
of drugs. For purposes of the Orphan Drug Act, FDA considers the real 
party or parties in interest to be a sponsor.

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



Sec. 316.4  Address for submissions.

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



  Subpart B--Written Recommendations for Investigations of Orphan Drugs



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

    (a) A sponsor's request for written recommendations from FDA 
concerning the nonclinical and clinical investigations necessary for 
approval of a marketing application shall be submitted in the form and 
contain the information required in this section. FDA may require the 
sponsor to submit information in addition to that specified in paragraph 
(b) of this section if FDA determines that the sponsor's initial request 
does not contain

[[Page 177]]

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;
    (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]

[[Page 178]]



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.
    (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

[[Page 179]]

and containing the information required in paragraph (b) of this 
section. A sponsor may request orphan-drug designation of a previously 
unapproved drug, or of a new orphan indication for an already marketed 
drug. In addition, a sponsor of a drug that is otherwise the same drug 
as an already approved orphan drug may seek and obtain orphan-drug 
designation for the subsequent drug for the same rare disease or 
condition if it can present a plausible hypothesis that its drug may be 
clinically superior to the first drug. More than one sponsor may receive 
orphan-drug designation of the same drug for the same rare disease or 
condition, but each sponsor seeking orphan-drug designation must file a 
complete request for designation as provided in paragraph (b) of this 
section.
    (b) A sponsor shall submit two copies of a completed, dated, and 
signed request for designation that contains the following:
    (1) A statement that the sponsor requests orphan-drug designation 
for a rare disease or condition, which shall be identified with 
specificity.
    (2) The name and address of the sponsor; the name of the sponsor's 
primary contact person and/or resident agent including title, address, 
and telephone number; the generic and trade name, if any, of the drug or 
drug product; and the name and address of the source of the drug if it 
is not manufactured by the sponsor.
    (3) A description of the rare disease or condition for which the 
drug is being or will be investigated, the proposed indication or 
indications for use of the drug, and the reasons why such therapy is 
needed.
    (4) A description of the drug and a discussion of the scientific 
rationale for the use of the drug for the rare disease or condition, 
including all data from nonclinical laboratory studies, clinical 
investigations, and other relevant data that are available to the 
sponsor, whether positive, negative, or inconclusive. Copies of 
pertinent unpublished and published papers are also required.
    (5) Where the sponsor of a drug that is otherwise the same drug as 
an already-approved orphan drug seeks orphan-drug designation for the 
subsequent drug for the same rare disease or condition, an explanation 
of why the proposed variation may be clinically superior to the first 
drug.
    (6) Where a drug is under development for only a subset of persons 
with a particular disease or condition, a demonstration that the subset 
is medically plausible.
    (7) A summary of the regulatory status and marketing history of the 
drug in the United States and in foreign countries, e.g., IND and 
marketing application status and dispositions, what uses are under 
investigation and in what countries; for what indication is the drug 
approved in foreign countries; what adverse regulatory actions have been 
taken against the drug in any country.
    (8) Documentation, with appended authoritative references, to 
demonstrate that:
    (i) The disease or condition for which the drug is intended affects 
fewer than 200,000 people in the United States or, if the drug is a 
vaccine, diagnostic drug, or preventive drug, the persons to whom the 
drug will be administered in the United States are fewer than 200,000 
per year as specified in Sec. 316.21(b), or
    (ii) For a drug intended for diseases or conditions affecting 
200,000 or more people, or for a vaccine, diagnostic drug, or preventive 
drug to be administered to 200,000 or more persons per year in the 
United States, there is no reasonable expectation that costs of research 
and development of the drug for the indication can be recovered by sales 
of the drug in the United States as specified in Sec. 316.21(c).
    (9) A statement as to whether the sponsor submitting the request is 
the real party in interest of the development and the intended or actual 
production and sales of the product.
    (c) Any of the information previously provided by the sponsor to FDA 
under subpart B of this part may be referenced by specific page or 
location if it duplicates information required elsewhere in this 
section.



Sec. 316.21  Verification of orphan-drug status.

    (a) So that FDA can determine whether a drug qualifies for orphan-
drug designation under section 526(a) of

[[Page 180]]

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

[[Page 181]]

for one or more other indications (in addition to the indication for 
which orphan-drug designation is being sought), a clear explanation of 
and justification for the method that is used to apportion the 
development costs among the various indications.
    (4) A statement of and justification for any development costs that 
the sponsor expects to incur after the submission of the designation 
request. In cases where the extent of these future development costs are 
not clear, the sponsor should request FDA's advice and assistance in 
estimating the scope of nonclinical laboratory studies and clinical 
investigations and other data that are needed to support marketing 
approval. Based on these recommendations, a cost estimate should be 
prepared.
    (5) A statement of and justification for production and marketing 
costs that the sponsor has incurred in the past and expects to incur 
during the first 7 years that the drug is marketed.
    (6) An estimate of and justification for the expected revenues from 
sales of the drug in the United States during its first 7 years of 
marketing. The justification should assume that the total market for the 
drug is equal to the prevalence of the disease or condition that the 
drug will be used to treat. The justification should include:
    (i) An estimate of the expected market share of the drug in each of 
the first 7 years that it is marketed, together with an explanation of 
the basis for that estimate;
    (ii) A projection of and justification for the price at which the 
drug will be sold; and
    (iii) Comparisons with sales of similarly situated drugs, where 
available.
    (7) The name of each country where the drug has already been 
approved for marketing for any indication, the dates of approval, the 
indication for which the drug is approved, and the annual sales and 
number of prescriptions in each country since the first approval date.
    (8) A report of an independent certified public accountant in 
accordance with Statement on Standards for Attestation established by 
the American Institute of Certified Public Accountants on agreed upon 
procedures performed with respect to the data estimates and 
justifications submitted pursuant to this section. Cost data shall be 
determined in accordance with generally accepted accounting principles.
    (d) A sponsor that is requesting orphan-drug designation for a drug 
designed to treat a disease or condition that affects 200,000 or more 
persons shall, at FDA's request, allow FDA or FDA-designated personnel 
to examine at reasonable times and in a reasonable manner all relevant 
financial records and sales data of the sponsor and manufacturer.



Sec. 316.22  Permanent-resident agent for foreign sponsor.

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



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

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

[[Page 182]]



Sec. 316.24  Granting orphan-drug designation.

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



Sec. 316.25  Refusal to grant orphan-drug designation.

    (a) FDA will refuse to grant a request for orphan-drug designation 
if any of the following reasons apply:
    (1) The drug is not intended for a rare disease or condition 
because:
    (i) There is insufficient evidence to support the estimate that the 
drug is intended for treatment of a disease or condition in fewer than 
200,000 people in the United States, or that the drug is intended for 
use in prevention or in diagnosis in fewer than 200,000 people annually 
in the United States; or
    (ii) Where the drug is intended for prevention, diagnosis, or 
treatment of a disease or condition affecting 200,000 or more people in 
the United States, the sponsor has failed to demonstrate that there is 
no reasonable expectation that development and production costs will be 
recovered from sales of the drug for the orphan indication in the United 
States. A sponsor's failure to comply with Sec. 316.21 shall constitute 
a failure to make the demonstration required in this paragraph.
    (2) There is insufficient information about the drug, or the disease 
or condition for which it is intended, to establish a medically 
plausible basis for expecting the drug to be effective in the 
prevention, diagnosis, or treatment of that disease or condition.
    (3) A drug that is otherwise the same drug as one that already has 
orphan-drug exclusive approval for the same rare disease or condition 
and the sponsor has not submitted a medically plausible hypothesis for 
the possible clinical superiority of the subsequent drug.
    (b) FDA may refuse to grant a request for orphan-drug designation if 
the request for designation contains an untrue statement of material 
fact or omits material information.



Sec. 316.26  Amendment to orphan-drug designation.

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



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

    (a) A sponsor may transfer ownership of or any beneficial interest 
in the orphan-drug designation of a drug to a new sponsor. At the time 
of the transfer, the new and former owners are required to submit the 
following information to FDA:
    (1) The former owner or assignor of rights shall submit a letter or 
other document that states that all or some rights to the orphan-drug 
designation of the drug have been transferred to the new owner or 
assignee and that a complete copy of the request for orphan-drug 
designation, including any amendments to the request, supplements to the 
granted request, and correspondence relevant to the orphan-drug 
designation, has been provided to the new owner or assignee.

[[Page 183]]

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



Sec. 316.29  Revocation of orphan-drug designation.

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



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

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

[[Page 184]]

disparity between the probable marketing indication and the designated 
indication as related to the need for an amendment to the orphan-drug 
designation pursuant to Sec. 316.26.



                Subpart D--Orphan-drug Exclusive Approval



Sec. 316.31  Scope of orphan-drug exclusive approval.

    (a) After approval of a sponsor's marketing application for a 
designated orphan-drug product for treatment of the rare disease or 
condition concerning which orphan-drug designation was granted, FDA will 
not approve another sponsor's marketing application for the same drug 
before the expiration of 7 years from the date of such approval as 
stated in the approval letter from FDA, except that such a marketing 
application can be approved sooner if, and such time as, any of the 
following occurs:
    (1) Withdrawal of exclusive approval or revocation of orphan-drug 
designation by FDA under any provision of this part; or
    (2) Withdrawal for any reason of the marketing application for the 
drug in question; or
    (3) Consent by the holder of exclusive approval to permit another 
marketing application to gain approval; or
    (4) Failure of the holder of exclusive approval to assure a 
sufficient quantity of the drug under section 527 of the act and 
Sec. 316.36.
    (b) If a sponsor's marketing application for a drug product is 
determined not to be approvable because approval is barred under section 
527 of the act until the expiration of the period of exclusive marketing 
of another drug product, FDA will so notify the sponsor in writing.



Sec. 316.34  FDA recognition of exclusive approval.

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



Sec. 316.36  Insufficient quantities of orphan drugs.

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

[[Page 185]]

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 Sec. 312.34 of this 
chapter.



                 Subpart F--Availability of Information



Sec. 316.50  Guidance documents.

    FDA's Office of Orphan Products Development will maintain and make 
publicly available a list of guidance documents that apply to the 
regulations in this part. The list is maintained on the Internet and is 
published annually in the Federal Register. A request for a copy of the 
list should be directed to the Office of Orphan Products Development 
(HF-35), Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 
20857.

[65 FR 56480, Sept. 19, 2000]



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

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



PART 320--BIOAVAILABILITY AND BIOEQUIVALENCE REQUIREMENTS--Table of Contents




                      Subpart A--General Provisions

Sec.
320.1 Definitions.

      Subpart B--Procedures for Determining the Bioavailability or 
                     Bioequivalence of Drug Products

320.21 Requirements for submission of in vivo bioavailability and 
          bioequivalence data.
320.22 Criteria for waiver of evidence of in vivo bioavailability or 
          bioequivalence.
320.23 Basis for demonstrating in vivo bioavailability or 
          bioequivalence.
320.24 Types of evidence to establish bioavailability or 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 
          study.
320.27 Guidelines on the design of a multiple-dose in vivo 
          bioavailability study.
320.28 Correlation of bioavailability with an acute pharmacological 
          effect or clinical evidence.
320.29 Analytical methods for an in vivo bioavailability study.
320.30 Inquiries regarding bioavailability and bioequivalence 
          requirements and review of protocols by the Food and Drug 
          Administration.

[[Page 186]]

320.31 Applicability of requirements regarding an ``Investigational New 
          Drug Application.''
320.32 Procedures for establishing or amending a bioequivalence 
          requirement.
320.33 Criteria and evidence to assess actual or potential 
          bioequivalence problems.
320.34 Requirements for batch testing and certification by the Food and 
          Drug Administration.
320.35 Requirements for in vitro testing of each batch.
320.36 Requirements for maintenance of records of bioequivalence 
          testing.
320.38 Retention of bioavailability samples.
320.63 Retention of bioequivalence samples.

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



                      Subpart A--General Provisions



Sec. 320.1  Definitions.

    (a) Bioavailability means the rate and extent to which the active 
ingredient or active moiety is absorbed from a drug product and becomes 
available at the site of action. For drug products that are not intended 
to be absorbed into the bloodstream, bioavailability may be assessed by 
measurements intended to reflect the rate and extent to which the active 
ingredient or active moiety becomes available at the site of action.
    (b) Drug product means a finished dosage form, e.g., tablet, 
capsule, or solution, that contains the active drug ingredient, 
generally, but not necessarily, in association with inactive 
ingredients.
    (c) Pharmaceutical equivalents means drug products that contain 
identical amounts of the identical active drug ingredient, i.e., the 
same sat or ester of the same therapeutic moiety, in identical dosage 
forms, but not necessarily containing the same inactive ingredients, and 
that meet the identical compendial or other applicable standard of 
identity, strength, quality, and purity, including potency and, where 
applicable, content uniformity, disintegration times and/or dissolution 
rates.
    (d) Pharmaceutical alternatives means drug products that contain the 
identical therapeutic moiety, or its precursor, but not necessarily in 
the same amount or dosage form or as the same salt or ester. Each such 
drug product individually meets either the identical or its own 
respective compendial or other applicable standard of identity, 
strength, quality, and purity, including potency and, where applicable, 
content uniformity, disintegration times and/or dissolution rates.
    (e) Bioequivalence means the absence of a significant difference in 
the rate and extent to which the active ingredient or active moiety in 
pharmaceutical equivalents or pharmaceutical alternatives becomes 
available at the site of drug action when administered at the same molar 
dose under similar conditions in an appropriately designed study. Where 
there is an intentional difference in rate (e.g., in certain controlled 
release dosage forms), certain pharmaceutical equivalents or 
alternatives may be considered bioequivalent if there is no significant 
difference in the extent to which the active ingredient or moiety from 
each product becomes available at the site of drug action. This applies 
only if the difference in the rate at which the active ingredient or 
moiety becomes available at the site of drug action is intentional and 
is reflected in the proposed labeling, is not essential to the 
attainment of effective body drug concentrations on chronic use, and is 
considered medically insignificant for the drug.
    (f) Bioequivalence requirement means a requirement imposed by the 
Food and Drug Administration for in vitro and/or in vivo testing of 
specified drug products which must be satisfied as a condition of 
marketing.

