[Title 21 CFR ]
[Code of Federal Regulations (annual edition) - April 1, 1998 Edition]
[From the U.S. Government Printing Office]
[[Page i]]
21
Food and Drugs
PARTS 300 TO 499
Revised as of April 1, 1998
CONTAINING
A CODIFICATION OF DOCUMENTS
OF GENERAL APPLICABILITY
AND FUTURE EFFECT
AS OF APRIL 1, 1998
With Ancillaries
Published by
the Office of the Federal Register
National Archives and Records
Administration
as a Special Edition of
the Federal Register
[[Page ii]]
U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 1998
For sale by U.S. Government Printing Office
Superintendent of Documents, Mail Stop: SSOP, Washington, DC 20402-9328
[[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.......... 1063
Table of CFR Titles and Chapters.......................... 1065
Alphabetical List of Agencies Appearing in the CFR........ 1081
List of CFR Sections Affected............................. 1091
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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.
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[[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
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To determine whether a Code volume has been amended since its
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Sections Affected (LSA),'' which is issued monthly, and the ``Cumulative
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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
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OMB CONTROL NUMBERS
The Paperwork Reduction Act of 1980 (Pub. L. 96-511) requires
Federal agencies to display an OMB control number with their information
collection request.
[[Page vi]]
Many agencies have begun publishing numerous OMB control numbers as
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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), and Acts Requiring Publication
in the Federal Register (Table II). 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.
[[Page vii]]
A List of CFR Sections Affected (LSA) is published monthly, keyed to
the revision dates of the 50 CFR titles.
REPUBLICATION OF MATERIAL
There are no restrictions on the republication of material appearing
in the Code of Federal Regulations.
INQUIRIES
For a legal interpretation or explanation of any regulation in this
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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.
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Raymond A. Mosley,
Director,
Office of the Federal Register.
April 1, 1998.
[[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, 1998.
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.
For this volume, Melanie L. Marcec was Chief Editor. The Code of
Federal Regulations publication program is under the direction of
Frances D. McDonald, assisted by Alomha S. Morris.
[[Page x]]
[[Page 1]]
TITLE 21--FOOD AND DRUGS
(This book contains parts 300 to 499)
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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 Meat and Poultry Inspection, 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)
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Editorial Note: The Food and Drug Administration published a document
at 49 FR 41019, Oct. 19, 1984, establishing July 1, 1987, as a uniform
effective date for compliance for regulations affecting the labeling of
food products. At 51 FR 34085, Sept. 25, 1986, FDA established January
1, 1989, as a new uniform effective date for compliance. The new uniform
effective date will apply only to final FDA food labeling regulations
published after July 1, 1986, and before January 1, 1988. At 55 FR 276,
Jan. 4, 1990, FDA established January 1, 1993 as a new uniform effective
date for compliance. The new uniform effective date will apply only to
final FDA food labeling regulations published after January 1, 1990 and
before January 1, 1992.
SUBCHAPTER D--DRUGS FOR HUMAN USE
Part Page
300 General..................................... 7
310 New drugs................................... 7
312 Investigational new drug application........ 61
314 Applications for FDA approval to market a
new drug or an antibiotic drug.......... 99
316 Orphan drugs................................ 179
320 Bioavailability and bioequivalence
requirements............................ 190
328 Over-the-counter drug products intended for
oral ingestion that contain alcohol..... 205
329 Habit-forming drugs......................... 206
330 Over-the-counter (OTC) human drugs which are
generally recognized as safe and
effective and not misbranded............ 211
331 Antacid products for over-the-counter (OTC)
human use............................... 223
332 Antiflatulent products for over-the-counter
human use............................... 227
333 Topical antimicrobial drug products for
over-the-counter human use.............. 228
336 Antiemetic drug products for over-the-
counter human use....................... 236
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338 Nighttime sleep-aid drug products for over-
the-counter human use................... 238
340 Stimulant drug products for over-the-counter
human use............................... 239
341 Cold, cough, allergy, bronchodilator, and
antiasthmatic drug products for over-
the-counter human use................... 240
344 Topical OTIC drug products for over-the-
counter human use....................... 256
346 Anorectal drug products for over-the-counter
human use............................... 257
347 Skin protectant drug products for over-the-
counter human use....................... 262
348 External analgesic drug products for over-
the-counter human use................... 263
349 Ophthalmic drug products for over-the-
counter human use....................... 265
355 Anticaries drug products for over-the-
counter human use....................... 270
357 Miscellaneous internal drug products for
over-the-counter human use.............. 275
358 Miscellaneous external drug products for
over-the-counter human use.............. 279
361 Prescription drugs for human use generally
recognized as safe and effective and not
misbranded: Drugs used in research...... 285
369 Interpretative statements re warnings on
drugs and devices for over-the-counter
sale.................................... 290
429 Drugs composed wholly or partly of insulin.. 299
430 Antibiotic drugs; general................... 310
431 Certification of antibiotic drugs........... 331
432 Packaging and labeling of antibiotic drugs.. 339
433 Exemptions from antibiotic certification and
labeling requirements................... 340
436 Tests and methods of assay of antibiotic and
antibiotic-containing drugs............. 351
440 Penicillin antibiotic drugs................. 483
441 Penem antibiotic drugs...................... 588
442 Cepha antibiotic drugs...................... 593
443 Carbacephem antibiotic drugs................ 696
444 Oligosaccharide antibiotic drugs............ 699
446 Tetracycline antibiotic drugs............... 761
448 Peptide antibiotic drugs.................... 826
449 Antifungal antibiotic drugs................. 865
450 Antitumor antibiotic drugs.................. 890
452 Macrolide antibiotic drugs.................. 911
453 Lincomycin antibiotic drugs................. 949
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455 Certain other antibiotic drugs.............. 968
460 Antibiotic drugs intended for use in
laboratory diagnosis of disease......... 1019
461-499
[Reserved]
Editorial Note: For nomenclature changes to chapter I see 59 FR 14366,
Mar. 28, 1994.
[[Page 7]]
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, 357, 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 or antibiotic monograph 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.0
[40 FR 13496, Mar. 27, 1975]
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 8]]
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.
310.516 Progestational drug products; labeling directed to the patient.
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.
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 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.
[[Page 9]]
(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.
(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]
[[Page 10]]
Sec. 310.4 Biologics; products subject to license control.
(a) Except for radioactive biological products intended for human
use, a new drug shall not be deemed to be subject to section 505 of the
act if it is a drug licensed under the Public Health Service Act of July
1, 1944 (58 Stat. 682, as amended (42 U.S.C. 201 et seq.)) or under the
animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832 (21
U.S.C. 151 et seq.)).
(b) A radioactive biological product (as defined in Sec. 600.3(ee)
of this chapter) intended for human use is subject to section 505 of the
act. Any license for such a radioactive biological product which is
issued under the Public Health Service Act of July 1, 1944 (58 Stat.
682, as amended (42 U.S.C. 201 et seq.)) and which has not been revoked
or suspended as of August 25, 1975 shall constitute an approved new drug
application in effect under the same terms and conditions as set forth
in such license and such portions of the establishment license relating
to such product, which include data and information required under part
314 of this chapter for a new drug application. Any such radioactive
biological product for which licensure under the Public Health Service
Act is pending on August 25, 1975 shall, upon determination that it is
acceptable for licensure, be approved as a new drug application in lieu
of issuance of a biological product license.
[40 FR 31312, July 25, 1975]
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
[[Page 11]]
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. 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
[[Page 12]]
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 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]
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
[[Page 13]]
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.
(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''.
[[Page 14]]
(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 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.
[[Page 15]]
(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 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
[[Page 16]]
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, 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.
[[Page 17]]
(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 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
[[Page 18]]
professed standards of identity, strength, quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 50 milligrams of
pamabrom per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the minor pains and discomforts that may occur a
few days before and during the menstrual period.
(vi) The dosages recommended or suggested in the labeling do not
exceed 50 milligrams of pamabrom per dose or 200 milligrams per 24-hour
period.
(22) Diphemanil methylsulfate (4-diphenylmethylene-1,1-dimethyl-
piperidinium methylsulfate) preparations meeting all the following
conditions:
(i) The diphemanil methylsulfate is prepared, with or without other
drugs, in a dosage form suitable for use in self-medication by external
application to the skin, and containing no drug limited to prescription
sale under the provisions of section 503(b)(1) of the act.
(ii) The diphemanil methylsulfate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 2.0 percent of
diphemanil methylsulfate.
(v) The preparation is labeled with adequate directions for use by
external application to the skin for the relief of symptoms of mild
poison ivy, oak, and sumac and other minor irritations and itching of
the skin.
(vi) The directions for use recommend or suggest not more than four
applications of the preparation per day, unless directed by a physician.
(vii) The labeling bears, in juxtaposition with the directions for
use, a clear warning statement, such as: ``Caution: If redness,
irritation, swelling, or pain persists or increases, discontinue use and
consult physician.''
(23) Dyclonine hydrochloride (4-butoxy-3-piperidinopropiophenone
hydrochloride; 4-n-butoxy--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.
[[Page 19]]
(ii) The chlorothen citrate and all other components of the
preparation meet their professed standards of identity, strength,
quality, and purity.
(iii) If the preparation is a new drug, an application pursuant to
section 505(b) of the act is approved for it.
(iv) The preparation contains not more than 25 milligrams of
chlorothen citrate per dosage unit.
(v) The preparation is labeled with adequate directions for use in
the temporary relief of the symptoms of hay fever and/or the symptoms of
other minor conditions in which it is indicated.
(vi) The dosages recommended or suggested in the labeling do not
exceed: For adults, 25 milligrams of chlorothen citrate per dose or 150
milligrams of chlorothen citrate per 24-hour period; for children 6 to
12 years of age, one-half of the maximum adult dose or dosage.
(vii) The labeling bears, in juxtaposition with the dosage
recommendations:
(a) Clear warning statements against administration of the drug to
children under 6 years of age or exceeding the recommended dosage,
unless directed by a physician, and against driving a car or operating
machinery while using the drug, since it may cause drowsiness.
(b) If the article is offered for the temporary relief of symptoms
of colds, a statement that continued administration for such use should
not exceed 3 days, unless directed by a physician.
(25) [Reserved]
(26) Methoxyphenamine hydrochloride (-(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-hydroxy-benzoate 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.
[[Page 20]]
(iv) The preparation contains not more than 1 percent of biphenamine
hydrochloride.
(v) The preparation is labeled with adequate directions for use for
the temporary relief of itching and scaling due to dandruff.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children.
(28) Tyloxapol (an alkylarylpolyether alcohol) and benzalkonium
chloride ophthalmic preparations meeting all the following conditions:
(i) The tyloxapol and benzalkonium chloride are prepared, with other
appropriate ingredients which are not drugs limited to prescription sale
under the provisions of section 503(b)(1) of the act, as a sterile,
isotonic aqueous solution suitable for use in self-medication on eye
prostheses.
(ii) The preparation is so packaged as to volume and type of
container as to afford adequate protection and be suitable for self-
medication with a minimum risk of contamination of the solution during
use. Any dispensing unit is sterile and so packaged as to maintain
sterility until the package is opened.
(iii) The tyloxapol, benzalkonium chloride, and other ingredients
used to prepare the isotonic aqueous solution meet their professed
standards of identity, strength, quality, and purity.
(iv) An application pursuant to section 505(b) of the act is
approved for the drug.
(v) The preparation contains 0.25 percent of tyloxapol and 0.02
percent of benzalkonium chloride.
(vi) The label bears a conspicuous warning to keep the drug out of
the reach of children and the labeling bears, in juxtaposition with the
dosage recommendations, a clear warning that if irritation occurs,
persists, or increases, use of the drug should be discontinued and a
physician consulted. The labeling includes a statement that the dropper
or other dispensing tip should not touch any surface, since this may
contaminate the solution.
(29) [Reserved]
(b) [Reserved]
[39 FR 11680, Mar. 29, 1974, as amended at 42 FR 36994, July 19, 1977;
52 FR 15892, Apr. 30, 1987; 52 FR 30055, Aug. 12, 1987; 55 FR 31779,
Aug. 3, 1990; 57 FR 58374, Dec. 9, 1992; 58 FR 49898, Sept. 23, 1993; 59
FR 4218, Jan. 28, 1994; 60 FR 52507, Oct. 6, 1995]
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
[[Page 21]]
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:-
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
[[Page 22]]
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 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
[[Page 23]]
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 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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0210)
[51 FR 24779, 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]
Effective Date Note: At 62 FR 52249, Oct. 7, 1997, Sec. 310.305 was
amended by adding a new sentence at the end of paragraph (a); by
revising paragraphs (b), (c), (d)(1), (d)(3)(ii), and (d)(4); by
removing in paragraph (d)(2), the introductory text of paragraph (d)(3),
and paragraph (d)(3)(i) the words ``Form FDA-1639'' or ``FDA-1639'' and
adding in their place ``FDA Form 3500A'', effective Apr. 6, 1998. For
the convenience of the user, the superseded text is set forth as
follows:
Sec. 310.305 Records and reports concerning adverse drug experiences on
marketed prescription drugs for human use without approved new
drug applications.
* * * * *
(b) Definitions. The following definitions of terms apply to this
section:
(1) FDA means the Food and Drug Administration.
(2) Adverse drug experience means 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.
(3) Unexpected means an adverse drug experience that is not listed
in the current labeling for the drug product and includes an event that
may be symptomatically and pathophysiologically related to an event
listed in the labeling, but differs 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
[[Page 24]]
and cerebral vasculitis would be unexpected (by virtue of greater
specificity) if the labeling only listed cerebral vascular accidents.
(4) Serious means an adverse drug experience that is fatal or life-
threatening, is permanently disabling, requires inpatient
hospitalization, or is a congenital anomaly, cancer, or overdose.
(c) Reporting requirements--15-day ``Alert reports.'' (1)(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 any case within 15
working days of initial receipt of the information. 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) Each person identified in paragraph (c)(1) of this section shall
submit one copy of each report 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.
(3) Each person identified in paragraph (c)(1) of this section shall
promptly investigate all serious, unexpected adverse drug experiences
that are the subject of these 15-day Alert reports and shall submit
followup reports within 15 working days of receipt of new information or
as requested by FDA. If additional information is not obtainable, a
followup report may be required that describes briefly the steps taken
to seek additional information and the reasons why it could not be
obtained.
(4) 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 3 working 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 drug experience report.
(ii) Date the report was received by the packer or distributor.
(iii) Date the report was submitted to the manufacturer.
(iv) Name and address of the manufacturer.
(5) 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.''
(d) Reporting form. (1) Except as provided in paragraph (d)(3) of
this section, each person identified in paragraph (c)(1) of this section
shall submit each report of a serious and unexpected adverse drug
experience on a Form FDA-1639 (Adverse Reaction Report).
* * * * *
(3)* * *
(i)* * *
(ii) The format is agreed to in advance by the Division of
Epidemiology and Surveillance (HFD-730).
(4) Single copies of Form FDA-1639 may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the
PHS Forms and Publications Distribution Center, 12100 Parklawn Dr.,
Rockville, MD 20857.
* * * * *
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
[[Page 25]]
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 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
[[Page 26]]
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 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
[[Page 27]]
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 Guidelines
(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 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
[[Page 28]]
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 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
[[Page 29]]
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 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.
[[Page 30]]
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 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
[[Page 31]]
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. plus-minus0.5 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 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 plus-minus2 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 plus-minus0.2 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.plus-minus0.5 deg.C., and allow the dissolution
medium to assume the temperature of the bath.
[[Page 32]]
Position the shaft so that there is a distance of 2.5 centimeters
plus-minus0.2 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 rpmplus-minus2 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 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]
[[Page 33]]
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.
(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.
[[Page 34]]
(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]
Sec. 310.502 Certain drugs accorded new drug status through rulemaking procedures.
(a) The drugs listed in this paragraph (a) have been determined by
rulemaking procedures to be new drugs within the meaning of section
201(p) of the act. Except as provided in paragraph (b) of this section,
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) Any drug listed in paragraph (a) of this section, when composed
wholly or partly of any antibiotic drug, must be certified under section
507 of the act or exempted from certification under section 507 of the
act for marketing.
[62 FR 12084, Mar. 14, 1997]
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
[[Page 35]]
for which safety and effectiveness can be demonstrated by new-drug
applications or through licensing by the Public Health Service 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.
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.
[[Page 36]]
Do................ Diethylenetri-amine Kidney scans.
pentaacetic acid
(DTPA).
Xenon 133............. Gas.................... Diagnosis of cardia
abnormalities.
Cerebral bloodflow
studies. Pulmonary
function studies.
Muscle bloodflow
studies.
------------------------------------------------------------------------
\1\ This item has been removed from the AEC list for kidney scans but is
included as the requirements of this order are applicable.
(d)(1) In view of the extent of experience with the isotopes listed
in paragraph (c) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that such isotopes should not
be distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(2) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, is terminated on March 3, 1972, except as provided in
paragraph (d)(3) of this section.
(3) The exemption referred to in paragraph (a) of this section, as
applied to any drug or biologic containing any of the isotopes listed in
paragraph (c) of this section, in the ``chemical form'' and intended for
the uses stated, for which drug a new drug application or a
``Investigational New Drug Application'' was submitted prior to March 3,
1972, or for which biologic an application for product license or
``Investigational New Drug Application'' was submitted prior to March 3,
1972, is terminated on August 20, 1976, unless an approvable notice was
issued on or before August 20, 1976, in which case the exemption is
terminated either upon the subsequent issuance of a nonapprovable notice
for the new drug application or on November 20, 1976, whichever occurs
first.
(e) No exemption from section 505 of the act or from part 312 of
this chapter is in effect or has been in effect for radioactive drugs
prepared from accelerator-produced radioisotopes, naturally occurring
isotopes, or nonradioactive substances used in conjunction with
isotopes.
(f)(1) Based on its experience in regulating investigational
radioactive pharmaceuticals, the Nuclear Regulatory Commission has
compiled a list of reactor-produced isotopes for which it considers that
applicants may reasonably be expected to submit adequate evidence of
safety and effectiveness for use as recommended in appropriate labeling;
such use may include, among others, the uses in this tabulation:
------------------------------------------------------------------------
Isotope Chemical form Use
------------------------------------------------------------------------
Fluorine 18........... Fluoride............... Bone imaging.
Indium-113m........... Diethylenetriamine Brain imaging; kidney
pentaacetic acid imaging.
(DTPA).
Do................ Chloride............... Placenta imaging; blood
pool imaging.
Technetium 99m........ Human serum albumin Lung imaging.
microspheres.
Do................ Diethylenetriamine Kidney imaging; kidney
pentaacetic acid (Sn). function studies.
Do................ ......do............... Brain imaging.
Do................ Polyphosphates......... Bone imaging.
Do................ Technetated aggregated Lung imaging.
albumin (human).
Do................ Disodium etidronate.... Bone imaging.
------------------------------------------------------------------------
(2) In view of the extent of experience with the isotopes listed in
paragraph (f)(1) of this section, the Nuclear Regulatory Commission and
the Food and Drug Administration conclude that they should not be
distributed under investigational-use labeling when they are actually
intended for use in medical practice.
(3) Any manufacturer or distributor interested in continuing to ship
in interstate commerce drugs containing the isotopes listed in paragraph
(f)(1) of this section for any of the indications listed, shall submit,
on or before August 25, 1975 to the Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857, a new drug application or a ``Investigational New Drug
Application'' for each such drug for which the manufacturer or
distributor does not have an approved new drug application pursuant to
section 505(b) of the act. If the drug is a biologic, a
``Investigational New Drug Application'' or an application for a license
under section 351 of the Public Health Service Act shall be submitted to
the Center for Biologics Evaluation and
[[Page 37]]
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 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]
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.
[[Page 38]]
(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.
(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.
[[Page 39]]
(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. 310.516 Progestational drug products; labeling directed to the patient.
(a) The Commissioner of Food and Drugs concludes that the safe and
effective use of any progestational drug product requires that patients
be informed that there is an increased risk of birth defects in children
whose mothers have taken this drug during the first 4 months of
pregnancy. Accordingly, except as provided by paragraph (d) of this
section, any progestational drug product that is the subject of a new
drug application approved either before or after October 9, 1962 and all
identical, related, or similar drug products as defined in Sec. 310.6,
whether or not the subject of an approved new drug application, shall be
dispensed to patients with labeling in lay language containing such a
warning. The patient labeling shall be provided as a separate printed
leaflet independent of any additional materials.
(b) The patient labeling shall specifically include the following:
(1) Name of the drug.
(2) Name and place of business of the manufacturer, packer, or
distributor.
(3) A warning that there is an increased risk of birth defects in
children whose mothers take this drug during the first 4 months of
pregnancy.
(4) A brief discussion of the nature of the risks of birth defects
resulting from the use of these drugs during the first 4 months of
pregnancy.
(5) A brief statement that these drugs are no longer considered safe
as a test for pregnancy.
(6) A statement that the patient should inform her physician as soon
as possible if she discovers that she was pregnant when she took the
drug.
(c) The patient labeling shall be printed in accordance with the
following specifications:
(1) The minimum letter size shall be one-sixteenth of an inch in
height.
(2) Letter heights pertain to the lower-case letter ``o'' or its
equivalent that shall meet the minumim height standard.
(3) Type used shall conform to the minimum letter height. The body
copy shall contain 1-point leading, noncondensed type, and shall not
contain any light-face type or small capital letters.
(d) This section does not apply to a progestogen-containing product
intended for contraception, which shall be labeled according to the
requirements of Sec. 310.501.
(e)(1) Patient labeling for each progestational drug product shall
be provided in or with each package intended to be dispensed to the
patient. Patient labeling for drug products 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 first administration of the drug and every 30 days thereafter, as
long as the therapy continues.
(2) In the case of progestational drug products in bulk packages
intended for multiple dispensing, a sufficient number of patient-
labeling pieces shall be included in or shall accompany each bulk
package to assure that one can be included with each package dispensed
to every patient. Each bulk package shall be labeled with instructions
to the dispenser to include one patient-labeling piece with each package
dispensed to the patient. This section does not preclude the
manufacturer or labeler from distributing additional patient-labeling
pieces to the dispenser.
(3) In the case of progestational drug products for injection, each
package shall include a sufficient number of patient-labeling pieces for
the volume of the vial, and instructions to the practitioner
administering the drug to give one patient-labeling piece to each
premenopausal woman, except those in
[[Page 40]]
whom childbearing is impossible, receiving the drug.
(4) This section does not apply to oral dosage forms labeled solely
for the treatment of advanced cancer.
