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Code of Federal Regulations
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[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.1]
[Page 58-65]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.1 Applications.
(a) Applications to be filed under section 512(b) of the act shall
be submitted in the form described in paragraph (b) of this section. If
any part of the application is in a foreign language, an accurate and
complete English translation shall be appended to such part.
Translations of literature printed in a foreign language shall be
accompanied by copies of the original publication. The application must
be signed by the applicant or by an authorized attorney, agent, or
official. If the applicant or such authorized representative does not
reside or have a place of business within the United States, the
application must also furnish the name and post office address of, and
must be countersigned by, an authorized attorney, agent, or official
residing or maintaining a place of business within the United States.
Pertinent information may be incorporated in, and will be considered as
part of, an application on the basis of specific reference to such
information, including information submitted under the provisions of
Sec. 511.1 of this chapter, in the files of the Food and Drug
Administration; however, the reference must be specific in identifying
the information. Any reference to information furnished by a person
other than the applicant may not be considered unless its use is
authorized in a written statement signed by the person who submitted it.
(b) Applications for new animal drugs shall be submitted in
triplicate and assembled in the manner prescribed by paragraph (b)(15)
of this section, and shall include the following information:
(1) Identification. Whether the submission is an original or
supplemental application; the name and the address of the applicant; the
date of the application; the trade name(s) (if one has been proposed)
and chemical name(s) of the new animal drug. Upon receipt, the
application will be assigned a number NADA ____, which shall be used for
all correspondence with respect to the application.
(2) Table of contents and summary. The application shall be
organized in a cohesive fashion, shall contain a table of contents which
identifies the data and other material submitted, and shall contain a
well-organized summary and evaluation of the data in the following form:
(i) Chemistry:
(a) Chemical structural formula or description for any new animal
drug substance.
(b) Relationship to other chemically or pharmacologically related
drugs.
(c) Description of dosage form and quantitative composition.
(ii) Scientific rationale and purpose the new animal drug is to
serve:
(a) Clinical purpose.
(b) Highlights of laboratory studies: The reasons why certain types
of studies were done or omitted as related to the proposed conditions of
use and to information already known about this class of compounds.
Emphasize any unusual or particularly significant pharmacological
effects or toxicological findings.
(c) Highlights of clinical studies: The rationale of the clinical
study plan showing why types of studies were done, amended, or omitted
as related to laboratory studies and prior clinical experience.
(d) Conclusions: A short statement of conclusions combining the
major points of effectiveness and safety as they relate to the use of
the new animal drug.
(3) Labeling. Three copies of each piece of all labeling to be used
for the article (total of 9).
(i) All labeling should be identified to show its position on, or
the manner in which it is to accompany the market package.
(ii) Labeling for nonprescription new animal drugs should include
adequate directions for use by the layman under all conditions of use
for which the new animal drug is intended, recommended, or suggested in
any of the labeling or advertising sponsored by the applicant.
[[Page 59]]
(iii) Labeling for prescription veterinary drugs should bear
adequate information for use under which veterinarians can use the new
animal drug safely and for the purposes for which it is intended,
including those purposes for which it is to be advertised or
represented, in accord with Sec. 201.105 of this chapter.
(iv) All labeling for prescription or nonprescription new animal
drugs shall be submitted with any necessary use restrictions prominently
and conspicuously displayed.
(v) Labeling for new animal drugs intended for use in the
manufacture of medicated feeds shall include:
(a) Specimens of labeling to be used for such new animal drug with
adequate directions for the manufacture and use of finished feeds for
all conditions for which the new animal drug is intended, recommended,
or suggested in any of the labeling, including advertising, sponsored by
the applicant. Ingredient labeling may utilize collective names as
provided in Sec. 501.110 of this chapter.
(b) Representative labeling proposed to be used for Type B and Type
C medicated feeds containing the new animal drug.
(vi) Draft labeling may be submitted for preliminary consideration
of an application. Final printed labeling will ordinarily be required
prior to approval of an application. Proposed advertising for veterinary
prescription drugs may be submitted for comment or approval.
(4) Components and composition. A complete list of all articles used
for production of the new animal drug including a full list of the
composition of each article:
(i) A full list of the articles used as components of the new animal
drug. This list should include all substances used in the synthesis,
extraction, or other method of preparation of any new animal drug and in
the preparation of the finished dosage form, regardless of whether they
undergo chemical change or are removed in the process. Each component
should be identified by its established name, if any, or complete
chemical name, using structural formulas when necessary for specific
identification. If any proprietary name is used, it should be followed
by a complete quantitative statement of composition. Reasonable
alternatives for any listed component may be specified.
(ii) A full statement of the composition of the new animal drug. The
statement shall set forth the name and amount of each ingredient,
whether active or not, contained in a stated quantity of the new animal
drug in the form in which it is to be distributed (for example, amount
per tablet or milliliter) and a batch formula representative of that to
be employed for the manufacture of the finished dosage form. All
components should be included in the batch formula regardless of whether
they appear in the finished product. Any calculated excess of an
ingredient over the label declaration should be designated as such and
percent excess shown. Reasonable variation may be specified.
(iii) If it is a new animal drug produced by fermentation:
(a) Source and type of microorganism used to produce the new animal
drug.
(b) Composition of media used to produce the new animal drug.
(c) Type of precursor used, if any, to guide or enhance production
of the antibiotic during fermentation.
(d) Name and composition of preservative, if any, used in the broth.
(e) A complete description of the extraction and purification
processes including the names and compositions of the solvents,
precipitants, ion exchange resins, emulsifiers, and all other agents
used.
(f) If the new animal drug is produced by a catalytic hydrogenation
process (such as tetracycline from chlortetracycline), a complete
description of each chemical reaction with graphic formulas used to
produce the new animal drug, including the names of the catalyst used,
how it is removed, and how the new animal drug is extracted and
purified.
(5) Manufacturing methods, facilities, and controls. A full
description of the methods used in, and the facilities and controls used
for, the manufacture, processing, and packing of the new animal drug.
This description should include full information with respect to
[[Page 60]]
any new animal drug in sufficient detail to permit evaluation of the
adequacy of the described methods of manufacture, processing, and
packing, and the described facilities and controls to determine and
preserve the identity, strength, quality, and purity of the new animal
drug, and the following:
(i) If the applicant does not himself perform all the manufacturing,
processing, packaging, labeling, and control operations for any new
animal drug, he shall: Identify each person who will perform any part of
such operations and designate the part; and provide a signed statement
from each such person fully describing, directly or by reference, the
methods, facilities, and controls he will use in his part of the
operation. The statement shall include a commitment that no changes will
be made without prior approval by the Food and Drug Administration,
unless permitted under Sec. 514.8.
(ii) A description of the qualifications, including educational
background and experience, of the technical and professional personnel
who are responsible for assuring that the new animal drug has the
identity, strength, quality, and purity it purports or is represented to
possess, and a statement of their responsibilities.
(iii) A description of the physical facilities including building
and equipment used in manufacturing, processing, packaging, labeling,
storage, and control operations.
(iv) The methods used in the synthesis, extraction, isolation, or
purification of any new animal drug. When the specifications and
controls applied to such new animal drugs are inadequate in themselves
to determine its identity, strength, quality, and purity, the methods
should be described in sufficient detail, including quantities used,
times, temperature, pH, solvents, etc., to determine these
characteristics. Alternative methods or variations in methods within
reasonable limits that do not affect such characteristics of the new
animal drug may be specified. A flow sheet and indicated equations
should be submitted when needed to explain the process.
(v) Precautions to insure proper identity, strength, quality, and
purity of the raw materials, whether active or not, including:
(a) The specifications for acceptance and methods of testing for
each lot of raw material.
(b) A statement as to whether or not each lot of raw materials is
given a serial number to identify it, and the use made of such numbers
in subsequent plant operations.
(vi) The instructions used in the manufacturing, processing,
packaging, and labeling of each dosage form of the new animal drug,
including:
(a) The method of preparation of the master formula records and
individual batch records and the manner in which these records are used.
(b) The number of individuals checking weight or volume of each
individual ingredient entering into each batch of the new animal drug.
(c) A statement as to whether or not the total weight or volume of
each batch is determined at any stage of the manufacturing process
subsequent to making up a batch according to the formula card and, if
so, at what stage and by whom it is done.
(d) The precautions used in checking the actual package yield
produced from a batch of the new animal drug with the theoretical yield.
This should include a description of the accounting for such items as
discards, breakage, etc., and the criteria used in accepting or
rejecting batches of drugs in the event of an unexplained discrepancy.
(e) The precautions used to assure that each lot of the new animal
drug is packaged with the proper label and labeling, including
provisions for labeling storage and inventory control.
(f) Any special precautions used in the operations.
(vii) The analytical controls used during the various stages of the
manufacturing, processing, packaging, and labeling of the new animal
drug, including a detailed description of the collection of samples and
the analytical procedures to which they are subjected. The analytical
procedures should be capable of determining the active components within
a reasonable degree of accuracy and of assuring the identity of such
components.
(a) A description of practicable methods of analysis of adequate
sensitivity
[[Page 61]]
to determine the amount of the new animal drug in the final dosage form
should be included. The dosage form may be a finished pharmaceutical
product, a Type A medicated article, a Type B or a Type C medicated
feed, or a product for use in animal drinking water. Where two or more
active ingredients are included, methods should be quantitative and
specific for each active ingredient.