[42 FR 1634, Jan. 7, 1977, as amended at 42 FR 1648, Jan. 7, 1977; 57 FR 
17997, Apr. 28, 1992]



      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 in vivo 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 demonstrating the in vivo bioavailability of the drug 
product

[[Page 187]]

that is the subject of the application; or
    (2) Information to permit FDA to waive the submission of evidence 
demonstrating 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)); 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 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 process, including a change in 
product formulation or dosage strength, beyond the variations provided 
for in the approved application.
    (2) A change in the labeling to provide for a new indication for use 
of the drug product, if clinical studies are required to support the new 
indication for use.
    (3) A change in the labeling to provide for a new dosage regimen or 
for an additional dosage regimen for a special patient population, e.g., 
infants, if clinical studies are required to support the new or 
additional dosage regimen.
    (d) FDA may approve a full new drug application, or a supplemental 
application proposing any of the changes set forth in paragraph (c) of 
this section, that does not contain evidence of in vivo bioavailability 
or information to permit waiver of the requirement for in vivo 
bioavailability data, if all of the following conditions are met.
    (1) The application was under review by FDA on July 7, 1977.
    (2) The application is otherwise approvable.
    (3) The application agrees to submit, within the time specified by 
FDA, either:
    (i) Evidence demonstrating the in vivo bioavailability of the drug 
product that is the subject of the application; or
    (ii) Information to permit FDA to waive demonstration of in vivo 
bioavailability.
    (e) Evidence demonstrating the in vivo bioavailability and 
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 
demonstrating the in vivo bioavailability or bioequivalence shall meet 
the criteria set forth in Sec. 320.24.
    (g) Any person holding an approved full or abbreviated new drug 
application shall submit to FDA a supplemental application containing 
new evidence demonstrating the in vivo bioavailability or 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 demonstrating 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 demonstrating in vivo bioavailability and 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]



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 demonstrating the in vivo bioavailability 
or bioequivalence of the

[[Page 188]]

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 (g) 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 
demonstrating the bioavailability or 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.
    (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.
    (3) The drug product:
    (i) Is a solution for application to the skin, an oral solution, 
elixir, syrup, tincture, or similar other solubilized form.
    (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; 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 that may significantly affect absorption of the active drug 
ingredient or active moiety.
    (c) FDA shall waive the requirement for the submission of evidence 
demonstrating the in vivo bioavailability of a solid oral dosage form 
(other than an enteric coated or controlled 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. 320.32, 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 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 demonstrating the bioavailability 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 
demonstrated;
    (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) This subparagraph does not apply to enteric coated or 
controlled release dosage forms.
    (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

[[Page 189]]

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 demonstrated; 
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 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]



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

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

[57 FR 17999, Apr. 28, 1992]



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

    (a) Bioavailability or bioequivalence may be determined by several 
in vivo and in vitro methods. FDA may require in vivo or in vitro 
testing, or both, to establish the bioavailability of a drug product or 
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

[[Page 190]]

section. The method used must be capable of demonstrating 
bioavailability or bioequivalence, as appropriate, for the product being 
tested.
    (b) The following in vivo and in vitro approaches, in descending 
order of accuracy, sensitivity, and reproducibility, are acceptable for 
determining the bioavailability or bioequivalence of a drug product.
    (1)(i) An in vivo test in humans in which the concentration of the 
active ingredient or active moiety, and, when appropriate, its active 
metabolite(s), in whole blood, plasma, serum, or other appropriate 
biological fluid is measured as a function of time. This approach is 
particularly applicable to dosage forms intended to deliver the active 
moiety to the bloodstream for systemic distribution within the body; or
    (ii) An in vitro test that has been correlated with and is 
predictive of human in vivo bioavailability data; or
    (iii) An in vivo test in animals that has been correlated with and 
is predictive of human bioavailability data.
    (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 in humans that establish the 
safety and effectiveness of the drug product, for purposes of 
establishing 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 determining bioavailability or 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 determining the 
bioavailability or 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 (unusually 
a dissolution rate test) that ensures human in vivo bioavailability.
    (6) Any other approach deemed adequate by FDA to establish 
bioavailability or bioequivalence.
    (c) FDA may, notwithstanding prior requirements for establishing 
bioavailability or 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;

[[Page 191]]

    (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]



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 shall not be conducted in 
humans if an appropriate animal model exists and correlation of results 
in animals and humans has been demonstrated. If an appropriate animal 
model does not exist, however, an in vivo bioavailability study shall 
ordinarily be done in normal adults under standardized conditions.
    (3) 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) The purpose of an in vivo bioavailability study involving 
a drug product containing an active drug ingredient or therapeutic 
moiety that has not been approved for marketing is to determine:
    (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) The purpose of an in vivo 
bioavailability study involving a drug product that is a new 
formulation, a new dosage form, or a new salt or ester of an active drug 
ingredient or therapeutic moiety that has been approved for marketing is 
to:
    (i) Determine 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

[[Page 192]]

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) Controlled release formulations. (1) The purpose of an in vivo 
bioavailability study involving a drug product for which a controlled 
release claim is made is to determine if all of the following conditions 
are met:
    (i) The drug product meets the controlled release claims made for 
it.
    (ii) The bioavailability profile established for the drug product 
rules out the occurrence of any dose dumping.
    (iii) The drug product's steady-state performance is equivalent to a 
currently marketed noncontrolled release or controlled 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 
controlled 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 controlled 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 controlled 
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:

[[Page 193]]

    (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.



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

    (a) Basic principles. (1) An in vivo bioavailability 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

[[Page 194]]

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.



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

    (a) Basic principles. (1) In selected circumstances it may be 
necessary for the test product and the reference material to be compared 
after repeated administration to determine steady-state levels of the 
active drug ingredient or therapeutic moiety in the body.
    (2) The test product and the reference material should be 
administered to subjects in the fasting or nonfasting state, depending 
upon the conditions reflected in the proposed labeling of the test 
product.
    (3) A multiple-dose study may be required to determine the 
bioavailability of a drug product in the following circumstances:
    (i) There is a difference in the rate of absorption but not in the 
extent of absorption.
    (ii) There is excessive variability in bioavailability from subject 
to subject.
    (iii) The concentration of the active drug ingredient or therapeutic 
moiety, or its metabolite(s), in the blood resulting from a single dose 
is too low for accurate determination by the analytical method.
    (iv) The drug product is a controlled 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 a controlled 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 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, sufficient samples of blood 
should be taken to define adequately the maximum (Cmax) and minimum 
(Cmin) blood concentrations on 2 or more consecutive days to establish 
that steady-state conditions are achieved.
    (2) Whenever comparison of the test product and the reference 
material is to be based on cumulative urinary excretion-time curves at 
steady-state, sufficient samples of urine should be taken to define the 
rate and extent of urinary excretion on 2 or more consecutive days to 
establish that steady-state conditions are achieved.
    (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

[[Page 195]]

during a dosing interval in a multiple-dose steady-state study is 
directly proportional to the fraction of the dose absorbed and is equal 
to the corresponding ``zero to infinity'' area under the curve for a 
single-dose study. Therefore, when steady-state conditions are achieved, 
a comparison of blood concentrations during a dosing interval may be 
used to define the fraction of the active drug ingredient or therapeutic 
moiety absorbed.
    (3) Other methods based on valid scientific reasons should be used 
to determine the bioavailability of a drug product having dose-dependent 
kinetics (non-linear system).
    (f) Measurement of an acute pharmacological effect. When comparison 
of the test product and the reference material is to be based on acute 
pharmacological effect-time curves, measurements of this effect should 
be made with sufficient frequency to demonstrate a maximum effect and a 
lack of significant difference between the test product and the 
reference material.



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 a controlled release preparation.



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

    (a) The analytical method used in an in vivo bioavailability study 
to measure the concentration of the active drug ingredient or 
therapeutic moiety, or its 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 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 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.



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, Division of 
Biopharmaceutics (HFD-420), 5600 Fishers Lane, Rockville, MD 20857.
    (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), 5600 Fishers Lane, Rockville, MD 20857.

[57 FR 18000, Apr. 28, 1992]



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:

[[Page 196]]

    (1) The test product contains a new chemical entity as defined in 
Sec. 314.108(a) of this chapter; or
    (2) The study involves a radioactively labeled drug product; or
    (3) The study involves a cytotoxic drug product.
    (b) Any person planning to conduct a bioavailability 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 a controlled 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, shall 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; and
    (2) An in vivo bioavailability or bioequivalence study in humans 
shall 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.

[57 FR 18000, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993]



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

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

[57 FR 18000, Apr. 28, 1992]

[[Page 197]]



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 for absorption of the 
active drug ingredient or therapeutic moiety or, alternatively, if 
present, may interfere with such absorption.
    (f) Pharmacokinetic evidence that:
    (1) The active drug ingredient, therapeutic moiety, or its precursor 
is absorbed in large part in a particular segment of the 
gastrointestinal tract or is absorbed from a localized site.
    (2) The degree of absorption of the active drug ingredient, 
therapeutic moiety, or its precursor is poor, e.g., less than 50 
percent, ordinarily in comparison to an intravenous dose, even when it 
is administered in pure form, e.g., in solution.
    (3) There is rapid metabolism of the therapeutic moiety in the 
intestinal wall or liver during the process of absorption (first-class 
metabolism) so the therapeutic effect and/or toxicity of such drug 
product is determined by the rate as well as the degree of absorption.
    (4) The therapeutic moiety is rapidly metabolized or excreted so 
that rapid dissolution and absorption are required for effectiveness.
    (5) The active drug ingredient or therapeutic moiety is unstable in 
specific portions of the gastrointestinal tract and requires special 
coatings or formulations, e.g., buffers, enteric coatings, and film 
coatings, to assure adequate absorption.
    (6) The drug product is subject to dose dependent kinetics in or 
near the

[[Page 198]]

therapeutic range, and the rate and extent of absorption are important 
to bioequivalence.

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



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

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

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



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

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

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



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

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

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



Sec. 320.38  Retention of bioavailability samples.

    (a) The applicant of an application or supplemental application 
submitted under section 505 of the Federal Food, Drug, and Cosmetic Act, 
or, if bioavailability testing was performed under contract, the 
contract research organization shall retain an appropriately identified 
reserve sample of the drug product for which the applicant is seeking 
approval (test article) and of the reference standard used to perform an 
in vivo bioavailability study in accordance with and for the studies 
described in paragraph (b) of this section that is representative of 
each sample of the test article and reference standard provided by the 
applicant for the testing.
    (b) Reserve samples shall be retained for the following test 
articles and reference standards and for the studies described:
    (1) If the formulation of the test article is the same as the 
formulation(s)

[[Page 199]]

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 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]

[[Page 200]]



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.



                      Subpart A--General Provisions



Sec. 328.1  Scope.

    Reference in this part to regulatory sections of the Code of Federal 
Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 328.3  Definitions.

    As used in this part:
    (a) Alcohol means the substance known as ethanol, ethyl alcohol, or 
Alcohol, USP.
    (b) Inactive ingredient means any component of a product other than 
an active ingredient as defined in Sec. 210.3(b)(7) of this chapter.



                         Subpart B--Ingredients



Sec. 328.10  Alcohol.

    (a) Any over-the-counter (OTC) drug product intended for oral 
ingestion shall not contain alcohol as an inactive ingredient in 
concentrations that exceed those established in this part, unless a 
specific exemption, as provided in paragraph (e) or (f) of this section, 
has been approved.
    (b) For any OTC drug product intended for oral ingestion and labeled 
for use by adults and children 12 years of age and over, the amount of 
alcohol in the product shall not exceed 10 percent.
    (c) For any OTC drug product intended for oral ingestion and labeled 
for use by children 6 to under 12 years of age, the amount of alcohol in 
the product shall not exceed 5 percent.
    (d) For any OTC drug product intended for oral ingestion and labeled 
for use by children under 6 years of age, the amount of alcohol in the 
product shall not exceed 0.5 percent.
    (e) The Food and Drug Administration will grant an exemption from 
paragraphs (b), (c), and (d) of this section where appropriate, upon 
petition under the provisions of Sec. 10.30 of this chapter. Appropriate 
cause, such as a specific solubility or manufacturing problem, must be 
adequately documented in the petition. Decisions with respect to 
requests for exemption shall be maintained in a permanent file for 
public review by the Dockets Management Branch (HFA-305), Food and Drug 
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
    (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

[[Page 201]]

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]



                           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.



PART 329--HABIT-FORMING DRUGS--Table of Contents




           Subpart A--Derivatives Designated as Habit Forming

Sec.
329.1 Habit-forming drugs which are chemical derivatives of substances 
          specified in section 502(d) of the Federal Food, Drug, and 
          Cosmetic Act.

                           Subpart B--Labeling

329.10 Labeling requirements for habit-forming drugs.

                          Subpart C--Exemptions

329.20 Exemption of certain habit-forming drugs from prescription 
          requirements.

    Authority: 21 U.S.C. 352, 353, 355, 371.

    Source: 39 FR 11736, Mar. 29, 1974, unless otherwise noted.

    Effective Date Note: At 67 FR 4907, Feb. 1, 2002, part 329 was 
removed, effective Apr. 2, 2002.



           Subpart A--Derivatives Designated as Habit Forming



Sec. 329.1  Habit-forming drugs which are chemical derivatives of substances specified in section 502(d) of the Federal Food, Drug, and Cosmetic Act.

    Each of the following chemical derivatives of a substance named in 
section 502(d) of the Federal Food, Drug, and Cosmetic Act is hereby 
designated as habit forming:

[[Page 202]]



------------------------------------------------------------------------
                                 Common or official  Some trade or other
    Chemical description of       name of chemical    names of chemical
          derivative             derivative or its    derivative or its
                                       salts              salts \1\
------------------------------------------------------------------------
                    PARENT SUBSTANCE--BARBITURIC ACID
 
------------------------------------------------------------------------
5-Allyl-5-sec-butylbarbituric   Talbutal...........  Lotusate.
 acid \2\.
5-Allyl-5-                      ...................  Cyclopal.
 cyclopentenylbarbituric acid.                       Cyclopen.
5-Allyl-5-isobutylbarbituric    Allylbarbituric      Sandoptal.
 acid.                           acid.
                                Allylisobutylbarbit
                                 uric acid..
5-Allyl-5-isopropylbarbituric   Aprobarbital.......  Alurate.
 acid.
                                Allylisopropylbarbi  Numal.
                                 turic acid.
                                Allylisopropylmalon
                                 ylurea..
5-Allyl-5-isopropyl-1-          ...................  Narconumal.
 methylbarbituric acid.
5-Allyl-5-(1-                   Secobarbital sodium  Seconal Sodium.
 methylbutyl)barbituric acid.
                                Soluble              Evronal Sodium.
                                 secobarbital.
5-Allyl-5-(1-methylbutyl)-2-    Sodium thiamylal...  Surital Sodium.
 thiobarbituric acid.
5-Allyl-1-methyl-5-(1-methyl-2- Sodium methohexital  Brevital Sodium.
 pentynyl) barbituric acid.
5-(2-Bromoallyl)-5-isoprophyl-  ...................  Eunarcon.
 1-methylbarbituric acid.
5-(2-Bromoallyl)-5-(1-          -           Sigmodal.
 methylbutyl)-barbituric acid.   Bromoallyl sec-     Rectidon.
                                 amylbarbituric      R239.
                                 acid.
5-sec-Butyl-5-(2-bromoallyl)-   Butallylonal.......  Pernoston.
 barbituric acid.                                    Pernocton.
5-(1-Cyclohepten-1-yl)-5-       Heptabarbital......  Medomin.
 ethylbarbituric acid.
5,5-Diallylbarbituric acid....  Diallyl barbituric   Dial.
                                 acid.               Allobarbital.
                                                     Allobarbitone.
                                                     Curral.
                                                     Diadol.
5,5-Diethylbarbituric acid....  Barbital...........  Deba.
                                Barbitone..........  Dormonal.
                                Diethylbarbituric    Hypnogene.
                                 acid.
                                Diethylmalonylurea.  Malonal.
                                                     Medinal.
                                                     Sedeval.
                                                     Veronal.
                                                     Uronal.
                                                     Vesperal.
5,5-Diethyl-1-methylbarbituric  Metharbital........  Gemonil.
 acid.
1,5-Dimethyl-5-(1-              Hexobarbital sodium  Cyclonal Sodium.
 cyclohexenyl)-barbituric acid.                      Dorico Soluble.
                                                     Evipal Sodium.
                                                     Evipan Sodium.
                                                     Hexanastab.
                                                     Hexobarbitone
                                                      Sodium.
                                                     Methenexyl Sodium.
5,5-Dipropylbarbituric acid...  Dipropylbarbituric   Proponal.
                                 acid.
5-Ethyl-5-butylbarbituric acid  Butethal...........  Etoval.
                                Butobarbital.......  Neonal
                                                      Butobarbital.
                                                     Soneryl.
5-Ethyl-5-sec-butylbarbituric   Butabarbital sodium  Butisol Sodium.
 acid.
5-Ethyl-5-(1-cyclohexenyl)-     Cyclobarbital......  Cyclobarbitone.
 barbituric acid.                                    Namuron.
                                                     Palinum.
                                                     Phanodorm.
                                                     Phanodorn.
                                                     Tetrahydro
                                                      phenobarbital.
5-Ethyl-5-cyclopentenyl-        ...................  Pentenal.
 barbituric acid.
5-Ethyl-5-hexylbarbituric acid  Hexethal sodium....  Hebaral.
                                                     Ortal Sodium.
5-Ethyl-5-isoamylbarbituric     Amobarbital........  Amytal.
 acid.
5-Ethyl-5-isopropylbarbituric   Probarbital........  Ipral.
 acid.
5-Ethyl-5-(1-methylbutyl)-      Pentobarbital        844.
 barbituric acid.                sodium.
                                Soluble              Embutal.
                                 pentobarbital.      Nembutal.
                                                     Napethal.
                                                     Pentyl.
5-Ethyl-5-(1-methylbutyl)-2-    Thiopental sodium..  Intraval Sodium.
 thiobarbituric acid.
                                Thiopentone sodium.  Nesdonal Sodium.
                                                     Pentothal Sodium.
                                                     Thiothal Sodium.
5-Ethyl-5-(1-methyl-1-butenyl)- Vinbarbital........  Delvinal Sodium.
 barbituric acid.
5-Ethyl-5-phenylbarbituric      Phenobarbital......  Barbenyl.
 acid.