(5) Any progestational drug product, except as noted in paragraphs
(d) and (e)(4) of this section, that is not labeled as required by this
section and is either introduced or delivered for introduction into
interstate commerce, or held for sale after shipment in interstate
commerce, is misbranded under section 502 of the Federal Food, Drug, and
Cosmetic Act. However, a progestational drug product in the possession
of a wholesaler or retailer before December 12, 1978, is not misbranded
if adequate numbers of copies of the patient labeling are furnished to
the wholesaler or retailer to permit any retail purchaser after that
date to obtain such labeling with the product. The requirement that any
progestational drug product be dispensed with patient labeling, as
applied to physicians who dispense or administer the drug, will not be
effective for supplies in their possession on the effective date, but
will apply only to supplies received thereafter.
(f) The Food and Drug Administration has available guideline patient
labeling for progestational drug products that includes information
responsive to all items specified in paragraph (b) of this section. This
labeling was published in a separate notice appearing in the Federal
Register of January 12, 1989. Any person may rely on this labeling as
complying with paragraph (b) of this section.
(g) Holders of approved new drug applications for progestational
drug products that are subject to the requirements of this section shall
submit supplements under Sec. 314.70(c) of this chapter to provide for
the labeling required by paragraph (a) of this section.
[43 FR 47181, Oct. 13, 1978, as amended at 46 FR 53657, Oct. 30, 1981;
54 FR 1163, Jan. 12, 1989]
Sec. 310.517 Labeling for oral hypoglycemic drugs of the sulfonylurea class.
(a) The University Group Diabetes Program clinical trial has
reported an association between the administration of tolbutamide and
increased cardiovascular mortality. The Food and Drug Administration has
concluded that this reported association provides adequate basis for a
warning in the labeling. In view of the similarities in chemical
structure and mode of action, the Food and Drug Administration also
believes it is prudent from a safety standpoint to consider that the
possible increased risk of cardiovascular mortality from tolbutamide
applies to all other sulfonylurea drugs as well. Therefore, the labeling
for oral hypoglycemic drugs of the sulfonylurea class shall include a
warning concerning the possible increased risk of cardiovascular
mortality associated with such use, as set forth in paragraph (b) of
this section.
(b) Labeling for oral hypoglycemic drugs of the sulfonylurea class
shall include in boldface type at the beginning of the ``Warnings''
section of the labeling the following statement:
Special Warning on Increased Risk of Cardiovascular Mortality
The administration of oral hypoglycemic drugs has been reported to
be associated with increased cardiovascular mortality as compared to
treatment with diet alone or diet plus insulin. This warning is based on
the study conducted by the University Group Diabetes Program (UGDP), a
long-term prospective clinical trial designed to evaluate the
effectiveness of glucose-lowering drugs in preventing or delaying
vascular complications in patients with non-insulin-dependent diabetes.
The study involved 823 patients who were randomly assigned to one of
four treatment groups (Diabetes, 19 (supp. 2): 747-830, 1970).
UGDP reported that patients treated for 5 to 8 years with diet plus
a fixed dose of tolbutamide (1.5 grams per day) had a rate of
cardiovascular mortality approximately 2\1/2\ times that of patients
treated with diet alone. A significant increase in total mortality was
not observed, but the use of tolbutamide was discontinued based on the
increase in cardiovascular mortality, thus limiting the opportunity for
the study to show an increase in overall mortality. Despite controversy
regarding the interpretation of these results, the findings of the UGDP
study provide an adequate basis for this warning. The patient should be
informed of the potential risks and advantages of (name of drug) and of
alternative modes of therapy.
Although only one drug in the sulfonylurea class (tolbutamide) was
included in this study, it is prudent from a safety standpoint to
consider that this warning may also apply
[[Page 41]]
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.
(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
[[Page 42]]
evidence presently available, there are no ingredients that can be
generally recognized as safe and effective for use as OTC daytime
sedatives.
(b) Any OTC drug product that is labeled, represented, or promoted
as an OTC daytime sedative (or any similar or related indication) is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act for which an approved new drug
application under section 505 of the act and part 314 of this chapter is
required for marketing.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted as an OTC daytime
sedative (or any similar or related indication) is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) Any OTC daytime sedative drug product introduced into interstate
commerce after December 24, 1979, that is not in compliance with this
section is subject to regulatory action.
[44 FR 36380, June 22, 1979; 45 FR 47422, July 15, 1980, as amended at
55 FR 11579, Mar. 29, 1990]
Sec. 310.527 Drug products containing active ingredients offered over-the-counter (OTC) for external use as hair growers or for hair loss prevention.
(a) Amino acids, aminobenzoic acid, ascorbic acid, benzoic acid,
biotin and all other B-vitamins, dexpanthenol, estradiol and other
topical hormones, jojoba oil, lanolin, nucleic acids, polysorbate 20,
polysorbate 60, sulfanilamide, sulfur 1 percent on carbon in a fraction
of paraffinic hydrocarbons, tetracaine hydrochloride, urea, and wheat
germ oil have been marketed as ingredients in OTC drug products for
external use as hair growers or for hair loss prevention. There is a
lack of adequate data to establish general recognition of the safety and
effectiveness of these or any other ingredients intended for OTC
external use as a hair grower or for hair loss prevention. Based on
evidence currently available, all labeling claims for OTC hair grower
and hair loss prevention drug products for external use are either
false, misleading, or unsupported by scientific data. Therefore, any OTC
drug product for external use containing an ingredient offered for use
as a hair grower or for hair loss prevention cannot be considered
generally recognized as safe and effective for its intended use.
(b) Any OTC drug product that is labeled, represented, or promoted
for external use as a hair grower or for hair loss prevention is
regarded as a new drug within the meaning of section 201(p) of the
Federal Food, Drug, and Cosmetic Act (the act), for which an approved
new drug application under section 505 of the act and part 314 of this
chapter is required for marketing. In the absence of an approved new
drug application, such product is also misbranded under section 502 of
the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC external use as a
hair grower or for hair loss prevention is safe and effective for the
purpose intended must 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
[[Page 43]]
are powerful hormones when administered internally and are not safe for
use except under the supervision of a physician. There is a lack of
adequate data to establish general recognition of the safety and
effectiveness of any of these ingredients, or any other ingredient, for
OTC use as an aphrodisiac. Labeling claims for aphrodisiacs for OTC use
are either false, misleading, or unsupported by scientific data. The
following claims are examples of some that have been made for
aphrodisiac drug products for OTC use: ``acts as an aphrodisiac;''
``arouses or increases sexual desire and improves sexual performance;''
``helps restore sexual vigor, potency, and performance;'' ``improves
performance, staying power, and sexual potency;'' and ``builds virility
and sexual potency.'' Based on evidence currently available, any OTC
drug product containing ingredients for use as an aphrodisiac cannot be
generally recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or prompted
for use as an aphrodisiac is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act, (the
act), for which an approved new drug application under section 505 of
the act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an
aphrodisiac is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After January 8, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[54 FR 28786, July 7, 1989]
Sec. 310.529 Drug products containing active ingredients offered over-the-counter (OTC) for oral use as insect repellents.
(a) Thiamine hydrochloride (vitamin B-1) has been marketed as an
ingredient in over-the-counter (OTC) drug products for oral use as an
insect repellent (an orally administered drug product intended to keep
insects away). There is a lack of adequate data to establish the
effectiveness of this, or any other ingredient for OTC oral use as an
insect repellent. Labeling claims for OTC orally administered insect
repellent drug products are either false, misleading, or unsupported by
scientific data. The following claims are examples of some that have
been made for orally administered OTC insect repellent drug products:
``Oral mosquito repellent,'' ``mosquitos avoid you,'' ``bugs stay
away,'' ``keep mosquitos away for 12 to 24 hours,'' and ``the newest way
to fight mosquitos.'' Therefore, any drug product containing ingredients
offered for oral use as an insect repellent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for oral use as an insect repellent is regarded as 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
[[Page 44]]
this section is subject to regulatory action.
[40 FR 25171, June 17, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.530 Topically applied hormone-containing drug products for over-the-counter (OTC) human use.
(a) The term ``hormone'' is used broadly to describe a chemical
substance formed in some organ of the body, such as the adrenal glands
or the pituitary, and carried to another organ or tissue, where it has a
specific effect. Hormones include, for example, estrogens, progestins,
androgens, anabolic steroids, and adrenal corticosteroids, and synthetic
analogs. Estrogens, progesterone, pregnenolone, and pregnenolone acetate
have been present as ingredients in OTC drug products marketed for
topical use as hormone creams. However, there is a lack of adequate data
to establish effectiveness for any OTC drug use of these ingredients.
Therefore, with the exception of those hormones identified in paragraph
(e) of this section, any OTC drug product containing an ingredient
offered for use as a topically applied hormone cannot be considered
generally recognized as safe and effective for its intended use. The
intended use of the product may be inferred from the product's labeling,
promotional material, advertising, and any other relevant factor. The
use of the word ``hormone'' in the text of the labeling or in the
ingredient statement is an implied drug claim. The claim implied by the
use of this term is that the product will have a therapeutic or some
other physiological effect on the body. Therefore, reference to a
product as a ``hormone cream'' or any statement in the labeling
indicating that ``hormones'' are present in the product, or any
statement that features or emphasizes the presence of a hormone
ingredient in the product, will be considered to be a therapeutic claim
for the product, or a claim that the product will affect the structure
or function of the body, and will consequently cause the product to be a
drug.
(b) Any OTC drug product that is labeled, represented, or promoted
as a topically applied hormone-containing product for drug use, with the
exception of those hormones identified in paragraph (e) of this section,
is regarded as a new drug within the meaning of section 201(p) of the
act, for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
topically applied hormone-containing drug product is safe and effective
for the purpose intended must comply with the requirements and
procedures governing the use of investigational new drugs set forth in
part 312 of this chapter.
(d) After March 9, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
(e) This section does not apply to hydrocortisone and hydrocortisone
acetate labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 47610, Sept. 9, 1993]
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
[[Page 45]]
these purposes. These ``drawing salves'' contained various ingredients.
Based on evidence currently available, any OTC drug product offered for
the treatment of boils cannot be considered generally recognized as safe
and effective.
(b) Any OTC drug product that is labeled, represented, or promoted
for the treatment of boils is regarded as a new drug within the meaning
of section 201(p) of the Federal Food, Drug, and Cosmetic Act (the act),
for which an approved application or abbreviated application under
section 505 of the act and part 314 of this chapter is required for
marketing. In the absence of an approved new drug application or
abbreviated new drug application, such product is also misbranded under
section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any OTC
boil treatment drug product is safe and effective for the purpose
intended must comply with the requirements and procedures governing the
use of investigational new drugs set forth in part 312 of this chapter.
(d) After May 7, 1991, any such OTC drug product that contains
aminacrine hydrochloride, bismuth subnitrate, calomel, camphor,
cholesterol, ergot fluid extract, hexachlorophene, isobutamben, juniper
tar (oil of cade), lanolin, magnesium sulfate, menthol, methyl
salicylate, oxyguinoline sulfate, petrolatum, phenol, pine tar, rosin,
rosin cerate, sassafras oil, thymol, or zinc oxide initially introduced
or initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(e) After May 16, 1994, any such OTC drug product that contains
benzocaine, ichthammol, sulfur, or triclosan initially introduced or
initially delivered for introduction into interstate commerce that is
not in compliance with this section is subject to regulatory action.
(f) This section does not apply to drug products that contain
benzocaine labeled, represented, or promoted for OTC topical use in
accordance with part 348 of this chapter.
[58 FR 60336, Nov. 15, 1993]
Sec. 310.532 Drug products containing active ingredients offered over-the-counter (OTC) to relieve the symptoms of benign prostatic hypertrophy.
(a) The amino acids glycine, alanine, and glutamic acid (alone or in
combination) and the ingredient sabal have been present in over-the-
counter (OTC) drug products to relieve the symptoms of benign prostatic
hypertrophy, e.g., urinary urgency and frequency, excessive urinating at
night, and delayed urination. There is a lack of adequate data to
establish general recognition of the safety and effectiveness of these
or any other ingredients for OTC use in relieving the symptoms of benign
prostatic hypertrophy. In addition, there is no definitive evidence that
any drug product offered for the relief of the symptoms of benign
prostatic hypertrophy would alter the obstructive or inflammatory signs
and symptoms of this condition. Therefore, self-medication with OTC drug
products might unnecessarily delay diagnosis and treatment of
progressive obstruction and secondary infections. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use in relieving the symptoms of benign prostatic hypertrophy cannot
be generally recognized as safe and effective.
(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.
[[Page 46]]
(d) After August 27, 1990, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[55 FR 6930, Feb. 27, 1990]
Sec. 310.533 Drug products containing active ingredients offered over-the-counter (OTC) for human use as an anticholinergic in cough-cold drug products.
(a) Atropine sulfate, belladonna alkaloids, and belladonna alkaloids
as contained in Atropa belladonna and Datura stramonium have been
present as ingredients in cough-cold drug products for use as an
anticholinergic. Anticholinergic drugs have been marketed OTC in cough-
cold drug products to relieve excessive secretions of the nose and eyes,
symptoms that are commonly associated with hay fever, allergy, rhinitis,
and the common cold. Atropine sulfate for oral use as an anticholinergic
is probably safe at dosages that have been used in marketed cough-cold
products (0.2 to 0.3 milligram); however, there are inadequate data to
establish general recognition of the effectiveness of this ingredient.
The belladonna alkaloids, which contain atropine (d, dl hyoscyamine) and
scopolamine (l- hyoscine), are probably safe for oral use at dosages
that have been used in marketed cough-cold products (0.2 milligram) but
there are inadequate data to establish general recognition of the
effectiveness of these ingredients as an anticholinergic for cough-cold
use. Belladonna alkaloids for inhalation use, as contained in Atropa
belladonna and Datura stramonium, are neither safe nor effective as an
OTC anticholinergic. There are inadequate safety and effectiveness data
to establish general recognition of the safety and/or effectiveness or
any of these ingredients, or any other ingredient, for OTC use as an
anticholinergic in cough-cold drug products.
(b) Any OTC cough-cold drug product that is labeled, represented, or
promoted for use as an anticholinergic is regarded as a new drug within
the meaning of section 201(p) of the Federal Food, Drug, and Cosmetic
Act, for which an approved new drug application under section 505 of the
act and part 314 of this chapter is required for marketing. In the
absence of an approved new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
cough-cold drug product labeled, represented, or promoted for OTC use as
an anticholinergic is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any such OTC
cough-cold drug product that is labeled, represented, or promoted for
use as an anticholinergic may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[50 FR 46587, Nov. 8, 1985, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.534 Drug products containing active ingredients offered over-the-counter (OTC) for human use as oral wound healing agents.
(a) Allantoin, carbamide peroxide in anhydrous glycerin, water
soluble chlorophyllins, and hydrogen peroxide in aqueous solution have
been present in oral mucosal injury drug products 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
[[Page 47]]
marketing. In the absence of an approved new drug application, such
product is also misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as an oral
wound healing agent is safe and effective for the purpose intended must
comply with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) After the effective date of the final regulation, any OTC drug
product that is labeled, represented, or promoted for use as an oral
wound healing agent may not be initially introduced or initially
delivered for introduction into interstate commerce unless it is the
subject of an approved new drug application.
[51 FR 26114, July 18, 1986, as amended at 55 FR 11579, Mar. 29, 1990]
Sec. 310.536 Drug products containing active ingredients offered over-the-counter (OTC) for use as a nailbiting or thumbsucking deterrent.
(a) Denatonium benzoate and sucrose octaacetate have been present in
OTC nailbiting and thumbsucking deterrent drug products. There is a lack
of adequate data to establish general recognition of the safety and
effectiveness of these and any other ingredients (e.g., cayenne pepper)
for OTC use as a nailbiting or thumbsucking deterrent. Based on evidence
currently available, any OTC drug product containing ingredients offered
for use as a nailbiting or thumbsucking deterrent cannot be generally
recognized as safe and effective.
(b) Any OTC drug product that is labeled, represented, and promoted
as a nailbiting or thumbsucking deterrent is regarded as a new drug
within the meaning of section 201(p) of the Federal Food, Drug, and
Cosmetic Act (the act) for which an approved application or abbreviated
application under section 505 of the act and part 314 of this chapter is
required for marketing. In the absence of an approved new drug
application or abbreviated new drug application, such product is also
misbranded under section 502 of the act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for OTC use as a
nailbiting or thumbsucking deterrent is safe and effective for the
purpose intended must comply with the requirements and procedures
governing the use of investigational new drugs set forth in part 312 of
this chapter.
(d) After March 2, 1994, any such OTC drug product initially
introduced or initially delivered for introduction into interstate
commerce that is not in compliance with this section is subject to
regulatory action.
[58 FR 46754, Sept. 2, 1993]
Sec. 310.537 Drug products containing active ingredients offered over-the-counter (OTC) for oral administration for the treatment of fever blisters and cold
sores.
(a) l-lysine (lysine, lysine hydrochloride), Lactobacillus
acidophilus, and Lactobacillus bulgaricus have been present in orally
administered OTC drug products to treat fever blisters and cold sores.
There is a lack of adequate data to establish general recognition of the
safety and effectiveness of these or any other orally administered
ingredients for OTC use to treat or relieve the symptoms or discomfort
of fever blisters and cold sores. Based on evidence currently available,
any 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,
[[Page 48]]
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 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
[[Page 49]]
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]
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,
[[Page 50]]
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 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
[[Page 51]]
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.
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
[[Page 52]]
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)
l-desoxyephedrine (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.
(7) Dandruff/seborrheic dermatitis/psoriasis drug products.
Alkyl isoquinolinium bromide
Allantoin
Benzalkonium chloride
Benzethonium chloride
Boric acid
Calcium undecylenate
Captan
Chloroxylenol
Colloidal oatmeal
Cresol, saponated
Ethohexadiol
Eucalyptol
Juniper tar
Lauryl isoquinolinium bromide
Menthol
Mercury oleate
Methylbenzethonium chloride
Methyl salicylate
Phenol
Phenolate sodium
Pine tar
Povidone-iodine
Resorcinol
Sodium borate
Sodium salicylate
Thymol
Undecylenic acid
(8) Digestive aid drug products--(i) Approved as of May 7, 1991.
Bismuth sodium tartrate
Calcium carbonate
Cellulase
Dehydrocholic acid
Dihydroxyaluminum sodium carbonate
Duodenal substance
Garlic, dehydrated
Glutamic acid hydrochloride
Hemicellulase
Homatropine methylbromide
Magnesium hydroxide
Magnesium trisilicate
Ox bile extract
Pancreatin
Pancrelipase
Papain
Peppermint oil
Pepsin
Sodium bicarbonate
[[Page 53]]
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
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
[[Page 54]]
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) Stimulant laxatives.
Aloin
Bile salts/acids
Calcium pantothenate
Calomel
Colocynth
Elaterin resin
Frangula
Gamboge
Ipomea
Jalap
Ox bile
Podophyllum resin
Prune concentrate dehydrate
Prune powder
Rhubarb, Chinese
Sodium Oleate
(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
[[Page 55]]
(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
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
[[Page 56]]
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
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
[[Page 57]]
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.
Aminobenzoic acid
Antipyrine
Aspirin, aluminum
Calcium salicylate
Codeine
Codeine phosphate
Codeine sulfate
Iodoantipyrine
Lysine aspirin
Methapyrilene fumarate
Phenacetin
Pheniramine maleate
Pyrilamine maleate
Quinine
Salsalate
Sodium aminobenzoate
(24) Orally administered menstrual drug products.
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)
[[Page 58]]
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
(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)
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
(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
[[Page 59]]
314 of this chapter is required for marketing. In the absence of an
approved new drug application, such product is also misbranded under
section 502 of the Act.
(c) Clinical investigations designed to obtain evidence that any
drug product labeled, represented, or promoted for the OTC uses and
containing any active ingredient(s) as specified in paragraph (a) of
this section is safe and effective for the purpose intended must comply
with the requirements and procedures governing the use of
investigational new drugs set forth in part 312 of this chapter.
(d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction into interstate commerce after the
dates specified in paragraphs (d)(1) through (d)(25) 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)(9) through (a)(10)(iii), (a)(12)(i) through (a)(12)(iv), (a)(14)
through (a)(15)(i), and (a)(16) through (a)(18)(i) of this section.
(2) February 10, 1992, for products subject to paragraph (a)(20) of
this section.
(3) December 4, 1992, for products subject to paragraph (a)(7) of
this section that contain menthol as an antipruritic in combination with
the antidandruff ingredient coal tar identified in Sec. 358.710(a)(1) of
this chapter.
(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 paragraph
(a)(18)(ii) of this section, except products that contain ferric
subsulfate.
(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.
[55 FR 46919, Nov. 7, 1990]
Editorial Note: For Federal Register citations affecting
Sec. 310.545, see the List of CFR Sections Affected in the Finding Aids
section of this volume.
Effective Date Notes: 1. At 60 FR 42436, Aug. 16, 1995, in
Sec. 310.545, paragraph (a)(15)(ii)
[[Page 60]]
was stayed for topical otic drug products for the drying of water-
clogged ears.
2. 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.
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.
(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
[[Page 61]]
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]
Effective Date Note: At 63 FR 13528, Mar. 20, 1998, Sec. 310.547 was
added to subpart E, effective Apr. 20, 1998.
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.
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 Guidelines.
[[Page 62]]
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, 356, 357, 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 or 507 of the Federal Food, Drug, and Cosmetic Act or to the
licensing provisions of the Public Health Service Act (58 Stat. 632, as
amended (42 U.S.C. 201 et seq.)).
(b) Exemptions. (1) The clinical investigation of a drug product
that is lawfully marketed in the United States is exempt from the
requirements of this part if all the following apply:
(i) The investigation is not intended to be reported to FDA as a
well-controlled study in support of a new indication for use nor
intended to be used to support any other significant change in the
labeling for the drug;
(ii) If the drug that is undergoing investigation is lawfully
marketed as a prescription drug product, the investigation is not
intended to support a significant change in the advertising for the
product;
(iii) The investigation does not involve a route of administration
or dosage level or use in a patient population or other factor that
significantly increases the risks (or decreases the acceptability of the
risks) associated with the use of the drug product;
(iv) The investigation is conducted in compliance with the
requirements for institutional review set forth in part 56 and with the
requirements for informed consent set forth in part 50; and
(v) The investigation is conducted in compliance with the
requirements of Sec. 312.7.
(2)(i) A clinical investigation involving an in vitro diagnostic
biological product listed in paragraph (b)(2)(ii) of this section is
exempt from the requirements of this part if (a) it is intended to be
used in a diagnostic procedure that confirms the diagnosis made by
another, medically established, diagnostic product or procedure and (b)
it is shipped in compliance with Sec. 312.160.