(b) If the article is one that is represented to be sterile, the
same information with regard to the manufacturing, processing,
packaging, and the collection of samples of the drug should be given for
sterility controls. Include the standards used for acceptance of each
lot of the finished drug.
(viii) An explanation of the exact significance of any batch control
numbers used in the manufacturing, processing, packaging, and labeling
of the new animal drug, including such control numbers that may appear
on the label of the finished article. State whether these numbers enable
determination of the complete manufacturing history of the product.
Describe any methods used to permit determination of the distribution of
any batch if its recall is required.
(ix) Adequate information with respect to the characteristics of and
the test methods employed for the container, closure, or other component
parts of the drug package to assure their suitability for the intended
use.
(x) A complete description of, and data derived from, studies of the
stability of the new animal drug in the final dosage form, including
information showing the suitability of the analytical methods used. A
description of any additional stability studies underway or planned.
Stability data for the finished dosage form of the new animal drug in
the container in which it is to be marketed, including any proposed
multiple dose container, and, if it is to be put into solution at the
time of dispensing, for the solution prepared as directed. If the new
animal drug is intended for use in the manufacture of Type C medicated
feed as defined in Sec. 558.3 of this chapter, stability data derived
from studies in which representative formulations of the medicated feed
articles are used. Similar data may be required for Type B medicated
feeds as determined by the Food and Drug Administration on a case-by-
case basis. Expiration dates shall be proposed for finished
pharmaceutical dosage forms and Type A medicated articles. If the data
indicate that an expiration date is needed for Type B or Type C
medicated feeds, the applicant shall propose such expiration date. If no
expiration date is proposed for Type B or Type C medicated feeds, the
applicant shall justify its absence with data.
(xi) Additional procedures employed which are designed to prevent
contamination and otherwise assure proper control of the product. An
application may be refused unless it includes adequate information
showing that the methods used in, and the facilities and controls used
for, the manufacturing, processing, and packaging of the new animal drug
are adequate to preserve its identity, strength, quality, and purity in
conformity with good manufacturing practice and identifies each
establishment, showing the location of the plant conducting these
operations.
(6) Samples. Samples of the new animal drug and articles used as
components and information concerning them may be requested by the
Center for Veterinary Medicine as follows:
(i) Each sample shall consist of four identical, separately packaged
subdivisions, each containing at least three times the amount required
to perform the laboratory test procedures described in the application
to determine compliance with its control specifications for identity and
assays. Each of the samples submitted shall be appropriately packaged
and labeled to preserve its characteristics, to identify the material
and the quantity in each subdivision of the sample, and to identify each
subdivision with the name of the applicant and the new animal drug
application to which it relates. Included are:
(a) A sample or samples of any reference standard and blank used in
the procedures described in the application for assaying each new animal
drug and other assayed components of the finished new animal drug.
(b) A representative sample or samples of each strength of the
finished
[[Page 62]]
dosage form proposed in the application and employed in the clinical
investigations and a representative sample or samples of each new animal
drug from the batch(es) employed in the production of such dosage form.
(c) A representative sample or samples of finished market packages
of each strength of the dosage form of the new animal drug prepared for
initial marketing and, if any such sample is not from a representative
commercial-scale production batch, such a sample from a representative
commercial-scale production batch, and a representative sample or
samples of each new animal drug from the batch(es) employed in the
production of such dosage form, provided that in the case of new animal
drugs marketed in large packages the sample should contain only three
times a sufficient quantity of the new animal drug to allow for
performing the control tests for drug identity and assays.
(ii) The following information shall be included for the samples
when requested:
(a) For each sample submitted, full information regarding its
identity and the origin of any new animal drug contained therein
(including a statement whether it was produced on a laboratory, pilot-
plant, or full-production scale) and detailed results of all laboratory
tests made to determine the identity, strength, quality, and purity of
the batch represented by the sample, including assays.
(b) For any reference standard submitted, a complete description of
its preparation and the results of all laboratory tests on it. If the
test methods used differed from those described in the application, full
details of the methods employed in obtaining the reporting results.
(7) Analytical methods for residues. Applications shall include a
description of practicable methods for determining the quantity, if any,
of the new animal drug in or on food, and any substance formed in or on
food because of its use, and the proposed tolerance or withdrawal period
or other use restrictions to ensure that the proposed use of this drug
will be safe. When data or other adequate information establish that it
is not reasonable to expect the new animal drug to become a component of
food at concentrations considered unsafe, a regulatory method is not
required.
(i) The kind of information required by this subdivision may
include: Complete experimental protocols for determining drug residue
levels in the edible products, and the length of time required for
residues to be eliminated from such products following the drug's use;
residue studies conducted under appropriate (consistent with the
proposed usage) conditions of dosage, time, and route of administration
to show levels, if any, of the drug and/or its metabolites in test
animals during and upon cessation of treatment and at intervals
thereafter in order to establish a disappearance curve; if the drug is
to be used in combination with other drugs, possible effects of
interaction demonstrated by the appropriate disappearance curve or
depletion patterns after drug withdrawal under appropriate (consistent
with the proposed usage) conditions of dosage, time, and route of
administration; if the drug is given in the feed or water, appropriate
consumption records of the medicated feed or water and appropriate
performance data in the treated animal; if the drug is to be used in
more than one species, drug residue studies or appropriate metabolic
studies conducted for each species that is food-producing. To provide
these data, a sufficient number of birds or animals should be used at
each sample interval. Appropriate use of labeled compounds (e.g.
radioactive tracers), may be utilized to establish metabolism and
depletion curves. Drug residue levels ordinarily should be determined in
muscle, liver, kidney, and fat and where applicable, in skin, milk, and
eggs (yolk and egg white). As a part of the metabolic studies, levels of
the drug or metabolite should be determined in blood where feasible.
Samples may be combined where necessary. Where residues are suspected or
known to be present in litter from treated animals, it may be necessary
to include data with respect to such residues becoming components of
other agricultural commodities because of use of litter from treated
animals.
(ii) A new animal drug that has the potential to contaminate human
food
[[Page 63]]
with residues whose consumption could present a risk of cancer to people
must satisfy the requirements of subpart E of part 500 of this chapter.
(8) Evidence to establish safety and effectiveness. (i) An
application may be refused unless it contains full reports of adequate
tests by all methods reasonably applicable to show whether or not the
new animal drug is safe and effective for use as suggested in the
proposed labeling.
(ii) An application may be refused unless it includes substantial
evidence of the effectiveness of the new animal drug as defined in
Sec. 514.4.
(iii) An application may be refused unless it contains detailed
reports of the investigations, including studies made on laboratory
animals, in which the purpose, methods, and results obtained are clearly
set forth of acute, subacute, and chronic toxicity, and unless it
contains appropriate clinical laboratory results related to safety and
efficacy. Such information should include identification of the person
who conducted each investigation, a statement of where the
investigations were conducted, and where the raw data are available in
the application.
(iv) All information pertinent to an evaluation of the safety and
effectiveness of the new animal drug received or otherwise obtained by
the applicant from any source, including information derived from other
investigations or commercial marketing (for example, outside the United
States), or reports in the scientific literature, both favorable and
unfavorable, involving the new animal drug that is the subject of the
application and related new animal drugs shall be submitted. An adequate
summary may be acceptable in lieu of a reprint of a published report
that only supports other data submitted. Include any evaluation of the
safety or effectiveness of the new animal drug that has been made by the
applicant's veterinary or medical department, expert committee, or
consultants.
(v) If the new animal drug is a combination of active ingredients or
animal drugs, an application may be refused unless it includes
substantial evidence of the effectiveness of the combination new animal
drug as required in Sec. 514.4.
(vi) An application shall include a complete list of the names and
post office addresses of all investigators who received the new animal
drug. This may be incorporated in whole or in part by reference to
information submitted under the provisions of Sec. 511.1 of this
chapter.
(vii) Explain any omission of reports from any investigator to whom
the investigational new animal drug has been made available. The
unexplained omission of any reports of investigations made with the new
animal drug by the applicant or submitted to him by an investigator or
the unexplained omission of any pertinent reports of investigations or
clinical experience received or otherwise obtained by the applicant from
published literature or other sources that would bias an evaluation of
the safety of the new animal drug or its effectiveness in use,
constitutes grounds for the refusal or withdrawal of the approval of an
application.
(viii) If a sponsor has transferred any obligations for the conduct
of any clinical study to a contract research organization, the
application is required to include a statement containing the name and
address of the contract research organization, identifying the clinical
study, and listing 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) If original subject records were audited or reviewed by the
sponsor in the course of monitoring any clinical study to verify the
accuracy of the case reports submitted to the sponsor, a list
identifying each clinical study so audited or reviewed.
(9) Veterinary feed directive. Three copies of a veterinary feed
directive (VFD) must be submitted in the format described under
Sec. 558.6(a)(4) of this chapter.
(10) Supplemental applications. If it is a supplemental application,
full information shall be submitted on each proposed change concerning
any statement made in the approved application.