[[Page 203]]

 
                                Phenobarbitone.....  Barbiphenyl.
                                Phenylethylmalonylu  Dormiral.
                                 rea.                Euneryl.
                                                     Gardenal.
                                                     Luminal.
                                                     Nunol.
                                                     Neurobarb.
                                                     Phenonyl.
                                                     Somonal.
5-Ethyl-5-phenyl-1-             Mephobarbital......  Mebaral.
 methylbarbituric acid.                              Phemitone.
                                                     Prominal.
5-Ethyl-5-(1 piperidyl)-        ...................  Eldoral.
 barbituric acid.
5-Isopropyl-5-(2-bromoallyl)-   Propallylonal......  Noctal.
 barbituric acid.                                    Nostal.
5-(1-Methylbutyl)-5-[2-         Methitural (sodium   Methioturiate.
 (methylthio)ethyl]-2-           salt).              Neraval.
 thiobarbituric acid.                                Thiogenal.
5-Methyl-5-phenylbarbituric     Phenylmethylbarbitu  Rutonal.
 acid.                           ric acid.
All lithium, sodium,
 potassium, magnesium,
 calcium, strontium, and
 ammonium salts of the
 foregoing chemical
 derivatives of barbituric
 acid.
 
------------------------------------------------------------------------
                 PARENT SUBSTANCE--CANNABIS (MARIHUANA)
 
------------------------------------------------------------------------
                                Extract of cannabis
                                Fluid extract of
                                 cannabis.
                                Tincture of
                                 cannabis.
 
------------------------------------------------------------------------
                        PARENT SUBSTANCE--BROMAL
 
------------------------------------------------------------------------
Tribromoacetaldehyde hydrate..  Bromal hydrate.....
Tribromomethane...............  Bromoform..........
2-(Tribromomethyl)-2-propanol.  Tribromo-tert-butyl  Acetone-Bromoform.
                                 alcohol.            Brometone.
 
------------------------------------------------------------------------
                       PARENT SUBSTANCE--CARBROMAL
 
------------------------------------------------------------------------
a-Bromo-a-ethylbutyryl-         Acetylcarbromal....  A basin.
 acetylurea.                                         Acetyl Adalin.
                                                     N-Acetyl-N-
                                                      bromodiethylacetyl
                                                      urea.
                                                     N-Acetyl-N'-a-bromo-
                                                      a-ethylbutyryl
                                                      carbamide.
a-Bromoisovalerylurea.........  Bromisovalum.......  Bromisoval.
                                                     a-Bromo--
                                                      dimethyl-
                                                      propanoylurea.
                                                     Bromural.
                                                     Bromvaletone.
                                                     Brovalurea.
                                                     B. V. U.
                                                     Dormigene.
                                                     Isobromyl.
                                                     2-
                                                      Monobromoisovalery
                                                      lurea.
                                                     Pivadorm.
                                                     Uvaleral.
a-Bromo-a,a-diethylacetamide..  Diethylbromo         Neuronal.
                                 acetamide.
a-Allylisovaleryl-urea........  ...................  Allyl-isopropyl-
                                                      acetyl-carbamide.
                                                     (2-Isopropyl-4-
                                                      pentenoyl)-urea.
                                                     Sedormid.
 
------------------------------------------------------------------------
                        PARENT SUBSTANCE--CHLORAL
 
------------------------------------------------------------------------
Trichloroacetaldehyde hydrate.  Chloral............  2,2,2-Trichloro-1,1-
                                                      ethanediol.
                                Chloral hydrate....  Trichloroethylidene
                                                      glycol.
Trichloroethylideneimine......  Chloralimide.......
N-(-Trichloro-a-       Chloralformamide...  Chloralamide.
 hydroxyethyl)-formamide.                            Chloramide.
a-(-trichloro-a-       a-Chloralose.......  A-D-
 hydroxyethyl)-D-glucoside.                           Glucochloralose.
                                                     Anhydro-
                                                      Glucochloral.
                                                     Glucochloral.
                                                     Chloralosone.

[[Page 204]]

 
2-(Trichloromethyl)-2-propanol  Chlorbutanol.......  Acetone chloroform.
                                Chlorbutol.........  Chloretone.
                                Chlorobutanol......  Methaform.
                                                     Sedaform.
                                                     1,1,1-trichloro-2-
                                                      methyl 2-propanol.
                                                     ,
                                                      ,-
                                                      trichloro-tert-
                                                      butylalcohol.
 
------------------------------------------------------------------------
                        PARENT SUBSTANCE--COCAINE
 
------------------------------------------------------------------------
All salts of cocaine obtained   Cocaine
 by combining cocaine with any   hydrochloride.
 acid.                          Cocainium chloride.
 
------------------------------------------------------------------------
                        PARENT SUBSTANCE--CODEINE
 
------------------------------------------------------------------------
Codeine methylbromide.........  Eucodin............
Dihydrocodeinone..............  ...................  Dicodid.
Dihydrohydroxycodeinone.......  Eucodal............  Oxycodone
                                                      hydrochloride.
                                                     14-
                                                      hydroxydihydrocode
                                                      inone.
All salts of the foregoing
 chemical derivatives of
 codeine obtained by combining
 any such derivative of
 codeine with any acid.
 
------------------------------------------------------------------------
                        PARENT SUBSTANCE--HEROIN
 
------------------------------------------------------------------------
All salts of heroin obtained
 by combining heroin with any
 acid.
 
------------------------------------------------------------------------
                       PARENT SUBSTANCE--MORPHINE
 
------------------------------------------------------------------------
Dihydromorphine...............  Paramorphan........
Dihydromorphinone.............  Dihydromorphinone    Dilaudid.
                                 hydrochloride.      Dimorphone.
                                Dihydromorphinonium  Hydromorphone
                                 chloride.            hydrochloride.
Ethylmorphine.................  Ethylmorphine        Dionin.
                                 hydrochloride.
                                Ethylmorphinium
                                 chloride..
All salts of the foregoing
 chemical derivatives of
 morphine and all salts of
 morphine obtained by
 combining any such derivative
 or morphine with any acid.
 
------------------------------------------------------------------------
                         PARENT SUBSTANCE--OPIUM
 
------------------------------------------------------------------------
                                Extract of opium...
                                Fluidextract of
                                 opium.
                                Camphorated opium
                                 tincture.
                                Deodorized opium
                                 tincture.
                                Laudanum...........
                                Opium tincture.....
                                Paregoric..........
                                Tincture of opium..
 
------------------------------------------------------------------------
                      PARENT SUBSTANCE--PARALDEHYDE
 
------------------------------------------------------------------------
Metaldehyde...................
 
------------------------------------------------------------------------
                     PARENT SUBSTANCE--SULFONMETHANE
 
------------------------------------------------------------------------
2,2-Diethylsulfonylbutane.....  Sulfonethylmethane.  Diethylsulfonmethyl
                                                      ethyl-methane.
                                                     Ethylsulfonal.
                                                     2,2-bis-
                                                      (Ethylsulfonyl)-
                                                      butane.
                                                     Methylsufonal.
                                                     Sulfonethlylmethanu
                                                      m.
                                                     Trional.
3,3-Diethylsulfonylpentane....  Sulfondiethylmethan
                                 e.
------------------------------------------------------------------------
\1\ This list of trade or other names is not a complete list of the many
  proprietary names under which the designated habit-forming chemical
  derivatives are distributed.
\2\ The name ``butalbital'' is obsolete for this compound;
  ``butalbital'' is the nonproprietary name assigned by the United
  States Adopted Name Council and the World Health Organization for 5-
  allyl-5-isobutylbarbituric acid.


[[Page 205]]



                           Subpart B--Labeling



Sec. 329.10  Labeling requirements for habit-forming drugs.

    (a)(1) The name of a substance or derivative required to be borne on 
the label of a drug by section 502(d) of the act shall be the common or 
usual name of such substance or derivative, unless it is designated 
solely by a name recognized in an official compendium and such 
designation complies with the provisions of section 502(c).
    (2) A statement on the label of a drug of the name of a constituent, 
which constituent is a chemical derivative of a substance named in 
section 502(d) of the act, shall show the substance from which such 
constituent is derived and that such constituent is a derivative 
thereof.
    (b) If the drug is in tablet, capsule, ampul, or other unit form, 
the statement of the quantity or proportion of such substance or 
derivative contained therein shall express the weight or measure of such 
substance or derivative in each such unit. If the drug is not in such 
unit form the statement shall express the weight or measure of such 
substance or derivative in a specified unit of weight or measure of the 
drug. Such statement shall be in terms which are informative to the 
ordinary consumer and user of the drug.
    (c) The names and quantities or proportions of all such substances 
and derivatives, and the statement ``Warning--May be habit forming'', 
shall immediately follow (without intervening written, printed, or 
graphic matter) the name by which such drug is titled in the part or 
panel of the label thereof which is presented or displayed under 
customary conditions of purchase.
    (d) A drug shall not be considered to be misbranded by reason of 
failure of its label to bear the statement ``Warning--May be habit 
forming'':
    (1) If such drug is not suitable for internal use, and is 
distributed and sold exclusively for such external use as involves no 
possibility of habit formation; or
    (2) If the only substance or derivative subject to section 502(d) of 
the act contained in such drug is chlorobutanol, which is present solely 
as a preservative and in a quantity not more than 0.5 percent by weight, 
and such drug is for parenteral use only; or
    (3) If the only substance or derivative subject to section 502(d) of 
the act contained in such drug is chlorobutanol which is present as an 
analgesic or as an analgesic and a preservative in a quantity not more 
than 3.0 percent, and such drug contains one or more other active 
ingredients and is for parenteral use only.

    Cross Reference: For the Spanish-language version of the required 
labeling statement, see Sec. 201.16(b) of this chapter.

[39 FR 11736, Mar. 29, 1974, as amended at 40 FR 13496, Mar. 27, 1975]



                          Subpart C--Exemptions



Sec. 329.20  Exemption of certain habit-forming drugs from prescription requirements.

    The prescription-dispensing requirements of section 503(b)(1)(A) of 
the act are not necessary for the protection of the public health with 
respect to the following drugs subject to section 502(d):
    (a) The following exempt narcotic preparations:
    (1) Pharmaceutical preparations containing not more than 100 
milligrams of opium per 100 milliliters or per 100 grams.
    (2) Pharmaceutical preparations containing not more than 16.2 
milligrams (\1/4\ grain) morphine, or any of its salts, per 29.5729 
cubic centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois 
ounce);
    (3) Pharmaceutical preparations containing not more than 64.8 
milligrams (1 grain) codeine, or any of its salts, per 29.5729 cubic 
centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois ounce);
    (4) Pharmaceutical preparations containing not more than 32.4 
milligrams (\1/2\ grain) dihydrocodeine, or any of its salts, per 
29.5729 cubic centimeters (1 fluid ounce) or per 28.3 grams (1 
avoirdupois ounce);
    (5) Pharmaceutical preparations containing not more than 16.2 
milligrams (\1/4\ grain) ethylmorphine, or any of its salts, per 29.5729 
cubic centimeters (1 fluid ounce) or per 28.3 grams (1 avoirdupois 
ounce);

[[Page 206]]


Provided, That the preparations described in this paragraph contain one 
or more nonnarcotic active medicinal ingredients in sufficient 
proportion to confer upon the preparation valuable medicinal qualities 
other than those possessed by the narcotic drug alone.
    (b) Drugs containing chlorobutanol, intended for external use only.
    (c) Epinephrine solution, 1 percent, preserved with chlorobutanol 
and intended for use solely as a spray.
    (d) Combination drugs listed in part 329 as exempted from section 
511 of the act.

[39 FR 11736, Mar. 29, 1974, as amended at 55 FR 11581, Mar. 29, 1990]



PART 330--OVER-THE-COUNTER (OTC) HUMAN DRUGS WHICH ARE GENERALLY RECOGNIZED AS SAFE AND EFFECTIVE AND NOT MISBRANDED--Table of Contents




                      Subpart A--General Provisions

Sec.
330.1 General conditions for general recognition as safe, effective and 
          not misbranded.
330.2 Pregnancy-nursing warning.
330.3 Imprinting of solid oral dosage form drug products.
330.5 Drug categories.

                  Subpart B--Administrative Procedures

330.10 Procedures for classifying OTC drugs as generally recognized as 
          safe and effective and not misbranded, and for establishing 
          monographs.
330.11 NDA deviations from applicable monograph.
330.12 Status of over-the-counter (OTC) drugs previously reviewed under 
          the Drug Efficacy Study (DESI).
330.13 Conditions for marketing ingredients recommended for over-the-
          counter (OTC) use under the OTC drug review.
330.14 Additional criteria and procedures for classifying OTC drugs as 
          generally recognized as safe and effective and not misbranded.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 39 FR 11741, Mar. 29, 1974, unless otherwise noted.



                      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 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

[[Page 207]]

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 Dockets Management Branch, Food 
and Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 
20857.
    (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''.
    (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''.

[[Page 208]]

    (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''.
    (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''.

[[Page 209]]

    (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]



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 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

[[Page 210]]

until the Commissioner places the panel's recommendations on public 
display at the office of the Dockets Management Branch. Thirty days 
thereafter such data and information shall be made publicly available 
and may be viewed at the office of the Dockets Management Branch 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 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

[[Page 211]]

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 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.