(ii) In accordance with paragraph (b)(2)(i) of this section, the
following products are exempt from the requirements of this part: (a)
blood grouping serum; (b) reagent red blood cells; and (c) anti-human
globulin.
(3) A drug intended solely for tests in vitro or in laboratory
research animals is exempt from the requirements of this part if shipped
in accordance with Sec. 312.160.
(4) FDA will not accept an application for an investigation that is
exempt under the provisions of paragraph (b)(1) of this section.
(5) A clinical investigation involving use of a placebo is exempt
from the requirements of this part if the investigation does not
otherwise require submission of an IND.
(6) A clinical investigation involving an exception from informed
consent under Sec. 50.24 of this chapter is not exempt from the
requirements of this part.
(c) Bioavailability studies. The applicability of this part to in
vivo bioavailability studies in humans is subject to the provisions of
Sec. 320.31.
[[Page 63]]
(d) Unlabeled indication. This part does not apply to the use in the
practice of medicine for an unlabeled indication of a new drug or
antibiotic 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]
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, antibiotic drug, or
biological drug that is used in a clinical investigation. The term also
includes a biological product that is used in vitro for diagnostic
purposes. The terms ``investigational drug'' and ``investigational new
drug'' are deemed to be synonymous for purposes of this part.
Investigator means an individual who actually conducts a clinical
investigation (i.e., under whose immediate direction the drug is
administered or dispensed to a subject). In the event an investigation
is conducted by a team of individuals, the investigator is the
responsible leader of the team. ``Subinvestigator'' includes any other
individual member of that team.
Marketing application means an application for a new drug submitted
under section 505(b) of the Act, a request to provide for certification
of an antibiotic submitted under section 507 of the Act, or a product
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.
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
[[Page 64]]
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 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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 19476, May 22, 1987]
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;
[[Page 65]]
(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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
Subpart B--Investigational New Drug Application (IND)
Sec. 312.20 Requirement for an IND.
(a) A sponsor shall submit an IND to FDA if the sponsor intends to
conduct a clinical investigation with an investigational new drug that
is subject to Sec. 312.2(a).
(b) A sponsor shall not begin a clinical investigation subject to
Sec. 312.2(a) until the investigation is subject to an IND which is in
effect in accordance with Sec. 312.40.
(c) A sponsor shall submit a separate IND for any clinical
investigation involving an exception from informed consent under
Sec. 50.24 of this chapter. Such a clinical investigation is not
permitted to proceed without the prior written authorization from FDA.
FDA shall provide a written determination 30 days after FDA receives the
IND or earlier.
[52 FR 8831, Mar. 19, 1987, as amended at 61 FR 51529, Oct. 2, 1996; 62
FR 32479, June 16, 1997]
Sec. 312.21 Phases of an investigation.
An IND may be submitted for one or more phases of an investigation.
The clinical investigation of a previously untested drug is generally
divided into three phases. Although in general the phases are conducted
sequentially, they may overlap. These three phases of an investigation
are a follows:
(a) Phase 1. (1) Phase 1 includes the initial introduction of an
investigational new drug into humans. Phase 1 studies are typically
closely monitored and may be conducted in patients or normal volunteer
subjects. These studies are designed to determine the metabolism and
pharmacologic actions of the drug in humans, the side effects associated
with increasing doses, and, if possible, to gain early evidence on
effectiveness. During Phase 1, sufficient information about the drug's
pharmacokinetics and pharmacological effects should be obtained to
permit the design of well-controlled, scientifically valid, Phase 2
studies. The total number of subjects and patients included in Phase 1
studies varies with the drug, but is generally in the range of 20 to 80.
(2) Phase 1 studies also include studies of drug metabolism,
structure-activity relationships, and mechanism of action in humans, as
well as studies in which investigational drugs are used as research
tools to explore biological phenomena or disease processes.
(b) Phase 2. Phase 2 includes the controlled clinical studies
conducted to evaluate the effectiveness of the drug for a particular
indication or indications in patients with the disease or condition
under study and to determine the common short-term side effects and
risks associated with the drug. Phase 2 studies are typically well
controlled, closely monitored, and conducted in a relatively small
number of 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.
[[Page 66]]
Sec. 312.22 General principles of the IND submission.
(a) FDA's primary objectives in reviewing an IND are, in all phases
of the investigation, to assure the safety and rights of subjects, and,
in Phase 2 and 3, to help assure that the quality of the scientific
evaluation of drugs is adequate to permit an evaluation of the drug's
effectiveness and safety. Therefore, although FDA's review of Phase 1
submissions will focus on assessing the safety of Phase 1
investigations, FDA's review of Phases 2 and 3 submissions will also
include an assessment of the scientific quality of the clinical
investigations and the likelihood that the investigations will yield
data capable of meeting statutory standards for marketing approval.
(b) The amount of information on a particular drug that must be
submitted in an IND to assure the accomplishment of the objectives
described in paragraph (a) of this section depends upon such factors as
the novelty of the drug, the extent to which it has been studied
previously, the known or suspected risks, and the developmental phase of
the drug.
(c) The central focus of the initial IND submission should be on the
general investigational plan and the protocols for specific human
studies. Subsequent amendments to the IND that contain new or revised
protocols should build logically on previous submissions and should be
supported by additional information, including the results of animal
toxicology studies or other human studies as appropriate. Annual reports
to the IND should serve as the focus for reporting the status of studies
being conducted under the IND and should update the general
investigational plan for the coming year.
(d) The IND format set forth in Sec. 312.23 should be followed
routinely by sponsors in the interest of fostering an efficient review
of applications. Sponsors are expected to exercise considerable
discretion, however, regarding the content of information submitted in
each section, depending upon the kind of drug being studied and the
nature of the available information. Section 312.23 outlines the
information needed for a commercially sponsored IND for a new molecular
entity. A sponsor-investigator who uses, as a research tool, an
investigational new drug that is already subject to a manufacturer's IND
or marketing application should follow the same general format, but
ordinarily may, if authorized by the manufacturer, refer to the
manufacturer's IND or marketing application in providing the technical
information supporting the proposed clinical investigation. A sponsor-
investigator who uses an investigational drug not subject to a
manufacturer's IND or marketing application is ordinarily required to
submit all technical information supporting the IND, unless such
information may be referenced from the scientific literature.
Sec. 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation
subject to this part shall submit an ``Investigational New Drug
Application'' (IND) including, in the following order:
(1) Cover sheet (Form FDA-1571). A cover sheet for the application
containing the following:
(i) The name, address, and telephone number of the sponsor, the date
of the application, and the name of the investigational new drug.
(ii) Identification of the phase or phases of the clinical
investigation to be conducted.
(iii) A commitment not to begin clinical investigations until an IND
covering the investigations is in effect.
(iv) A commitment that an Institutional Review Board (IRB) that
complies with the requirements set forth in 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
[[Page 67]]
review and evaluation of information relevant to the safety of the drug.
(viii) If a sponsor has transferred any obligations for the conduct
of any clinical study to a contract research organization, a statement
containing the name and address of the contract research organization,
identification of the clinical study, and a listing of the obligations
transferred. If all obligations governing the conduct of the study have
been transferred, a general statement of this transfer--in lieu of a
listing of the specific obligations transferred--may be submitted.
(ix) The signature of the sponsor or the sponsor's authorized
representative. If the person signing the application does not reside or
have a place of business within the United States, the IND is required
to contain the name and address of, and be countersigned by, an
attorney, agent, or other authorized official who resides or maintains a
place of business within the United States.
(2) A table of contents.
(3) Introductory statement and general investigational plan. (i) A
brief introductory statement giving the name of the drug and all active
ingredients, the drug's pharmacological class, the structural formula of
the drug (if known), the formulation of the dosage form(s) to be used,
the route of administration, and the broad objectives and planned
duration of the proposed clinical investigation(s).
(ii) A brief summary of previous human experience with the drug,
with reference to other IND's if pertinent, and to investigational or
marketing experience in other countries that may be relevant to the
safety of the proposed clinical investigation(s).
(iii) If the drug has been withdrawn from investigation or marketing
in any country for any reason related to safety or effectiveness,
identification of the country(ies) where the drug was withdrawn and the
reasons for the withdrawal.
(iv) A brief description of the overall plan for investigating the
drug product for the following year. The plan should include the
following: (a) The rationale for the drug or the research study; (b) the
indication(s) to be studied; (c) the general approach to be followed in
evaluating the drug; (d) the kinds of clinical trials to be conducted in
the first year following the submission (if plans are not developed for
the entire year, the sponsor should so indicate); (e) the estimated
number of patients to be given the drug in those studies; and (f) any
risks of particular severity or seriousness anticipated on the basis of
the toxicological data in animals or prior studies in humans with the
drug or related drugs.
(4) [Reserved]
(5) Investigator's brochure. If required under Sec. 312.55, a copy
of the investigator's brochure, containing the following information:
(i) A brief description of the drug substance and the formulation,
including the structural formula, if known.
(ii) A summary of the pharmacological and toxicological effects of
the drug in animals and, to the extent known, in humans.
(iii) A summary of the pharmacokinetics and biological disposition
of the drug in animals and, if known, in humans.
(iv) A summary of information relating to safety and effectiveness
in humans obtained from prior clinical studies. (Reprints of published
articles on such studies may be appended when useful.)
(v) A description of possible risks and side effects to be
anticipated on the basis of prior experience with the drug under
investigation or with related drugs, and of precautions or special
monitoring to be done as part of the investigational use of the drug.
(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
[[Page 68]]
monitoring of vital signs and blood chemistries. Modifications of the
experimental design of Phase 1 studies that do not affect critical
safety assessments are required to be reported to FDA only in the annual
report.
(ii) In Phases 2 and 3, detailed protocols describing all aspects of
the study should be submitted. A protocol for a Phase 2 or 3
investigation should be designed in such a way that, if the sponsor
anticipates that some deviation from the study design may become
necessary as the investigation progresses, alternatives or contingencies
to provide for such deviation are built into the protocols at the
outset. For example, a protocol for a controlled short-term study might
include a plan for an early crossover of nonresponders to an alternative
therapy.
(iii) A protocol is required to contain the following, with the
specific elements and detail of the protocol reflecting the above
distinctions depending on the phase of study:
(a) A statement of the objectives and purpose of the study.
(b) The name and address and a statement of the qualifications
(curriculum vitae or other statement of qualifications) of each
investigator, and the name of each subinvestigator (e.g., research
fellow, resident) working under the supervision of the investigator; the
name and address of the research facilities to be used; and the name and
address of each reviewing Institutional Review Board.
(c) The criteria for patient selection and for exclusion of patients
and an estimate of the number of patients to be studied.
(d) A description of the design of the study, including the kind of
control group to be used, if any, and a description of methods to be
used to minimize bias on the part of subjects, investigators, and
analysts.
(e) The method for determining the dose(s) to be administered, the
planned maximum dosage, and the duration of individual patient exposure
to the drug.
(f) A description of the observations and measurements to be made to
fulfill the objectives of the study.
(g) A description of clinical procedures, laboratory tests, or other
measures to be taken to monitor the effects of the drug in human
subjects and to minimize risk.
(7) Chemistry, manufacturing, and control information. (i) As
appropriate for the particular investigations covered by the IND, a
section describing the composition, manufacture, and control of the drug
substance and the drug product. Although in each phase of the
investigation sufficient information is required to be submitted to
assure the proper identification, quality, purity, and strength of the
investigational drug, the amount of information needed to make that
assurance will vary with the phase of the investigation, the proposed
duration of the investigation, the dosage form, and the amount of
information otherwise available. FDA recognizes that modifications to
the method of preparation of the new drug substance and dosage form and
changes in the dosage form itself are likely as the investigation
progresses. Therefore, the emphasis in an initial Phase 1 submission
should generally be placed on the identification and control of the raw
materials and the new drug substance. Final specifications for the drug
substance and drug product are not expected until the end of the
investigational process.
(ii) It should be emphasized that the amount of information to be
submitted depends upon the scope of the proposed clinical investigation.
For example, although stability data are required in all phases of the
IND to demonstrate that the new drug substance and drug product are
within acceptable chemical 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.
[[Page 69]]
(iv) Reflecting the distinctions described in this paragraph (a)(7),
and based on the phase(s) to be studied, the submission is required to
contain the following:
(a) Drug substance. A description of the drug substance, including
its physical, chemical, or biological characteristics; the name and
address of its manufacturer; the general method of preparation of the
drug substance; the acceptable limits and analytical methods used to
assure the identity, strength, quality, and purity of the drug
substance; and information sufficient to support stability of the drug
substance during the toxicological studies and the planned clinical
studies. Reference to the current edition of the United States
Pharmacopeia--National Formulary may satisfy relevant requirements in
this paragraph.
(b) Drug product. A list of all components, which may include
reasonable alternatives for inactive compounds, used in the manufacture
of the investigational drug product, including both those components
intended to appear in the drug product and those which may not appear
but which are used in the manufacturing process, and, where applicable,
the quantitative composition of the investigational drug product,
including any reasonable variations that may be expected during the
investigational stage; the name and address of the drug product
manufacturer; a brief general description of the manufacturing and
packaging procedure as appropriate for the product; the acceptable
limits and analytical methods used to assure the identity, strength,
quality, and purity of the drug product; and information sufficient to
assure the product's stability during the planned clinical studies.
Reference to the current edition of the United States Pharmacopeia--
National Formulary may satisfy certain requirements in this paragraph.
(c) A brief general description of the composition, manufacture, and
control of any placebo used in a controlled clinical trial.
(d) Labeling. A copy of all labels and labeling to be provided to
each investigator.
(e) Environmental analysis requirements. A claim for categorical
exclusion under Sec. 25.30 or 25.31 or an environmental assessment under
Sec. 25.40.
(8) Pharmacology and toxicology information. Adequate information
about pharmacological and toxicological studies of the drug involving
laboratory animals or in vitro, on the basis of which the sponsor has
concluded that it is reasonably safe to conduct the proposed clinical
investigations. The kind, duration, and scope of animal and other tests
required varies with the duration and nature of the proposed clinical
investigations. Guidelines 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
[[Page 70]]
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.
(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) 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
[[Page 71]]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
Sec. 312.30 Protocol amendments.
Once an IND is in effect, a sponsor shall amend it as needed to
ensure that the clinical investigations are conducted according to
protocols included in the application. This section sets forth the
provisions under which new protocols may be submitted and changes in
previously submitted protocols may be made. Whenever a sponsor intends
to conduct a clinical investigation with an exception from informed
consent for emergency research as set forth in Sec. 50.24 of this
chapter, the sponsor shall submit a separate IND for such investigation.
(a) New protocol. Whenever a sponsor intends to conduct a study that
is not covered by a protocol already contained in the IND, the sponsor
shall submit to FDA a protocol amendment containing the protocol for the
study. Such study may begin provided two conditions are met: (1) The
sponsor has submitted the protocol to FDA for its review; and (2) the
protocol has been approved by the Institutional Review Board (IRB) with
responsibility for review and approval of the study in accordance with
the requirements of part 56. The sponsor may comply with these two
conditions in either order.
(b) Changes in a protocol. (1) A sponsor shall submit a protocol
amendment describing any change in a Phase 1 protocol that significantly
affects the safety of subjects or any change in a Phase 2 or 3 protocol
that significantly affects the safety of subjects, the scope of the
investigation, or the scientific quality of the study. Examples of
changes requiring an amendment under this paragraph include:
(i) Any increase in drug dosage or duration of exposure of
individual subjects to the drug beyond that in the current protocol, or
any significant increase in the number of subjects under study.
(ii) Any significant change in the design of a protocol (such as the
addition or dropping of a control group).
(iii) The addition of a new test or procedure that is intended to
improve monitoring for, or reduce the risk of, a side effect or adverse
event; or the dropping of a test intended to monitor safety.
(2)(i) A protocol change under paragraph (b)(1) of this section may
be made provided two conditions are met:
(a) The sponsor has submitted the change to FDA for its review; and
(b) The change has been approved by the IRB with responsibility for
review and approval of the study. The sponsor may comply with these two
conditions in either order.
(ii) Notwithstanding paragraph (b)(2)(i) of this section, a protocol
change intended to eliminate an apparent immediate hazard to subjects
may be implemented immediately provided FDA is subsequently notified by
protocol amendment and the reviewing 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.
[[Page 72]]
(d) Content and format. A protocol amendment is required to be
prominently identified as such (i.e., ``Protocol Amendment: New
Protocol'', ``Protocol Amendment: Change in Protocol'', or ``Protocol
Amendment: New Investigator''), and to contain the following:
(1)(i) In the case of a new protocol, a copy of the new protocol and
a brief description of the most clinically significant differences
between it and previous protocols.
(ii) In the case of a change in protocol, a brief description of the
change and reference (date and number) to the submission that contained
the protocol.
(iii) In the case of a new investigator, the investigator's name,
the qualifications to conduct the investigation, reference to the
previously submitted protocol, and all additional information about the
investigator's study as is required under Sec. 312.23(a)(6)(iii)(b).
(2) Reference, if necessary, to specific technical information in
the IND or in a concurrently submitted information amendment to the IND
that the sponsor relies on to support any clinically significant change
in the new or amended protocol. If the reference is made to supporting
information already in the IND, the sponsor shall identify by name,
reference number, volume, and page number the location of the
information.
(3) If the sponsor desires FDA to comment on the submission, a
request for such comment and the specific questions FDA's response
should address.
(e) When submitted. A sponsor shall submit a protocol amendment for
a new protocol or a change in protocol before its implementation.
Protocol amendments to add a new investigator or to provide additional
information about investigators may be grouped and submitted at 30-day
intervals. When several submissions of new protocols or protocol changes
are anticipated during a short period, the sponsor is encouraged, to the
extent feasible, to include these all in a single submission.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 53
FR 1918, Jan. 25, 1988]
Sec. 312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this
section:-
[[Page 73]]
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
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
[[Page 74]]
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, 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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
Effective Date Note: At 62 FR 52250, Oct. 7, 1997, Sec. 312.32 was
amended by revising paragraphs (a), (b), (c)(1)(i), (c)(2), and (d)(3);
by adding in the second sentence of paragraph (c)(3) the words ``new
drug review'' before the phrase ``division in the Center for Drug
Evaluation and Research'' and the words ``the director of the product
review division in'' before the phrase ``the Center for Biologics
Evaluation and Research''; and by removing in paragraph (e) the word
``section'' and replacing it with the word ``part'', effective Apr. 6,
1998. For the convenience of the user, the superseded text is set forth
as follows:
Sec. 312.32 IND safety reports.
(a) Definitions. The following definitions of terms apply to this
section:
Associated with the use of the drug means that there is a reasonable
possibility that the experience may have been caused by the drug.
Serious adverse experience means any experience that suggests a
significant hazard, contraindication, side effect, or precaution. With
respect to human clinical experience, a serious adverse drug experience
includes any experience that is fatal or life-threatening, is
permanently disabling, requires inpatient hospitalization, or is a
congenital anomaly, cancer, or overdose. With respect to results
obtained from tests in laboratory animals, a
[[Page 75]]
serious adverse drug experience includes any experience suggesting a
significant risk for human subjects, including any finding of
mutagenicity, teratogenicity, or carcinogenicity.
Unexpected adverse experience means any adverse experience that is
not identified in nature, severity, or frequency in the current
investigator brochure; or, if an investigator brochure is not required,
that is not identified in nature, severity, or freuquency in the risk
information described in the general investigational plan or elsewhere
in the current application, as amended.
(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 clinical investigations, animal investigations,
commercial marketing experience, reports in the scientific literature,
and unpublished scientific papers.
(c) IND safety reports. (1) Written reports. (i) The sponsor shall
notify FDA and all participating investigators in a written IND safety
report of any adverse experience associated with use of the drug that is
both serious and unexpected. Such notification shall be made as soon as
possible and in no event later than 10 working days after the sponsor's
initial receipt of the information. Each written notification shall bear
prominent identification of its contents, i.e., ``IND Safety Report.''
Each written notification to FDA shall be transmitted to the FDA
division of the Center for Drug Evaluation and Research or the Center
for Biologics Evaluation and Research which has responsibility for
review of the IND.
(ii)* * *
(2) Telephone report. The sponsor shall also notify FDA by telephone
of any unexpected fatal or life-threatening experience associated with
use of the drug in the clinical studies conducted under the IND no later
than 3 working days after receipt of the information. Each telephone
call to FDA shall be transmitted to the FDA division of the Center for
Drug Evaluation and Research or the Center for Biologics Evaluation and
Research which has responsibility for review of the IND. For purposes of
this section, life-threatening means that the patient was, in the view
of the investigator, at immediate (emphasis added) risk of death from
the reaction as it occurred, i.e., it does not include a reaction that,
had it occurred in a more serious form, might have caused death. For
example, drug-induced hepatitis that resolved without evidence of
hepatic failure would not be considered life-threatening even though
drug-induced hepatitis can be fatal.
* * * * *
(d)* * *
(3) If the results of a sponsor's investigation show that an adverse
experience not initially determined to be reportable under paragraph (c)
of this section is so reportable, the sponsor shall report such
experience in a safety report as soon as possible after the
determination is made, but in no event longer than 10-working days.
* * * * *
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.
[[Page 76]]
(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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63
FR 6862, Feb. 11, 1998]
Effective Date Note: At 63 FR 6862, Feb. 11, 1998, Sec. 312.33 was
amended by revising paragraph (a)(2), effective Aug. 10, 1998. For the
convenience of the user, the superseded text is set forth as follows:
Sec. 312.33 Annual reports.
* * * * *
(a) * * *
(2) The total number of subjects initially planned for inclusion in
the study, the number entered into the study to date, the number whose
participation in the study was completed as planned, and the number who
dropped out of the study for any reason.
* * * * *
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
[[Page 77]]
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 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.
[[Page 78]]
(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.
(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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 19477, May 22, 1987, as amended at 57 FR 13249, Apr. 15, 1992]
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
[[Page 79]]
as practicable after receiving the authorization.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55
FR 11579, Mar. 29, 1990]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
Subpart C--Administrative Actions
Sec. 312.40 General requirements for use of an investigational new drug in a clinical investigation.
(a) An investigational new drug may be used in a clinical
investigation if the following conditions are met:
(1) The sponsor of the investigation submits an IND for the drug to
FDA; the IND is in effect under paragraph (b) of this section; and the
sponsor complies with all applicable requirements in this part and parts
50 and 56 with respect to the conduct of the clinical investigations;
and
(2) Each participating investigator conducts his or her
investigation in compliance with the requirements of this part and parts
50 and 56.
(b) An IND goes into effect:
(1) Thirty days after FDA receives the IND, unless FDA notifies the
sponsor that the investigations described in the IND are subject to a
clinical hold under Sec. 312.42; or
(2) On earlier notification by FDA that the clinical investigations
in the IND may begin. FDA will notify the sponsor in writing of the date
it receives the IND.