[[Page 64]]
(11) Applicant's commitment. It is understood that the labeling and
advertising for the new animal drug will prescribe, recommend, or
suggest its use only under the conditions stated in the labeling which
is part of this application and if the article is a prescription new
animal drug, it is understood that any labeling which furnishes or
purports to furnish information for use or which prescribes, recommends,
or suggests a dosage for use of the new animal drug will also contain,
in the same language and emphasis, information for its use including
indications, effects, dosages, routes, methods, and frequency and
duration of administration, any relevant hazards, contraindications,
side effects, and precautions contained in the labeling which is part of
this application. It is understood that all representations in this
application apply to the drug produced until changes are made in
conformity with Sec. 514.8.
(12) Additional commitments. (i) New animal drugs as defined in
Sec. 510.3 of this chapter, intended for use in the manufacture of
animal feeds in any State will be shipped only to persons who may
receive such drugs in accordance with Sec. 510.7 of this chapter.
(ii) The methods, facilities, and controls described under item 5 of
this application conform to the current good manufacturing practice
regulations in subchapter C of this chapter.
(iii) With respect to each nonclinical laboratory study contained in
the application, either a statement that the study was conducted in
compliance with the good laboratory practice regulations set forth in
part 58 of this chapter, or, if the study was not conducted in
compliance with such regulations, a brief statement of the reason for
the noncompliance.
(13) [Reserved]
(14) Environmental assessment. The applicant is required to submit
either a claim for categorical exclusion under Sec. 25.30 or Sec. 25.33
of this chapter or an environmental assessment under Sec. 25.40 of this
chapter.
(15) Assembling and binding the application. Assemble and bind an
original and two copies of the application as follows:
(i) Bind the original or ribbon copy of the application as copy No.
1.
(ii) Bind two identical copies as copy No. 2 and copy No. 3.
(iii) Identify each front cover with the name of the applicant, new
animal drug, and the copy number.
(iv) Number each page of the application sequentially in the upper
right hand corner or in another location so that the page numbers remain
legible after the application has been bound, and organize the
application consistent with paragraphs (b) (1) through (14) of this
section. Each copy should bear the same page numbering, whether
sequential in each volume or continuous and sequential throughout the
application.
(v) Include complete labeling in each of the copies. It is suggested
that labeling be identified by date of printing or date of preparation.
(vi) Submit separate applications for each different dosage form of
the drug proposed. Repeating basic information pertinent to all dosage
forms in each application is unnecessary if reference is made to the
application containing such information. Include in each application
information applicable to the specific dosage form, such as labeling,
composition, stability data, and method of manufacture.
(vii) Submit in folders amendments, supplements, and other
correspondence sent after submission of an original application. The
front cover of these submissions should be identified with the name of
the applicant, new animal drug, copy number, and the new animal drug
application number, if known.
(c) When a new animal drug application is submitted for a new animal
drug which has a stimulant, depressant, or hallucinogenic effect on the
central nervous system, if it appears that the drug has a potential for
abuse, the Commissioner shall forward that information to the Attorney
General of the United States.
(d) Minor use applications. Applications for minor use new animal
drugs:
(1) Definitions. For the purpose of this section:
(i) Minor use means the use of: (a) New animal drugs in minor animal
species, or (b) new animal drugs in any
[[Page 65]]
animal species for the control of a disease that (1) occurs infrequently
or (2) occurs in limited geographic areas.
(ii) Minor species means animals other than cattle, horses, swine,
chickens, turkeys, dogs, and cats.
(2) Animal safety, effectiveness, human food safety, and
environmental considerations. Guidance documents for the preparation and
submission of data to satisfy the requirements of section 512 of the act
regarding animal safety, effectiveness, human food safety, and
environmental considerations for new animal drugs intended for a minor
use (as defined in paragraph (d)(1)(i) of this section) are available
from the Industry Information Staff (HFV-11), Center for Veterinary
Medicine, Food and Drug Administration, 7500 Standish Pl., Rockville, MD
20855.
(i) Animal safety and effectiveness. Where the guidance documents do
not specifically provide for a particular minor use, the Center for
Veterinary Medicine, upon request, will advise interested persons on the
effectiveness and animal safety data regarding the minor use that will
be needed to satisfy the requirements of section 512 of the act. Where
scientifically appropriate, the Center for Veterinary Medicine will
allow the use of animal models and the extrapolation of data from a
major species to a minor species to satisfy the requirements of the act.
(ii) Human food safety and environmental considerations. These
guidance documents do not specifically provide for a particular minor
use. Therefore, the Center for Veterinary Medicine will, upon request,
advise interested persons of the data that will be needed. Where
scientifically appropriate, the Center for Veterinary Medicine will
allow the extrapolation of data from a major species to a minor species
to satisfy the requirements of the act.
(Approved by the Office of Management and Budget under control number
0910-0032)
[40 FR 13825, Mar. 27, 1975]
Editorial Note: For Federal Register citations affecting Sec. 514.1,
see the List of CFR Sections Affected, which appears in the Finding Aids
section of the printed volume and on GPO Access.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.4]
[Page 65-67]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.4 Substantial evidence.
(a) Definition of substantial evidence. Substantial evidence means
evidence consisting of one or more adequate and well-controlled studies,
such as a study in a target species, study in laboratory animals, field
study, bioequivalence study, or an in vitro study, on the basis of which
it could fairly and reasonably be concluded by experts qualified by
scientific training and experience to evaluate the effectiveness of the
new animal drug involved that the new animal drug will have the effect
it purports or is represented to have under the conditions of use
prescribed, recommended, or suggested in the labeling or proposed
labeling thereof. Substantial evidence shall include such adequate and
well-controlled studies that are, as a matter of sound scientific
judgment, necessary to establish that a new animal drug will have its
intended effect.
(b) Characteristics of substantial evidence--(1) Qualifications of
experts. Any study that is intended to be part of substantial evidence
of the effectiveness of a new animal drug shall be conducted by experts
qualified by scientific training and experience.
(2) Intended uses and conditions of use. Substantial evidence of
effectiveness of a new animal drug shall demonstrate that the new animal
drug is effective for each intended use and associated conditions of use
for and under which approval is sought.
(i) Dose range labeling. Sponsors should, to the extent possible,
provide for a dose range because it increases the utility of the new
animal drug by providing the user flexibility in the selection of a safe
and effective dose. In general, substantial evidence to support dose
range labeling for a new animal drug intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of disease must consist of at
least one adequate and well-controlled study on the basis of which
qualified experts could fairly and reasonably conclude that the new
animal drug will be effective for the intended use at the lowest dose of
the dose range suggested in the proposed labeling for that intended use.
Substantial evidence to support dose range labeling for a new animal
drug intended to affect the
[[Page 66]]
structure or function of the body of an animal generally must consist of
at least one adequate and well-controlled study on the basis of which
qualified experts could fairly and reasonably conclude that the new
animal drug will be effective for the intended use at all doses within
the range suggested in the proposed labeling for the intended use.
(ii) [Reserved]
(3) Studies--(i) Number. Substantial evidence of the effectiveness
of a new animal drug for each intended use and associated conditions of
use shall consist of a sufficient number of current adequate and well-
controlled studies of sufficient quality and persuasiveness to permit
qualified experts:
(A) To determine that the parameters selected for measurement and
the measured responses reliably reflect the effectiveness of the new
animal drug;
(B) To determine that the results obtained are likely to be
repeatable, and that valid inferences can be drawn to the target animal
population; and
(C) To conclude that the new animal drug is effective for the
intended use at the dose or dose range and associated conditions of use
prescribed, recommended, or suggested in the proposed labeling.
(ii) Types. Adequate and well-controlled studies that are intended
to provide substantial evidence of the effectiveness of a new animal
drug may include, but are not limited to, published studies, foreign
studies, studies using models, and studies conducted by or on behalf of
the sponsor. Studies using models shall be validated to establish an
adequate relationship of parameters measured and effects observed in the
model with one or more significant effects of treatment.
(c) Substantial evidence for combination new animal drugs--(1)
Definitions. The following definitions of terms apply to this section:
(i) Combination new animal drug means a new animal drug that
contains more than one active ingredient or animal drug that is applied
or administered simultaneously in a single dosage form or simultaneously
in or on animal feed or drinking water.
(ii) Dosage form combination new animal drug means a combination new
animal drug intended for use other than in animal feed or drinking
water.
(iii) Antibacterial with respect to a particular target animal
species means an active ingredient or animal drug: That is approved in
that species for the diagnosis, cure, mitigation, treatment, or
prevention of bacterial disease; or that is approved for use in that
species for any other use that is attributable to its antibacterial
properties. But, antibacterial does not include ionophores or arsenicals
intended for use in combination in animal feed or drinking water.
(iv) Appropriate concurrent use exists when there is credible
evidence that the conditions for which the combination new animal drug
is intended can occur simultaneously.
(2) Combination new animal drugs that contain only active
ingredients or animal drugs that have previously been separately
approved.
(i) For dosage form combination new animal drugs, except for those
that contain a nontopical antibacterial, that contain only active
ingredients or animal drugs that have previously been separately
approved for the particular uses and conditions of use for which they
are intended in combination, a sponsor shall demonstrate:
(A) By substantial evidence, as defined in this section, that any
active ingredient or animal drug intended only for the same use as
another active ingredient or animal drug in the combination makes a
contribution to the effectiveness of the combination new animal drug;
(B) That each active ingredient or animal drug intended for at least
one use that is different from all the other active ingredients or
animal drugs used in the combination provides appropriate concurrent use
for the intended target animal population; and
(C) That the active ingredients or animal drugs are physically
compatible and do not have disparate dosing regimens if FDA, based on
scientific information, has reason to believe the active ingredients or
animal drugs are physically incompatible or have disparate dosing
regimens.