[[Page 212]]

    (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 Dockets Management Branch 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 Dockets Management Branch between 
the hours of 9

[[Page 213]]

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 
Dockets Management Branch; 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 Dockets Management Branch, 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 Dockets Management Branch, 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 Dockets Management Branch, 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 Dockets Management Branch, Food and Drug Administration.
    (v) New data and information submitted after the time specified in 
this paragraph but prior to the establishment of a final monograph will 
be considered as a petition to amend the monograph and will be 
considered by the Commissioner only after a final monograph has been 
published in the Federal Register unless the Commisisoner finds that 
good cause has been shown that warrants earlier consideration.
    (8) Oral hearing before the Commissioner. After reviewing objections 
filed in response to the tentative final monograph, the Commissioner, if 
he finds reasonable grounds in support thereof, shall by notice in the 
Federal Register schedule an oral hearing. The notice scheduling an oral 
hearing shall specify the length of the hearing and how the time shall 
be divided among the parties requesting the hearing. The hearing shall 
be conducted by the Commissioner and may not be delegated.
    (9) Final monograph. After reviewing the objections, the entire 
administrative record including all new data and information and 
comments, and considering the arguments made at any oral hearing, the 
Commissioner shall publish in the Federal Register a final

[[Page 214]]

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 Dockets 
Management Branch 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 Dockets Management Branch 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 Dockets Management Branch, 
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 Dockets Management Branch between the 
hours of 9 a.m. and 4 p.m., Monday through Friday. After reviewing the 
comments, the Commissioner shall publish a final order amending the 
monograph established under the provisions of paragraph (a)(9) of this 
section or withdraw the proposal if comments opposing the amendment are 
persuasive. A new drug application

[[Page 215]]

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 Secs. 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 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

[[Page 216]]

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, l971 (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 (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

[[Page 217]]

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.
    (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

[[Page 218]]

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.
    (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

[[Page 219]]

thereafter exempted from such limitation pursuant to Sec. 310.200 of 
this chapter, or
    (2) An active ingredient at a dosage level higher than that 
available in any OTC drug product on December 4, 1975, which ingredient 
and/or dosage level is classified by the panel in category III 
(conditions subject to Sec. 330.10(a)(6)(iii)), may be marketed only 
after:
    (i) The Center for Drug Evaluation and Research or the Commissioner 
tentatively determines that the ingredient is generally recognized as 
safe and effective, and the Commissioner states by notice in the Federal 
Register (separately or as part of another document) that marketing 
under specified conditions will be permitted;
    (ii) The ingredient is determined by the Commissioner to be 
generally recognized as safe and effective and is included in the 
appropriate published OTC drug final monograph; or
    (iii) A new drug application for the product has been approved.
    (e) This section applies only to conditions under consideration as 
part of the OTC drug review initiated on May 11, 1972, and evaluated 
under the procedures set forth in Sec. 330.10. Section 330.14(h) applies 
to the marketing of all conditions under consideration and evaluated 
using the criteria and procedures set forth in Sec. 330.14.

[41 FR 32582, Aug. 4, 1976, as amended at 47 FR 17739, Apr. 23, 1982; 50 
FR 8996, Mar. 6, 1985; 55 FR 11581, Mar. 29, 1990; 67 FR 3074, Jan. 23, 
2002]



Sec. 330.14  Additional criteria and procedures for classifying OTC drugs as generally recognized as safe and effective and not misbranded.

    (a) Introduction. This section sets forth additional criteria and 
procedures by which over the counter (OTC) drugs initially marketed in 
the United States after the OTC drug review began in 1972 and OTC drugs 
without any U.S. marketing experience can be considered in the OTC drug 
monograph system. This section also addresses conditions regulated as a 
cosmetic or dietary supplement in a foreign country that would be 
regulated as OTC drugs in the United States. For purposes of this 
section, ``condition'' means an active ingredient or botanical drug 
substance (or a combination of active ingredients or botanical drug 
substances), dosage form, dosage strength, or route of administration, 
marketed for a specific OTC use, except as excluded in paragraph (b)(2) 
of this section. For purposes of this part, ``botanical drug substance'' 
means a drug substance derived from one or more plants, algae, or 
macroscopic fungi, but does not include a highly purified or chemically 
modified substance derived from such a source.
    (b) Criteria. To be considered for inclusion in the OTC drug 
monograph system, the condition must meet the following criteria:
    (1) The condition must be marketed for OTC purchase by consumers. If 
the condition is marketed in another country in a class of OTC drug 
products that may be sold only in a pharmacy, with or without the 
personal involvement of a pharmacist, it must be established that this 
marketing restriction does not indicate safety concerns about the 
condition's toxicity or other potentiality for harmful effect, the 
method of its use, or the collateral measures necessary to its use.
    (2) The condition must have been marketed OTC for a minimum of 5 
continuous years in the same country and in sufficient quantity, as 
determined in paragraphs (c)(2)(ii), (c)(2)(iii), and (c)(2)(iv) of this 
section. Depending on the condition's extent of marketing in only one 
country with 5 continuous years of marketing, marketing in more than one 
country may be necessary.
    (c) Time and extent application. Certain information must be 
provided when requesting that a condition subject to this section be 
considered for inclusion in the OTC drug monograph system. The following 
information must be provided in the format of a time and extent 
application (TEA):
    (1) Basic information about the condition that includes a 
description of the active ingredient(s) or botanical drug substance(s), 
pharmacologic class(es), intended OTC use(s), OTC strength(s) and dosage 
form(s), route(s) of administration, directions for use, and the 
applicable existing OTC drug monograph(s) under which the condition 
would be marketed or the request

[[Page 220]]

and rationale for creation of a new OTC drug monograph(s).
    (i) A detailed chemical description of the active ingredient(s) that 
includes a full description of the drug substance, including its 
physical and chemical characteristics, the method of synthesis (or 
isolation) and purification of the drug substance, and any 
specifications and analytical methods necessary to ensure the identity, 
strength, quality, and purity of the drug substance.
    (ii) For a botanical drug substance(s), a detailed description of 
the botanical ingredient (including proper identification of the plant, 
plant part(s), alga, or macroscopic fungus used; a certificate of 
authenticity; and information on the grower/supplier, growing 
conditions, harvest location and harvest time); a qualitative 
description (including the name, appearance, physical/chemical 
properties, chemical constituents, active constituent(s) (if known), and 
biological activity (if known)); a quantitative description of the 
chemical constituents, including the active constituent(s) or other 
chemical marker(s) (if known and measurable); the type of manufacturing 
process (e.g., aqueous extraction, pulverization); and information on 
any further processing of the botanical substance (e.g., addition of 
excipients or blending).
    (iii) Reference to the current edition of the U.S. Pharmacopeia 
(USP)-National Formulary (NF) or foreign compendiums may help satisfy 
the requirements in this section.
    (2) A list of all countries in which the condition has been 
marketed. Include the following information for each country. (For a 
condition that has been marketed OTC in 5 or more countries with a 
minimum of 5 continuous years of marketing in at least one country, the 
sponsor may submit information in accordance with paragraph (c)(4) of 
this section):
    (i) How the condition has been marketed (e.g., OTC general sales 
direct-to-consumer; sold only in a pharmacy, with or without the 
personal involvement of a pharmacist; dietary supplement; or cosmetic). 
If the condition has been marketed as a nonprescription pharmacy-only 
product, establish that this marketing restriction does not indicate 
safety concerns about its toxicity or other potentiality for harmful 
effect, the method of its use, or the collateral measures necessary to 
its use.
    (ii) The cumulative total number of dosage units (e.g., tablets, 
capsules, ounces) sold for each dosage form of the condition. 
Manufacturers or suppliers of OTC active ingredients may provide dosage 
unit information as the total weight of active ingredient sold. List the 
various package sizes for each dosage form in which the condition is 
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.

[[Page 221]]

    (4) For a condition that has been marketed OTC in five or more 
countries with a minimum of 5 continuous years of marketing in at least 
one country, the sponsor may select at least five of these countries 
from which to submit information in accord with paragraphs (c)(2)(i) 
through (c)(2)(iv) of this section. Selected countries must include the 
country with a minimum of 5 continuous years of OTC marketing, countries 
that have the longest duration of marketing, and countries having the 
most support for extent of marketing, i.e., a large volume of sales with 
cultural diversity among users of the product. If the condition meets 
these criteria in countries listed in section 802(b)(1)(A) of the 
Federal Food, Drug, and Cosmetic Act, some of these countries should be 
included among the five selected. Sponsors should provide information 
from more than five countries if they believe that it is needed to 
support eligibility. Sponsors should explain the basis for the countries 
selected in the TEA.
    (5) A list of all countries where the condition is marketed only as 
a prescription drug and the reasons why its marketing is restricted to 
prescription in these countries.
    (6) A list of all countries in which the condition has been 
withdrawn from marketing or in which an application for OTC marketing 
approval has been denied. Include the reasons for such withdrawal or 
application denial.
    (7) The information requested in paragraphs (c)(2), (c)(2)(i) 
through (c)(2)(iv), and (c)(3) of this section must be provided in a 
table format. The labeling required by paragraph (c)(3) of this section 
must be attached to the table.
    (8) For OTC drugs that have been marketed for more than 5 years in 
the United States under a new drug application, the information 
requested in paragraphs (c)(2)(i), (c)(2)(iii), (c)(2)(v), (c)(3), and 
(c)(5) of this section need not be provided.
    (d) Submission of information; confidentiality. The sponsor must 
submit three copies of the TEA to the Central Document Room, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852. The Food and Drug 
Administration will handle the TEA as confidential until such time as a 
decision is made on the eligibility of the condition for consideration 
in the OTC drug monograph system. If the condition is found eligible, 
the TEA will be placed on public display in the Dockets Management 
Branch 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 Dockets Management Branch.
    (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 Dockets Management Branch.
    (f) Request for data and views. The notice of eligibility shall 
request interested persons to submit published and unpublished data to 
demonstrate the safety and effectiveness of the condition for its 
intended OTC use(s). These data shall be submitted to a docket 
established in the Dockets Management Branch and shall be publicly 
available for viewing at that office, except data deemed confidential 
under 18 U.S.C. 1905, 5 U.S.C. 552(b), or 21 U.S.C. 331(j). Data 
considered confidential under these provisions must be clearly 
identified. Any proposed compendial standards for the condition shall 
not be considered confidential. The safety and effectiveness submissions 
shall include the following:
    (1) All data and information listed in Sec. 330.10(a)(2) under the 
outline ``OTC Drug Review Information,'' items III through VII.
    (2) All serious adverse drug experiences as defined in Secs. 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

[[Page 222]]

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 Secs. 330.10(a)(2) and 330.10(a)(6) through 
(a)(10).
    (3) If the condition is initially determined to be generally 
recognized as safe and effective for OTC use in the United States, the 
agency will propose to include it in an appropriate OTC drug 
monograph(s), either by amending an existing monograph(s) or 
establishing a new monograph(s), if necessary.
    (4) If the condition is initially determined not to be generally 
recognized as safe and effective for OTC use in the United States, the 
agency will inform the sponsor and other interested parties who have 
submitted data of its determination by letter, a copy of which will be 
placed on public display in the docket established in the Dockets 
Management Branch. The agency will publish a notice of proposed 
rulemaking to include the condition in Sec. 310.502 of this chapter.
    (5) Interested parties will have an opportunity to submit comments 
and new data. The agency will subsequently publish a final rule (or 
reproposal if necessary) in the Federal Register.
    (h) Marketing. A condition submitted under this section for 
consideration in the OTC drug monograph system may be marketed in 
accordance with an applicable final OTC drug monograph(s) only after the 
agency determines that the condition is generally recognized as safe and 
effective and includes it in the appropriate OTC drug final 
monograph(s), and the condition complies with paragraph (i) of this 
section. When an OTC drug monograph has not been finalized and 
finalization is not imminent, after the agency has evaluated the 
comments to a proposed rule to include a new condition in a tentative 
final monograph as generally recognized as safe and effective and the 
agency has not changed its position as a result of the comments, and the 
condition complies with paragraph (i) of this section, the agency may 
publish a notice of enforcement policy that allows marketing to begin 
pending completion of the final monograph subject to the risk that the 
agency may, prior to or in the final monograph, adopt a different 
position that could require relabeling, recall, or other regulatory 
action.
    (i) Compendial monograph. Any active ingredient or botanical drug 
substance included in a final OTC drug monograph or the subject of an 
enforcement notice described in paragraph (h) of this section must be 
recognized in an official USP-NF drug monograph that sets forth its 
standards of identity, strength, quality, and purity. Sponsors must 
include an official or proposed compendial monograph as part of the 
safety and effectiveness data submission listed in Sec. 330.10(a)(2) 
under item VII of the outline entitled ``OTC DRUG REVIEW INFORMATION.''

[67 FR 3074, Jan. 23, 2002]



PART 331--ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE--Table of Contents




                      Subpart A--General Provisions

Sec.
331.1 Scope.

                      Subpart B--Active Ingredients

331.10 Antacid active ingredients.
331.11 Listing of specific active ingredients.

[[Page 223]]

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.
    (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.

[[Page 224]]

    (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 30030 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 x100)/
(Total mEq. Antacid Product).

[61 FR 4823, Feb. 8, 1996]



Sec. 331.21  Test modifications.

    The formulation or mode of administration of certain products may 
require a modification of the United States Pharmacopeia 23/National 
Formulary 18 acid neutralizing capacity test. Any proposed modification 
and the data to support it shall be submitted as a petition under the 
rules established in Sec. 10.30 of this chapter. All information 
submitted will be subject to the disclosure rules in part 20 of this 
chapter.

[61 FR 4823, Feb. 8, 1996]



                           Subpart D--Labeling



Sec. 331.30  Labeling of antacid products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antacid.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``For the relief of'' (optional, 
any or all of the following:) ``heartburn,'' ``sour stomach,''

[[Page 225]]

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 50 mEq. of magnesium in the 
recommended daily dosage: ``Do not use this product except under the 
advice and supervision of a physician if you have kidney disease.''
    (5) For products containing more than 25 mEq. potassium in the 
maximum recommended daily dose: ``Do not use this product except under 
the advice and supervision of a physician if you have kidney disease.''
    (6) 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]

[[Page 226]]



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 227]]



                      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 ANTI-MICROBIAL 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 228]]

                  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 229]]

    (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

[[Page 230]]

single generally recognized as safe and effective amine or ``caine''-
type local anesthetic active ingredient in a suitable vehicle.