(c) A sponsor may ship an investigational new drug to investigators
named in the IND:
(1) Thirty days after FDA receives the IND; or
(2) On earlier FDA authorization to ship the drug.
(d) An investigator may not administer an investigational new drug
to human subjects until the IND goes into effect under paragraph (b) of
this section.
Sec. 312.41 Comment and advice on an IND.
(a) FDA may at any time during the course of the investigation
communicate with the sponsor orally or in writing about deficiencies in
the IND or about FDA's need for more data or information.
(b) On the sponsor's request, FDA will provide advice on specific
matters relating to an IND. Examples of such advice may include advice
on the adequacy of technical data to support an investigational plan, on
the design of a clinical trial, and on whether proposed investigations
are likely to produce the data and information that is needed to meet
requirements for a marketing application.
(c) Unless the communication is accompanied by a clinical hold order
under Sec. 312.42, FDA communications with a sponsor under this section
are solely advisory and do not require any modification in the planned
or ongoing clinical investigations or response to the agency.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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
[[Page 80]]
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.
(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 paragraph (b)(1)(i) through (iv) of
this section apply; or
(ii) The plan or protocol for the investigation is clearly deficient
in design to meet its stated objectives.
(3) Clinical hold of 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
[[Page 81]]
adequate and well-controlled investigation of the same or another
investigational drug; or
(iii) Insufficient quantities of the investigational drug exist to
adequately conduct both the investigation that is not designed to be
adequate and well-controlled and the investigations that are designed to
be adequate and well-controlled; or
(iv) The drug has been studied in one or more adequate and well-
controlled investigations that strongly suggest lack of effectiveness;
or
(v) Another drug under investigation or approved for the same
indication and available to the same patient population has demonstrated
a better potential benefit/risk balance; or
(vi) The drug has received marketing approval for the same
indication in the same patient population; or
(vii) The sponsor of the study that is designed to be an adequate
and well-controlled investigation is not actively pursuing marketing
approval of the investigational drug with due diligence; or
(viii) The Commissioner determines that it would not be in the
public interest for the study to be conducted or continued. FDA
ordinarily intends that clinical holds under paragraphs (b)(4)(ii),
(b)(4)(iii) and (b)(4)(v) of this section would only apply to additional
enrollment in nonconcurrently controlled trials rather than eliminating
continued access to individuals already receiving the investigational
drug.
(5) Clinical hold of any investigation involving an exception from
informed consent under Sec. 50.24 of this chapter. FDA may place a
proposed or ongoing investigation involving an exception from informed
consent under Sec. 50.24 of this chapter on clinical hold if it is
determined that:
(i) Any of the conditions in paragraphs (b)(1) or (b)(2) of this
section apply; or
(ii) The pertinent criteria in Sec. 50.24 of this chapter for such
an investigation to begin or continue are not submitted or not
satisfied.
(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. If, by the terms of the
clinical hold order, resumption of the affected investigation is
permitted without prior notification by FDA once a stated correction or
modification is made, the investigation may proceed as soon as the
correction or modification is made. In all other cases, an investigation
may only resume after the Division Director (or the Director's designee)
with responsibility for review of the IND has notified the sponsor that
the investigation may proceed. In these cases resumption of the affected
investigation(s) will be authorized when the sponsor corrects the
deficiency(ies) previously cited or otherwise satisfied the agency that
the investigation(s) can proceed. Resumption of a study may be
authorized by telephone or other means of rapid communication.
(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]
[[Page 82]]
Sec. 312.44 Termination.
(a) General. This section describes the procedures under which FDA
may terminate an IND. If an IND is terminated, the sponsor shall end all
clinical investigations conducted under the IND and recall or otherwise
provide for the disposition of all unused supplies of the drug. A
termination action may be based on deficiencies in the IND or in the
conduct of an investigation under an IND. Except as provided in
paragraph (d) of this section, a termination shall be preceded by a
proposal to terminate by FDA and an opportunity for the sponsor to
respond. FDA will, in general, only initiate an action under this
section after first attempting to resolve differences informally or,
when appropriate, through the clinical hold procedures described in
Sec. 312.42.
(b) Grounds for termination--(1) Phase 1. FDA may propose to
terminate an IND during Phase 1 if it finds that:
(i) Human subjects would be exposed to an unreasonable and
significant risk of illness or unjury.
(ii) The IND does not contain sufficient information required under
Sec. 312.23 to assess the safety to subjects of the clinical
investigations.
(iii) The methods, facilities, and controls used for the
manufacturing, processing, and packing of the investigational drug are
inadequate to establish and maintain appropriate standards of identity,
strength, quality, and purity as needed for subject safety.
(iv) The clinical investigations are being conducted in a manner
substantially different than that described in the protocols submitted
in the IND.
(v) The drug is being promoted or distributed for commercial
purposes not justified by the requirements of the investigation or
permitted by Sec. 312.7.
(vi) The IND, or any amendment or report to the IND, contains an
untrue statement of a material fact or omits material information
required by this part.
(vii) The sponsor fails promptly to investigate and inform the Food
and Drug Administration and all investigators of serious and unexpected
adverse experiences in accordance with Sec. 312.32 or fails to make any
other report required under this part.
(viii) The sponsor fails to submit an accurate annual report of the
investigations in accordance with Sec. 312.33.
(ix) The sponsor fails to comply with any other applicable
requirement of this part, part 50, or part 56.
(x) The IND has remained on inactive status for 5 years or more.
(xi) The sponsor fails to delay a proposed investigation under the
IND or to suspend an ongoing investigation that has been placed on
clinical hold under Sec. 312.42(b)(4).
(2) Phase 2 or 3. FDA may propose to terminate an IND during Phase 2
or Phase 3 if FDA finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (b)(1)(xi)
of this section apply; or
(ii) The investigational plan or protocol(s) is not reasonable as a
bona fide scientific plan to determine whether or not the drug is safe
and effective for use; or
(iii) There is convincing evidence that the drug is not effective
for the purpose for which it is being investigated.
(3) FDA may propose to terminate a treatment IND if it finds that:
(i) Any of the conditions in paragraphs (b)(1)(i) through (x) of
this section apply; or
(ii) Any of the conditions in Sec. 312.42(b)(3) apply.
(c) Opportunity for sponsor response. (1) If FDA proposes to
terminate an IND, FDA will notify the sponsor in writing, and invite
correction or explanation within a period of 30 days.
(2) On such notification, the sponsor may provide a written
explanation or correction or may request a conference with FDA to
provide the requested explanation or correction. If the sponsor does not
respond to the notification within the allocated time, the IND shall be
terminated.
(3) If the sponsor responds but FDA does not accept the explanation
or correction submitted, FDA shall inform the sponsor in writing of the
reason for 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
[[Page 83]]
receipt of FDA's notification of nonacceptance.
(d) Immediate termination of IND. Notwithstanding paragraphs (a)
through (c) of this section, if at any time FDA concludes that
continuation of the investigation presents an immediate and substantial
danger to the health of individuals, the agency shall immediately, by
written notice to the sponsor from the Director of the Center for Drug
Evaluation and Research or the Director of the Center for Biologics
Evaluation and Research, terminate the IND. An IND so terminated is
subject to reinstatement by the Director on the basis of additional
submissions that eliminate such danger. If an IND is terminated under
this paragraph, the agency will afford the sponsor an opportunity for a
regulatory hearing under part 16 on the question of whether the IND
should be reinstated.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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
[[Page 84]]
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 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, 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 technical information to support Phase 3
studies and/or a marketing application may also be discussed. 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'' 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 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:
[[Page 85]]
(i) A brief summary of the clinical studies to be submitted in the
application.
(ii) A proposed format for organizing the submission, including
methods for presenting the data.
(iii) Any other information for discussion at the meeting.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55
FR 11580, Mar. 29, 1990]
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.
[[Page 86]]
Sec. 312.52 Transfer of obligations to a contract research organization.
(a) A sponsor may transfer responsibility for any or all of the
obligations set forth in this part to a contract research organization.
Any such transfer shall be described in writing. If not all obligations
are transferred, the writing is required to describe each of the
obligations being assumed by the contract research organization. If all
obligations are transferred, a general statement that all obligations
have been transferred is acceptable. Any obligation not covered by the
written description shall be deemed not to have been transferred.
(b) A contract research organization that assumes any obligation of
a sponsor shall comply with the specific regulations in this chapter
applicable to this obligation and shall be subject to the same
regulatory action as a sponsor for failure to comply with any obligation
assumed under these regulations. Thus, all references to ``sponsor'' in
this part apply to a contract research organization to the extent that
it assumes one or more obligations of the sponsor.
Sec. 312.53 Selecting investigators and monitors.
(a) Selecting investigators. A sponsor shall select only
investigators qualified by training and experience as appropriate
experts to investigate the drug.
(b) Control of drug. A sponsor shall ship investigational new drugs
only to investigators participating in the investigation.
(c) Obtaining information from the investigator. Before permitting
an investigator to begin participation in an investigation, the sponsor
shall obtain the following:
(1) A signed investigator statement (Form FDA-1572) containing:
(i) The name and address of the investigator;
(ii) The name and code number, if any, of the protocol(s) in the IND
identifying the study(ies) to be conducted by the investigator;
(iii) The name and address of any medical school, hospital, or other
research facility where the clinical investigation(s) will be conducted;
(iv) The name and address of any clinical laboratory facilities to
be used in the study;
(v) The name and address of the IRB that is responsible for review
and approval of the study(ies);
(vi) A commitment by the investigator that he or she:
(a) Will conduct the study(ies) in accordance with the relevant,
current protocol(s) and will only make changes in a protocol after
notifying the sponsor, except when necessary to protect the safety, the
rights, or welfare of subjects;
(b) Will comply with all requirements regarding the obligations of
clinical investigators and all other pertinent requirements in this
part;
(c) Will personally conduct or supervise the described
investigation(s);
(d) Will inform any potential subjects that the drugs are being used
for investigational purposes and will ensure that the requirements
relating to obtaining informed consent (21 CFR part 50) and
institutional review board review and approval (21 CFR part 56) are met;
(e) Will report to the sponsor adverse experiences that occur in the
course of the investigation(s) in accordance with Sec. 312.64;
(f) Has read and understands the information in the investigator's
brochure, including the potential risks and side effects of the drug;
and
(g) Will ensure that all associates, colleagues, and employees
assisting in the conduct of the study(ies) are informed about their
obligations in meeting the above commitments.
(vii) A commitment by the investigator that, for an investigation
subject 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.
[[Page 87]]
(viii) A list of the names of the subinvestigators (e.g., research
fellows, residents) who will be assisting the investigator in the
conduct of the investigation(s).
(2) Curriculum vitae. A curriculum vitae or other statement of
qualifications of the investigator showing the education, training, and
experience that qualifies the investigator as an expert in the clinical
investigation of the drug for the use under investigation.
(3) Clinical protocol. (i) For Phase 1 investigations, a general
outline of the planned investigation including the estimated duration of
the study and the maximum number of subjects that will be involved.
(ii) For Phase 2 or 3 investigations, an outline of the study
protocol including an approximation of the number of subjects to be
treated with the drug and the number to be employed as controls, if any;
the clinical uses to be investigated; characteristics of subjects by
age, sex, and condition; the kind of clinical observations and
laboratory tests to be conducted; the estimated duration of the study;
and copies or a description of case report forms to be used.
(4) Financial disclosure information. Sufficient accurate financial
information to allow the sponsor to submit complete and accurate
certification or disclosure statements required under part 54 of this
chapter. The sponsor shall obtain a commitment from the clinical
investigator to promptly update this information if any relevant changes
occur during the course of the investigation and for 1 year following
the completion of the study.
(d) Selecting monitors. A sponsor shall select a monitor qualified
by training and experience to monitor the progress of the investigation.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 312.53 was
amended by adding new paragraph (c)(4), effective Feb. 2, 1999.
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.
[[Page 88]]
Important safety information is required to be relayed to investigators
in accordance with Sec. 312.32.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
Sec. 312.56 Review of ongoing investigations.
(a) The sponsor shall monitor the progress of all clinical
investigations being conducted under its IND.
(b) A sponsor who discovers that an investigator is not complying
with the signed agreement (Form FDA-1572), the general investigational
plan, or the requirements of this part or other applicable parts shall
promptly either secure compliance or discontinue shipments of the
investigational new drug to the investigator and end the investigator's
participation in the investigation. If the investigator's participation
in the investigation is ended, the sponsor shall require that the
investigator dispose of or return the investigational drug in accordance
with the requirements of Sec. 312.59 and shall notify FDA.
(c) The sponsor shall review and evaluate the evidence relating to
the safety and effectiveness of the drug as it is obtained from the
investigator. The sponsors shall make such reports to FDA regarding
information relevant to the safety of the drug as are required under
Sec. 312.32. The sponsor shall make annual reports on the progress of
the investigation in accordance with Sec. 312.33.
(d) A sponsor who determines that its investigational drug presents
an unreasonable and significant risk to subjects shall discontinue those
investigations that present the risk, notify FDA, all institutional
review boards, and all investigators who have at any time participated
in the investigation of the discontinuance, assure the disposition of
all stocks of the drug outstanding as required by Sec. 312.59, and
furnish FDA with a full report of the sponsor's actions. The sponsor
shall discontinue the investigation as soon as possible, and in no event
later than 5 working days after making the determination that the
investigation should be discontinued. Upon request, FDA will confer with
a sponsor on the need to discontinue an investigation.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 312.57 was
amended by redesignating paragraphs (b) and (c) as paragraphs (c) and
[[Page 89]]
(d) and by adding a new paragraph (b), effective Feb. 2, 1999.
Sec. 312.58 Inspection of sponsor's records and reports.
(a) FDA inspection. A sponsor shall upon request from any properly
authorized officer or employee of the Food and Drug Administration, at
reasonable times, permit such officer or employee to have access to and
copy and verify any records and reports relating to a clinical
investigation conducted under this part. Upon written request by FDA,
the sponsor shall submit the records or reports (or copies of them) to
FDA. The sponsor shall discontinue shipments of the drug to any
investigator who has failed to maintain or make available records or
reports of the investigation as required by this part.
(b) Controlled substances. If an investigational new drug is a
substance listed in any schedule of the Controlled Substances Act (21
U.S.C. 801; 21 CFR part 1308), records concerning shipment, delivery,
receipt, and disposition of the drug, which are required to be kept
under this part or other applicable parts of this chapter shall, upon
the request of a properly authorized employee of the Drug Enforcement
Administration of the U.S. Department of Justice, be made available by
the investigator or sponsor to whom the request is made, for inspection
and copying. In addition, the sponsor shall assure that adequate
precautions are taken, including storage of the investigational drug in
a securely locked, substantially constructed cabinet, or other securely
locked, substantially constructed enclosure, access to which is limited,
to prevent theft or diversion of the substance into illegal channels of
distribution.
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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.
[[Page 90]]
(b) Case histories. An investigator is required to prepare and
maintain adequate and accurate case histories that record all
observations and other data pertinent to the investigation on each
individual administered the investigational drug or employed as a
control in the investigation. Case histories include the case report
forms and supporting data including, for example, signed and dated
consent forms and medical records including, for example, progress notes
of the physician, the individual's hospital chart(s), and the nurses'
notes. The case history for each individual shall document that informed
consent was obtained prior to participation in the study.
(c) Record retention. An investigator shall retain records required
to be maintained under this part for a period of 2 years following the
date a marketing application is approved for the drug for the indication
for which it is being investigated; or, if no application is to be filed
or if the application is not approved for such indication, until 2 years
after the investigation is discontinued and FDA is notified.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 61
FR 57280, Nov. 5, 1996]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 63
FR 5252, Feb. 2, 1998]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 312.64 was
amended by adding new paragraph (d), effective Feb. 2, 1999.
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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
[[Page 91]]
there is reason to believe that the records do not represent actual case
studies, or do not represent actual results obtained.
Sec. 312.69 Handling of controlled substances.
If the investigational drug is subject to the Controlled Substances
Act, the investigator shall take adequate precautions, including storage
of the investigational drug in a securely locked, substantially
constructed cabinet, or other securely locked, substantially constructed
enclosure, access to which is limited, to prevent theft or diversion of
the substance into illegal channels of distribution.
Sec. 312.70 Disqualification of a clinical investigator.
(a) If FDA has information indicating that an investigator
(including a sponsor-investigator) has repeatedly or deliberately failed
to comply with the requirements of this part, part 50, or part 56 of
this chapter, or has submitted to FDA or to the sponsor false
information in any required report, the Center for Drug Evaluation and
Research or the Center for Biologics Evaluation and Research will
furnish the investigator written notice of the matter complained of and
offer the investigator an opportunity to explain the matter in writing,
or, at the option of the investigator, in an informal conference. If an
explanation is offered but not accepted by the Center for Drug
Evaluation and Research or the Center for Biologics Evaluation and
Research, the investigator will be given an opportunity for a regulatory
hearing under part 16 on the question of whether the investigator is
entitled to receive investigational new drugs.
(b) After evaluating all available information, including any
explanation presented by the investigator, if the 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
[[Page 92]]
provisions of this part and of parts 50 and 56.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[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]
Subpart E--Drugs Intended to Treat Life-threatening and Severely-
debilitating Illnesses
Authority: Secs. 501, 502, 503, 505, 506, 507, 701, 52 Stat. 1049-
1053 as amended, 1055-1056 as amended, 55 Stat. 851, 59 Stat. 463 as
amended (21 U.S.C. 351, 352, 353, 355, 356, 357, 371); sec. 351, 58
Stat. 702 as amended (42 U.S.C. 262); 21 CFR 5.10, 5.11.
Source: 53 FR 41523, Oct. 21, 1988, unless otherwise noted.
Sec. 312.80 Purpose.
The purpose of this section is to establish procedures designed to
expedite the development, evaluation, and marketing of new therapies
intended to treat persons with life-threatening and severely-
debilitating illnesses, especially where no satisfactory alternative
therapy exists. As stated Sec. 314.105(c) of this chapter, while the
statutory standards of safety and effectiveness apply to all drugs, the
many kinds of drugs that are subject to them, and the wide range of uses
for those drugs, demand flexibility in applying the standards. The Food
and Drug Administration (FDA) has determined that it is appropriate to
exercise the broadest flexibility in applying the statutory standards,
while preserving appropriate guarantees for safety and effectiveness.
These procedures reflect the recognition that physicians and patients
are generally willing to accept greater risks or side effects from
products that treat life-threatening and severely-debilitating
illnesses, than they would accept from products that treat less serious
illnesses. These procedures also reflect the recognition that the
benefits of the drug need to be evaluated in light of the severity of
the disease being treated. The procedure outlined in this section should
be interpreted consistent with that purpose.
Sec. 312.81 Scope.
This section applies to new drug, antibiotic, 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.
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, 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
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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. 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.
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 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.
[[Page 94]]
Sec. 312.87 Active monitoring of conduct and evaluation of clinical trials.
For drugs covered under this section, the Commissioner and other
agency officials will monitor the progress of the conduct and evaluation
of clinical trials and be involved in facilitating their appropriate
progress.
Sec. 312.88 Safeguards for patient safety.
All of the safeguards incorporated within parts 50, 56, 312, 314,
and 600 of this chapter designed to ensure the safety of clinical
testing and the safety of products following marketing approval apply to
drugs covered by this section. This includes the requirements for
informed consent (part 50 of this chapter) and institutional review
boards (part 56 of this chapter). These safeguards further include the
review of animal studies prior to initial human testing (Sec. 312.23),
and the monitoring of adverse drug experiences through the requirements
of IND safety reports (Sec. 312.32), safety update reports during agency
review of a marketing application (Sec. 314.50 of this chapter), and
postmarketing adverse reaction reporting (Sec. 314.80 of this chapter).
Subpart F--Miscellaneous
Sec. 312.110 Import and export requirements.
(a) Imports. An investigational new drug offered for import into the
United States complies with the requirements of this part if it is
subject to an IND that is in effect for it under Sec. 312.40 and: (1)
The consignee in the United States is the sponsor of the IND; (2) the
consignee is a qualified investigator named in the IND; or (3) the
consignee is the domestic agent of a foreign sponsor, is responsible for
the control and distribution of the investigational drug, and the IND
identifies the consignee and describes what, if any, actions the
consignee will take with respect to the investigational drug.
(b) Exports. An investigational new drug 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.
[[Page 95]]
(4) This paragraph does not apply to the export of an antibiotic
drug product shipped in accordance with the provisions of section 801(d)
of the act.
(5) This paragraph does not apply to the export of new drugs
(including biological products) approved for export under section 802 of
the act or section 351(h)(1)(A) of the Public Health Service Act.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987]
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 or antibiotic 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;
(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
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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 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
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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.
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 56
FR 22113, May 14, 1991]
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 or
antibiotic 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]
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,
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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 Administration,
5600 Fishers Lane, Rockville, MD 20857.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987; 55
FR 11580, Mar. 29, 1990]
Sec. 312.145 Guidelines.
(a) FDA has made available guidelines under Sec. 10.90(b) to help
persons to comply with certain requirements of this part.
(b) The Center for Drug Evaluation and Research and the Center for
Biologics Evaluation and Research maintain lists of guidelines that
apply to the Centers' regulations. The lists state how a person can
obtain a copy of each guideline. A request for a copy of the lists
should be directed to the CDER Executive Secretariat Staff (HFD-8),
Center for Drug Evaluation and Research, Food and Drug Administration,
5600 Fishers Lane, Rockville, MD 20857, for drug products, and the
Congressional, Consumer, and International Affairs Staff (HFB-142),
Center for Biologics Evaluation and Research, Food and Drug
Administration, 8800 Rockville Pike, Bethesda, MD 20892, for biological
products.
[52 FR 8831, Mar. 19, 1987, as amended at 55 FR 11580, Mar. 29, 1990; 56
FR 3776, Jan. 31, 1991; 57 FR 10814, Mar. 31, 1992]
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
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the new drug will actually be used for tests in vitro or in animals used
only for laboratory research.
(3) A person who ships a drug under paragraph (a) of this section
shall maintain adequate records showing the name and post office address
of the expert to whom the drug is shipped and the date, quantity, and
batch or code mark of each shipment and delivery. Records of shipments
under paragraph (a)(1)(i) of this section are to be maintained for a
period of 2 years after the shipment. Records and reports of data and
shipments under paragraph (a)(1)(ii) of this section are to be
maintained in accordance with Sec. 312.57(b). The person who ships the
drug shall upon request from any properly authorized officer or employee
of the Food and Drug Administration, at reasonable times, permit such
officer or employee to have access to and copy and verify records
required to be maintained under this section.