(ii) For combination new animal drugs intended for use in animal
feed
[[Page 67]]
or drinking water that contain only active ingredients or animal drugs
that have previously been separately approved for the particular uses
and conditions of use for which they are intended in combination, the
sponsor shall demonstrate:
(A) By substantial evidence, as defined in this section, that any
active ingredient or animal drug intended only for the same use as
another active ingredient or animal drug in the combination makes a
contribution to the effectiveness of the combination new animal drug;
(B) For such combination new animal drugs that contain more than one
antibacterial ingredient or animal drug, by substantial evidence, as
defined in this section, that each antibacterial makes a contribution to
labeled effectiveness;
(C) That each active ingredient or animal drug intended for at least
one use that is different from all other active ingredients or animal
drugs used in the combination provides appropriate concurrent use for
the intended target animal population; and
(D) That the active ingredients or animal drugs intended for use in
drinking water are physically compatible if FDA, based on scientific
information, has reason to believe the active ingredients or animal
drugs are physically incompatible.
(3) Other combination new animal drugs. For all other combination
new animal drugs, the sponsor shall demonstrate by substantial evidence,
as defined in this section, that the combination new animal drug will
have the effect it purports or is represented to have under the
conditions of use prescribed, recommended, or suggested in the proposed
labeling and that each active ingredient or animal drug contributes to
the effectiveness of the combination new animal drug.
[64 FR 40756, July 28, 1999]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.6]
[Page 67]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.6 Amended applications.
The applicant may submit an amendment to an application that is
pending, including changes that may alter the conditions of use, the
labeling, safety, effectiveness, identity, strength, quality, or purity
of the drug or the adequacy of the manufacturing methods, facilities,
and controls to preserve them, in which case the unamended application
may be considered as withdrawn and the amended application may be
considered resubmitted on the date on which the amendment is received by
the Food and Drug Administration. The applicant will be notified of such
date.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.7]
[Page 67]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.7 Withdrawal of applications without prejudice.
The sponsor may withdraw his pending application from consideration
as a new animal drug application upon written notification to the Food
and Drug Administration. Such withdrawal may be made without prejudice
to a future filing. Upon resubmission, the time limitation will begin to
run from the date the resubmission is received by the Food and Drug
Administration. The original application will be retained by the Food
and Drug Administration although it is considered withdrawn. The
applicant shall be furnished a copy at cost on request.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.8]
[Page 67-71]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.8 Supplemental new animal drug applications.
(a)(1) After a new animal drug application is approved, a
supplemental new animal drug application may propose changes. A
supplemental application may omit statements made in the approved
application concerning which no change is proposed. Each supplemental
application shall include up-to-date reports of any of the kinds of
information required by Sec. 510.300(a) of this chapter that has not
previously been submitted. A supplemental application shall be
accompanied by either a claim for categorical exclusion under Sec. 25.30
or Sec. 25.33 of this chapter or an environmental assessment under
Sec. 25.40 of this chapter.
(2) A supplemental new animal drug application shall be submitted
for any change beyond the variations provided for in the application,
including changes in the scale of production such as from pilot-plant to
production batch, that may alter the conditions of use, the labeling,
safety, effectiveness, identity, strength, quality, or purity of the new
animal drug, or the adequacy of the manufacturing methods, facilities,
or controls to preserve them.
[[Page 68]]
(3) If it is a prescription drug, any mailing or promotional piece
used after the drug is placed on the market is labeling requiring a
supplemental application, unless:
(i) The parts of the labeling furnishing directions, warnings, and
information for use of the drug are the same in language and emphasis as
labeling approved or permitted; and
(ii) Any other parts of the labeling are consistent with and not
contrary to such approved or permitted labeling.
(4) The supplemental application shall be submitted as follows. A
communication proposing a change in a new animal drug application should
provide for any one of the following kinds of changes:
(i) Revision in labeling, such as updating information pertaining to
effects, dosages, and side effects and contraindications, which includes
information headed ``side effects,'' ``warnings,'' ``precautions,'' and
``contraindications.''
(ii) Addition of claim.
(iii) Revision in manufacturing or control procedures; for example,
changes in components, composition, method of manufacture, analytical
control procedures, package or tablet size, etc.
(iv) Change in manufacturing facilities.
(v) Provision for outside firm to participate in the preparation,
distribution, or packaging of a new animal drug (new distributor,
packer, supplier, manufacturer, etc.); one firm per submission.
Any number of changes may be submitted at any one time; but if they fall
into different categories as listed in paragraphs (a)(4) (i) through (v)
of this section, the proposed changes should be covered by separate
communications. Where, however, a change necessitates an overlap in
categories, it should be submitted in a single communication. For
example, a change in tablet potency would require other changes such as
in components, composition, and labeling and should be submitted in a
single communication.
(5) The following kinds of changes may be placed into effect without
the approval of a supplemental application, if such change is fully
described in the next periodic report required under Sec. 510.300(b)(4)
of this chapter or, when such a report is not required, in a written
communication to the Food and Drug Administration within 60 days of the
effective date of the change (this does not apply to a change proposed
because of any mixup or any bacteriological or significant chemical,
physical, or other change or deterioration in the drug or any failure of
one or more distributed batches of the drug to meet its specifications):
(i) A different container size for solid oral dosage forms where
container and closure are of the same materials as those provided for in
the approved application.
(ii) Change in personnel not involving new facilities.
(iii) Change in equipment that does not alter the method of
manufacture of a new animal drug.
(iv) Change from one commercial batch size to another without any
change in manufacturing procedure.
(v) Change to more stringent specification without altering the
method described in the approved application.
(vi) Inclusion of additional specifications and methods without
deletion of those described in the approved application.
(vii) Alteration of specifications or methods for inactive
ingredients to bring them into compliance with new or revised
specifications or methods in an official compendium.
(viii) Initiation of a product identification coding system.
(ix) Addition to labeling of a reasonable expiration date where none
was previously used, with related conditions of drug storage when
appropriate, except when evidence shows that a significant deterioration
of the drug under marketing conditions has occurred which necessitates
the immediate submission of a report under Sec. 510.300(b)(1) of this
chapter. The report or written communication describing such change in
labeling should include stability data justifying the expiration date
and recommended conditions of storage.
(x) Change from paper labels to direct printing on glass or other
kinds of immediate containers without a change in text.
[[Page 69]]
(6) Approval of a supplemental new animal drug application will not
be required to provide for an additional distributor to distribute a
drug which is the subject of an approved new animal drug application if
the conditions described below are met prior to putting such a change
into effect. An order may issue refusing approval if any condition is
not met or if any of the reasons for refusing or withdrawing approval,
as stated in section 512(d) and (e) of the act or Sec. 514.110 applies.
For the purposes of maintaining records and making reports under the
requirements of Sec. 510.300 of this chapter, a distributor provided for
under this section shall be considered an applicant within the meaning
of Sec. 510.300(b) of this chapter. Said conditions are:
(i) A supplemental application is furnished to the Food and Drug
Administration to provide for a designated distributor.
(ii) There are no changes from the conditions of the approved
application except for a different and suitable proprietary name of the
new animal drug (if one is used) and the name and address of the
distributor as used on the label and labeling. The name of the
distributor shall be accompanied by an appropriate qualifying phrase
such as ``manufactured for'' or ``distributed by.''
(iii) A distributor's statement is furnished to the Food and Drug
Administration identifying the category of his operations (for example,
wholesaler, retailer) and stating: That he will distribute the new
animal drug only under the labeling provided for in the new animal drug
application; that any other labeling or advertising for the drug will
prescribe, recommend, or suggest its use only under the conditions
stated in the labeling provided for in the application; and, if the drug
is a prescription article, that he is regularly and lawfully engaged in
the distribution or dispensing of prescription drugs.
(iv) Nine copies of the printed labels and other labeling to be used
by the distributor are submitted, identified with the new animal drug
application number.
(b) When necessary for the safety or effectiveness of the drug, a
supplemental new animal drug application shall specify a period of time
within which the proposed change will be made.
(c) If a material change is made in the components' composition,
manufacturing methods, facilities, or controls, or in the labeling or
advertising, from the representations in an approved application for a
new animal drug (except changes conforming to the conditions set forth
in paragraph (a)(5) and (6) and/or paragraphs (d), (e), (f), and (g) of
this section), and the drug is marketed before a supplement is approved
for such change, approval of the application may be suspended or
withdrawn as provided in section 512(e) of the act.
(d) Changes of the following kinds proposed in supplemental new
animal drug applications should be placed into effect at the earliest
possible time:
(1) The addition to package labeling, promotional labeling, and
prescription drug advertising of additional warning, contraindication,
side effect, and precaution information.
(2) The deletion from package labeling, promotional labeling, and
drug advertising of false, misleading, or unsupported indications for
use or claims for effectiveness.
(3) Changes in the methods, facilities, or controls used for the
manufacture, processing, packing, or holding of the new animal drug
(other than utilization of establishments not covered by the approval
that is in effect) that give increased assurance that the drug will have
the characteristics of identity, strength, quality, and purity which it
purports or is represented to possess.