[52 FR 47322, Dec. 11, 1987; 52 FR 48792, Dec. 24, 1987, as amended at 
53 FR 18838, May 25, 1988; 55 FR 9722, Mar. 15, 1990; 55 FR 40381, Oct. 
3, 1990; 55 FR 50172, Dec. 5, 1990; 64 FR 403, Jan. 5, 1999]



Sec. 333.150  Labeling of first aid antibiotic drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``first aid antibiotic.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``First aid to help'' [select 
one of the following: ``prevent,'' (``decrease'' (``the risk of'' or 
``the chance of'')), (``reduce'' (``the risk of'' or ``the chance 
of'')), ``guard against,'' or ``protect against''] [select one of the 
following: ``infection,'' ``bacterial contamination,'' or ``skin 
infection''] ``in minor cuts, scrapes, and burns.'' Other truthful and 
nonmisleading statements describing only the indications for use that 
have been established and listed in this paragraph (b), may also be 
used, as provided in Sec. 330.1(c)(2), subject to the provisions of 
section 502 of the act relating to misbranding and the prohibition in 
section 301(d) of the act against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``For external use only. Do not use in the eyes or apply over 
large areas of the body. In case of deep or puncture wounds, animal 
bites, or serious burns, consult a doctor.''
    (2) For products containing chlortetracycline hydrochloride or 
tetracycline hydrochloride.``Stop use and consult a doctor if the 
condition persists or gets worse. Do not use longer than 1 week unless 
directed by doctor.''
    (3) For any product containing bacitracin, bacitracin zinc, 
neomycin, neomycin sulfate, polymyxin B, and/or polymyxin B sulfate. 
``Stop use and consult a doctor if the condition persists or gets worse, 
or if a rash or other allergic reaction develops. Do not use if you are 
allergic to any of the ingredients. Do not use longer than 1 week unless 
directed by a doctor.''
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'': (1) For ointment and cream 
products. ``Clean the affected area. Apply a small amount of this 
product (an amount equal to the surface area of the tip of a finger) on 
the area 1 to 3 times daily. May be covered with a sterile bandage.''
    (2) For powder products. ``Clean the affected area. Apply a light 
dusting of the powder on the area 1 to 3 times daily. May be covered 
with a sterile bandage.''
    (3) For aerosol products. ``Clean the affected area. Spray a small 
amount of this product on the area 1 to 3 times daily. May be covered 
with a sterile bandage.''
    (e) The word ``doctor'' may be substituted for the word 
``physician'' in any of the labeling statements in this subpart.

[52 FR 47332, Dec. 11, 1987, as amended at 61 FR 58472, Nov. 15, 1996]



Sec. 333.160  Labeling of permitted combinations of active ingredients.

    Statements of identity, indications, warnings, and directions for 
use, respectively, applicable to each ingredient in the product may be 
combined to eliminate duplicative words or phrases so that the resulting 
information is clear and understandable.
    (a) Statement of identity. For a combination drug product that has 
an established name, the labeling of the product states the established 
name of the combination drug product, followed by the statement of 
identity for each ingredient in the combination, as established in the 
statement of identity sections of the applicable OTC drug monographs. 
For a combination drug product that does not have an established name, 
the labeling of the product states the statement of identity for each 
ingredient in the combination, as established in the statement of 
identity sections of the applicable OTC drug monographs.

[[Page 231]]

    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the indication(s) for each ingredient in the 
combination, as established in the ``Indications'' sections of the 
applicable OTC drug monographs, unless otherwise stated in this 
paragraph. Other truthful and nonmisleading statements, describing only 
the indications for use that have been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2), 
subject to the provisions of section 502 of the act relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (1) For permitted combinations identified in Sec. 333.120(a). The 
indications in Sec. 333.150 should be used.
    (2) For permitted combinations identified in Sec. 333.120(b). In 
addition to the required indication identified in Sec. 333.150, the 
labeling of the product may state, under the heading ``Indications,'' 
the following additional indication: ``First aid for the temporary 
relief of'' (select one of the following: ``pain,'' ``discomfort,'' 
``pain or discomfort'' or ``pain and itching'') ``in minor cuts, 
scrapes, and burns.''
    (c) Warnings. The labeling of the product states, under the heading 
``Warnings,'' the warning(s) for each ingredient in the combination, as 
established in the warnings sections of the applicable OTC drug 
monographs.
    (d) Directions. The labeling of the product states, under the 
heading ``Directions,'' directions that conform to the directions 
established for each ingredient in the directions sections of the 
applicable OTC drug monographs. When the time intervals or age 
limitations for administrations of the individual ingredients differ, 
the directions for the combination product may not exceed any maximum 
dosage limits established for the individual ingredients in the 
applicable OTC drug monograph.



               Subpart C--Topical Antifungal Drug Products

    Source: 58 FR 49898, Sept. 23, 1993, unless otherwise noted.



Sec. 333.201  Scope.

    (a) An over-the-counter antifungal drug product in a form suitable 
for topical administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this subpart 
and each general condition established in Sec. 330.1 of this chapter.
    (b) Reference in this subpart to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 333.203  Definitions.

    As used in this subpart:
    (a) Antifungal. A drug which inhibits the growth and reproduction of 
fungal cells and decreases the number of fungi present.
    (b) Athlete's foot. An infection of the feet caused by certain 
dermatophytic fungi.
    (c) Dermatophyte. A fungus that invades and lives upon the skin or 
in the hair or nails.
    (d) Fungus. Any of a large division of plants, including 
dermatophytes, yeasts, and molds, characterized by a simple cell 
structure and the absence of chlorophyll.
    (e) Jock itch. A chronic and recurrent infection caused by certain 
dermatophytic fungi; affects the upper, inner thighs and sometimes 
extends to the groin and the pubic area; the condition most frequently 
occurs in men, but may also occur in women.
    (f) Ringworm. A skin infection caused by certain dermatophytic 
fungi.



Sec. 333.210  Antifungal active ingredients.

    The active ingredient of the product consists of any one of the 
following within the specified concentration established for each 
ingredient:
    (a) Clioquinol 3 percent.
    (b) Haloprogin 1 percent.
    (c) Miconazole nitrate 2 percent.
    (d) Povidone-iodine 10 percent.
    (e) Tolnaftate 1 percent.
    (f) Undecylenic acid, calcium undecylenate, copper undecylenate, and 
zinc undecylenate may be used individually or in any ratio that provides 
a total undecylenate concentration of 10 to 25 percent.

[[Page 232]]

    (g) Clotrimazole 1 percent.

[58 FR 49898, Sept. 23, 1993, as amended at 67 FR 5943, Feb. 8, 2002]



Sec. 333.250  Labeling of antifungal drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antifungal.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the phrase listed in paragraph (b)(1)(i) of 
this section and may contain the additional phrase listed in paragraph 
(b)(1)(ii) of this section. Other truthful and nonmisleading statements, 
describing only the indications for use that have been established in 
paragraph (b) of this section, may also be used, as provided in 
Sec. 330.1(c)(2) of this chapter, subject to the provisions of section 
502 of the Federal Food, Drug, and Cosmetic Act (the act) relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (1) For products containing any ingredient identified in 
Sec. 333.210 labeled for the treatment of athlete's foot, jock itch, and 
ringworm. (i) (Select one of the following: ``Treats,'' ``For the 
treatment of,'' ``For effective treatment of,'' ``Cures,'' ``For the 
cure of,'' ``Clears up,'' or ``Proven clinically effective in the 
treatment of'') (select one condition from any one or more of the 
following groups of conditions:
    (A) ``Athlete's foot,'' athlete's foot (dermatophytosis),'' 
``athlete's foot (tinea pedis),'' or ``tinea pedis (athlete's foot)'';
    (B) ``Jock itch,'' ``jock itch (tinea cruris),'' or ``tinea cruris 
(jock itch)''; or
    (C) ``Ringworm,'' ``ringworm (tinea corporis),'' or ``tinea corporis 
(ringworm).'')
    (ii) In addition to the information identified in paragraph 
(b)(1)(i) of this section, the labeling of the product may contain the 
following statement: (Select one of the following: ``Relieves,'' ``For 
relief of,'' ``For effective relief of,'' or ``Soothes,'') (select one 
or more of the following: ``Itching,'' ``scaling,'' ``cracking,'' 
``burning,'' ``redness,'' ``soreness,'' ``irritation,'' ``discomfort,'' 
``chafing associated with jock itch,'' ``itchy, scaly skin between the 
toes,'' or ``itching, burning feet'').
    (2) For products containing the ingredient identified in 
Sec. 333.210(e) labeled for the prevention of athlete's foot. (i) 
(Select one of the following: ``Clinically proven to prevent,'' 
``Prevents,'' ``Proven effective in the prevention of,'' ``Helps 
prevent'', ``For the prevention of,'' ``For the prophylaxis (prevention) 
of,'' ``Guards against,'' or ``Prevents the recurrence of'') (select one 
of the following: ``Athlete's foot,'' ``athlete's foot 
(dermatophytosis),'' ``athlete's foot (tinea pedis),'' or ``tinea pedis 
(athlete's foot)'') ``with daily use.''
    (ii) In addition to the information identified in paragraph 
(b)(2)(i) of this section, the labeling of the product may contain the 
following statement: ``Clears up athlete's foot infection and with daily 
use helps keep it from coming back.''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredient identified in 
Sec. 330.210. (i) ``Do not use on children under 2 years of age unless 
directed by a doctor.''
    (ii) ``For external use only.''
    (iii) ``Avoid contact with the eyes.''
    (2) For products labeled according to paragraph (b)(1) of this 
section for the treatment of athlete's foot and ringworm. ``If 
irritation occurs or if there is no improvement within 4 weeks, 
discontinue use and consult a doctor.''
    (3) For products labeled according to paragraph (b)(1) of this 
section for the treatment of jock itch. ``If irritation occurs or if 
there is no improvement within 2 weeks, discontinue use and consult a 
doctor.''
    (4) For products labeled according to paragraph (b)(2) of this 
section for the prevention of athlete's foot. ``If irritation occurs, 
discontinue use and consult a doctor.''
    (5) For products containing the ingredient identified in 
Sec. 333.210(a) labeled according to paragraph (b)(1) of this section. 
The following statements must appear in boldface type as the first

[[Page 233]]

warnings under the ``Warnings'' heading. (i) ``Do not use on children 
under 2 years of age.'' (This warning is to be used in place of the 
warning in paragraph (c)(1)(i) of this section.)
    (ii) ``Do not use for diaper rash.''
    (d) Directions. The labeling of the product contains the following 
statements under the heading ``Directions'':
    (1) For products labeled according to paragraph (b)(1) of this 
section for the treatment of athlete's foot, jock itch, and ringworm. 
[Select one of the following: ``Clean'' or ``Wash''] ``the affected area 
and dry thoroughly. Apply'' (the word ``spray'' may be used to replace 
the word ``apply'' for aerosol products) ``a thin layer of the product 
over affected area twice daily (morning and night) or as directed by a 
doctor. Supervise children in the use of this product. For athlete's 
foot: Pay special attention to spaces between the toes; wear well-
fitting, ventilated shoes, and change shoes and socks at least once 
daily. For athlete's foot and ringworm, use daily for 4 weeks; for jock 
itch, use daily for 2 weeks. If condition persists longer, consult a 
doctor. This product is not effective on the scalp or nails.''
    (2) For products labeled according to paragraph (b)(2) of this 
section for the prevention of athlete's foot. ``To prevent athlete's 
foot,'' (select one of the following: ``clean'' or ``wash'') ``the feet 
and dry thoroughly. Apply'' (the word ``spray'' may be used to replace 
the word ``apply'' for aerosol products) ``a thin layer of the product 
to the feet once or twice daily (morning and/or night). Supervise 
children in the use of this product. Pay special attention to spaces 
between the toes; wear well-fitting, ventilated shoes, and change shoes 
and socks at least once daily.''
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

    Effective Date Note: At 67 FR 52305, Aug. 29, 2000, Sec. 333.250 was 
amended by revising the introductory texts of paragraphs (b)(1)(i) and 
(b)(2)(i) and by revising paragraph (b)(2)(ii), effective May 16, 2002. 
For the convenience of the user, the revised text is set for as follows:

  

    (b) * * *
    (1) * * * (i) (Select one of the following: ``Treats,'' ``For the 
treatment of,'' ``For effective treatment of,'' ``Cures,'' ``For the 
cure of,'' ``Clears up,'' or ``Proven clinically effective in the 
treatment of'') ``most'' (select one condition from any one or more of 
the following groups of conditions:

                                * * * * *

    (2) * * * (i) (Select one of the following: ``Clinically proven to 
prevent,'' ``Prevents,'' ``Proven effective in the prevention of,'' 
``Helps prevent,'' ``For the prevention of,'' ``For the prophylaxis 
(prevention) of,'' ``Guards against,'' or ``Prevents the recurrence 
of'') ``most'' (select one of the following: ``Athlete's foot,'' 
``athlete's foot (dermatophytosis),'' ``athlete's foot (tinea pedis),''' 
or ``tinea pedis (athlete's foot)'') ``with daily use.''
    (ii) In addition to the information identified in paragraph 
(b)(2)(i) of this section, the labeling of the product may contain the 
following statement: ``Clears up most athlete's foot infection and with 
daily use helps keep it from coming back.''



Sec. 333.280  Professional labeling.

    The labeling provided to health professionals (but not to the 
general public) may contain the following additional indication:
    (a) For products containing haloprogin or miconazole nitrate 
identified in Sec. 333.210 (a) and (c). ``For the treatment of 
superficial skin infections caused by yeast (Candida albicans).''
    (b) [Reserved]



                  Subpart D--Topical Acne Drug Products

    Source: 56 FR 41019, Aug. 16, 1991, unless otherwise noted.



Sec. 333.301  Scope.

    (a) An over-the-counter acne drug product in a form suitable for 
topical application is generally recognized as safe and effective and is 
not misbranded if it meets each of the conditions in this subpart and 
each general condition established in Sec. 330.1 of this chapter.
    (b) References in this subpart to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.

[[Page 234]]



Sec. 333.303  Definitions.

    As used in this subpart:
    (a) Acne. A disease involving the oil glands and hair follicles of 
the skin which is manifested by blackheads, whiteheads, acne pimples, 
and acne blemishes.
    (b) Acne blemish. A flaw in the skin resulting from acne.
    (c) Acne drug product. A drug product used to reduce the number of 
acne blemishes, acne pimples, blackheads, and whiteheads.
    (d) Acne pimple. A small, prominent, inflamed elevation of the skin 
resulting from acne.
    (e) Blackhead. A condition of the skin that occurs in acne and is 
characterized by a black tip.
    (f) Whitehead. A condition of the skin that occurs in acne and is 
characterized by a small, firm, whitish elevation of the skin.



Sec. 333.310  Acne active ingredients.

    The active ingredient of the product consists of any of the 
following when labeled according to Sec. 333.350.
    (a) Resorcinol 2 percent when combined in accordance with 
Sec. 333.320(a).
    (b) Resorcinol monoacetate 3 percent when combined in accordance 
with Sec. 333.320(b).
    (c) Salicylic acid 0.5 to 2 percent.
    (d) Sulfur 3 to 10 percent.
    (e) Sulfur 3 to 8 percent when combined in accordance with 
Sec. 333.320.



Sec. 333.320  Permitted combinations of active ingredients.

    (a) Resorcinol identified in Sec. 333.310(a) when combined with 
sulfur identified in Sec. 333.310(e) provided the product is labeled 
according to Sec. 333.350.
    (b) Resorcinol monoacetate identified in Sec. 333.310(b) when 
combined with sulfur identified in Sec. 333.310(e) provided the product 
is labeled according to Sec. 333.350.