(b) Termination of authorization to ship. FDA may terminate
authorization to ship a drug under this section if it finds that:
(1) The sponsor of the investigation has failed to comply with any
of the conditions for shipment established under this section; or
(2) The continuance of the investigation is unsafe or otherwise
contrary to the public interest or the drug is used for purposes other
than bona fide scientific investigation. FDA will notify the person
shipping the drug of its finding and invite immediate correction. If
correction is not immediately made, the person shall have an opportunity
for a regulatory hearing before FDA pursuant to part 16.
(c) Disposition of unused drug. The person who ships the drug under
paragraph (a) of this section shall assure the return of all unused
supplies of the drug from individual investigators whenever the
investigation discontinues or the investigation is terminated. The
person who ships the drug may authorize in writing alternative
disposition of unused supplies of the drug provided this alternative
disposition does not expose humans to risks from the drug, either
directly or indirectly (e.g., through food-producing animals). The
shipper shall maintain records of any alternative disposition.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0014)
[52 FR 8831, Mar. 19, 1987, as amended at 52 FR 23031, June 17, 1987.
Redesignated at 53 FR 41523, Oct. 21, 1988]
PART 314--APPLICATIONS FOR FDA APPROVAL TO MARKET A NEW DRUG OR AN ANTIBIOTIC 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.
314.60 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.
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Subpart D--FDA Action on Applications and Abbreviated Applications
314.100 Timeframes for reviewing applications and abbreviated
applications.
314.101 Filing an application and an abbreviated antibiotic 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 or abbreviated antibiotic
application.
314.126 Adequate and well-controlled studies.
314.127 Refusal to approve an abbreviated new drug application.
314.150 Withdrawal of approval of an application or abbreviated
application.
314.151 Withdrawal of approval of an abbreviated new drug application
under section 505(j)(5) of the act.
314.152 Notice of withdrawal of approval of an application or
abbreviated application for a new drug.
314.153 Suspension of approval of an abbreviated new drug application.
314.160 Approval of an application or abbreviated application for which
approval was previously refused, suspended, or withdrawn.
314.161 Determination of reasons for voluntary withdrawal of a listed
drug.
314.162 Removal of a drug product from the list.
314.170 Adulteration and misbranding of an approved drug.
Subpart E--Hearing Procedures for New Drugs
314.200 Notice of opportunity for hearing; notice of participation and
request for hearing; grant or denial of hearing.
314.201 Procedure for hearings.
314.235 Judicial review.
Subpart F--Administrative Procedures for Antibiotics
314.300 Procedure for the issuance, amendment, or repeal of
regulations.
Subpart G--Miscellaneous Provisions
314.410 Imports and exports of new drugs and antibiotics.
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 Guidelines.
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, 356, 357, 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, as well as amendments,
supplements, and postmarketing reports to them, by persons seeking or
holding approval from FDA of the following:
(1) An application or abbreviated application under section 505 of
the Federal Food, Drug, and Cosmetic Act to market a new drug.
(2) An application or abbreviated application under section 507 of
the Federal Food, Drug, and Cosmetic Act to market an antibiotic drug.
(b) This part does not apply to drug products subject to licensing
by FDA under the Public Health Service Act (58 Stat. 632 as amended (42
U.S.C. 201 et seq.)) and subchapter F of chapter I of title 21 of the
Code of Federal Regulations.
[[Page 101]]
(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]
Sec. 314.2 Purpose.
The purpose of this part is to establish an efficient and thorough
drug review process in order to: (a) Facilitate the approval of drugs
shown to be safe and effective; and (b) ensure the disapproval of drugs
not shown to be safe and effective. These regulations are also intended
to establish an effective system for FDA's surveillance of marketed
drugs. These regulations shall be construed in light of these
objectives.
Sec. 314.3 Definitions.
(a) The definitions and interpretations contained in section 201 of
the act apply to those terms when used in this part.
(b) The following definitions of terms apply to this part:
Abbreviated application means the application described under
Sec. 314.94, including all amendments and supplements to the
application. ``Abbreviated application'' applies to both an abbreviated
new drug application and an abbreviated antibiotic application.
Act means the Federal Food, Drug, and Cosmetic Act (sections 201-901
(21 U.S.C. 301-392)).
Applicant means any person who submits an application or abbreviated
application or an amendment or supplement to them under this part to
obtain FDA approval of a new drug or an antibiotic drug and any person
who owns an approved application or abbreviated application.
Application means the application described under Sec. 314.50,
including all amendements and supplements to the application.
505(b)(2) Application means an application submitted under section
505(b)(1) of the act for a drug for which the investigations described
in section 505(b)(1)(A) of the act and relied upon by the applicant for
approval of the application were not conducted by or for the applicant
and for which the applicant has not obtained a right of reference or use
from the person by or for whom the investigations were conducted.
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.
[[Page 102]]
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. Other applications will generally contain
only some of those items, and information will be limited to that needed
to support the particular submission. These include an application of
the type described in section 505(b)(2) of the act, an amendment, and a
supplement. The application is required to contain reports of all
investigations of the drug product sponsored by the applicant, and all
other information about the drug pertinent to an evaluation of the
application that is received or otherwise obtained by the applicant from
any source. FDA will maintain guidelines 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)
[[Page 103]]
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 for the drug, with annotations
to the information in the summary and technical sections of the
application that support the inclusion of each statement in the
labeling, and, if the application is for a prescription drug, statements
describing the reasons for omitting a section or subsection of the
labeling format in Sec. 201.57.
(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) or 507 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
[[Page 104]]
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 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
[[Page 105]]
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 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
[[Page 106]]
clinical investigations, including controlled and uncontrolled studies
of uses of the drug other than those proposed in the application,
commercial marketing experience, reports in the scientific literature,
and unpublished scientific papers.
(v) An integrated summary of the data demonstrating substantial
evidence of effectiveness for the claimed indications. Evidence is also
required to support the dosage and administration section of the
labeling, including support for the dosage and dose interval
recommended. The effectiveness data shall be presented by gender, age,
and racial subgroups and shall identify any modifications of dose or
dose interval needed for specific subgroups. Effectiveness data from
other subgroups of the population of patients treated, when appropriate,
such as patients with renal failure or patients with different levels of
severity of the disease, also shall be presented.
(vi) A summary and updates of safety information, as follows:
(a) The applicant shall submit an integrated summary of all
available information about the safety of the drug product, including
pertinent animal data, demonstrated or potential adverse effects of the
drug, clinically significant drug/drug interactions, and other safety
considerations, such as data from epidemiological studies of related
drugs. The safety data shall be presented by gender, age, and racial
subgroups. When appropriate, safety data from other subgroups of the
population of patients treated also shall be presented, such as for
patients with renal failure or patients with different levels of
severity of the disease. A description of any statistical analyses
performed in analyzing safety data should also be included, unless
already included under paragraph (d)(5)(ii) of this section.
(b) The applicant shall, under section 505(i) of the act, update
periodically its pending application with new safety information learned
about the drug that may reasonably affect the statement of
contraindications, warnings, precautions, and adverse reactions in the
draft labeling. 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
[[Page 107]]
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.
(e) Samples and labeling. (1) Upon request from FDA, the applicant
shall submit the samples described below to the places identified in the
agency's request. FDA will generally ask applicants to submit samples
directly to two or more agency laboratories that will perform all
necessary tests on the samples and validate the applicant's analytical
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 (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.
[[Page 108]]
(2) Case report forms. The application is required to contain copies
of individual case report forms for each patient who died during a
clinical study or who did not complete the study because of an adverse
event, whether believed to be drug related or not, including patients
receiving reference drugs or placebo. This requirement may be waived by
FDA for specific studies if the case report forms are unnecessary for a
proper review of the study.
(3) Additional data. The applicant shall submit to FDA additional
case report forms and tabulations needed to conduct a proper review of
the application, as requested by the director of the FDA division
responsible for reviewing the application. The applicant's failure to
submit information requested by FDA within 30 days after receipt of the
request may result in the agency viewing any eventual submission as a
major amendment under Sec. 314.60 and extending the review period as
necessary. If desired by the applicant, the FDA division director will
verify in writing any request for additional data that was made orally.
(4) Applicants are invited to meet with FDA before submitting an
application to discuss the presentation and format of supporting
information. If the applicant and FDA agree, the applicant may submit
tabulations of patient data and case report forms in a form other than
hard copy, for example, on microfiche or computer tapes.
(g) Other. The following general requirements apply to the
submission of information within the summary under paragraph (c) of this
section and within the technical sections under paragraph (d) of this
section.
(1) The applicant ordinarily is not required to resubmit information
previously submitted, but may incorporate the information by reference.
A reference to information submitted previously is required to identify
the file by name, reference number, volume, and page number in the
agency's records where the information can be found. A reference to
information submitted to the agency by a person other 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'';
[[Page 109]]
(3) The date on which the patent will expire. The applicant shall
entitle such a certification ``Paragraph III Certification''; or
(4) That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for which
the application is submitted. The applicant shall entitle such a
certification ``Paragraph IV Certification''. This certification shall
be submitted in the following form:
I, (name of applicant), certify that Patent No. ____________ (is
invalid, unenforceable, or will not be infringed by the manufacture,
use, or sale of) (name of proposed drug product) for which this
application is submitted.
The certification shall be accompanied by a statement that the applicant
will comply with the requirements under Sec. 314.52(a) with respect to
providing a notice to each owner of the patent or their representatives
and to the holder of the approved application for the drug product which
is claimed by the patent or a use of which is claimed by the patent and
with the requirements under Sec. 314.52(c) with respect to the content
of the notice.
(B) If the drug on which investigations that are relied upon by the
applicant were conducted is itself a licensed generic drug of a patented
drug first approved under section 505(b) of the act, the appropriate
patent certification under this section with respect to each patent that
claims the first-approved patented drug or that claims an approved use
for such a drug.
(ii) No relevant patents. If, in the opinion of the applicant and to
the best of its knowledge, there are no patents described in paragraph
(i)(1)(i) of this section, a certification in the following form:
In the opinion and to the best knowledge of (name of applicant), there
are no patents that claim the drug or drugs on which investigations that
are relied upon in this application were conducted or that claim a use
of such drug or drugs.
(iii) Method of use patent. (A) If information that is submitted
under section 505(b) or (c) of the act and Sec. 314.53 is for 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
[[Page 110]]
statement under paragraph (i)(1)(iii) of this section as to that patent.
(5) Disputed patent information. If an applicant disputes the
accuracy or relevance of patent information submitted to FDA, the
applicant may seek a confirmation of the correctness of the patent
information in accordance with the procedures under Sec. 314.53(f).
Unless the patent information is withdrawn or changed, the applicant
must submit an appropriate certification for each relevant patent.
(6) Amended certifications. A certification submitted under
paragraphs (i)(1)(i) through (i)(1)(iii) of this section may be amended
at any time before the effective date of the approval of the
application. An applicant shall submit an amended certification as an
amendment to a pending application or by letter to an approved
application. If an applicant with a pending application voluntarily
makes a patent certification for an untimely filed patent, the applicant
may withdraw the patent certification for the untimely filed patent.
Once an amendment or letter for the change in certification has been
submitted, the application will no longer be considered to be one
containing the prior certification.
(i) After finding of infringement. An applicant who has submitted a
certification under paragraph (i)(1)(i)(A)(4) of this section and is
sued for patent infringement within 45 days of the receipt of notice
sent under Sec. 314.52 shall amend the certification if a final judgment
in the action is entered finding the patent to be infringed unless the
final judgment also finds the patent to be invalid. In the amended
certification, the applicant shall certify under paragraph
(i)(1)(i)(A)(3) of this section that the patent will expire on a
specific date.
(ii) After removal of a patent from the list. If a patent is removed
from the list, any applicant with a pending application (including a
tentatively approved application with a delayed effective date) who has
made a certification with respect to such patent 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
[[Page 111]]
in the drug for which the applicant is seeking approval.
(4) If the applicant claims exclusivity under Sec. 314.108(b)(4) or
(b)(5), the following information to show that the application contains
``new clinical investigations'' that are ``essential to approval of the
application or supplement'' and were ``conducted or sponsored by the
applicant:''
(i) ``New clinical investigations.'' A certification that to the
best of the applicant's knowledge each of the clinical investigations
included in the application meets the definition of ``new clinical
investigation'' set forth in Sec. 314.108(a).
(ii) ``Essential to approval.'' A list of all published studies or
publicly available reports of clinical investigations known to the
applicant through a literature search that are relevant to the
conditions for which the applicant is seeking approval, a certification
that the applicant has thoroughly searched the scientific literature
and, to the best of the applicant's knowledge, the list is complete and
accurate and, in the applicant's opinion, such published studies or
publicly available reports do not provide a sufficient basis for the
approval of the conditions for which the applicant is seeking approval
without reference to the new clinical investigation(s) in the
application, and an explanation as to why the studies or reports are
insufficient.
(iii) ``Conducted or sponsored by.'' If the applicant was the
sponsor named in the Form FDA-1571 for an investigational new drug
application (IND) under which the new clinical investigation(s) that is
essential to the approval of its application was conducted,
identification of the IND by number. If the applicant was not the
sponsor of the IND under which the clinical investigation(s) was
conducted, a certification that the applicant or its predecessor in
interest provided substantial support for the clinical investigation(s)
that is essential to the approval of its application, and information
supporting the certification. To demonstrate ``substantial support,'' an
applicant must 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, 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.
[[Page 112]]
(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.
(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 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]
Effective Date Note: 1. At 63 FR 5252, Feb. 2, 1998, Sec. 314.50 was
amended by redesignating paragraph (k) as paragraph (l) and by adding a
new paragraph (k), effective Feb. 2, 1999.
2. At 63 FR 6862, Feb. 11, 1998, Sec. 314.50 was amended by revising
the second sentence and adding two new sentences after the second
sentence in paragraph (d)(5)(v), and by adding two new sentences after
the first sentence in paragraph (d)(5)(vi)(a), effective Aug. 10, 1998.
For the convenience of the user, the superseded text is set forth as
follows:
Sec. 314.50 Content and format of an application.
* * * * *
(d) * * *
(5) * * *
(v) * * * Evidence is also required to support the dosage and
administration section of the labeling, including support for the dosage
and dose interval recommended, and modifications for specific subgroups
(for example, pediatrics, geriatrics, patients with renal failure).
* * * * *
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
[[Page 113]]
content requirement under paragraph (c) of this section.
(c) Content of a notice. In the notice, the applicant shall cite
section 505(b)(3)(B) of the act and shall include, but not be limited
to, the following information:
(1) A statement that a 505(b)(2) application submitted by the
applicant has been filed by FDA.
(2) The application number.
(3) The established name, if any, as defined in section 502(e)(3) of
the act, of the proposed drug product.
(4) The active ingredient, strength, and dosage form of the proposed
drug product.
(5) The patent number and expiration date, as submitted to the
agency or as known to the applicant, of each patent alleged to be
invalid, unenforceable, or not infringed.
(6) A detailed statement of the factual and legal basis of the
applicant's opinion that the patent is not valid, unenforceable, or will
not be infringed. The applicant shall include in the detailed statement:
(i) For each claim of a patent alleged not to be infringed, a full
and detailed explanation of why the claim is not infringed.
(ii) For each claim of a patent alleged to be invalid or
unenforceable, a full and detailed explanation of the grounds supporting
the allegation.
(7) If the applicant does not reside or have a place of business in
the United States, the name and address of an agent in the United States
authorized to accept service of process for the applicant.
(d) Amendment to an application. If an application is amended to
include the certification described in Sec. 314.50(i), the applicant
shall send the notice required by paragraph (a) of this section at the
same time that the amendment to the application is submitted to FDA.
(e) Documentation of receipt of notice. The applicant shall amend
its application to document receipt of the notice required under
paragraph (a) of this section by each person provided the notice. The
applicant shall include a copy of the return receipt or other similar
evidence of the date the notification was received. FDA will accept as
adequate documentation of the date of receipt a return receipt or a
letter acknowledging receipt by the person provided the notice. An
applicant may rely on another form of documentation only if FDA has
agreed to such documentation in advance. A copy of the notice itself
need not be submitted to the agency.
(f) Approval. If the requirements of this section are met, the
agency will presume the notice to be complete and sufficient, and it
will count the day following the date of receipt of the notice 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
[[Page 114]]
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.
(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
[[Page 115]]
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 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]
[[Page 116]]
Sec. 314.54 Procedure for submission of an application requiring investigations for approval of a new indication for, or other change from, a listed drug.
(a) The act does not permit approval of an abbreviated new drug
application for a new indication, nor does it permit approval of other
changes in a listed drug if investigations, other than bioavailability
or bioequivalence studies, are essential to the approval of the change.
Any person seeking approval of a drug product that represents a
modification of a listed drug (e.g., a new indication or new dosage
form) and for which investigations, other than bioavailability or
bioequivalence studies, are essential to the approval of the changes
may, except as provided in paragraph (b) of this section, submit a
505(b)(2) application. This application need contain only that
information needed to support the modification(s) of the listed drug.
(1) The applicant shall submit a complete archival copy of the
application that contains the following:
(i) The information required under Sec. 314.50(a), (b), (c), (d)(1),
(d)(3), (e), and (g), except that Sec. 314.50(d)(1)(ii)(c) shall contain
the proposed or actual master production record, including a description
of the equipment, to be used for the manufacture of a commercial lot of
the drug product.
(ii) The information required under Sec. 314.50 (d)(2), (d)(4) (if
an anti-infective drug), (d)(5), (d)(6), and (f) as needed to support
the safety and effectiveness of the drug product.
(iii) Identification of the listed drug for which FDA has made a
finding of safety and effectiveness and on which finding the applicant
relies in seeking approval of its proposed drug product by established
name, if any, proprietary name, dosage form, strength, route of
administration, name of listed drug's application holder, and listed
drug's approved application number.
(iv) If the applicant is seeking approval only for a new indication
and not for the indications approved for the listed drug on which the
applicant relies, a certification so stating.
(v) Any patent information required under section 505(b)(1) of the
act with respect to any patent which claims the drug for which approval
is sought or a method of using such drug and to which a claim of patent
infringement could reasonably be asserted if a person not licensed by
the owner of the patent engaged in the manufacture, use, or sale of the
drug product.
(vi) Any patent certification or statement required under section
505(b)(2) of the act with respect to any relevant patents that claim the
listed drug or that claim any other drugs on which investigations relied
on by the applicant for approval of the application were conducted, or
that claim a use for the listed or other drug.
(vii) If the applicant believes the change for which it is seeking
approval is entitled to a period of exclusivity, the information
required under Sec. 314.50(j).
(2) The applicant shall submit a review copy that contains the
technical sections described in Sec. 314.50(d)(1), except that
Sec. 314.50(d)(1)(ii)(c) shall contain the proposed or actual master
production record, including a description of the equipment, to be used
for the manufacture of a commercial lot of the drug product, and
paragraph (d)(3), and the technical sections described in paragraphs
(d)(2), (d)(4), (d)(5), (d)(6), and (f) when needed to support the
modification. Each of the technical 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
[[Page 117]]
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. 314.60 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]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 314.60 was
amended in paragraph (a) by adding a new sentence at the end of the
paragraph, effective Feb. 2, 1999.
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
[[Page 118]]
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 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 guideline, 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,
[[Page 119]]
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.
(xii) To add a code imprint by embossing, debossing, or engraving on
a modified release solid oral dosage form drug product.
(3) Labeling. Any change in labeling, except one described in
paragraph (c)(2) or (d) of this section.
(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
[[Page 120]]
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.
(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
[[Page 121]]
(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, 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
[[Page 122]]
type of change reduces the potential risk of an adverse effect.
(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; 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]
Sec. 314.71 Procedures for submission of a supplement to an approved application.
(a) Only the applicant may submit a supplement to an application.
(b) All procedures and actions that apply to an application under
Sec. 314.50 also apply to supplements, except that the information
required in the supplement is limited to that needed to support the
change. A supplement is required to contain an archival copy and a
review copy that include an application form and appropriate technical
sections, samples, and labeling; except that a supplement for a change
other than a change in labeling is required also to contain a field
copy.
(c) All procedures and actions that apply to applications under this
part, including actions by applicants and the Food and Drug
Administration, also apply to supplements.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 58
FR 47352, Sept. 8, 1993]
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.
(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]
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
[[Page 123]]
occurred in a more severe form, might have caused death.
Serious adverse drug experience. Any adverse drug experience
occurring at any dose that results in any of the following outcomes:
Death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect. Important medical events that may not result in
death, be life-threatening, or require hospitalization may be considered
a serious adverse drug experience when, based upon appropriate medical
judgment, they may jeopardize the patient or subject and may require
medical or surgical intervention to prevent one of the outcomes listed
in this definition. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home, blood dyscrasias or convulsions that do not result in inpatient
hospitalization, or the development of drug dependency or drug abuse.
Unexpected adverse drug experience. Any adverse drug experience that
is not listed in the current labeling for the drug product. This
includes events that may be symptomatically and pathophysiologically
related to an event listed in the labeling, but differ from the event
because of greater severity or specificity. For example, under this
definition, hepatic necrosis would be unexpected (by virtue of greater
severity) if the labeling only referred to elevated hepatic enzymes or
hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis
would be unexpected (by virtue of greater specificity) if the labeling
only listed cerebral vascular accidents. ``Unexpected,'' as used in this
definition, refers to an adverse drug experience that has not been
previously observed (i.e., included in the labeling) rather than from
the perspective of such experience not being anticipated from the
pharmacological properties of the pharmaceutical product.
(b) Review of adverse drug experiences. Each applicant having an
approved application under Sec. 314.50 or, in the case of a 505(b)(2)
application, an effective approved application, shall promptly review
all adverse drug experience information obtained or otherwise received
by the applicant from any source, foreign or domestic, including
information derived from commercial marketing experience, postmarketing
clinical investigations, postmarketing epidemiological/surveillance
studies, reports in the scientific literature, and unpublished
scientific papers. Applicants are not required to resubmit to FDA
adverse drug experience reports forwarded to the applicant by FDA;
however, applicants must submit all followup information on such reports
to FDA. Any person subject to the reporting requirements under paragraph
(c) of this section shall also develop written procedures for the
surveillance, receipt, evaluation, and reporting of postmarketing
adverse drug experiences to FDA.