(e) The Food and Drug Administration will take no action against a
new animal drug or applicant solely because changes of the kinds
described in paragraph (d) of this section are placed into effect by the
applicant prior to his receipt of a written notice of approval of the
supplemental new animal drug application if all the following conditions
are met:
(1) The supplemental new animal drug application providing a full
explanation of the basis for the changes has been submitted, plainly
marked on the mailing cover and on the supplement,
[[Page 70]]
``Special new animal drug application Supplement--changes being
effected.''
(2) The applicant specifically informs the Food and Drug
Administration of the date on which such changes are being effected and
submits to the Administration nine printed copies of any revised
labeling to be placed in use, identified with the new animal drug
application number.
(3) All promotional labeling and all drug advertising are promptly
revised consistent with the changes made in the labeling on or within
the new animal drug package.
(f) When a supplemental new animal drug application proposes changes
only of the kinds described in paragraph (d) of this section, and the
applicant informs the Food and Drug Administration that the changes are
being put into effect, such notification will be regarded as an
agreement by the applicant to an extension of the time for formal action
on the application.
(g) In addition to changes as permitted by paragraphs (d) and (e) of
this section, an applicant may place into effect changes proposed in a
supplement to a new animal drug application that became effective prior
to October 10, 1962, upon written notification from the Food and Drug
Administration that such action is permitted, without approval of the
supplemental application, pending the completion of the review of the
effectiveness of such drug by the National Academy of Sciences-National
Research Council and a determination as to whether there are grounds for
refusing approval under section 512(d) of the act or for invoking
section 512(e) of the act. The Food and Drug Administration will take no
action against a new animal drug or an applicant solely because changes
that have been permitted in a written communication are placed into
effect by the applicant prior to his receipt of a written notice of
approval of the supplemental new animal drug application.
(h) Except as provided in paragraphs (e) and (g) of this section, no
provision of this section shall limit the authority of the Secretary or
of the Commissioner to suspend or withdraw approval of a new animal drug
application in accord with the provisions of section 512(e) of the act
or to initiate any other regulatory proceedings with respect to a drug
or applicant under provisions of the act.
(i) Changes from the conditions of an approved new animal drug
application in accord with the provisions of paragraphs (d), (e), and
(g) of this section are permitted on the basis of a temporary deferral
of final action on the supplemental application under the provisions of
section 512 (c), (d), or (e) of the act.
(j) When an applicant receives written notification from the Food
and Drug Administration, under the provisions of paragraph (g) of this
section, that he may place into effect changes proposed in a
supplemental application without approval of the supplemental
application, he may within 30 days submit a written request that the
Food and Drug Administration process the supplemental application. In
such case, the change shall not be put into effect until approved.
Within 180 days of the receipt of such written request, the Food and
Drug Administration will approve the supplemental application or furnish
notice of an opportunity for a hearing under the provisions of section
512 (d) or (e), or both, of the act on a proposal to refuse approval of
the supplemental application or to withdraw approval of the application
and supplements thereto.
(k) A supplement to an application that became effective prior to
October 10, 1962, may include a written statement to the effect that a
temporary deferral of final action under the provisions of paragraph
(d), (e), or (g) of this section is unacceptable to the applicant and
that the applicant requests action as provided in section 512(c) of the
act. Final action on such supplemental applications will be expedited in
accord with applicable provisions of section 512 of the act and
regulations in this subchapter E. In such cases, if the applicant places
into effect any of the proposed changes prior to his receipt of a
written notice of approval of the supplemental new animal drug
application, such action may be regarded by the Food and Drug
Administration as a basis for invoking the provisions of section
512(e)(1)(D) of the act; that
[[Page 71]]
is, the applicant may be furnished notice of an opportunity for a
hearing on a proposal to withdraw approval of the application on the
ground that the application contains an untrue statement of a material
fact related to the changes from the conditions approved in the
application.
(l) A supplemental application that contains nonclinical laboratory
studies shall include, with respect to each nonclinical study, either a
statement that the study was conducted in compliance with the
requirements set forth in part 58 of this chapter, or, if the study was
not conducted in compliance with such regulations, a brief statement of
the reason for the noncompliance.
[40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 50
FR 16668, Apr. 26, 1985; 62 FR 40600, July 29, 1997]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.11]
[Page 71-72]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.11 Confidentiality of data and information in a new animal drug application file.
(a) For purposes of this section the NADA file includes all data and
information submitted with or incorporated by reference in the NADA,
INAD's incorporated into the NADA, supplemental NADA's, reports under
Secs. 510.300 and 510.301 of this chapter, master files, and other
related submissions. The availability for public disclosure of any
record in the NADA file shall be handled in accordance with the
provisions of this section.
(b) The existence of an NADA file will not be disclosed by the Food
and Drug Administration before an approval has been published in the
Federal Register, unless it has previously been publicly disclosed or
acknowledged.
(c) If the existence of an NADA file has not been publicly disclosed
or acknowledged, no data or information in the NADA file is available
for public disclosure.
(d) If the existence of an NADA file has been publicly disclosed or
acknowledged before an approval has been published in the Federal
Register, no data or information contained in the file is available for
public disclosure before such approval is published, but the
Commissioner may, in his discretion, disclose a summary of such selected
portions of the safety and effectiveness data as are appropriate for
public consideration of a specific pending issue, e.g., at an open
session of a Food and Drug Administration advisory committee or pursuant
to an exchange of important regulatory information with a foreign
government.
(e) After an approval has been published in the Federal Register,
the following data and information in the NADA file are immediately
available for public disclosure unless extraordinary circumstances are
shown:
(1) All safety and effectiveness data and information previously
disclosed to the public, as defined in Sec. 20.81 of this chapter.
(2) A summary or summaries of the safety and effectiveness data and
information submitted with or incorporated by reference in the NADA
file. Such summaries do not constitute the full reports of
investigations under section 512(b)(1) of the act (21 U.S.C. 360b(b)(1))
on which the safety or effectiveness of the drug may be approved. Such
summaries shall consist of the following:
(i) For an NADA approved prior to July 1, 1975, internal agency
records that describe such data and information, e.g., a summary of
basis for approval or internal reviews of the data and information,
after deletion of:
(a) Names and any information that would identify the investigators.
(b) Any inappropriate gratuitous comments unnecessary to an
objective analysis of the data and information.
(ii) For an NADA approved on or after July 1, 1975, a summary of
such data and information prepared in one of the following two
alternative ways shall be publicly released when the approval is
published in the Federal Register.
(a) The Center for Veterinary Medicine may at an appropriate time
prior to approval of the NADA require the applicant to prepare a summary
of such data and information, which will be reviewed and, where
appropriate, revised by the Center.
(b) The Center for Veterinary Medicine may prepare its own summary
of such data and information.
(3) A protocol for a test or study, unless it is shown to fall
within the exemption established for trade secrets
[[Page 72]]
and confidential commercial information in Sec. 20.61 of this chapter.
(4) Adverse reaction reports, product experience reports, consumer
complaints, and other similar data and information, after deletion of:
(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, hospital, or other
institution.
(5) A list of all active ingredients and any inactive ingredients
previously disclosed to the public as defined in Sec. 20.81 of this
chapter.
(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 in Sec. 20.61 of this chapter.
(7) All correspondence and written summaries of oral discussions
relating to the NADA, in accordance with the provisions of part 20 of
this chapter.
(f) All safety and effectiveness data and information not previously
disclosed to the public are available for public disclosure at the time
any one of the following events occurs unless extraordinary
circumstances are known:
(1) The NADA has been abandoned and no further work is being
undertaken with respect to it.
(2) A final determination is made that the NADA is not approvable,
and all legal appeals have been exhausted.
(3) Approval of the NADA is withdrawn, and all legal appeals have
been exhausted.
(4) A final determination has been made that the animal drug is not
a new animal drug.
(5) A final determination has been made that the animal drug may be
marketed without submission of such safety and/or effectiveness data and
information.
(g) The following data and information in an NADA file are not
available for public disclosure unless they have been previously
disclosed to the public as defined in Sec. 20.81 of this chapter or they
relate to a product or ingredient that has been abandoned and they no
longer represent a trade secret or confidential commercial or financial
information as defined in 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 such 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) For purposes of this regulation, safety and effectiveness data
include all studies and tests of an animal drug on animals and all
studies and tests on the animal drug for identity, stability, purity,
potency, and bioavailability.
[40 FR 13825, Mar. 27, 1975, as amended at 42 FR 3109, Jan. 14, 1977; 42
FR 15675, Mar. 22, 1977; 54 FR 18280, Apr. 28, 1989]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.12]
[Page 72]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.12 Confidentiality of data and information in an investigational new animal drug notice.
(a) The existence of an INAD notice will not be disclosed by the
Food and Drug Administration unless it has previously been publicly
disclosed or acknowledged.
(b) The availability for public disclosure of all data and
information in an INAD file shall be handled in accordance with
provisions established in Sec. 514.11.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.15]
[Page 72-73]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart A--General Provisions
Sec. 514.15 Untrue statements in applications.