Sec. 333.350  Labeling of acne drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``acne medication,'' ``acne treatment,'' ``acne medication'' (insert 
dosage form, e.g., ``cream,'' ``gel,'' ``lotion,'' or ``ointment''), or 
``acne treatment'' (insert dosage form, e.g., ``cream,'' ``gel,'' 
``lotion,'' or ``ointment'').
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the phrase listed in paragraph (b)(1) of this 
section and may contain any of the additional phrases listed in 
paragraph (b)(2) of this section. Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in paragraph (b) of this section, may also be 
used, as provided in Sec. 330.1(c)(2) of this chapter, subject to the 
provisions of section 502 of the Federal Food, Drug, and Cosmetic Act 
(the act) relating to misbranding and the prohibition in section 301(d) 
of the act against the introduction or delivery for introduction into 
interstate commerce of unapproved new drugs in violation of section 
505(a) of the act.
    (1) ``For the'' (select one of the following: ``management'' or 
``treatment'') ``of acne.''
    (2) In addition to the information identified in paragraph (b)(1) of 
this section, the labeling of the product may contain any one or more of 
the following statements:
    (i) (Select one of the following: ``Clears,'' ``Clears up,'' 
``Clears up most,'' ``Dries,'' ``Dries up,'' ``Dries and clears,'' 
``Helps clear,'' ``Helps clear up,'' ``Reduces the number of,'' or 
``Reduces the severity of'') (select one or more of the following: 
``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or ``whiteheads'') 
which may be followed by ``and allows skin to heal.''
    (ii) ``Penetrates pores to'' (select one of the following: 
``eliminate most,'' ``control,'' ``clear most,'' or ``reduce the number 
of'') (select one or more of the following: ``acne blemishes,'' ``acne 
pimples,'' ``blackheads,'' or ``whiteheads'').
    (iii) ``Helps keep skin clear of new'' (select one or more of the 
following: ``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or 
``whiteheads'').
    (iv) ``Helps prevent new'' (select one or more of the following: 
``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or ``whiteheads'') 
which may be followed by ``from forming.''

[[Page 235]]

    (v) ``Helps prevent the development of new'' (select one or more of 
the following: ``acne blemishes,'' ``acne pimples,'' ``blackheads,'' or 
``whiteheads'').
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For products containing any ingredient identified in 
Sec. 333.310. (i) ``For external use only.''
    (ii) ``Using other topical acne medications at the same time or 
immediately following use of this product may increase dryness or 
irritation of the skin. If this occurs, only one medication should be 
used unless directed by a doctor.''
    (2) For products containing sulfur identified in Secs. 333.310 (d) 
and (e). ``Do not get into eyes. If excessive skin irritation develops 
or increases, discontinue use and consult a doctor.''
    (3) For products containing any combination identified in 
Sec. 333.320. ``Apply to affected areas only. Do not use on broken skin 
or apply to large areas of the body.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) ``Cleanse the skin thoroughly before applying medication. Cover 
the entire affected area with a thin layer one to three times daily. 
Because excessive drying of the skin may occur, start with one 
application daily, then gradually increase to two or three times daily 
if needed or as directed by a doctor. If bothersome dryness or peeling 
occurs, reduce application to once a day or every other day.''
    (2) The directions described in paragraph (d)(1) of this section are 
intended for products that are applied and left on the skin. Other 
products, such as soaps or masks, may be applied and removed and should 
have appropriate directions.
    (3) Optional directions. In addition to the required directions in 
paragraphs (d)(1) and (d)(2) of this section, the product may contain 
the following optional labeling: ``Sensitivity Test for a New User. 
Apply product sparingly to one or two small affected areas during the 
first 3 days. If no discomfort occurs, follow the directions stated: 
(select one of the following: `elsewhere on this label,' `above,' or 
`below.')''
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.



PART 336--ANTIEMETIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents




                      Subpart A--General Provisions

Sec.
336.1 Scope.
336.3 Definition.

                      Subpart B--Active Ingredients

336.10 Antiemetic active ingredients.

                           Subpart C--Labeling

336.50 Labeling of antiemetic drug products.
336.80 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 52 FR 15892, Apr. 30, 1987, unless otherwise noted.



                      Subpart A--General Provisions



Sec. 336.1  Scope.

    (a) An over-the-counter antiemetic drug product in a form suitable 
for oral administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this part 
and each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 336.3  Definition.

    As used in this part:
    Antiemetic. An agent that prevents or treats nausea and vomiting.



                      Subpart B--Active Ingredients



Sec. 336.10  Antiemetic active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient in Sec. 336.50(d):
    (a) Cyclizine hydrochloride.
    (b) Dimenhydrinate.
    (c) Diphenhydramine hydrochloride.

[[Page 236]]

    (d) Meclizine hydrochloride.



                           Subpart C--Labeling



Sec. 336.50  Labeling of antiemetic drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antiemetic.''
    (b) Indications. The labeling of the product states the following 
under the heading ``Indications,'' ``For the prevention and treatment of 
the nausea, vomiting, or dizziness associated with motion sickness.'' 
Other truthful and nonmisleading statements, describing only the 
indications for use that have been established and listed in this 
paragraph (b), may also be used, as provided in Sec. 330.1(c)(2), 
subject to the provisions of section 502 of the act relating to 
misbranding and the prohibition in section 301(d) of the act against the 
introduction or delivery for introduction into interstate commerce of 
unapproved new drugs in violation of section 505(a) of the act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings:''
    (1) For products containing any ingredient identified in 
Sec. 336.10--(i) When labeled for use in adults and for those products 
that can be and are labeled for use in children under 12 years of age. 
``Do not take this product, unless directed by a doctor, if you have a 
breathing problem such as emphysema or chronic bronchitis, or if you 
have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (ii) For those products that can be and are labeled only for 
children under 12 years of age. ``Do not give this product to children 
who have a breathing problem such as chronic bronchitis or who have 
glaucoma, without first consulting the child's doctor.''
    (2) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a). ``Do not give to children under 6 years of age unless 
directed by a doctor.''
    (3) For products containing dimenhydrinate identified in 
Sec. 336.10(b). ``Do not give to children under 2 years of age unless 
directed by a doctor.''
    (4) For products containing diphenhydramine hydrochloride identified 
in Sec. 336.10(c). ``Do not give to children under 6 years of age unless 
directed by a doctor.''
    (5) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). ``Do not give to children under 12 years of age unless 
directed by a doctor.''
    (6) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a) or meclizine hydrochloride identified in Sec. 330.10(d). 
``May cause drowsiness; alcohol, sedatives, and tranquilizers may 
increase the drowsiness effect. Avoid alcoholic beverages while taking 
this product. Do not take this product if you are taking sedatives or 
tranquilizers, without first consulting your doctor. Use caution when 
driving a motor vehicle or operating machinery.''
    (7) For products containing dimenhydrinate identified in 
Sec. 336.10(b) or diphenhydramine hydrochloride identified in 
Sec. 336.10(c). ``May cause marked drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing cyclizine hydrochloride identified in 
Sec. 336.10(a). Adults and children 12 years of age and over: Oral 
dosage is 50 milligrams every 4 to 6 hours, not to exceed 200 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: Oral dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor.
    (2) For products containing dimenhydrinate identified in 
Sec. 336.10(b). Adults and children 12 years of age and over: Oral 
dosage is 50 to 100 milligrams every 4 to 6 hours, not to exceed 400 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: Oral dosage is 25 to 50 milligrams every 6 to 8 hours, 
not to exceed 150 milligrams in 24 hours, or as directed by a doctor. 
Children 2 to

[[Page 237]]

under 6 years of age: Oral dosage is 12.5 to 25 milligrams every 6 to 8 
hours, not to exceed 75 milligrams in 24 hours, or as directed by a 
doctor.
    (3) For products containing diphenhydramine hydrochloride identified 
in Sec. 336.10(c). Adults and children 12 years of age and over: Oral 
dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: Oral dosage is 12.5 to 25 milligrams every 4 to 6 
hours, not to exceed 150 milligrams in 24 hours, or as directed by a 
doctor.
    (4) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). Adults and children 12 years of age and over: Oral 
dosage is 25 to 50 milligrams once daily, or as directed by a doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[52 FR 15892, Apr. 30, 1987, as amended at 53 FR 35809, Sept. 15, 1988; 
59 FR 16982, Apr. 11, 1994]



Sec. 336.80  Professional labeling.

    The labeling provided to health professionals (but not to the 
general public) may contain the following additional indications.
    (a) For products containing cyclizine hydrochloride, dimenhydrinate, 
and diphenhydramine hydrochloride identified in Sec. 336.10 (a), (b), 
and (c). ``For the treatment of vertigo of motion sickness.''
    (b) For products containing meclizine hydrochloride identified in 
Sec. 336.10(d). ``For the treatment of vertigo.''



PART 338--NIGHTTIME SLEEP-AID DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents




                      Subpart A--General Provisions

Sec.
338.1 Scope.
338.3 Definition.

                      Subpart B--Active Ingredients

338.10 Nighttime sleep-aid active ingredients.

                           Subpart C--Labeling

338.50 Labeling of nighttime sleep-aid drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 54 FR 6826, Feb. 14, 1989, unless otherwise noted.



                      Subpart A--General Provisions



Sec. 338.1  Scope.

    (a) An over-the-counter nighttime sleep-aid drug product in a form 
suitable for oral administration is generally recognized as safe and 
effective and is not misbranded if it meets each condition in this part 
and each general condition established in Sec. 330.1 of this chapter.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 338.3  Definition.

    As used in this part:
    Nighttime sleep-aid. A drug that is useful for the relief of 
occasional sleeplessness by individuals who have difficulty falling 
asleep.



                      Subpart B--Active Ingredients



Sec. 338.10  Nighttime sleep-aid active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient in Sec. 338.50(d):
    (a) Diphenhydramine hydrochloride.
    (b) Diphenhydramine citrate.



                           Subpart C--Labeling



Sec. 338.50  Labeling of nighttime sleep-aid drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``nighttime sleep-aid.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' one or more of the phrases listed in this 
paragraph. Other truthful and nonmisleading statements, describing only 
the indications for use that have been established and listed in

[[Page 238]]

this paragraph (b), may also be used, as provided in Sec. 330.1(c)(2) of 
this chapter, subject to the provisions of section 502 of the act 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) (``Helps you'' or ``Reduces time to'') ``fall asleep if you have 
difficulty falling asleep.''
    (2) ``For relief of occasional sleeplessness.''
    (3) ``Helps to reduce difficulty falling asleep.''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``Do not give to children under 12 years of age.''
    (2) ``If sleeplessness persists continuously for more than 2 weeks, 
consult your doctor. Insomnia may be a symptom of serious underlying 
medical illness.''
    (3) ``Do not take this product, unless directed by a doctor, if you 
have a breathing problem such as emphysema or chronic bronchitis, or if 
you have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (4) ``Avoid alcoholic beverages while taking this product. Do not 
take this product if you are taking sedatives or tranquilizers, without 
first consulting your doctor.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing diphenhydramine hydrochloride identified 
in Sec. 338.10(a). Adults and children 12 years of age and over: Oral 
dosage is 50 milligrams at bedtime if needed, or as directed by a 
doctor.
    (2) For products containing diphenhydramine citrate identified in 
Sec. 338.10(b). Adults and children 12 years of age and over: Oral 
dosage is 76 milligrams at bedtime if needed, or as directed by a 
doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[54 FR 6826, Feb. 14, 1989, as amended at 59 FR 16983, Apr. 11, 1994]



PART 340--STIMULANT DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents




                      Subpart A--General Provisions

Sec.
340.1 Scope.
340.3 Definition.

                      Subpart B--Active Ingredient

340.10 Stimulant active ingredient.

                           Subpart C--Labeling

340.50 Labeling of stimulant drug products.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

    Source: 53 FR 6105, Feb. 29, 1988, unless otherwise noted.



                      Subpart A--General Provisions



Sec. 340.1  Scope.

    (a) An over-the-counter stimulant drug product in a form suitable 
for oral administration is generally recognized as safe and effective 
and is not misbranded if it meets each of the conditions in this part 
and each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.



Sec. 340.3  Definition.

    As used in this part:
    Stimulant. A drug which helps restore mental alertness or 
wakefulness during fatigue or drowsiness.



                      Subpart B--Active Ingredient



Sec. 340.10  Stimulant active ingredient.

    The active ingredient of the product consists of caffeine when used 
within the dosage limits established in Sec. 340.50(d).



                           Subpart C--Labeling



Sec. 340.50  Labeling of stimulant drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies

[[Page 239]]

the product as an ``altertness aid'' or a ``stimulant.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' the following: ``Helps restore mental alertness 
or wakefulness when experiencing fatigue or drowsiness.'' Other truthful 
and nonmisleading statements, describing only the indications for use 
that have been established and listed in this paragraph (b), may also be 
used, as provided in Sec. 330.1(c)(2), subject to the provisions of 
section 502 of the Act relating to misbranding and the prohibition in 
section 301(d) of the Act against the introduction or delivery for 
introduction into interstate commerce of unapproved new drugs in 
violation of section 505(a) of the Act.
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) ``The recommended dose of this product contains about as much 
caffeine as a cup of coffee. Limit the use of caffeine-containing 
medications, foods, or beverages while taking this product because too 
much caffeine may cause nervousness, irritability, sleeplessness, and, 
occasionally, rapid heart beat.''
    (2) ``For occasional use only. Not intended for use as a substitute 
for sleep. If fatigue or drowsiness persists or continues to recur, 
consult a'' (select one of the following: ``physician'' or ``doctor'').
    (3) ``Do not give to children under 12 years of age.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'': Adults and children 12 
years of age and over: Oral dosage is 100 to 200 milligrams not more 
often than every 3 to 4 hours.



PART 341--COLD, COUGH, ALLERGY, BRONCHODILATOR, AND ANTIASTHMATIC DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE--Table of Contents




                      Subpart A--General Provisions

Sec.
341.1 Scope.
341.3 Definitions.

                      Subpart B--Active Ingredients

341.12 Antihistamine active ingredients.
341.14 Antitussive active ingredients.
341.16 Bronchodilator active ingredients.
341.18 Expectorant active ingredient.
341.20 Nasal decongestant active ingredients.

                           Subpart C--Labeling

341.70 Labeling of OTC drug products containing ingredients that are 
          used for treating concurrent symptoms (in either a single-
          ingredient or combination drug product).
341.72 Labeling of antihistamine drug products.
341.74 Labeling of antitussive drug products.
341.76 Labeling of bronchodilator drug products.
341.78 Labeling of expectorant drug products.
341.80 Labeling of nasal decongestant drug products.
341.90 Professional labeling.

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.



                      Subpart A--General Provisions



Sec. 341.1  Scope.

    (a) An over-the-counter cold, cough, allergy, bronchodilator, or 
antiasthmatic drug product in a form suitable for oral, inhalant, or 
topical administration is generally recognized as safe and effective and 
is not misbranded if it meets each of the conditions in this part and 
each of the general conditions established in Sec. 330.1.
    (b) References in this part to regulatory sections of the Code of 
Federal Regulations are to chapter I of title 21 unless otherwise noted.

[51 FR 35339, Oct. 2, 1986]



Sec. 341.3  Definitions.

    As used in this part:
    (a) Bronchodilator drug. A drug used to overcome spasms that cause 
narrowing of the bronchial air tubes, such as in the symptomatic 
treatment of the wheezing and shortness of breath of asthma.
    (b) Oral antitussive drug. A drug that either is taken by mouth or 
is dissolved in the mouth in the form of a lozenge and acts systemically 
to relieve cough.

[[Page 240]]

    (c) Topical antitussive drug. A drug that relieves cough when 
inhaled after being applied topically to the throat or chest in the form 
of an ointment or from a steam vaporizer, or when dissolved in the mouth 
in the form of a lozenge for a local effect.
    (d) Expectorant drug. A drug taken orally to promote or facilitate 
the removal of secretions from the respiratory airways.
    (e) Antihistamine drug. A drug used for the relief of the symptoms 
of hay fever and upper respiratory allergies (allergic rhinitis).
    (f) Oral nasal decongestant drug. A drug that is taken by mouth and 
acts systemically to reduce nasal congestion caused by acute or chronic 
rhinitis.
    (g) Topical nasal decongestant drug. A drug that when applied 
topically inside the nose, in the form of drops, jellies, or sprays, or 
when inhaled intranasally reduces nasal congestion caused by acute or 
chronic rhinitis.
    (h) Calibrated dropper. A dropper calibrated such that the volume 
error incurred in measuring any liquid does not exceed 15 percent under 
normal use conditions.