(c) Reporting requirements. The applicant shall report to FDA
adverse drug experience information, as described in this section. The
applicant shall submit two copies of each report described in this
section to the Central Document Room, 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
[[Page 124]]
Alert reports, shall also apply to any person other than the applicant
(nonapplicant) whose name appears on the label of an approved drug
product as a manufacturer, packer, or distributor. To avoid unnecessary
duplication in the submission to FDA of reports required by paragraphs
(c)(1)(i) and (c)(1)(ii) of this section, obligations of a nonapplicant
may be met by submission of all reports of serious adverse drug
experiences to the applicant. If a nonapplicant elects to submit adverse
drug experience reports to the applicant rather than to FDA, the
nonapplicant shall submit each report to the applicant within 5 calendar
days of receipt of the report by the nonapplicant, and the applicant
shall then comply with the requirements of this section. Under this
circumstance, the nonapplicant shall maintain a record of this action
which shall include:
(A) A copy of each adverse drug experience report;
(B) The date the report was received by the nonapplicant;
(C) The date the report was submitted to the applicant; and
(D) The name and address of the applicant.
(iv) Report identification. Each report submitted under this
paragraph shall bear prominent identification as to its contents, i.e.,
``15-day Alert report,'' or ``15-day Alert report-followup.''
(2) Periodic adverse drug experience reports. (i) The applicant
shall report each adverse drug experience not reported under paragraph
(c)(1)(i) of this section at quarterly intervals, for 3 years from the
date of approval of the application, and then at annual intervals. The
applicant shall submit each quarterly report within 30 days of the close
of the quarter (the first quarter beginning on the date of approval of
the application) and each annual report within 60 days of the
anniversary date of approval of the application. Upon written notice,
FDA may extend or reestablish the requirement that an applicant submit
quarterly reports, or require that the applicant submit reports under
this section at different times than those stated. For example, the
agency may reestablish a quarterly reporting requirement following the
approval of a major supplement. Followup information to adverse drug
experiences submitted in a periodic report may be submitted in the next
periodic report.
(ii) Each periodic report is required to contain: (a) a narrative
summary and analysis of the information in the report and an analysis of
the 15-day Alert reports submitted during the reporting interval (all
15-day Alert reports being appropriately referenced by the applicant's
patient identification number, adverse reaction term(s), and date of
submission to FDA); (b) a FDA Form 3500A (Adverse Reaction Report) for
each adverse drug experience not reported under paragraph (c)(1)(i) of
this section (with an index consisting of a line listing of the
applicant's patient identification number and adverse reaction term(s));
and (c) a history of actions taken since the last report because of
adverse drug experiences (for example, labeling changes or studies
initiated).
(iii) Periodic reporting, except for information regarding 15-day
Alert reports, does not apply to adverse drug experience information
obtained from postmarketing studies (whether or not conducted under an
investigational new drug application), from reports in the scientific
literature, and from foreign marketing experience.
(d) Scientific literature. (1) A 15-day Alert report based on
information from 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.
[[Page 125]]
(e) Postmarketing studies. (1) An applicant is not required to
submit a 15-day Alert report under paragraph (c) of this section for an
adverse drug experience obtained from a postmarketing study (whether or
not conducted under an investigational new drug application) unless the
applicant concludes that there is a reasonable possibility that the drug
caused the adverse experience.
(2) The applicant shall separate and clearly mark reports of adverse
drug experiences that occur during a postmarketing study as being
distinct from those experiences that are being reported spontaneously to
the applicant.
(f) Reporting FDA Form 3500A. (1) Except as provided in paragraph
(f)(3) of this section, the applicant shall complete FDA Form 3500A for
each report of an adverse drug experience (foreign events may be
submitted either on an FDA Form 3500A or, if preferred, on a CIOMS I
form).
(2) Each completed FDA Form 3500A should refer only to an individual
patient or a single attached publication.
(3) Instead of using FDA Form 3500A, an applicant may use a
computer-generated FDA Form 3500A or other alternative format (e.g., a
computer-generated tape or tabular listing) provided that: (i) The
content of the alternative format is equivalent in all elements of
information to those specified in FDA Form 3500A; and (ii) The format is
agreed to in advance by 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
[[Page 126]]
provision, the term ``applicant'' also includes any person reporting
under paragraph (c)(1)(iii) of this section.
(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; 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]
Effective Date Note: At 62 FR 52251, Oct. 7, 1997, Sec. 314.80 was
amended by revising paragraphs (a), (c)(1), (f)(1), (f)(3)(ii), and
(f)(4) and the introductory text of paragraph (c); by adding two new
sentences at the end of paragraph (b); by removing in paragraph (d)(2)
the words ``Epidemiology and Surveillance'' and adding in their place
the words ``Pharmacovigilance and Epidemiology''; by removing in
paragraphs (c)(2)(ii)(b), (d)(2), (f)(2), and (f)(3) and in the heading
for paragraph (f) the words ``Form FDA-1639'' or ``FDA-1639'' and adding
in their place the words ``FDA Form 3500A''; and by removing paragraph
(j) and redesignating paragraphs (k) and (l) as paragraphs (j) and (k),
respectively, effective Apr. 6, 1998. For the convenience of the user,
the superseded text is set forth as follows:
Sec. 314.80 Postmarketing reporting of adverse drug experiences.
(a) Definitions. The following definitions of terms apply to this
section:
Adverse drug experience means 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.
Serious means an adverse drug experience that is fatal or life-
threatening, is permanently disabling, requires inpatient
hospitalization, or is a congenital anomaly, cancer, or overdose.
Unexpected means an adverse drug experience that is not listed in
the current labeling for the drug and includes an event that may be
symptomatically and pathophysiologically related to an event listed in
the labeling, but differs 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.
* * * * *
(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, Park Bldg., Rm. 214, 12420
Parklawn Dr., Rockville, MD 20852. FDA may waive the requirement for the
second copy in appropriate instances.
(1) Fifteen-day ``Alert reports.'' (i) The applicant shall report
each adverse drug experience that is both serious and unexpected,
regardless of source, as soon as possible but in any case within 15
working days of initial receipt of the information. These reports are
required to be submitted on Form FDA-1639 (Adverse Reaction Report). The
applicant shall promptly investigate all adverse drug experiences that
are the subject of these 15-day Alert reports and shall submit followup
reports within 15 working days of receipt of new information or as
requested by FDA. If additional information is not obtainable, a
followup report may be required that describes briefly the steps taken
to seek additional information and the reasons why it could not be
obtained. These 15-day Alert reports and followups to them are required
to be submitted under separate cover and may not be included, except for
summary or tabular purposes, in a periodic report.
(ii) The requirements of paragraph (c)(1)(i) of this section,
concerning the submission of 15-day Alert reports, shall also apply to
any person (other than the applicant) whose name appears on the label of
an approved drug product as a manufacturer, packer, or distributor.
However, to avoid unnecessary duplication in the submission to FDA of,
and followup to, reports required by paragraph (c)(1)(i) 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, it shall submit each report to the
applicant within 3 working days of its receipt 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 the drug experience report.
(b) Date the report was received by the nonapplicant.
(c) Date the report was submitted to the applicant.
(d) Name and address of the applicant.
[[Page 127]]
(iii) 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.''
* * * * *
(f) Reporting Form FDA-1639. (1) Except as provided in paragraph
(f)(3) of this section, the applicant shall complete a Form FDA-1639
(Adverse Reaction Report) for each report of an adverse drug experience.
* * * * *
(3) * * *
(ii) the format is agreed to in advance by the Division of
Epidemiology and Surveillance (HFD-730).
(4) Single copies of Form FDA-1639 may be obtained from the Division
of Epidemiology and Surveillance (HFD-730), Center for Drug Evaluation
and Research, Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857. Supplies of Form FDA-1639 may be obtained from the
PHS Forms and Publications Distribution Center, 12100 Parklawn Dr.,
Rockville, MD 20857.
* * * * *
(j) Guideline. FDA has prepared under Sec. 10.90(b) a guideline for
the submission of reports of adverse drug experiences and suggested
followup investigation of reports.
* * * * *
2. At 63 FR 14611, Mar. 26, 1998, Sec. 314.80 was amended by
correcting the reference to ``paragraph (c)(1)(ii)'' in the last
sentence in newly redesignated paragraph (k) to read ``paragraph
(c)(1)(iii)'', effective Apr. 6, 1998.
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 sections 505(k) and 507(g) of the act.
(b) Reporting requirements. The applicant shall submit to the Food
and Drug Administration at the specified times two copies of the
following reports:
(1) NDA--Field alert report. The applicant shall submit information
of the following kinds about distributed drug products and articles to
the FDA district office that is responsible for the facility involved
within 3 working days of receipt by the applicant. The information may
be provided by telephone or other rapid communication means, with prompt
written followup. The report and its mailing cover should be plainly
marked: ``NDA--Field Alert Report.''
(i) Information concerning any incident that causes the drug product
or its labeling to be mistaken for, or applied to, another article.
(ii) Information concerning any bacteriological contn, 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 the following
information in the order listed each year within 60 days of the
anniversary date of approval of the application. The applicant shall
submit 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) which may be obtained from the PHS Forms and
Publications Distribution Center, 12100 Parklawn Dr., Rockville, MD
20857, and is required to include all the information required under
this section that the applicant received or otherwise obtained during
the annual reporting interval which ends on the anniversary date. The
report is required to contain the following:
(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.
(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),
[[Page 128]]
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, 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.)
(vii) Status reports. A statement on the current status of any
postmarketing studies performed by, or on behalf of, the applicant. 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.
(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.
[[Page 129]]
(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 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]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985]
Subpart C--Abbreviated Applications
Source: 57 FR 17983, Apr. 28, 1992, unless otherwise noted.
[[Page 130]]
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) Drug products that are duplicates of, or that meet the monograph
for, an antibiotic drug for which FDA has approved an application.
(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.
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 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.
[[Page 131]]
(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 guidelines on the format and content of
applications to assist applicants in their preparation.
(a) Abbreviated new drug applications. Except as provided in
paragraph (b) of this section, the applicant shall submit a complete
archival copy of the abbreviated new drug application that includes the
following:
(1) Application form. The applicant shall submit a completed and
signed application form that contains the information described under
Sec. 314.50(a)(1), (a)(3), (a)(4), and (a)(5). The applicant shall state
whether the submission is an abbreviated application under this section
or a supplement to an abbreviated application under Sec. 314.97.
(2) Table of contents. the archival copy of the abbreviated new drug
application is required to contain a table of
[[Page 132]]
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 product differs from the reference listed drug and the abbreviated
application is submitted under an approved
[[Page 133]]
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 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) Proposed labeling. Copies of the label and all labeling for the
drug product (4 copies of draft labeling or 12 copies of final printed
labeling).
(iii) A statement that the applicant's proposed labeling 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) A side-by-side comparison of the applicant's proposed labeling
with the approved labeling for the reference listed drug with all
differences annotated and explained. Labeling (including the container
label and package insert) proposed for the drug product must be the same
as the labeling approved for the reference listed drug, except for
changes required because of differences approved under a petition filed
under Sec. 314.93 or because the drug product and the reference listed
drug are produced or distributed by different manufacturers. Such
differences between the applicant's proposed labeling and labeling
approved for the reference listed drug may include differences in
expiration date, formulation, bioavailability, or pharmacokinetics,
labeling revisions made to comply with current FDA labeling guidelines
or other guidance, or omission of an indication or other aspect of
labeling protected by patent or accorded exclusivity under section
505(j)(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
[[Page 134]]
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:
(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
[[Page 135]]
``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.
(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
[[Page 136]]
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.
(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) Abbreviated antibiotic application. For applications submitted
under section 507 of the act, the applicant shall submit a complete
archival copy of the abbreviated application that contains the
information described under Sec. 314.50 (a)(1), (a)(3), (a)(4), and
(a)(5), (b), (d)(1) and (d)(3), (e), and (g). The applicant
[[Page 137]]
shall state whether the submission is an abbreviated application under
this section or a supplement to an abbreviated application under
Sec. 314.97.
(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) For abbreviated antibiotic applications, the applicant shall
submit a review copy that contains the technical sections described in
Sec. 314.50 (d)(1) and (d)(3). Each of the technical sections in the
review copy is required to be separate with a copy of the application
form required under Sec. 314.50(a).
(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]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 314.94 was
amended by adding new paragraph (a)(13), effective Feb. 2, 1999.
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 138]]
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 139]]
(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.
(c) Abbreviated antibiotic application. The applicant shall comply
with the provisions of Sec. 314.60.
[57 FR 17983, Apr. 28, 1992, as amended at 58 FR 47352, Sept. 8, 1993]
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 antibiotic application under
Sec. 314.94 or 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 sections 505(k) and 507(g) of the act for each of its approved
abbreviated applications.
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, or of an application or
abbreviated application for an antibiotic drug under section 507 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]
[[Page 140]]
Sec. 314.101 Filing an application and an abbreviated antibiotic application and receiving an abbreviated new drug application.
(a)(1) Within 60 days after FDA receives an application or
abbreviated antibiotic application, the agency will determine whether
the application or abbreviated antibiotic application may be filed. The
filing of an application or abbreviated antibiotic application means
that FDA has made a threshold determination that the application or
abbreviated antibiotic 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 or abbreviated
antibiotic apply, the agency will file the application or abbreviated
antibiotic application and notify the applicant in writing. The date of
filing will be the date 60 days after the date FDA received the
application or abbreviated antibiotic 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 or abbreviated antibiotic
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 or abbreviated antibiotic
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 or abbreviated antibiotic
application. If, following the informal conference, the applicant
requests that FDA file the application or abbreviated antibiotic
application (with or without amendments to correct the deficiencies),
the agency will file the application or abbreviated antibiotic
application over protest under paragraph (a)(2) of this section, notify
the applicant in writing, and review it as filed. If the application or
abbreviated antibiotic 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 or abbreviated antibiotic application that is filed over
protest. If FDA refuses to file the application or abbreviated
antibiotic application under paragraph (e) of this section, the
applicant may amend the application or abbreviated antibiotic
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 abbreviated antibiotic
application or may not consider an abbreviated new drug application to
be received if any of the following applies:
(1) The application or abbreviated application does not contain a
completed application form.
(2) The application or abbreviated 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
[[Page 141]]
not on its face contain information required under section 505(b),
section 505(j), or section 507 of the act and Sec. 314.50 or
Sec. 314.94.
(4) The applicant fails to submit a complete environmental
assessment, which addresses each of the items specified in the
applicable format under Sec. 25.40 of this chapter or fails to provide
sufficient information to establish that the requested action is subject
to categorical exclusion under Sec. 25.30 or Sec. 25.31 of this chapter.
(5) The application or abbreviated application does not contain an
accurate and complete English translation of each part of the
application that is not in English.
(6) The application does not contain a statement for each
nonclinical laboratory study that it was conducted in compliance with
the requirements set forth in part 58 of this chapter, or, for each
study not conducted in compliance with part 58 of this chapter, a brief
statement of the reason for the noncompliance.
(7) The application does not contain a statement for each clinical
study that it was conducted in compliance with the institutional review
board regulations in part 56 of this chapter, or was not subject to
those regulations, and that it was conducted in compliance with the
informed consent regulations in part 50 of this chapter, or, if the
study was subject to but was not conducted in compliance with those
regulations, the application does not contain a brief statement of the
reason for the noncompliance.
(8) The drug product that is the subject of the submission is
already covered by an approved application or abbreviated application
and the applicant of the submission:
(i) Has an approved application or abbreviated application for the
same drug product; or
(ii) Is merely a distributor and/or repackager of the already
approved drug product.
(9) The application is submitted as a 505(b)(2) application for a
drug that is a duplicate of a listed drug and is eligible for approval
under section 505(j) of the act.
(e) The agency will refuse to file an application or abbreviated
antibiotic 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 abbreviated antibiotic 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
or abbreviated antibiotic 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]
[[Page 142]]
Sec. 314.102 Communications between FDA and applicants.
(a) General principles. During the course of reviewing an
application or an abbreviated application, FDA shall communicate with
applicants about scientific, medical, and procedural issues that arise
during the review process. Such communication may take the form of
telephone conversations, letters, or meetings, whichever is most
appropriate to discuss the particular issue at hand. Communications
shall be appropriately documented in the application in accordance with
Sec. 10.65 of this chapter. Further details on the procedures for
communication between FDA and applicants are contained in a staff manual
guide that is publicly available.
(b) Notification of easily correctable deficiencies. FDA reviewers
shall make every reasonable effort to communicate promptly to applicants
easily correctable deficiencies found in an application or an
abbreviated application when those deficiencies are discovered,
particularly deficiencies concerning chemistry, manufacturing, and
controls issues. The agency will also inform applicants promptly of its
need for more data or information or for technical changes in the
application or the abbreviated application needed to facilitate the
agency's review. This early communication is intended to permit
applicants to correct such readily identified deficiencies relatively
early in the review process and to submit an amendment before the review
period has elapsed. Such early communication would not ordinarily apply
to major scientific issues, which require consideration of the entire
pending application or abbreviated application by agency managers as
well as reviewing staff. Instead, major scientific issues will
ordinarily be addressed in 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
[[Page 143]]
and FDA reviewing divisions with respect to technical requirements for
applications or abbreviated applications as quickly and amicably as
possible through the cooperative exchange of information and views.
(b) Administrative and procedural issues. When administrative or
procedural disputes arise, the applicant should first attempt to resolve
the matter with the division responsible for reviewing the application
or abbreviated application, beginning with the consumer safety officer
assigned to the application or abbreviated application. If resolution is
not achieved, the applicant may raise the matter with the person
designated as ombudsman, whose function shall be to investigate what has
happened and to facilitate a timely and equitable resolution.
Appropriate issues to raise with the ombudsman include resolving
difficulties in scheduling meetings, obtaining timely replies to
inquiries, and obtaining timely completion of pending reviews. Further
details on this procedure are contained in a staff manual guide that is
publicly available under FDA's public information regulations in part
20.
(c) Scientific and medical disputes. (1) Because major scientific
issues are ordinarily communicated to applicants in 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 or
an abbreviated antibiotic application and sent the applicant an approval
letter if none of the reasons in Sec. 314.125 for refusing to approve
the application or abbreviated antibiotic 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.
When FDA sends an applicant an approval letter for an antibiotic, it
will promulgate a regulation under Sec. 314.300 providing for
[[Page 144]]
certification of the drug, if necessary. A new drug product or
antibiotic approved under this paragraph may not be marketed until an
approval is effective. Marketing of an antibiotic need not await the
promulgation of a regulation under Sec. 314.300.
(b) FDA will approve an application or abbreviated antibiotic
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 or abbreviated antibiotic
application concern editorial or similar minor deficiencies in the draft
labeling. Such approval will be conditioned upon the applicant
incorporating the specified labeling changes exactly as directed, and
upon the applicant submitting to FDA a copy of the final printed
labeling prior to marketing.
(c) FDA will approve an application after it determines that the
drug meets the statutory standards for safety and effectiveness,
manufacturing and controls, and labeling, and an abbreviated application
after it determines that the drug meets the statutory standards for
manufacturing and controls, labeling, and, where applicable,
bioequivalence. While the statutory standards apply to all drugs, the
many kinds of drugs that are subject to the statutory standards and the
wide range of uses for those drugs demand flexibility in applying the
standards. Thus FDA is required to exercise its scientific judgment to
determine the kind and quantity of data and information an applicant is
required to provide for a particular drug to meet the statutory
standards. FDA makes its views on drug products and classes of drugs
available through guidelines, 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]
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
[[Page 145]]
under Sec. 314.105 for the application or abbreviated application.
(b) Effect of patent on the listed drug. If approval of an
abbreviated new drug application submitted under section 505(j) of the
act or of a 505(b)(2) application is granted, that approval will become
effective in accordance with the following:
(1) Date of approval letter. Except as provided in paragraphs
(b)(3), (b)(4), and (c) of this section, approval will become effective
on the date FDA issues an approval letter under Sec. 314.105 if the
applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that:
(i) There are no relevant patents; or
(ii) The applicant is aware of a relevant patent but the patent
information required under section 505 (b) or (c) of the act has not
been submitted to FDA; or
(iii) The relevant patent has expired; or
(iv) The relevant patent is invalid, unenforceable, or will not be
infringed.
(2) Patent expiration. If the applicant certifies under
Sec. 314.50(i) or Sec. 314.94(a)(12) that the relevant patent will
expire on a specified date, approval will become effective on the
specified date.
(3) Disposition of patent litigation. (i)(A) Except as provided in
paragraphs (b)(3)(ii), (b)(3)(iii), and (b)(3)(iv) of this section, if
the applicant certifies under Sec. 314.50(i) or Sec. 314.94(a)(12) that
the relevant patent is invalid, unenforceable, or will not be infringed,
and the patent owner or its representative or the exclusive patent
licensee brings suit for patent infringement within 45 days of receipt
by the patent owner of the notice of certification from the applicant
under Sec. 314.52 or Sec. 314.95, approval may be made effective 30
months after the date of the receipt of the notice of certification by
the patent owner or by the exclusive licensee (or their representatives)
unless the court has extended or reduced the period because of a failure
of either the plaintiff or defendant to cooperate reasonably in
expediting the action; or
(B) If the patented drug product qualifies for 5 years of exclusive
marketing under Sec. 314.108(b)(2) and the patent owner or its
representative or the exclusive patent licensee brings suit for patent
infringement during the 1-year period beginning 4 years after the date
the patented drug was approved and within 45 days of receipt by the
patent owner of the notice of certification, the approval may be made
effective at the expiration of the 7\1/2\ years from the date of
approval of the application for the patented drug product.
(ii) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court issues a final order that the patent
is invalid, unenforceable, or not infringed, approval may be made
effective on the date the court enters judgment;
(iii) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court issues a final order or judgment that
the patent has been infringed, approval may be made effective on the
date the court determines that the patent will expire or otherwise
orders; or
(iv) If before the expiration of the 30-month period, or 7\1/2\
years where applicable, the court grants a preliminary injunction
prohibiting the applicant 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.
[[Page 146]]
(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 and the
applicant submitting the first application has successfully defended
against a suit for patent infringement brought within 45 days of the
patent owner's receipt of notice submitted under Sec. 314.95, approval
of the subsequent abbreviated new drug application will be made
effective no sooner than 180 days from whichever of the following dates
is earlier:
(i) The date the applicant submitting the first application first
commences commercial marketing of its drug product; or
(ii) The date of a decision of the court holding the relevant patent
invalid, unenforceable, or not infringed.
(2) For purposes of paragraph (c)(1) of this section, the
``applicant submitting the first application'' is the applicant that
submits an application that is both substantially complete and contains
a certification that the patent was invalid, unenforceable, or not
infringed prior to the submission of any other application for the same
listed drug that is both substantially complete and contains the same
certification. A ``substantially complete'' application must contain the
results of any required bioequivalence studies, or, if applicable, a
request for a waiver of such studies.
(3) For purposes of paragraph (c)(1) of this section, if FDA
concludes that the applicant submitting the first application is not
actively pursuing approval of its abbreviated application, FDA will make
the approval of subsequent abbreviated applications immediately
effective if they are otherwise eligible for an immediately effective
approval.