Among the reasons why an application for a new animal drug or animal
feed bearing or containing a new animal drug may contain an untrue
statement of a material fact are:
(a) Differences in:
(1) Conditions of use prescribed, recommended, or suggested by the
applicant for the product from the conditions of such use stated in the
application;
(2) Articles used as components of the product from those listed in
the application;
(3) Composition of the product from that stated in the application;
[[Page 73]]
(4) Methods used in or the facilities and controls used for the
manufacture, processing, or packing of the product from such methods,
facilities, and controls described in the application;
(5) Labeling from the specimens contained in the application; or
(b) The unexplained omission in whole or in part from an application
or from an amendment or supplement to an application or from any record
or report required under the provisions of section 512 of the act and
Sec. 510.300 or Sec. 510.301 of this chapter of any information obtained
from:
(1) Investigations as to the safety, effectiveness, identity,
strength, quality, or purity of the drug, made by the applicant on the
drug, or
(2) Investigations or experience with the product that is the
subject of the application, or any related product, available to the
applicant from any source if such information is pertinent to an
evaluation of the safety, effectiveness, identity, strength, quality, or
purity of the drug, when such omission would bias an evaluation of the
safety or effectiveness of the product.
(c) Any nonclinical laboratory study contained in the application
was not conducted in compliance with the good laboratory practice
regulations as set forth in part 58 of this chapter, and the application
fails to include a brief statement of the reason for the noncompliance.
[40 FR 13825, Mar. 27, 1975, as amended at 49 FR 7226, Feb. 28, 1984; 50
FR 7517, Feb. 22, 1985]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.100]
[Page 73-74]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.100 Evaluation and comment on applications.
(a) After the filed application has been evaluated, the applicant
will be furnished written comment on any apparent deficiencies in the
application.
(b) When the description of the methods used in, and the facilities
and controls used for, the manufacture, processing, and packing of such
new animal drug appears adequate on its face, but it is not feasible to
reach a conclusion as to the safety and effectiveness of the new animal
drug solely from consideration of this description, the applicant may be
notified that an establishment inspection is required to verify their
adequacy.
(c) A request for samples of a new animal drug or any edible tissues
and byproducts of animals treated with such a drug, shall specify the
quantity deemed adequate to permit tests of analytical methods to
determine their adequacy for regulatory purposes. The request should be
made as early in the 180-day period as possible to assure timely
completion. The date used for computing the 180-day limit for the
purposes of section 512(c) of the act shall be moved forward 1 day for
each day after the mailing date of the request until all of the
requested samples are received. If the samples are not received within
90 days after the request, the application will be considered withdrawn
without prejudice.
(d) The information contained in an application may be insufficient
to determine whether a new animal drug is safe or effective in use if it
fails to include (among other things) a statement showing whether such
drug is to be limited to prescription sale and exempt under section
502(f) of the act from the requirement that its labeling bear adequate
directions for lay use. If such drug is to be exempt, the information
may also be insufficient if:
(1) The specimen labeling proposed fails to bear adequate
information for professional use including indications, effects,
dosages, routes, methods, and frequency and duration of administration
and any relevant hazards, contraindications, side effects, and
precautions under which practitioners licensed by law to administer such
drug can use the drug for the purposes for which it is intended,
including all purposes for which it is to be advertised, or represented,
in accordance with Sec. 201.105 of this chapter, and information
concerning hazards, contraindications, side effects, and precautions
relevant with respect to any uses for which such drug is to be
prescribed.
(2) The application fails to show that the labeling and advertising
of such drug will offer the drug for use only under those conditions for
which it is offered in the labeling that is part of the application.
[[Page 74]]
(3) The application fails to show that all labeling that furnishes
or purports to furnish information for professional use of such drug
will contain, in the same language and emphasis, the information for use
including indications, effects, dosages, routes, methods, and frequency
and duration of administration and any relevant warnings, hazards,
contraindications, side effects, and precautions, which is contained in
the labeling that is part of the application in accordance with
Sec. 201.105 of this chapter.
(e) The information contained in an application will be considered
insufficient to determine whether a new animal drug is safe and
effective for use when there is a refusal or failure upon written notice
to furnish inspectors authorized by the Food and Drug Administration an
adequate opportunity to inspect the facilities, controls, and records
pertinent to the application.
(f) On the basis of preliminary consideration of an application or
supplemental application containing typewritten or other draft labeling
in lieu of final printed labeling, an applicant may be informed that
such application is approvable when satisfactory final printed labeling
identical in content to such draft copy is submitted.
(g) When an application has been found incomplete on the basis of a
need for the kind of information described in Sec. 514.6, such
application shall be considered withdrawn without prejudice to future
filing on the date of issuance of the letter citing the inadequacies
contained in the application, unless within 30 days the sponsor chooses
to avail himself of the opportunity for hearing as prescribed by
Sec. 514.111.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.105]
[Page 74]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.105 Approval of applications.
(a) The Commissioner shall forward for publication in the Federal
Register a regulation prescribing the conditions under which the new
animal drug may be used, including the name and address of the
applicant; the conditions and indications for use covered by the
application; any tolerance, withdrawal period, or other use
restrictions; any tolerance required for the new animal drug substance
or its metabolites in edible products of food-producing animals; and, if
such new animal drug is intended for use in animal feed, appropriate
purposes and conditions of use (including special labeling requirements)
applicable to any animal feed; and such other information the
Commissioner deems necessary to assure safe and effective use.
(b) He shall notify the applicant by sending him a copy of the
proposed publication as described in paragraph (a)(1) of this section.
[40 FR 13825, Mar. 27, 1975, as amended at 51 FR 7392, Mar. 3, 1986; 64
FR 63203, Nov. 19, 1999]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.106]
[Page 74-75]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.106 Approval of supplemental applications.
(a) Within 180 days after a supplement to an approved application is
filed pursuant to Sec. 514.8, the Commissioner shall approve the
supplemental application in accordance with procedures set forth in
Sec. 514.105(a)(1) and (2) if he/she determines that the application
satisfies the requirements of applicable statutory provisions and
regulations.
(b) The Commissioner will assign a supplemental application to its
proper category to ensure processing of the application.
(1) Category I. Supplements that ordinarily do not require a
reevaluation of any of the safety or effectiveness data in the parent
application. Category I supplements include the following:
(i) A corporate change that alters the identity or address of the
sponsor of the new animal drug application (NADA).
(ii) The sale, purchase, or construction of manufacturing
facilities.
(iii) The sale or purchase of an NADA.
(iv) A change in container, container style, shape, size, or
components.
(v) A change in approved labeling (color, style, format, addition,
deletion, or revision of certain statements, e.g., trade name, storage,
expiration dates, etc).
(vi) A change in promotional material for a prescription drug not
exempted by Sec. 514.8(a)(3)(i) and (a)(3)(ii).
(vii) Changes in manufacturing processes that do not alter the
method of manufacture or change the final dosage form.
[[Page 75]]
(viii) A change in bulk drug shipments.
(ix) A change in an analytical method or control procedures that do
not alter the approved standards.
(x) A change in an expiration date.
(xi) Addition of an alternate manufacturer, repackager, or relabeler
of the drug product.
(xii) Addition of an alternate supplier of the new drug substance.
(xiii) A change permitted in advance of approval as listed in
Sec. 514.8(d).
(xiv) Changes not requiring prior approval which are listed under
Sec. 514.8(a)(5) when submitted as supplemental applications.
(2) Category II. Supplements that may require a reevaluation of
certain safety or effectiveness data in the parent application. Category
II supplements include the following:
(i) A change in the active ingredient concentration or composition
of the final product.
(ii) A change in quality, purity, strength, and identity
specifications of the active or inactive ingredients.
(iii) A change in dose (amount of drug administered per dose).
(iv) A change in the treatment regimen (schedule of dosing).
(v) Addition of a new therapeutic claim to the approved uses of the
product.
(vi) Addition of a new or revised animal production claim.
(vii) Addition of a new species.
(viii) A change in the prescription or over-the-counter status of a
drug product.
(ix) A change in statements regarding side effects, warnings,
precautions, and contraindications, except the addition of approved
statements to container, package, and promotional labeling, and
prescription drug advertising.
(x) A change in the drug withdrawal period prior to slaughter or in
the milk discard time.
(xi) A change in the tolerance for drug residues.
(xii) A change in analytical methods for drug residues.
(xiii) A revised method of synthesis or fermentation of the new drug
substance.
(xiv) Updating or changes in the manufacturing process of the new
drug substance and/or final dosage form (other than a change in
equipment that does not alter the method of manufacture of a new animal
drug, or a change from one commercial batch size to another without any
change in manufacturing procedure), or changes in the methods,
facilities, or controls used for the manufacture, processing, packaging,
or holding of the new animal drug (other than use of an establishment
not covered by the approval that is in effect) that give increased
assurance that the drug will have the characteristics of identity,
strength, quality, and purity which it purports or is represented to
possess.
[55 FR 46052, Nov. 1, 1990; 55 FR 49973, Dec. 3, 1990; 56 FR 12422, Mar.
25, 1991]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.110]
[Page 75-76]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.110 Reasons for refusing to file applications.
(a) The date of receipt of an application for a new animal drug
shall be the date on which the application shall be deemed to be filed.
(b) An application for a new animal drug shall not be considered
acceptable for filing for any of the following reasons:
(1) It does not contain complete and accurate English translations
of any pertinent part in a foreign language.
(2) Fewer than three copies are submitted.
(3) It is incomplete on its face in that it is not properly
organized and indexed.
(4) On its face the information concerning required matter is so
inadequate that the application is clearly not approvable.