[51 FR 35339, Oct. 2, 1986, as amended at 54 FR 8509, Feb. 28, 1989; 55 
FR 40382, Oct. 3, 1990; 57 FR 58374, Dec. 9, 1992; 59 FR 43409, Aug. 23, 
1994]



                      Subpart B--Active Ingredients



Sec. 341.12  Antihistamine active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits established for each 
ingredient:
    (a) Brompheniramine maleate.
    (b) Chlorcyclizine hydrochloride.
    (c) Chlorpheniramine maleate.
    (d) Dexbrompheniramine maleate.
    (e) Dexchlorpheniramine maleate.
    (f) Diphenhydramine citrate.
    (g) Diphenhydramine hydrochloride.
    (h) Doxylamine succinate.
    (i) Phenindamine tartrate.
    (j) Pheniramine maleate.
    (k) Pyrilamine maleate.
    (l) Thonzylamine hydrochloride.
    (m) Triprolidine hydrochloride.

[57 FR 58374, Dec. 9, 1992, as amended at 59 FR 4218, Jan. 28, 1994]



Sec. 341.14  Antitussive active ingredients.

    The active ingredients of the product consist of any of the 
following when used within the dosage limits and in the dosage forms 
established for each ingredient in Sec. 341.74(d):
    (a) Oral antitussives. (1) Chlophedianol hydrochloride.
    (2) Codeine ingredients. The following ingredients may be used only 
in combination in accordance with Secs. 329.20(a) and 341.40 and 21 CFR 
1308.15(c).
    (i) Codeine.
    (ii) Codeine phosphate.
    (iii) Codeine sulfate.
    (3) Dextromethorphan.
    (4) Dextromethorphan hydrobromide.
    (5) Diphenhydramine citrate.
    (6) Diphenhydramine hydrochloride.
    (b) Topical antitussives.
    (1) Camphor.
    (2) Menthol.

[52 FR 30055, Aug. 12, 1987, as amended at 59 FR 29174, June 3, 1994]

    Effective Date Note: At 67 FR 4907, Feb. 1, 2002, Sec. 341.14 was 
amended in paragraph (a)(2) by removing ``Secs. 329.20(a) and 341.40'' 
and by adding in its place ``Sec. 290.2'', effective Apr. 2, 2002.



Sec. 341.16  Bronchodilator active ingredients.

    The active ingredients of the product consist of any of the 
following when used within the dosage limits established for each 
ingredient:
    (a) Ephedrine.
    (b) Ephedrine hydrochloride.
    (c) Ephedrine sulfate.
    (d) Epinephrine.
    (e) Epinephrine bitartrate.
    (f) Racephedrine hydrochloride.
    (g) Racepinephrine hydrochloride.

[51 FR 35339, Oct. 2, 1986]



Sec. 341.18  Expectorant active ingredient.

    The active ingredient of the product is guaifenesin when used within 
the dosage limits established in Sec. 341.78(d).

[54 FR 8509, Feb. 28, 1989]



Sec. 341.20  Nasal decongestant active ingredients.

    The active ingredient of the product consists of any of the 
following when used within the dosage limits and in the dosage forms 
established for each ingredient:

[[Page 241]]

    (a) Oral nasal decongestants. (1) Phenylephrine hydrochloride.
    (2) Pseudoephedrine hydrochloride.
    (3) Pseudoephedrine sulfate.
    (b) Topical nasal decongestants. (1) Levmetamfetamine.
    (2) Ephedrine.
    (3) Ephedrine hydrochloride.
    (4) Ephedrine sulfate.
    (5) [Reserved]
    (6) Naphazoline hydrochloride.
    (7) Oxymetazoline hydrochloride.
    (8) Phenylephrine hydrochloride.
    (9) Propylhexedrine.
    (10) Xylometazoline hydrochloride.

[59 FR 43409, Aug. 23, 1994, as amended at 63 FR 40650, July 30, 1998]



                           Subpart C--Labeling



Sec. 341.70  Labeling of OTC drug products containing ingredients that are used for treating concurrent symptoms (in either a single-ingredient or combination 
          drug product).

    The statements of identity, indications, warnings, and directions 
for use, respectively, applicable to each ingredient in the product may 
be combined to eliminate duplicative words or phrases so that the 
resulting information is clear and understandable.
    (a) For products containing diphenhydramine citrate and 
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and 
(a)(6). The labeling of the product contains the established name of the 
drug, if any, and identifies the product as an ``antihistamine/cough 
suppressant'' or ``antihistamine/antitussive (cough suppressant).'' The 
indications shall be combined from Secs. 341.72(b) and 341.74(b). The 
warnings shall be combined from Secs. 341.72(c)(1), (c)(2), (c)(4), and 
(c)(6) and 341.74(c)(1), (c)(2), (c)(3), and (c)(4). Alternatively, all 
of the warnings in Sec. 341.74(c) shall be used. The directions for OTC 
labeling shall follow Secs. 341.74(d)(1)(iv) or (d)(1)(v), as 
applicable. The directions for professional labeling shall follow 
Sec. 341.90(j) or (k), as applicable.
    (b) (Reserved)

[61 FR 15703, Apr. 9, 1996]



Sec. 341.72  Labeling of antihistamine drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as an 
``antihistamine.''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' any of the phrases listed in paragraph (b) of 
this section, as appropriate. Other truthful and nonmisleading 
statements, describing only the indications for use that have been 
established and listed in this paragraph, may also be used, as provided 
in Sec. 330.1(c)(2) of this chapter, subject to the provisions of 
section 502 of the Federal Food, Drug, and Cosmetic Act (the act) 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) ``Temporarily'' (select one of the following: ``relieves,'' 
``alleviates,'' ``decreases,'' ``reduces,'' or ``dries'') ``runny nose 
and'' (select one of the following: ``relieves,'' ``alleviates,'' 
``decreases,'' or ``reduces'') ``sneezing, itching of the nose or 
throat, and itchy, watery eyes due to hay fever'' (which may be followed 
by one or both of the following: ``or other upper respiratory 
allergies'' or ``(allergic rhinitis)'').
    (2) ``For the temporary relief of runny nose, sneezing, itching of 
the nose or throat, and itchy, watery eyes due to hay fever'' (which may 
be followed by one or both of the following: ``or other upper 
respiratory allergies'' or ``(allergic rhinitis)'').
    (c) Warnings. The labeling of the product contains the following 
warnings, under the heading ``Warnings'':
    (1) ``May cause excitability especially in children.''
    (2) ``Do not take this product, unless directed by a doctor, if you 
have a breathing problem such as emphysema or chronic bronchitis, or if 
you have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (3) For products containing brompheniramine maleate, chlorcyclizine 
hydrochloride, chlorpheniramine maleate, dexbrompheniramine maleate, 
dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, 
pyrilamine maleate, thonzylamine hydrochloride, or triprolidine 
hydrochloride identified in Sec. 341.12(a), (b), (c), (d), (e),

[[Page 242]]

(i), (j), (k), (l), and (m). ``May cause drowsiness; alcohol, sedatives, 
and tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (4) For products containing diphenhydramine citrate, diphenhydramine 
hydrochloride, or doxylamine succinate identified in Sec. 341.12(f), 
(g), and (h). ``May cause marked drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (5) For products containing phenindamine tartrate identified in 
Sec. 341.12(i). ``May cause nervousness and insomnia in some 
individuals.''
    (6) For products that are labeled only for use by children under 12 
years of age. The labeling of the product contains only the warnings 
identified in paragraphs (c)(1) and (c)(5) of this section as well as 
the following:
    (i) ``Do not give this product to children who have a breathing 
problem such as chronic bronchitis, or who have glaucoma, without first 
consulting the child's doctor.''
    (ii) For products containing brompheniramine maleate, 
chlorpheniramine maleate, dexbrompheniramine maleate, 
dexchlorpheniramine maleate, phenindamine tartrate, pheniramine maleate, 
pyrilamine maleate, thonzylamine hydrochloride, or triprolidine 
hydrochloride identified in Sec. 341.12(a), (c), (d), (e), (i), (j), 
(k), (l), and (m). ``May cause drowsiness. Sedatives and tranquilizers 
may increase the drowsiness effect. Do not give this product to children 
who are taking sedatives or tranquilizers, without first consulting the 
child's doctor.''
    (iii) For products containing diphenhydramine citrate, 
diphenhydramine hydrochloride, or doxylamine succinate identified in 
Sec. 341.12(f), (g), and (h). ``May cause marked drowsiness. Sedatives 
and tranquilizers may increase the drowsiness effect. Do not give this 
product to children who are taking sedatives or tranquilizers, without 
first consulting the child's doctor.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) For products containing brompheniramine maleate identified in 
Sec. 341.12(a). Adults and children 12 years of age and over: oral 
dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (2) For products containing chlorcyclizine hydrochloride identified 
in Sec. 341.12(b). Adults and children 12 years of age and over: oral 
dosage is 25 milligrams every 6 to 8 hours, not to exceed 75 milligrams 
in 24 hours, or as directed by a doctor. Children under 12 years of age: 
consult a doctor.
    (3) For products containing chlorpheniramine maleate identified in 
Sec. 341.12(c). Adults and children 12 years of age and over: oral 
dosage is 4 milligrams every 4 to 6 hours, not to exceed 24 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (4) For products containing dexbrompheniramine maleate identified in 
Sec. 341.12(d). Adults and children 12 years of age and over: oral 
dosage is 2 milligrams every 4 to 6 hours, not to exceed 12 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 1 milligram every 4 to 6 hours, not to exceed 6 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (5) For products containing dexchlorpheniramine maleate identified 
in Sec. 341.12(e). Adults and children 12 years of age and over: oral 
dosage is 2 milligrams every 4 to 6 hours, not to exceed

[[Page 243]]

12 milligrams in 24 hours, or as directed by a doctor. Children 6 to 
under 12 years of age: oral dosage is 1 milligram every 4 to 6 hours, 
not to exceed 6 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.
    (6) For products containing diphenhydramine citrate identified in 
Sec. 341.12(f). Adults and children 12 years of age and over: oral 
dosage is 38 to 76 milligrams every 4 to 6 hours, not to exceed 456 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 19 to 38 milligrams every 4 to 6 hours, 
not to exceed 228 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.
    (7) For products containing diphenhydramine hydrochloride identified 
in Sec. 341.12(g). Adults and children 12 years of age and over: oral 
dosage is 25 to 50 milligrams every 4 to 6 hours, not to exceed 300 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 12.5 to 25 milligrams every 4 to 6 
hours, not to exceed 150 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
    (8) For products containing doxylamine succinate identified in 
Sec. 341.12(h). Adults and children 12 years of age and over: oral 
dosage is 7.5 to 12.5 milligrams every 4 to 6 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 3.75 to 6.25 milligrams every 4 to 6 
hours, not to exceed 37.5 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
    (9) For products containing phenindamine tartrate identified in 
Sec. 341.12(i). Adults and children 12 years of age and over: oral 
dosage is 25 milligrams every 4 to 6 hours, not to exceed 150 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 12.5 milligrams every 4 to 6 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (10) For products containing pheniramine maleate identified in 
Sec. 341.12(j). Adults and children 12 years of age and over: oral 
dosage is 12.5 to 25 milligrams every 4 to 6 hours, not to exceed 150 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 6.25 to 12.5 milligrams every 4 to 6 
hours, not to exceed 75 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
    (11) For products containing pyrilamine maleate identified in 
Sec. 341.12(k). Adults and children 12 years of age and over: oral 
dosage is 25 to 50 milligrams every 6 to 8 hours, not to exceed 200 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 12.5 to 25 milligrams every 6 to 8 
hours, not to exceed 100 milligrams in 24 hours, or as directed by a 
doctor. Children under 6 years of age: consult a doctor.
    (12) For products containing thonzylamine hydrochloride identified 
in Sec. 341.12(l). Adults and children 12 years of age and over: oral 
dosage is 50 to 100 milligrams every 4 to 6 hours, not to exceed 600 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: oral dosage is 25 to 50 milligrams every 4 to 6 hours, 
not to exceed 300 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: consult a doctor.
    (13) For products containing triprolidine hydrochloride identified 
in Sec. 341.12(m). Adults and children 12 years of age and over: oral 
dosage is 2.5 milligrams every 4 to 6 hours, not to exceed 10 milligrams 
in 24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 1.25 milligrams every 4 to 6 hours, not to exceed 5 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.

[57 FR 58374, Dec. 9, 1992, as amended at 59 FR 4218, Jan. 28, 1994]



Sec. 341.74  Labeling of antitussive drug products.

    (a) Statement of identity. The labeling of the product contains the 
established name of the drug, if any, and identifies the product as a 
``cough suppressant''

[[Page 244]]

or an ``antitussive (cough suppressant).''
    (b) Indications. The labeling of the product states, under the 
heading ``Indications,'' any 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, may also be used, as provided in 
Sec. 330.1(c)(2), subject to the provisions of section 502 of the act 
relating to misbranding and the prohibition in section 301(d) of the act 
against the introduction or delivery for introduction into interstate 
commerce of unapproved new drugs in violation of section 505(a) of the 
act.
    (1) ``Temporarily'' (select one of the following: ``alleviates,'' 
``calms,'' ``controls,'' ``decreases,'' ``quiets,'' ``reduces,'' 
``relieves,'' or ``suppresses'') ``cough due to'' (select one of the 
following: ``minor bronchial irritation'' or ``minor throat and 
bronchial irritation'') (select one of the following: ``as may occur 
with,'' ``associated with,'' or ``occurring with'') (select one of the 
following: ``A cold'' or ``the common cold'') ``or inhaled irritants.''
    (2) ``Temporarily'' (select one of the following: ``alleviates,'' 
``calms,'' ``controls,'' ``decreases,'' ``quiets,'' ``reduces,'' 
``relieves,'' or ``suppresses'') ``cough'' (select one of the following: 
``as may occur with,'' ``associated with,'' or ``occurring with'') 
(select one of the following: ``A cold,'' ``the common cold,'' or 
``inhaled irritants'').
    (3) In addition to the required information identified in paragraphs 
(b) (1) and (2) of this section, the labeling of the product may contain 
any (one or more) of the following statements:
    (i) ``Cough suppressant which temporarily'' (select one of the 
following: ``Alleviates,'' ``controls,'' ``decreases,'' ``reduces,'' 
``relieves,'' or ``suppresses'') ``the impulse to cough.''
    (ii) ``Temporarily helps you cough less.''
    (iii) ``Temporarily helps to'' (select one of the following: 
``Alleviate,'' ``control,'' ``decrease,'' ``reduce,'' ``relieve,'' or 
``suppress'') ``the cough reflex that causes coughing.''
    (iv) ``Temporarily'' (select one of the following: ``Alleviates,'' 
``controls,'' ``decreases,'' ``reduces,'' ``relieves,'' or 
``suppresses'') ``the intensity of coughing.''
    (v) (Select one of the following: ``Alleviates,'' ``Controls,'' 
``Decreases,'' ``Reduces,'' ``Relieves,'' or ``Suppresses'') (select one 
of the following: ``Cough,'' ``the impulse to cough,'' or ``your 
cough'') ``to help you'' (select one of the following: ``Get to sleep,'' 
``sleep,'' or ``rest'').
    (vi) For products containing chlophedianol hydrochloride, codeine 
ingredients, dextromethorphan, or dextromethorphan hydrobromide 
identified in Sec. 341.14(a) (1), (2), (3), and (4). ``Calms the cough 
control center and relieves coughing.''
    (vii) For products containing chlophedianol hydrochloride, 
dextromethorphan, dextromethorphan hydrobromide, camphor, or menthol 
identified in Sec. 341.14(a) (1), (3), (4) and (b) (1) and (2). (a) 
``Nonnarcotic cough suppressant for the temporary'' (select one of the 
following: ``alleviation,'' ``control,'' ``decrease,'' ``reduction,'' 
``relief,'' or ``suppression'') ``of cough.''
    (b) (Select one of the following: ``Alleviates,'' ``Controls,'' 
``Decreases,'' ``Reduces,'' ``Relieves,'' or ``Suppresses'') ``cough 
impulses without narcotics.''
    (c) Warnings. The labeling of the product contains the following 
warnings under the heading ``Warnings'':
    (1) For oral and topical antitussives. ``A persistent cough may be a 
sign of a serious condition. If cough persists for more than 1 week, 
tends to recur, or is accompanied by fever, rash, or persistent 
headache, consult a doctor.''
    (2) For oral and topical antitussives labeled for adults or for 
adults and children under 12 years of age. ``Do not take this product 
for persistent or chronic cough such as occurs with smoking, asthma, or 
emphysema, or if cough is accompanied by excessive phlegm (mucus) unless 
directed by a doctor.''
    (3) For oral and topical antitussives labeled only for children 
under 12 years of age. ``Do not give this product for persistent or 
chronic cough such as occurs with asthma or if cough is accompanied by 
excessive phlegm (mucus) unless directed by a doctor.''
    (4) Oral antitussives--(i) For products containing codeine 
ingredients identified