(4) For purposes of paragraph (c)(1)(i) of this section, the
applicant submitting the first application shall, if sued for patent
infringement, 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) Court actions. (1) References to actions of ``the court'' in
paragraphs (b) and (c) of this section are to the court that enters
final judgment from which no appeal can be or has been taken.
(2) For purposes of establishing the effective date of approval
based on a court judgment, the following dates shall be deemed to be the
date of the final decision of the court on the patent issues:
(i) If the district court enters a decision that the patent is
invalid, unenforceable, or not infringed, and the decision is not
appealed, the date on which the right to appeal lapses.
(ii) If the district court enters a decision that the patent is
invalid, unenforceable, or not infringed, and the decision is appealed,
the date of the first decision or order by a higher court holding or
affirming the decision of the district court that the patent is invalid,
unenforceable, or not infringed.
(iii) If the district court enters a decision that the patent is
infringed, and the decision is appealed, the date on
[[Page 147]]
which the district court enters a judgment that the patent is invalid,
unenforceable, or not infringed pursuant to a mandate issued by a court
of appeals.
(iv) 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 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]
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
[[Page 148]]
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.
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
[[Page 149]]
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 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 or an
abbreviated antibiotic application, the applicant shall, within 10 days
after the date of the approvable letter:
(1) Amend the application or abbreviated antibiotic 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 or abbreviated antibiotic 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 or the abbreviated antibiotic application
under Sec. 314.99. A decision to withdraw an application or abbreviated
antibiotic application is without prejudice to a refiling;
[[Page 150]]
(3) For a new drug application or abbreviated antibiotic
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 or abbreviated antibiotic application under Sec. 314.105 or
refuse to approve the application or abbreviated antibiotic 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) For an antibiotic, file a petition or notify FDA of an intent to
file a petition proposing the issuance, amendment, or repeal of a
regulation under Sec. 314.300 and section 507(f) of the act; or
(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),
(a)(3), or (a)(4) 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 the abbreviated antibiotic
application under Sec. 314.99. A decision to withdraw an application or
abbreviated antibiotic 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]
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 or
abbreviated antibiotic 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
[[Page 151]]
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 or abbreviated antibiotic 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;
(4) For an antibiotic application, file a petition or notify FDA of
an intent to file a petition proposing the issuance, amendment, or
repeal of a regulation under Sec. 314.300 and section 507(f) of the act;
or
(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), (a)(3), or (a)(4) 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]
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.
(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
[[Page 152]]
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 or abbreviated antibiotic application.
(a) The Food and Drug Administration will refuse to approve the
application or abbreviated antibiotic 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, or for an
antibiotic publish a proposed regulation based on an acceptable petition
under Sec. 314.300, 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 or files a
petition for an antibiotic proposing the issuance, amendment, or repeal
of a regulation; 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 or abbreviated
antibiotic 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) or 507 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 or abbreviated antibiotic 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 or abbreviated antibiotic 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 or
abbreviated antibiotic application under Sec. 314.101(d), if the
deficiency is not corrected.
(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 or abbreviated antibiotic 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
[[Page 153]]
drug product do not comply with the current good manufacturing practice
regulations in parts 210 and 211.
(14) The application or abbreviated antibiotic 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 antibiotic application that is
received or otherwise obtained by the applicant from any source.
(15) A nonclinical laboratory study that is described in the
application or abbreviated antibiotic 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 or abbreviated antibiotic 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 or
abbreviated antibiotic 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]
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 sections
505 and 507 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 and antibiotics. 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 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
[[Page 154]]
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 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
[[Page 155]]
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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[50 FR 7493, Feb. 22, 1985, as amended at 50 FR 21238, May 23, 1985; 55
FR 11580, Mar. 29, 1990]
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:
(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
[[Page 156]]
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 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
[[Page 157]]
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 described in Sec. 320.63 of this
chapter that is contained in the abbreviated new drug application
refuses to permit an
[[Page 158]]
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, or, for an antibiotic, rescind a
certification or release, or amend or repeal a regulation providing for
certification under section 507 of the act and under the procedure in
Sec. 314.300, 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, or, for an antibiotic,
rescind a certification or release, or amend or repeal a regulation
providing for certification under section 507 of the act and the
procedure in Sec. 314.300, 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
[[Page 159]]
the facilities and controls used for, the manufacture, processing, and
packing of the drug are inadequate to ensure and preserve its identity,
strength, quality, and purity and were not made adequate within a
reasonable time after receipt of written notice from the agency.
(3) That on the basis of new information before FDA, evaluated
together with the evidence available when the application or abbreviated
application was approved, the labeling of the drug, based on a fair
evaluation of all material facts, is false or misleading in any
particular, and the labeling was not corrected by the applicant within a
reasonable time after receipt of written notice from the agency.
(4) That the applicant has failed to comply with the notice
requirements of section 510(j)(2) of the act.
(5) That the applicant has failed to submit bioavailability or
bioequivalence data required under part 320 of this chapter.
(6) The application or abbreviated application does not contain an
explanation of the omission of a report of any investigation of the drug
product sponsored by the applicant, or an explanation of the omission of
other information about the drug pertinent to an evaluation of the
application or abbreviated application that is received or otherwise
obtained by the applicant from any source.
(7) That any nonclinical laboratory study that is described in the
application or abbreviated application and that is essential to show
that the drug is safe for use under the conditions prescribed,
recommended, or suggested in its labeling was not conducted in
compliance with the good laboratory practice regulations in part 58 of
this chapter and no reason for the noncompliance was provided or, if it
was, the differences between the practices used in conducting the study
and the good laboratory practice regulations do not support the validity
of the study.
(8) Any clinical investigation involving human subjects described in
the application or abbreviated application, subject to the institutional
review board regulations in part 56 of this chapter or informed consent
regulations in part 50 of this chapter, was not conducted in compliance
with those regulations such that the rights or safety of human subjects
were not adequately protected.
(9) That the applicant or contract research organization that
conducted a bioavailability or bioequivalence study described in
Sec. 320.38 or Sec. 320.63 of this chapter that is contained in the
application or abbreviated application refuses to permit an inspection
of facilities or records relevant to the study by a properly authorized
officer or employee of the Department of Health and Human Services or
refuses to submit reserve samples of the drug products used in the study
when requested by FDA.
(10) That the labeling for the drug product that is the subject of
the abbreviated new drug application is no longer consistent with that
for the listed drug referred to in the abbreviated new drug application,
except for differences approved in the abbreviated new drug application
or those differences resulting from:
(i) A patent on the listed drug issued after approval of the
abbreviated new drug application; or
(ii) Exclusivity accorded to the listed drug after approval of the
abbreviated new drug application that do not render the drug product
less safe or effective than the listed drug for any remaining,
nonprotected condition(s) of use.
(c) FDA will withdraw approval of an application or abbreviated
application if the applicant requests its withdrawal because the drug
subject to the application or abbreviated application is no longer being
marketed, provided none of the conditions listed in paragraphs (a) and
(b) of this section applies to the drug. FDA will consider a written
request for a withdrawal under this paragraph to be a waiver of an
opportunity for hearing otherwise provided for in this section.
Withdrawal of approval of an application or abbreviated application
under this paragraph is without prejudice to refiling.
(d) FDA may notify an applicant that it believes a potential problem
associated with a drug is sufficiently serious that the drug should be
removed from the market and may ask the applicant to waive the
opportunity for hearing
[[Page 160]]
otherwise provided for under this section, to permit FDA to withdraw
approval of the application or abbreviated application for the product,
and to remove voluntarily the product from the market. If the applicant
agrees, the agency will not make a finding under paragraph (b) of this
section, but will withdraw approval of the application or abbreviated
application in a notice published in the Federal Register that contains
a brief summary of the agency's and the applicant's views of the reasons
for withdrawal.
[57 FR 17993, Apr. 28, 1992, as amended at 58 FR 25927, Apr. 28, 1993]
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.
[[Page 161]]
(7) Except as provided in paragraph (d) of this section, any
abbreviated new drug application whose holder submitted comments on the
notice of opportunity for hearing shall be withdrawn upon the issuance
of a final decision concluding that the listed drug should be withdrawn
for grounds as described in Sec. 314.150(a). The final decision shall be
in writing and shall constitute final agency action, reviewable in a
judicial proceeding.
(8) Documents in the record will be publicly available in accordance
with Sec. 10.20(j) of this chapter. Documents available for examination
or copying will be placed on public display in the 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
[[Page 162]]
the issuance of the initial decision to present, in writing, comments
and information bearing on the initial decision. If no comments or
information is received, the initial decision will become final at the
expiration of 30 days.
(3) Comments and information received within 30 days of the issuance
of the initial decision will be considered by the agency and responded
to in a final decision.
(4) The agency may, in its discretion, hold a limited oral hearing
to resolve dispositive factual issues that cannot be resolved on the
basis of written submissions.
(5) If the final decision affirms the agency's initial decision that
the listed drug was withdrawn for reasons of safety or effectiveness,
the decision will be published in the Federal Register in compliance
with Sec. 314.152, and will, except as provided in paragraph (b)(6) of
this section, suspend approval of all abbreviated new drug applications
identified under paragraph (b)(1) of this section and remove from the
list the listed drug and any drug whose approval was suspended under
this paragraph. The notice will satisfy the requirement of
Sec. 314.162(b). The agency's final decision and copies of materials on
which it relies will also be filed with the 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 163]]
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, or provides for certification of, under sections 505, 506, and
507 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 and approved antibiotic drugs
by regulations issued through informal rulemaking under sections 501,
502, and 503 of the act.
Subpart E--Hearing Procedures for New Drugs
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Redesignated at 57 FR 17983, Apr. 28, 1992.
Sec. 314.200 Notice of opportunity for hearing; notice of participation and request for hearing; grant or denial of hearing.
(a) Notice of opportunity for hearing. The Director of the Center
for Drug Evaluation and Research, Food and Drug Administration, will
give the applicant, and all other persons who manufacture or distribute
identical, related, or similar drug products as defined in Sec. 310.6 of
this chapter, notice and an opportunity for a hearing on the Center's
proposal to refuse to approve an application or to withdraw the approval
of an application or abbreviated application under section 505(e) of the
act. The notice will state the reasons for the action and the proposed
grounds for the order.
(1) The notice may be general (that is, simply summarizing in a
general way the information resulting in the notice) or specific (that
is, either referring to specific requirements in the statute and
regulations with which there is a lack of compliance, or providing a
detailed description and analysis of the specific facts resulting in the
notice).
(2) FDA will publish the notice in the Federal Register and will
state that
[[Page 164]]
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 (c)(1)(ii) of this section the studies (including all
protocols and underlying raw data) on which the person relies to
[[Page 165]]
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 clearly and a waiver
obtained under Sec. 314.126 is required to be submitted.
[[Page 166]]
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 should be submitted to support
the statement.
[[Page 167]]
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
abbreviated application or the withdrawal of approval of the application
or
[[Page 168]]
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.
(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 17996, Apr.
28, 1992; 59 FR 14364, Mar. 28, 1994; 63 FR 5252, Feb. 2, 1998]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 314.200 was
amended in paragraph (d)(3) by adding a new sentence after the first
sentence, effective Feb. 2, 1999.
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
[[Page 169]]
record. In any case in which the Commissioner enters an order without a
hearing under Sec. 314.200(g), the record certified by the Commissioner
is required to include the requests for hearing together with the data
and information submitted and the Commissioner's findings and
conclusion.
(b) A manufacturer or distributor of an identical, related, or
similar drug product under Sec. 310.6 may seek judicial review of an
order withdrawing approval of a new drug application, whether or not a
hearing has been held, in a United States court of appeals under section
505(h) of the act.
Subpart F--Administrative Procedures for Antibiotics
Source: 50 FR 7493, Feb. 22, 1985, unless otherwise noted.
Redesignated at 57 FR 17983, Apr. 28, 1992.
Sec. 314.300 Procedure for the issuance, amendment, or repeal of regulations.
(a) The procedures in part 10 apply to the issuance, amendment, or
repeal of regulations under section 507 of the act.
(b)(1) The Commissioner of Food and Drugs, on his or her own
initiative or on the application or request of any interested person,
may publish in the Federal Register a notice of proposed rulemaking and
order to issue, amend, or repeal any regulation contemplated by section
507 of the act. The notice and order may be general (that is, simply
summarizing in a general way the information resulting in the notice and
order) 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 and order).
(2) The Food and Drug Administration will give interested persons an
opportunity to submit written comments and to request an informal
conference on the proposal, unless the notice and opportunity for
comment and informal conference have already been provided in connection
with the announcement of the reports of the National Academy of
Sciences/National Research Council, Drug Efficacy Study Group, to
persons who will be adversely affected, or as provided in Secs. 10.40(e)
and 12.20(c)(2). A person is required to request an informal conference
within 30 days of the notice of proposed rulemaking unless otherwise
specified in the notice. If an informal conference is requested and
granted, those persons participating in the conference may submit
comments, within 30 days of the conference, unless otherwise specified
in the proposal.
(3) It is the responsibility of every manufacturer and distributor
of an antibiotic drug product to review every proposal published in the
Federal Register to determine whether it covers any drug product that
person manufactures or distributes.
(4) After considering the written comments, the results of any
conference, and the data available, the Commissioner will publish an
order in the Federal Register acting on the proposal, with an
opportunity for any person who will be adversely affected to file
objections, to request a hearing, and to show reasonable grounds for the
hearing. Any person 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 order a written
notice of participation and request for a hearing and (ii) within 60
days after the date of publication of the order, unless a different
period of time is specified in the order, the studies on which the
person relies to justify a hearing as specified in paragraph (b)(6) of
this section. The person may incorporate by reference the raw data
underlying a study if the data were previously submitted to FDA as part
of an application or other report.
(5) FDA will not consider data or analysis 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 order and the
results of the studies were not available within 60 days after the date
of publication of the order. Nevertheless, FDA may consider other
studies on the basis of a showing by the person requesting a hearing of
inadvertent omission and
[[Page 170]]
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 hearing. The person shall
submit under paragraph (b)(4)(ii) of this section a copy of the complete
protocol, a list of the participating investigators, and a brief status
report of the studies.
(6) The person requesting a hearing is required to submit as
required under Sec. 314.200(c)(1)(ii) the studies (including all
protocols and underlying raw data) on which the person relies to justify
a hearing with respect to the drug product. A financial certification or
disclosure statement or both as required by part 54 of this chapter must
accompany all clinical data submitted with the request for hearing.
Except, a person who requests a hearing on a proposal is not required to
submit additional studies and analyses if the studies upon which the
person relies have been submitted in an application and in the format
and containing the summaries required under Sec. 314.50.
(i) If the grounds for FDA 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, any unfavorable
analyses, views, or judgments with respect to the studies. No other
data, information, or studies may be submitted.
(ii) The submission is required to include a factual analysis of all
the studies submitted. If the grounds for FDA 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 entity 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.
(iii) 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. 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
[[Page 171]]
a point-by-point basis, each of the criteria required by Sec. 314.126.
2. An analysis showing clearly how each requirement of Sec. 300.50
has been satisfied.
III. A summary of the data and views setting forth the medical
rationale and purpose for the drug and its ingredients and the
scientific basis for the conclusion that the drug and its ingredients
have been proven safe and/or effective for the intended use. If there is
an absence of controlled studies in the material submitted or the
requirements of any element of Sec. 300.50 or Sec. 314.126 have not been
fully met, that fact is required to be stated clearly and a waiver
obtained under Sec. 314.126 is required to be submitted.
IV. A statement signed by the person responsible for such submission
that it includes in full (or incorporates by reference as permitted in
Sec. 314.200(c)(2)) all studies and information specified in
Sec. 314.200(d).
(Warning: A willfully false statement is a criminal offense, 18
U.S.C. 1001.)
(7) Separation of functions. Separation of functions commences upon
receipt of a request for hearing. The Director of the Center for Drug
Evaluation and Research 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 (b)(8) (ii) or (iii) of this section will be
submitted to the Office of the Commissioner 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 Evaluatioon 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.
(8) 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.
(i) Where a specific notice of opportunity for hearing (as defined
in paragraph (b)(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 the
withdrawal of approval of the 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, 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.
(ii) When following a general notice of opportunity for a hearing
(as defined in paragraph (b)(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
[[Page 172]]
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.
(iii) 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.
(iv) If review of the data, information, and analyses submitted show
that the basis for the order is not valid, for example, that substantial
evidence of effectiveness exists, the Commissioner will enter summary
judgment for the person requesting the hearing, and revoke the order. If
a hearing is not requested, the order will become effective as
published.
(v) If the Commissioner grants a hearing, it will be conducted under
part 12.
(vi) 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.
(9) The repeal of any regulation constitutes a revocation of all
outstanding certificates based upon such regulation. However, the
Commissioner may, in his or her discretion, defer or stay such action
pending a ruling on any related request for a hearing or pending any
related hearing or other administrative or judicial proceeding.
(c) Whenever any interested person submits an application or request
under section 507 of the act and part 314 and FDA sends the person an
approvable letter under Sec. 314.110 or a not approvable letter under
Sec. 314.120, the person may file a petition proposing the issuance,
amendment, or repeal of the regulation under the provisions of section
507(f) of the act and part 10. The Commissioner shall cause the
regulation proposed in the petition to be published in the Federal
Register within 60 days of the receipt of an acceptable petition and
further proceedings shall be in accord with the provisions of sections
507(f) and 701 (f) and (g) of the act and part 10.
(d) (1) FDA will not promulgate a regulation providing for the
certification of any batch of any drug composed wholly or in part of any
kind of penicillin, streptomycin, chlortetracycline, chloramphenicol,
bacitracin, or any other antibiotic drug, or any derivative thereof,
intended for human use and no existing regulation will be continued in
effect unless it is established by substantial evidence that the drug
will have such characteristics of identity, strength, quality, and
purity necessary to adequately ensure safety and efficacy of use.
``Substantial evidence'' has been defined by Congress to mean ``evidence
consisting of adequate and well-controlled investigations, including
clinical investigations, by experts qualified by scientific training and
experience to evaluate the effectiveness of the drug involved, on the
basis of which it could fairly and responsibly be concluded by such
experts that the drug will have the effect it purports or is represented
to have under the conditions prescribed, recommended, or suggested in
the labeling or proposed labeling thereof.'' This definition is made
applicable to a number of antibiotic drugs by section 507(h) of the act
and it is the test of efficacy that FDA will apply in promulgating,
amending, or repealing regulations for all antibiotics under section
507(a) of the act as well.
(2) The scientific essentials of an adequate and well-controlled
clinical investigation are described in Sec. 314.126.
(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; 59 FR 14365, Mar.
28, 1994; 63 FR 5252, Feb. 2, 1998]
[[Page 173]]
Effective Date Note: At 63 FR 5252, Feb. 2, 1998, Sec. 314.300 was
amended in the introductory text of paragraph (b)(6) by adding a new
sentence after the first sentence, effective Feb. 2, 1999.
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 and antibiotics.
(a) Imports. (1) A new drug or an antibiotic may be imported into
the United States if: (i) It is the subject of an approved application
under this part or, in the case of an antibiotic not exempt from
certification under part 433, it is also certified or released; 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 or an antibiotic may be exported if it
is the subject of an approved application under this part, and, in the
case of an antibiotic, it is certified or released, 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) An antibiotic drug product or drug substance that is subject to
certification under section 507 of the act, but which has not been
certified or released, may be exported under section 801(e) of the act
if it meets the following conditions:
(i) It meets the specifications of the foreign purchaser;
(ii) It is not in conflict with the laws of the country to which it
is intended for export;
(iii) It is labeled on the outside of the shipping package that it
is intended for export; and
(iv) It is not sold or offered for sale in the United States.
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) Manufacturing site, facilities, operating procedures, and
personnel (because an FDA on-site inspection of a foreign drug
manufacturing facility presents unique problems of planning and travel
not presented by an inspection of a domestic manufacturing facility,
this information is only recommended for foreign manufacturing
establishments);
(2) Drug substance, drug substance intermediate, and materials used
in their preparation, or drug product;
(3) Packaging materials;
(4) Excipient, colorant, flavor, essence, or materials used in their
preparation;
[[Page 174]]
(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 I through IV DMF's must first submit a letter of intent
to the Drug Master File Staff, Food and Drug Administration, 12420
Parklawn Dr., Rm. 2-14, Rockville, MD 20852. FDA will then contact the
person to discuss the proposed submission.)
(b) An investigational new drug application or an application,
abbreviated application, amendment, or supplement may incorporate by
reference all or part of the contents of any drug master file in support
of the submission if the holder authorizes the incorporation in writing.
Each incorporation by reference is required to describe the incorporated
material by name, reference number, volume, and page number of the drug
master file.
(c) A drug master file is required to be submitted in two copies.
The agency has prepared under Sec. 10.90(b) a guideline 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.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0001)
[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]
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
[[Page 175]]
been publicly disclosed or acknowledged before the agency sends an
approval letter to the applicant, no data or information contained in
the application or abbreviated application is available for public
disclosure before the agency sends an approval letter, but the
Commissioner may, in his or her discretion, disclose a summary of
selected portions of the safety and effectiveness data that are
appropriate for public consideration of a specific pending issue; for
example, for consideration of an open session of an FDA advisory
committee.
(2) Notwithstanding paragraph (d)(1) of this section, FDA will make
available to the public upon request the information in the
investigational new drug application that was required to be filed in
Docket Number 95S-0158 in the 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.
[[Page 176]]
(7) All correspondence and written summaries of oral discussions
between FDA and the applicant relating to the application, under the
provisions of part 20.
(8) All records showing the testing of an action on a particular lot
of a certifiable antibiotic by FDA.
(f) All safety and effectiveness data and information which have
been submitted in an application and which have not previously been
disclosed to the public are available to the public, upon request, at
the time any one of the following events occurs unless extraordinary
circumstances are shown:
(1) No work is being or will be undertaken to have the application
approved.
(2) A final determination is made that the application is not
approvable and all legal appeals have been exhausted.
(3) Approval of the application is withdrawn and all legal appeals
have been exhausted.
(4) A final determination has been made that the drug is not a new
drug.
(5) For applications submitted under section 505(b) of the act, the
effective date of the approval of the first abbreviated application
submitted under section 505(j) of the act which refers to such drug, or
the date on which the approval of an abbreviated application under
section 505(j) of the act which refers to such drug could be made
effective if such an abbreviated application had been submitted.
(6) For applications or abbreviated applications submitted under
sections 505(j), 506, and 507 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]
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
[[Page 177]]
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 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 Guidelines.
(a) The Food and Drug Administration prepares guidelines under
Sec. 10.90(b) to help persons comply with requirements in this part.