(5) The new animal drug is to be manufactured, prepared, propagated,
compounded, or processed in whole or in part in any State in an
establishment that has not been registered or exempted from registration
under the provisions of section 510 of the act.
(6) The sponsor does not reside or maintain a place of business
within the United States and the application has not been countersigned
by an attorney, agent, or other representative of the applicant, which
representative resides in the United States and has been duly authorized
to act on behalf of the applicant and to receive communications
[[Page 76]]
on all matters pertaining to the application.
(7) The new animal drug is a drug subject to licensing under the
animal virus, serum, and toxin law of March 4, 1913 (37 Stat. 832; 21
U.S.C. 151 et seq.). Such applications will be referred to the U.S.
Department of Agriculture for action.
(8) It fails to include, with respect to each nonclinical laboratory
study contained in the application, either a statement that the study
was conducted in compliance with the good laboratory practice
regulations set forth in part 58 of this chapter, or, if the study was
not conducted in compliance with such regulations, a brief statement of
the reasons for the noncompliance.
(9) [Reserved]
(10) The applicant fails to submit a complete environmental
assessment under Sec. 25.40 of this chapter or fails to provide
sufficient information to establish that the requested action is subject
to categorical exclusion under Sec. 25.30 or Sec. 25.33 of this chapter.
(c) If an application is determined not to be acceptable for filing,
the applicant shall be notified within 30 days of receipt of the
application and shall be given the reasons therefore.
(d) If the applicant disputes the findings that his application is
not acceptable for filing, he may make written request that the
application be filed over protest, in which case it will be filed as of
the day originally received.
[40 FR 13825, Mar. 27, l975, as amended at 50 FR 7517, Feb. 22, 1985; 50
FR 16668, Apr. 26, 1985; 62 FR 40600, July 29, 1997]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.111]
[Page 76-77]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.111 Refusal to approve an application.
(a) The Commissioner shall, within 180 days after the filing of the
application, inform the applicant in writing of his intention to issue a
notice of opportunity for a hearing on a proposal to refuse to approve
the application, if the Commissioner determines upon the basis of the
application, or upon the basis of other information before him with
respect to a new animal drug, that:
(1) The reports of investigations required to be submitted pursuant
to section 512(b) of the act do not include adequate tests by all
methods reasonably applicable to show whether or not such drug is safe
for use under the conditions prescribed, recommended, or suggested in
the proposed labeling thereof; or
(2) The results of such tests show that such drug is unsafe for use
under such conditions or do not show that such drug is safe for use
under such conditions; or
(3) The methods used in and the facilities and controls used for the
manufacture, processing, and packing of such drug are inadequate to
preserve its identity, strength, quality, and purity; or
(4) Upon the basis of the information submitted to the Food and Drug
Administration as part of the application, or upon the basis of any
other information before it with respect to such drug, it has
insufficient information to determine whether such drug is safe for use
under such conditions. In making this determination the Commissioner
shall consider, among other relevant factors:
(i) The probable consumption of such drug and of any substance
formed in or on food because of the use of such drug;
(ii) The cumulative effect on man or animal of such drug, taking
into account any chemically or pharmacologically related substances;
(iii) Safety factors which, in the opinion of experts qualified by
scientific training and experience to evaluate the safety of such drugs,
are appropriate for the use of animal experimentation data; and
(iv) Whether the conditions of use prescribed, recommended, or
suggested in the proposed labeling are reasonably certain to be followed
in practice; or
(5) Evaluated on the basis of information submitted as part of the
application and any other information before the Food and Drug
Administration with respect to such drug, there is lack of substantial
evidence as defined in Sec. 514.4.
(6) Failure to include an appropriate proposed tolerance for
residues in edible products derived from animals or a withdrawal period
or other restrictions for use of such drug if any tolerance or
withdrawal period or other restrictions for use are required in order to
assure
[[Page 77]]
that the edible products derived from animals treated with such drug
will be safe.
(7) Based on a fair evaluation of all material facts, the labeling
is false or misleading in any particular; or
(8) Such drug induces cancer when ingested by man or animal or,
after appropriate tests for evaluation of the safety of such drug,
induces cancer in man or animal, except that this subparagraph shall not
apply with respect to such drug if the Commissioner finds that, under
the conditions of use specified in proposed labeling and reasonably
certain to be followed in practice:
(i) Such drug will not adversely affect the animal for which it is
intended; and
(ii) No residue of such drug will be found (by methods of
examination prescribed or approved by the Commissioner by regulations)
in any edible portion of such animal after slaughter or in any food
yielded by, or derived from the living animals.
(9) The applicant fails to submit an adequate environmental
assessment under Sec. 25.40 of this chapter or fails to provide
sufficient information to establish that the requested action is subject
to categorical exclusion under Sec. 25.30 or Sec. 25.33 of this chapter.
(10) The drug fails to satisfy the requirements of subpart E of part
500 of this chapter.
(11) Any nonclinical laboratory study that is described in the
application and that is essential to show that the drug is safe for use
under the conditions prescribed, recommended, or suggested in its
proposed labeling, was not conducted in compliance with the good
laboratory practice regulations as set forth 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.
(b) The Commissioner, as provided in Sec. 514.200 of this chapter,
shall expeditiously notify the applicant of an opportunity for a hearing
on the question of whether such application is approvable, unless by the
30th day following the date of issuance of the letter informing the
applicant of the intention to issue a notice of opportunity for a
hearing the applicant:
(1) Withdraws the application; or
(2) Waives the opportunity for a hearing; or
(3) Agrees with the Commissioner on an additional period to precede
issuance of such notice of hearing.
[40 FR 13825, Mar. 27, 1975, as amended at 43 FR 22675, May 26, 1978; 44
FR 16007, Mar. 16, 1979; 50 FR 7517, Feb. 22, 1985; 50 FR 16668, Apr.
26, 1985; 52 FR 49588, Dec. 31, 1987; 54 FR 18280, Apr. 28, 1989; 62 FR
40600, July 29, 1997; 63 FR 10770, Mar. 5, 1998; 64 FR 40757, July 28,
1999; 64 FR 63204, Nov. 19, 1999]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.115]
[Page 77-78]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.115 Withdrawal of approval of applications.
(a) The Secretary may suspend approval of an application approved
pursuant to section 512(c) of the act and give the applicant prompt
notice of his action and afford the applicant the opportunity for an
expedited hearing on a finding that there is an imminent hazard to the
health of man or of the animals for which such new animal drug or animal
feed is intended.
(b) The Commissioner shall notify in writing the person holding an
application approved pursuant to section 512(c) of the act and afford an
opportunity for a hearing on a proposal to withdraw approval of such
application if he finds:
(1) That the application contains any untrue statement of a material
fact; or
(2) That the applicant has made any changes from the standpoint of
safety or effectiveness beyond the variations provided for in the
application unless he has supplemented the application by filing with
the Secretary adequate information respecting all such changes and
unless there is in effect an approval of the supplemental application,
or such changes are those for which written authorization or approval is
not required as provided for in Sec. 514.8. The supplemental application
shall be treated in the same manner as the original application.
(3) That in the case of an application for use of a new animal drug
approved or deemed approved pursuant to section 512(c) of the act:
(i) Experience or scientific data show that such drug is unsafe for
use under
[[Page 78]]
the conditions of use upon the basis of which the application was
approved; or
(ii) New evidence not contained in such application or not available
to the Secretary until after such application was approved, or tests by
new methods, or tests by methods not deemed reasonably applicable when
such application was approved, evaluated together with the evidence
available to the Secretary when the application was approved, shows that
such drug is not shown to be safe for use under the conditions of use
upon the basis of which the application was approved or that section 512
(d)(1)(H) of the act applies to such drug; or
(iii) On the basis of new information before him with respect to
such drug, evaluated together with the evidence available to him when
the application was approved, there is a lack of substantial evidence
that such drug will have the effect it purports or is represented to
have under the conditions of use prescribed, recommended, or suggested
in the labeling thereof.
(4) That any nonclinical laboratory study that is described in the
application and that is essential to show that the drug is safe for use
under the conditions prescribed, recommended, or suggested in its
proposed labeling, was not conducted in compliance with the good
laboratory practice regulations as set forth 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.
(c) The Commissioner may notify in writing the person holding an
application approved pursuant to section 512(c) of the act and afford an
opportunity for a hearing on a proposal to withdraw approval of such
application if he finds:
(1) That the applicant has failed to establish a system for
maintaining required records, or has repeatedly or deliberately failed
to maintain such records or to make required reports in accordance with
a regulation or order under section 512(l)(1) of the act, or the
applicant has refused to permit access to, or copying, or verification
of, such records as required by section 512(l)(2) of the act; or
(2) That on the basis of new information before him evaluated
together with the evidence before him when the application was approved,
the methods used in, or the facilities and controls used for, the
manufacture, processing, and packing of such drug or animal feed are
inadequate to assure and preserve its identity, strength, quality, and
purity and were not made adequate within a reasonable time after receipt
of written notice from the Secretary specifying the matter complained
of; or
(3) That on the basis of new information before him, evaluated
together with the evidence before him when the application was approved,
the labeling of such drug, based on a fair evaluation of all material
facts, is false or misleading in any particular and was not corrected
within a reasonable time after receipt of written notice from the
Secretary specifying the matter complained of.