[[Page 245]]

in Sec. 341.14(a)(2). ``May cause or aggravate constipation.''
    (ii) For products containing codeine ingredients identified in 
Sec. 341.14(a)(2) when labeled only for adults. ``Do not take this 
product if you have a chronic pulmonary disease or shortness of breath 
unless directed by a doctor.''
    (iii) For products containing codeine ingredients identified in 
Sec. 341.14(a)(2) when labeled only for children under 12 years of age. 
``Do not give this product to children who have a chronic pulmonary 
disease, shortness of breath, or who are taking other drugs unless 
directed by a doctor.''
    (iv) For products containing codeine ingredients identified in 
Sec. 341.14(a)(2) when labeled for use in adults and children under 12 
years of age. ``Adults and children who have a chronic pulmonary disease 
or shortness of breath, or children who are taking other drugs, should 
not take this product unless directed by a doctor.''
    (v) For products containing dextromethorphan or dextromethorphan 
hydrobromide as identified in Sec. 341.14(a)(3) and (a)(4) when labeled 
for adults or for adults and children under 12 years of age. Drug 
interaction precaution. ``Do not use if you are now taking a 
prescription monoamine oxidase inhibitor (MAOI) (certain drugs for 
depression, psychiatric, or emotional conditions, or Parkinson's 
disease), or for 2 weeks after stopping the MAOI drug. If you do not 
know if your prescription drug contains an MAOI, ask a doctor or 
pharmacist before taking this product.''
    (vi) For products containing dextromethorphan or dextromethorphan 
hydrobromide as identified in Sec. 341.14(a)(3) and (a)(4) when labeled 
only for children under 12 years of age. Drug interaction precaution. 
``Do not use in a child who is taking a prescription monoamine oxidase 
inhibitor (MAOI) (certain drugs for depression, psychiatric, or 
emotional conditions, or Parkinson's disease), or for 2 weeks after 
stopping the MAOI drug. If you do not know if your child's prescription 
drug contains an MAOI, ask a doctor or pharmacist before giving this 
product.''
    (vii) For products containing diphenhydramine citrate or 
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and 
(a)(6). ``May cause excitability especially in children.''
    (viii) For products containing diphenhydramine citrate or 
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and (a)(6) 
when labeled only for children under 12 years of age--(A) ``Do not give 
this product to children who have a breathing problem such as chronic 
bronchitis, or who have glaucoma, without first consulting the child's 
doctor.''
    (B) ``May cause marked drowsiness. Sedatives and tranquilizers may 
increase the drowsiness effect. Do not give this product to children who 
are taking sedatives or tranquilizers, without first consulting the 
child's doctor.''
    (ix) For products containing diphenhydramine citrate or 
diphenhydramine hydrochloride identified in Sec. 341.14(a)(5) and (a)(6) 
when labeled for use in adults and children under 12 years of age--(A) 
``Do not take this product, unless directed by a doctor, if you have a 
breathing problem such as emphysema or chronic bronchitis, or if you 
have glaucoma or difficulty in urination due to enlargement of the 
prostate gland.''
    (B) ``May cause marked drowsiness; alcohol, sedatives, and 
tranquilizers may increase the drowsiness effect. Avoid alcoholic 
beverages while taking this product. Do not take this product if you are 
taking sedatives or tranquilizers, without first consulting your doctor. 
Use caution when driving a motor vehicle or operating machinery.''
    (5) Topical antitussives--(i) For products containing camphor or 
menthol identified in Sec. 341.14(b) (1) and (2) in a suitable ointment 
vehicle. ``For external use only. Do not take by mouth or place in 
nostrils.''
    (ii) For products containing camphor or menthol identified in 
Sec. 341.14(b) (1) and (2) for steam inhalation use. ``For steam 
inhalation only. Do not take by mouth.''
    (d) Directions. The labeling of the product contains the following 
information under the heading ``Directions'':
    (1) Oral antitussives--(i) For products containing chlophedianol 
hydrochloride identified in Sec. 341.14(a)(1). Adults and children 12 
years of age and over: Oral dosage is 25 milligrams every 6 to 8

[[Page 246]]

hours, not to exceed 100 milligrams in 24 hours, or as directed by a 
doctor. Children 6 to under 12 years of age: Oral dosage is 12.5 
milligrams every 6 to 8 hours, not to exceed 50 milligrams in 24 hours, 
or as directed by a doctor. Children under 6 years of age: Consult a 
doctor.
    (ii) For products containing codeine ingredients identified in 
Sec. 341.14(a)(2). Adults and children 12 years of age and over: Oral 
dosage is 10 to 20 milligrams every 4 to 6 hours, not to exceed 120 
milligrams in 24 hours, or as directed by a doctor. Children 6 to under 
12 years of age: Oral dosage is 5 to 10 milligrams every 4 to 6 hours, 
not to exceed 60 milligrams in 24 hours, or as directed by a doctor. 
Children under 6 years of age: Consult a doctor. A special measuring 
device should be used to give an accurate dose of this product to 
children under 6 years of age. Giving a higher dose than recommended by 
a doctor could result in serious side effects for your child.
    (iii) For products containing dextromethorphan or dextromethorphan 
hydrobromide identified in Sec. 341.14(a) (3) and (4). The dosage is 
equivalent to dextromethorphan hydrobromide. Adults and children 12 
years of age and over: Oral dosage is 10 to 20 milligrams every 4 hours 
or 30 milligrams every 6 to 8 hours, not to exceed 120 milligrams in 24 
hours, or as directed by a doctor. Children 6 to under 12 years of age: 
Oral dosage is 5 to 10 milligrams every 4 hours or 15 milligrams every 6 
to 8 hours, not to exceed 60 milligrams in 24 hours, or as directed by a 
doctor. Children 2 to under 6 years of age: Oral dosage is 2.5 to 5 
milligrams every 4 hours or 7.5 milligrams every 6 to 8 hours, not to 
exceed 30 milligrams in 24 hours, or as directed by a doctor. Children 
under 2 years of age: Consult a doctor.
    (iv) For products containing diphenhydramine citrate identified in 
Sec. 341.14(a)(5). Adults and children 12 years of age and over: oral 
dosage is 38 milligrams every 4 hours, not to exceed 228 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 19 milligrams every 4 hours, not to exceed 114 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (v) For products containing diphenhydramine hydrochloride identified 
in Sec. 341.14(a)(6). Adults and children 12 years of age and over: oral 
dosage is 25 milligrams every 4 hours, not to exceed 150 milligrams in 
24 hours, or as directed by a doctor. Children 6 to under 12 years of 
age: oral dosage is 12.5 milligrams every 4 hours, not to exceed 75 
milligrams in 24 hours, or as directed by a doctor. Children under 6 
years of age: consult a doctor.
    (2) Topical antitussives--(i) For products containing camphor 
identified in Sec. 341.14(b)(1) in a suitable ointment vehicle. The 
product contains 4.7 to 5.3 percent camphor. Adults and children 2 to 
under 12 years of age: Rub on the throat and chest as a thick layer. The 
area of application may be covered with a warm, dry cloth if desired. 
However, clothing should be left loose about the throat and chest to 
help the vapors rise to reach the nose and mouth. Applications may be 
repeated up to three times daily or as directed by a doctor. Children 
under 2 years of age: consult a doctor.
    (ii) For products containing menthol identified in Sec. 341.14(b)(2) 
in a suitable ointment vehicle. The product contains 2.6 to 2.8 percent 
menthol. Adults and children 2 to under 12 years of age: Rub on the 
throat and chest as a thick layer. The area of application may be 
covered with a warm, dry cloth if desired. However, clothing should be 
left loose about the throat and chest to help the vapors rise to reach 
the nose and mouth. Applications may be repeated up to three times daily 
or as directed by a doctor. Children under 2 years of age: consult a 
doctor.
    (iii) For products containing menthol identified in 
Sec. 341.14(b)(2) in a lozenge. The product contains 5 to 10 milligrams 
menthol. Adults and children 2 to under 12 years of age: Allow lozenge 
to dissolve slowly in the mouth. May be repeated every hour as needed or 
as directed by a doctor. Children under 2 years of age: Consult a 
doctor.
    (iv) For products containing camphor identified in Sec. 341.14(b)(1) 
for steam inhalation use. The product contains 6.2 percent camphor. 
Adults and children 2 to under 12 years of age: Add 1 tablespoonful of 
solution, for each quart of water,

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directly to the water in a hot steam vaporizer, bowl, or wash basin; or 
add 1\1/2\ teaspoonsful of solution, for each pint of water, to an open 
container of boiling water. Breathe in the medicated vapors. May be 
repeated up to three times daily or as directed by a doctor. Children 
under 2 years of age: consult a doctor.
    (v) For products containing menthol identified in Sec. 341.14(b)(2) 
for steam inhalation use. The product contains 3.2 percent menthol. 
Adults and children 2 to under 12 years of age: Add 1 tablespoonful of 
solution, for each quart of water, directly to the water in a hot steam 
vaporizer, bowl, or wash basin; or add 1\1/2\ teaspoonsful of solution, 
for each pint of water, to an open container of boiling water. Breathe 
in the medicated vapors. May be repeated up to three times daily or as 
directed by a doctor. Children under 2 years of age: consult a doctor.
    (e) The word ``physician'' may be substituted for the word 
``doctor'' in any of the labeling statements in this section.
    (f) Exemption from the general accidental overdose warning. The 
labeling for antitussive drug products containing the active ingredient 
identified in Sec. 341.14(b)(2) marketed in accordance with 
Sec. 341.74(d)(2)(iii) is 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.''

[52 FR 30055, Aug. 12, 1987; 52 FR 35610, Sept. 22, 1987; 53 FR 35809, 
Sept. 15, 1988; 55 FR 27808, July 6, 1990; 55 FR 40383, Oct. 3, 1990; 58 
FR 54236, Oct. 20, 1993; 59 FR 29174, June 3, 1994; 59 FR 36051, July 
15, 1994; 64 FR 13295, Mar. 17, 1999; 65 FR 8, Jan. 3, 2000]

    Effective Date Note: At 65 FR 46867, Aug. 1, 2000, Sec. 341.74 was 
amended by adding new paragraphs (c)(5)(iii) through (c)(5)(vii), and by 
revising paragraphs (d)(2)(i), (d)(2)(ii), (d)(2)(iv), and (d)(2)(v), 
effective May 16, 2002. For the convenience of the user, the revised 
text is set forth as follows:

Sec. 341.74  Labeling of antitussive drug products.

                                * * * * *

    (c) * * *
    (5) * * *
    (iii) For any product containing camphor or menthol in a suitable 
ointment vehicle or for steam inhalation use and meets the definition of 
one of the signal words (``extremely flammable,'' ``flammable,'' 
``combustible'') as described in 16 CFR 1500.3(b)(10). The labeling 
contains the appropriate flammability signal word(s) followed by a colon 
and the statement ``Keep away from fire or flame.''
    (iv) For any product containing camphor or menthol in a suitable 
ointment vehicle and that does not contain a flammability signal word as 
described in 16 CFR 1500.3(b)(10). ``When using this product, do not 
[bullet] \1\ heat [bullet] microwave [bullet] add to hot water or any 
container where heating water. May cause splattering and result in 
burns.'' [Information highlighted in bold type.]
---------------------------------------------------------------------------

    \1\ For a definition of the term ``bullet,'' see Sec. 201.66(b)(4) 
of this chapter.
---------------------------------------------------------------------------

    (v) For any product containing camphor or menthol in a suitable 
ointment vehicle and that contains a flammability signal word as 
described in 16 CFR 1500.3(b)(10). ``When using this product, do not 
[bullet] heat [bullet] microwave [bullet] use near an open flame 
[bullet] add to hot water or any container where heating water. May 
cause splattering and result in burns.'' [Information highlighted in 
bold type.]
    (vi) For any product containing camphor or menthol for steam 
inhalation use. ``When using this product, do not [bullet] heat [bullet] 
microwave [bullet] use near an open flame [bullet] add to hot water or 
any container where heating water except when adding to cold water only 
in a hot steam vaporizer. May cause splattering and result in burns.'' 
[Information highlighted in bold type.]
    (vii) For any product formulated in a volatile vehicle. The labeling 
contains the following statement under the heading ``Other 
information'': ``Close container tightly and store at room temperature 
away from heat.''
    (d) * * *
    (2) * * *
    (i) For products containing camphor identified in Sec. 341.14(b)(1) 
in a suitable ointment vehicle. The product contains 4.7 to 5.3 percent 
camphor. ``[bullet] see important warnings under `When using this 
product' '' [appears as the first statement under the heading 
``Directions'' and is highlighted in bold type] [bullet] adults and 
children 2 years and older: [bullet] rub on the throat and chest in a 
thick layer [bullet] cover with a warm, dry cloth if desired [bullet] 
clothing should be loose about throat and chest to help vapors reach the 
nose and mouth [bullet] use up to

[[Page 248]]

three times daily or as directed by a doctor [bullet] children under 2 
years of age: Ask a doctor.
    (ii) For products containing menthol identified in Sec. 341.14(b)(2) 
in a suitable ointment vehicle. The product contains 2.6 to 2.8 percent 
menthol. ``[bullet] see important warnings under `When using this 
product' '' [appears as the first statement under the heading 
``Directions'' and is highlighted in bold type] [bullet] adults and 
children 2 yea