(b) The Center for Drug Evaluation and Research will maintain and
make publicly available a list of guidelines that apply to the Center's
regulations. The list states how a person can obtain a copy of each
guideline. A request for a copy of the list should be directed to the
CDER Executive Secretariat Staff (HFD-8), Center for Drug Evaluation and
Research, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD
20857.
[50 FR 7493, Feb. 22, 1985, as amended at 55 FR 11581, Mar. 29, 1990; 56
FR 3776, Jan. 31, 1991]
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 and antibiotic 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).
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
[[Page 178]]
trials establishing that the drug product has an effect on a surrogate
endpoint that is reasonably likely, based on epidemiologic, therapeutic,
pathophysiologic, or other evidence, to predict clinical benefit or on
the basis of an effect on a clinical endpoint other than survival or
irreversible morbidity. Approval under this section will be subject to
the requirement that the applicant study the drug further, to verify and
describe its clinical benefit, where there is uncertainty as to the
relation of the surrogate endpoint to clinical benefit, or of the
observed clinical benefit to ultimate outcome. Postmarketing studies
would usually be studies already underway. When required to be
conducted, such studies must also be adequate and well-controlled. The
applicant shall carry out any such studies with due diligence.
Sec. 314.520 Approval with restrictions to assure safe use.
(a) If FDA concludes that a drug product shown to be effective can
be safely used only if distribution or use is restricted, FDA will
require such postmarketing restrictions as are needed to assure safe use
of the drug product, such as:
(1) Distribution restricted to certain facilities or physicians with
special training or experience; or
(2) Distribution conditioned on the performance of specified medical
procedures.
(b) The limitations imposed will be commensurate with the specific
safety concerns presented by the drug product.
Sec. 314.530 Withdrawal procedures.
(a) For new drugs and antibiotics 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
[[Page 179]]
the conclusion of the person's presentation. No other person attending
the hearing may question a person making a presentation. The presiding
officer may, as a matter of discretion, permit questions to be submitted
to the presiding officer for response by a person making a presentation.
(f) Judicial review. The Commissioner's decision constitutes final
agency action from which the applicant may petition for judicial review.
Before requesting an order from a court for a stay of action pending
review, an applicant must first submit a petition for a stay of action
under Sec. 10.35 of this chapter.
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 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.
[[Page 180]]
Subpart E--Open Protocols for Investigations
316.40 Treatment use of a designated orphan drug.
Subpart F--Availability of Information
316.50 Guidelines.
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:
(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.
[[Page 181]]
(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, a request for certification
of an antibiotic under section 507 of the act, or an application for a
biological product/establishment license submitted under section 351 of
the Public Health Service Act (42 U.S.C. 262).
(10) Orphan drug means a drug intended for use in a rare disease or
condition as defined in section 526 of the act.
(11) Orphan-drug designation means FDA's act of granting a request
for designation under section 526 of the act.
(12) Orphan-drug exclusive approval or exclusive approval means
that, effective on the date of FDA approval as stated in the approval
letter of a marketing application for a sponsor of a designated orphan
drug, no approval will be given to a subsequent sponsor of the same drug
product for the same indication for 7 years, except as otherwise
provided by law or in this part.
(13) Same drug means:
(i) If it is a drug composed of small molecules, a drug that
contains the same active moiety as a previously approved drug and is
intended for the same use as the previously approved drug, even if the
particular ester or salt (including a salt with hydrogen or coordination
bonds) or other noncovalent derivative such as a complex, chelate or
clathrate has not been previously approved, except that if the
subsequent drug can be shown to be clinically superior to the first
drug, it will not be considered to be the same drug.
(ii) If it is a drug composed of large molecules (macromolecules), a
drug that contains the same principal molecular structural features (but
not necessarily all of the same structural features) and is intended for
the same use as a previously approved drug, except that, if the
subsequent drug can be shown to be clinically superior, it will not be
considered to be the same drug. This criterion will be applied as
follows to different kinds of macromolecules:
(A) Two protein drugs would be considered the same if the only
differences in structure between them were due to post-translational
events or infidelity of translation or transcription or were minor
differences in amino acid sequence; other potentially important
differences, such as different glycosylation patterns or different
tertiary structures, would not cause the drugs to be considered
different unless the 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.
[[Page 182]]
Sec. 316.4 Address for submissions.
All correspondence and requests for FDA action pursuant to the
provisions of this rule should be addressed as follows: Office of Orphan
Products Development (HF-35), Food and Drug Administration, 5600 Fishers
Lane, Rockville, MD 20857.
Subpart B--Written Recommendations for Investigations of Orphan Drugs
Sec. 316.10 Content and format of a request for written recommendations.
(a) A sponsor's request for written recommendations from FDA
concerning the nonclinical and clinical investigations necessary for
approval of a marketing application shall be submitted in the form and
contain the information required in this section. FDA may require the
sponsor to submit information in addition to that specified in paragraph
(b) of this section if FDA determines that the sponsor's initial request
does not contain adequate information on which to base recommendations.
(b) A sponsor shall submit two copies of a completed, dated, and
signed request for written recommendations that contains the following:
(1) The sponsor's name and address.
(2) A statement that the sponsor is requesting written
recommendations on orphan-drug development under section 525 of the act.
(3) The name of the sponsor's primary contact person and/or resident
agent, and the person's title, address, and telephone number.
(4) The generic name and trade name, if any, of the drug and a list
of the drug product's components or description of the drug product's
formulation, and chemical and physical properties.
(5) The proposed dosage form and route of administration.
(6) A description of the disease or condition for which the drug is
proposed to be investigated and the proposed indication or indications
for use for such disease or condition.
(7) Current regulatory and marketing status and history of the drug
product, including:
(i) Whether the product is the subject of an IND or a marketing
application (if the product is the subject of an IND or a marketing
application, the IND or marketing application numbers should be stated
and the investigational or approved indication or indications for use
specified);
(ii) Known marketing experience or investigational status outside
the United States;
(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
[[Page 183]]
to expeditious development, evaluation, and marketing under 21 CFR part
312, subpart E.
(11) An explanation of how the data summarized and analyzed under
paragraphs (b)(9) and (b)(10) of this section support the rationale for
use of the drug in the rare disease or condition.
(12) A definition of the population from which subjects will be
identified for clinical trials, if known.
(13) A detailed outline of any protocols under which the drug has
been or is being studied for the rare disease or condition and a summary
and analysis of any available data from such studies.
(14) The sponsor's proposal as to the scope of nonclinical and
clinical investigations needed to establish the safety and effectiveness
of the drug.
(15) Detailed protocols for each proposed United States or foreign
clinical investigation, if available.
(16) Specific questions to be addressed by FDA in its
recommendations for nonclinical laboratory studies and clinical
investigations.
[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]
Sec. 316.12 Providing written recommendations.
(a) FDA will provide the sponsor with written recommendations
concerning the nonclinical laboratory studies and clinical
investigations necessary for approval of a marketing application if none
of the reasons described in Sec. 316.14 for refusing to do so applies.
(b) When a sponsor seeks written recommendations at a stage of drug
development at which advice on any clinical investigations, or on
particular investigations would be premature, FDA's response may be
limited to written recommendations concerning only nonclinical
laboratory studies, or only certain of the clinical studies (e.g., Phase
1 studies as described in Sec. 312.21 of this chapter). Prior to
providing written recommendations for the clinical investigations
required to achieve marketing approval, FDA may require that the results
of the nonclinical laboratory studies or completed early clinical
studies be submitted to FDA for agency review.
Sec. 316.14 Refusal to provide written recommendations.
(a) FDA may refuse to provide written recommendations concerning the
nonclinical laboratory studies and clinical investigations necessary for
approval of a marketing application for any of the following reasons:
(1) The information required to be submitted by Sec. 316.10(b) has
not been submitted, or the information submitted is incomplete.
(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,
[[Page 184]]
FDA will describe the information or material it requires or the
conditions the sponsor must meet for FDA to provide recommendations.
(c) Within 90 days after the date of a letter from FDA requesting
additional information or material or setting forth the conditions that
the sponsor is asked to meet, the sponsor shall either:
(1) Provide the information or material or amend the request for
written recommendations to meet the conditions sought by FDA; or
(2) Withdraw the request for written recommendations. FDA will
consider a sponsor's failure to respond within 90 days to an FDA letter
requesting information or material or setting forth conditions to be met
to be a withdrawal of the request for written recommendations.
Subpart C--Designation of an Orphan Drug
Sec. 316.20 Content and format of a request for orphan-drug designation.
(a) A sponsor that submits a request for orphan-drug designation of
a drug for a specified rare disease or condition shall submit each
request in the form and containing the information required in paragraph
(b) of this section. A sponsor may request orphan-drug designation of a
previously unapproved drug, or of a new orphan indication for an already
marketed drug. In addition, a sponsor of a drug that is otherwise the
same drug as an already approved orphan drug may seek and obtain orphan-
drug designation for the subsequent drug for the same rare disease or
condition if it can present a plausible hypothesis that its drug may be
clinically superior to the first drug. More than one sponsor may receive
orphan-drug designation of the same drug for the same rare disease or
condition, but each sponsor seeking orphan-drug designation must file a
complete request for designation as provided in paragraph (b) of this
section.
(b) A sponsor shall submit two copies of a completed, dated, and
signed request for designation that contains the following:
(1) A statement that the sponsor requests orphan-drug designation
for a rare disease or condition, which shall be identified with
specificity.
(2) The name and address of the sponsor; the name of the sponsor's
primary contact person and/or resident agent including title, address,
and telephone number; the generic and trade name, if any, of the drug or
drug product; and the name and address of the source of the drug if it
is not manufactured by the sponsor.
(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
[[Page 185]]
drug, or preventive drug, the persons to whom the drug will be
administered in the United States are fewer than 200,000 per year as
specified in Sec. 316.21(b), or
(ii) For a drug intended for diseases or conditions affecting
200,000 or more people, or for a vaccine, diagnostic drug, or preventive
drug to be administered to 200,000 or more persons per year in the
United States, there is no reasonable expectation that costs of research
and development of the drug for the indication can be recovered by sales
of the drug in the United States as specified in Sec. 316.21(c).
(9) A statement as to whether the sponsor submitting the request is
the real party in interest of the development and the intended or actual
production and sales of the product.
(c) Any of the information previously provided by the sponsor to FDA
under subpart B of this part may be referenced by specific page or
location if it duplicates information required elsewhere in this
section.
Sec. 316.21 Verification of orphan-drug status.
(a) So that FDA can determine whether a drug qualifies for orphan-
drug designation under section 526(a) of the act, the sponsor shall
include in its request to FDA for orphan-drug designation under
Sec. 316.20 either:
(1) Documentation as described in paragraph (b) of this section that
the number of people affected by the disease or condition for which the
drug product is indicated is fewer than 200,000 persons; or
(2) Documentation as described in paragraph (c) of this section that
demonstrates that there is no reasonable expectation that the sales of
the drug will be sufficient to offset the costs of developing the drug
for the U.S. market and the costs of making the drug available in the
United States.
(b) For the purpose of documenting that the number of people
affected by the disease or condition for which the drug product is
indicated is less than 200,000 persons, ``prevalence'' is defined as the
number of persons in the United States who have been diagnosed as having
the disease or condition at the time of the submission of the request
for orphan-drug designation. To document the number of persons in the
United States who have the disease or condition for which the drug is to
be indicated, the sponsor shall submit to FDA evidence showing:
(1) The estimated prevalence of the disease or condition for which
the drug is being developed, together with a list of the sources
(including dates of information provided and literature citations) for
the estimate;
(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.
[[Page 186]]
(2) If the drug was developed wholly or in part outside the United
States, in addition to the documentation listed in paragraph (c)(1) of
this section:
(i) Data on and justification for all costs that the sponsor has
incurred outside of the United States in the course of developing the
drug for the U.S. market. The justification, in addition to
demonstrating the reasonableness of the cost data, must also explain the
method that was used to determine which portion of the foreign
development costs should be applied to the U.S. market, and what percent
these costs are of total worldwide development costs. Any data submitted
to foreign government authorities to support drug pricing determinations
must be included with this information.
(ii) Data that show which foreign development costs were recovered
through cost recovery procedures that are allowed during drug
development in some foreign countries. For example, if the sponsor
charged patients for the drug during clinical investigations, the
revenues collected by the sponsor must be reported to FDA.
(3) In cases where the drug has already been approved for marketing
for any indication or in cases where the drug is currently under
investigation for one or more other indications (in addition to the
indication for which orphan-drug designation is being sought), a clear
explanation of and justification for the method that is used to
apportion the development costs among the various indications.
(4) A statement of and justification for any development costs that
the sponsor expects to incur after the submission of the designation
request. In cases where the extent of these future development costs are
not clear, the sponsor should request FDA's advice and assistance in
estimating the scope of nonclinical laboratory studies and clinical
investigations and other data that are needed to support marketing
approval. Based on these recommendations, a cost estimate should be
prepared.
(5) A statement of and justification for production and marketing
costs that the sponsor has incurred in the past and expects to incur
during the first 7 years that the drug is marketed.
(6) An estimate of and justification for the expected revenues from
sales of the drug in the United States during its first 7 years of
marketing. The justification should assume that the total market for the
drug is equal to the prevalence of the disease or condition that the
drug will be used to treat. The justification should include:
(i) An estimate of the expected market share of the drug in each of
the 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
[[Page 187]]
behalf of the sponsor. Notifications of changes in such agents or
changes of address of agents should preferably be provided in advance,
but not later than 60 days after the effective date of such changes. The
permanent-resident agent may be an individual, firm, or domestic
corporation and may represent any number of sponsors. The name of the
permanent-resident agent shall be provided to: Office of Orphan Products
Development (HF-35), Food and Drug Administration, 5600 Fishers Lane,
Rockville, MD 20857.
Sec. 316.23 Timing of requests for orphan-drug designation; designation of already approved drugs.
(a) A sponsor may request orphan-drug designation at any time in the
drug development process prior to the submission of a marketing
application for the drug product for the orphan indication.
(b) A sponsor may request orphan-drug designation of an already
approved drug product for an unapproved use without regard to whether
the prior marketing approval was for an orphan-drug indication.
Sec. 316.24 Granting orphan-drug designation.
(a) FDA will grant the request for orphan-drug designation if none
of the reasons described in Sec. 316.25 for requiring or permitting
refusal to grant such a request applies.
(b) When a request for orphan-drug designation is granted, FDA will
notify the sponsor in writing and will publicize the orphan-drug
designation in accordance with Sec. 316.28.
Sec. 316.25 Refusal to grant orphan-drug designation.
(a) FDA will refuse to grant a request for orphan-drug designation
if any of the following reasons apply:
(1) The drug is not intended for a rare disease or condition
because:
(i) There is insufficient evidence to support the estimate that the
drug is intended for treatment of a disease or condition in fewer than
200,000 people in the United States, or that the drug is intended for
use in prevention or in diagnosis in fewer than 200,000 people annually
in the United States; or
(ii) Where the drug is intended for prevention, diagnosis, or
treatment of a disease or condition affecting 200,000 or more people in
the United States, the sponsor has failed to demonstrate that there is
no reasonable expectation that development and production costs will be
recovered from sales of the drug for the orphan indication in the United
States. A sponsor's failure to comply with Sec. 316.21 shall constitute
a failure 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
[[Page 188]]
of the amendment request, the amendment would not result in exceeding
the prevalence or cost recovery thresholds in Sec. 316.21 (a)(1) or
(a)(2) upon which the drug was originally designated.
Sec. 316.27 Change in ownership of orphan-drug designation.
(a) A sponsor may transfer ownership of or any beneficial interest
in the orphan-drug designation of a drug to a new sponsor. At the time
of the transfer, the new and former owners are required to submit the
following information to FDA:
(1) The former owner or assignor of rights shall submit a letter or
other document that states that all or some rights to the orphan-drug
designation of the drug have been transferred to the new owner or
assignee and that a complete copy of the request for orphan-drug
designation, including any amendments to the request, supplements to the
granted request, and correspondence relevant to the orphan-drug
designation, has been provided to the new owner or assignee.
(2) The new owner or assignee of rights shall submit a statement
accepting orphan-drug designation and a letter or other document
containing the following:
(i) The date that the change in ownership or assignment of rights is
effective;
(ii) A statement that the new owner has a complete copy of the
request for orphan-drug designation including any amendments to the
request, supplements to the granted request, and correspondence relevant
to the orphan-drug designation; and
(iii) A specific description of the rights that have been assigned
and those that have been reserved. This may be satisfied by the
submission of either a list of rights assigned and reserved or copies of
all relevant agreements between assignors and assignees; and
(iv) The name and address of a new primary contact person or
resident agent.
(b) No sponsor may relieve itself of responsibilities under the
Orphan Drug Act or under this part by assigning rights to another person
without:
(1) Assuring that the sponsor or the assignee will carry out such
responsibilities; or
(2) Obtaining prior permission from FDA.
[57 FR 62085, Dec. 29, 1992; 58 FR 6167, Jan. 26, 1993]
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
[[Page 189]]
ground that the prevalence of the disease or condition (or the target
population) becomes more than 200,000 persons.
Sec. 316.30 Annual reports of holder of orphan-drug designation.
Within 14 months after the date on which a drug was designated as an
orphan drug and annually thereafter until marketing approval, the
sponsor of a designated drug shall submit a brief progress report to the
FDA Office of Orphan Products Development on the drug that includes:
(a) A short account of the progress of drug development including a
review of preclinical and clinical studies initiated, ongoing, and
completed and a short summary of the status or results of such studies.
(b) A description of the investigational plan for the coming year,
as well as any anticipated difficulties in development, testing, and
marketing; and
(c) A brief discussion of any changes that may affect the orphan-
drug status of the product. For example, for products nearing the end of
the approval process, sponsors should discuss any disparity between the
probable marketing indication and the designated indication as related
to the need for an amendment to the orphan-drug designation pursuant to
Sec. 316.26.
Subpart D--Orphan-drug Exclusive Approval
Sec. 316.31 Scope of orphan-drug exclusive approval.
(a) After approval of a sponsor's marketing application for a
designated orphan-drug product for treatment of the rare disease or
condition concerning which orphan-drug designation was granted, FDA will
not approve another sponsor's marketing application for the same drug
before the expiration of 7 years from the date of such approval as
stated in the approval letter from FDA, except that such a marketing
application can be approved sooner if, and such time as, any of the
following occurs:
(1) Withdrawal of exclusive approval or revocation of orphan-drug
designation by FDA under any provision of this part; or
(2) Withdrawal for any reason of the marketing application for the
drug in question; or
(3) Consent by the holder of exclusive approval to permit another
marketing application to gain approval; or
(4) Failure of the holder of exclusive approval to assure a
sufficient quantity 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
[[Page 190]]
exercised by a time that the Director specifies:
(1) Provide the Director in writing, or orally, or both, at the
Director's discretion, views and data as to how the holder can assure
the availability of sufficient quantities of the orphan drug within a
reasonable time to meet the needs of patients with the disease or
condition for which the drug was designated; or
(2) Provide the Director in writing the holder's consent for the
approval of other marketing applications for the same drug before the
expiration of the 7-year period of exclusive approval.
(b) If, within the time that the Director specifies, the holder
fails to consent to the approval of other marketing applications and if
the Director finds that the holder has not shown that it can assure the
availability of sufficient quantities of the orphan drug to meet the
needs of patients with the disease or condition for which the drug was
designated, the Director will issue a written order withdrawing the drug
product's exclusive approval. This order will embody the Director's
findings and conclusions and will constitute final agency action. An
order withdrawing the sponsor's exclusive marketing rights may issue
whether or not there are other sponsors that can assure the availability
of alternative sources of supply. Once withdrawn under this section,
exclusive approval may not be reinstated for that drug.
Subpart E--Open Protocols for Investigations
Sec. 316.40 Treatment use of a designated orphan drug.
Prospective investigators seeking to obtain treatment use of
designated orphan drugs may do so as provided in Sec. 312.34 of this
chapter.
Subpart F--Availability of Information
Sec. 316.50 Guidelines.
FDA's Office of Orphan Products Development will maintain and make
publicly available a list of guidelines that apply to the regulations in
this part. The list states how a person can obtain a copy of each
guideline. A request for a copy of the list or for any guideline should
be directed to the Office of Orphan Products Development (HF-35), Food
and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857.
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.
[[Page 191]]
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.
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, 357, 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
[[Page 192]]
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 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
[[Page 193]]
(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 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
[[Page 194]]
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 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]
[[Page 195]]
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 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
[[Page 196]]
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;
(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
[[Page 197]]
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
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.
[[Page 198]]
(3) The Food and Drug Administration may permit a bioavailability
study involving a combination drug product to determine the rate and
extent of absorption of selected, but not all, active drug ingredients
or therapeutic moieties in the combination drug product. The Food and
Drug Administration may permit this determination if the
pharmacokinetics and the interactions of the active drug ingredients or
therapeutic moieties in the combination drug product are well known and
the therapeutic activity of the combination drug product is generally
recognized to reside in only one of the active drug ingredients or
therapeutic moieties, e.g., ampicillin in an ampicillin-probenecid
combination drug product.
(h) Use of a placebo as the reference material. Where appropriate or
where necessary to demonstrate the sensitivity of the test, the
reference material in a bioavailability study may be a placebo if:
(1) The study measures the therapeutic or acute pharmacological
effect of the active drug ingredient or therapeutic moiety; or
(2) The study is a clinical trial to establish the safety and
effectiveness of the drug product.
(i) Standards for test drug product and reference material. (1) Both
the drug product to be tested and the reference material, if it is
another drug product, shall be shown to meet all compendial or other
applicable standards of identity, strength, quality, and purity,
including potency and, where applicable, content uniformity,
disintegration times, and dissolution rates.
(2) Samples of the drug product to be tested shall be manufactured
using the same equipment and under the same conditions as those used for
full-scale production.
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
[[Page 199]]
reference material is to be based on cumulative urinary excretion-time
curves, unless some other approach is more appropriate for valid
scientific reasons, samples of the urine should be collected with
sufficient frequency to permit an estimate of the rate and extent of
urinary excretion of the active drug ingredient or therapeutic moiety,
or its metabolite(s), measured.
(e) Measurement of an acute pharmacological effect. (1) When
comparison of the test product and the reference material is to be based
on acute pharmacological effect-time curves, measurements of this effect
should be made with sufficient frequency to permit a reasonable estimate
of the total area under the curve for a time period at least three times
the half-life of decay of the pharmacological effect, unless some other
approach is more appropriate for valid scientific reasons.
(2) The use of an acute pharmacological effect to determine
bioavailability may further require demonstration of dose-related
response. In such a case, bioavailability may be determined by
comparison of the dose-response curves as well as the total area under
the acute pharmacological effect-time curves for any given dose.
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,
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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 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.