(d) Approval of an application pursuant to section 512(c) of the act
will be withdrawn on the basis of a request for its withdrawal submitted
in writing by a person holding an approved new animal drug application
on the grounds that the drug subject to such application is no longer
being marketed and information is included in support of this finding,
provided none of the conditions cited in paragraphs (a), (b), and (c) of
this section pertain to the subject drug. A written request for such
withdrawal shall be construed as a waiver of the opportunity for a
hearing as otherwise provided for in this section. Withdrawal of
approval of an application under the provisions of this paragraph shall
be without prejudice.
(e) On the basis of the withdrawal of approval of an application for
a new animal drug approved pursuant to section 512(c) of the act, the
regulation published pursuant to section 512(i) of the act covering the
conditions of use of such drug as provided for in the application shall
be revoked.
[40 FR 13825, Mar. 27, 1975, as amended at 50 FR 7517, Feb. 22, 1985; 64
FR 63204, Nov. 19, 1999]
[[Page 79]]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.116]
[Page 79]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.116 Notice of withdrawal of approval of application.
When an approval of an application submitted pursuant to section 512
of the act is withdrawn by the Commissioner, he will give appropriate
public notice of such action by publication in the Federal Register.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.117]
[Page 79-81]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.117 Adequate and well-controlled studies.
(a) Purpose. The primary purpose of conducting adequate and well-
controlled studies of a new animal drug is to distinguish the effect of
the new animal drug from other influences, such as spontaneous change in
the course of the disease, normal animal production performance, or
biased observation. One or more adequate and well-controlled studies are
required to establish, by substantial evidence, that a new animal drug
is effective. The characteristics described in paragraph (b) of this
section have been developed over a period of years and are generally
recognized as the essentials of an adequate and well-controlled study.
Well controlled, as used in the phrase adequate and well controlled,
emphasizes an important aspect of adequacy. The Food and Drug
Administration (FDA) considers these characteristics in determining
whether a study is adequate and well controlled for purposes of section
512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C.
360b). Adequate and well-controlled studies, in addition to providing a
basis for determining whether a new animal drug is effective, may also
be relied upon to support target animal safety. The report of an
adequate and well-controlled study 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) Characteristics. An adequate and well-controlled study has the
following characteristics:
(1) The protocol for the study (protocol) and the report of the
study results (study report) must include a clear statement of the study
objective(s).
(2) The study is conducted in accordance with an appropriate
standard of conduct that addresses, among other issues, study conduct,
study personnel, study facilities, and study documentation. The protocol
contains a statement acknowledging the applicability of, and intention
to follow, a standard of conduct acceptable to FDA. The study report
contains a statement describing adherence to the standard.
(3) The study is conducted with a new animal drug that is produced
in accordance with appropriate manufacturing practices, which include,
but are not necessarily limited to, the manufacture, processing,
packaging, holding, and labeling of the new animal drug such that the
critical characteristics of identity, strength, quality, purity, and
physical form of the new animal drug are known, recorded, and
reproducible, to permit meaningful evaluations of and comparisons with
other studies conducted with the new animal drug. The physical form of a
new animal drug includes the formulation and physical characterization
(including delivery systems thereof, if any) of the new animal drug as
presented to the animal. The protocol and study report must include an
identification number which can be correlated with the specific
formulation and production process used to manufacture the new animal
drug used in the study.
(4) The study uses a design that permits a valid comparison with one
or more controls to provide a quantitative evaluation of drug effects.
The protocol and the study report must describe the precise nature of
the study design, e.g., duration of treatment periods, whether
treatments are parallel, sequential, or crossover, and the determination
of sample size. Within the broad range of studies conducted to support a
determination of the effectiveness of a new animal drug, certain of the
controls listed below would be appropriate and preferred depending on
the study conducted:
(i) Placebo concurrent control. The new animal drug is compared with
an inactive preparation designed to resemble the new animal drug as far
as possible.
(ii) Untreated concurrent control. The new animal drug is compared
with the absence of any treatment. The use of this control may be
appropriate when
[[Page 80]]
objective measurements of effectiveness, not subject to observer bias,
are available.
(iii) Active treatment concurrent control. The new animal drug is
compared with known effective therapy. The use of this control is
appropriate when the use of a placebo control or of an untreated
concurrent control would unreasonably compromise the welfare of the
animals. Similarity of the new animal drug and the active control drug
can mean either that both drugs were effective or that neither was
effective. The study report should assess the ability of the study to
have detected a difference between treatments. The evaluation of the
study should explain why the new animal drugs should be considered
effective in the study, for example, by reference to results in previous
placebo-controlled studies of the active control.
(iv) Historical control. The results of treatment with the new
animal drug are quantitatively compared with experience historically
derived from the adequately documented natural history of the disease or
condition, or with a regimen (therapeutic, diagnostic, prophylactic)
whose effectiveness is established, in comparable animals. 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 in which the effect of the new
animal drug is self-evident or studies of diseases with high and
predictable mortality, or signs and symptoms of predictable duration or
severity, or, in the case of prophylaxis, predictable morbidity.
(5) The study uses a method of selecting animals that provides
adequate assurances that the animals are suitable for the purposes of
the study. For example, the animals can reasonably be expected to have
animal production characteristics typical of the class(es) of animals
for which the new animal drug is intended, there is adequate assurance
that the animals have the disease or condition being studied, or, in the
case of prophylactic agents, evidence of susceptibility and exposure to
the condition against which prophylaxis is desired has been provided.
The protocol and the study report describe the method of selecting
animals for the study.
(6) The study uses a method to assign a treatment or a control to
each experimental unit of animals that is random and minimizes bias.
Experimental units of animals are groups of animals that are comparable
with respect to pertinent variables such as age, sex, class of animal,
severity of disease, duration of disease, dietary regimen, level of
animal production, and use of drugs or therapy other than the new animal
drug. The protocol and the study report describe the method of
assignment of animals to an experimental unit to account for pertinent
variables and method of assignment of a treatment or a control to the
experimental units. When the effect of such variables is accounted for
by an appropriate design, and when, within the same animal, effects due
to the test drug can be obtained free of the effects of such variables,
the same animal may be used for both the test drug and the control using
the controls set forth in paragraph (b)(4) of this section.
(7) The study uses methods to minimize bias on the part of observers
and analysts of the data that are adequate to prevent undue influences
on the results and interpretation of the study data. The protocol and
study report explain the methods of observation and recording of the
animal response variables and document the methods, such as ``blinding''
or ``masking,'' used in the study for excluding or minimizing bias in
the observations.
(8) The study uses methods to assess animal response that are well
defined and reliable. The protocol and study report describe the methods
for conducting the study, including any appropriate analytical and
statistical methods, used to collect and analyze the data resulting from
the conduct of the study, describe the criteria used to assess response,
and, when appropriate, justify the selection of the methods to assess
animal response.
(9) There is an analysis and evaluation of the results of the study
in accord with the protocol adequate to assess the effects of the new
animal drug.
[[Page 81]]
The study report evaluates the methods used to conduct, and presents and
evaluates the results of, the study as to their adequacy to assess the
effects of the new animal drug. This evaluation of the results of the
study assesses, among other items, the comparability of treatment and
control groups with respect to pertinent variables and the effects of
any interim analyses performed.
(c) Field studies. (1) Field conditions as used in this section
refers to conditions which closely approximate the conditions under
which the new animal drug, if approved, is intended to be applied or
administered.
(2) Studies of a new animal drug conducted under field conditions
shall, consistent with generally recognized scientific principles and
procedures, use an appropriate control that permits comparison, employ
procedures to minimize bias, and have the characteristics generally
described in paragraph (b) of this section. However, because field
studies are conducted under field conditions, it is recognized that the
level of control over some study conditions need not or should not be
the same as the level of control in laboratory studies. While not all
conditions relating to a field study need to be or should be controlled,
observations of the conditions under which the new animal drug is tested
shall be recorded in sufficient detail to permit evaluation of the
study. Adequate and well-controlled field studies shall balance the need
to control study conditions with the need to observe the true effect of
the new animal drug under closely approximated actual use conditions.
(d) Waiver. The Director of the Center for Veterinary Medicine (the
Director) 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 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 study, 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
studies so conducted will yield, or have yielded, substantial evidence
of effectiveness, notwithstanding nonconformance with the criteria for
which waiver is requested.
(e) Uncontrolled studies. Uncontrolled studies or partially
controlled studies are not acceptable as the sole basis for the approval
of claims of effectiveness or target animal safety. Such studies,
carefully conducted and documented, may provide corroborative support of
adequate and well-controlled studies regarding effectiveness and may
yield valuable data regarding safety of the new animal drug. Such
studies will be considered on their merits in light of the
characteristics listed here. Isolated case reports, random experience,
and reports lacking the details which permit scientific evaluation will
not be considered.
[63 FR 10770, Mar. 5, 1998]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.120]
[Page 81]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.120 Revocation of order refusing to approve an application or suspending or withdrawing approval of an application.
The Commissioner, upon his own initiative or upon request of an
applicant stating reasonable grounds therefor and if he finds that the
facts so require, may issue an order approving an application that
previously has had its approval refused, suspended, or withdrawn.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.121]
[Page 81]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart B--Administrative Actions on Applications
Sec. 514.121 Service of notices and orders.
All notices and orders under this subchapter E and section 512 of
the act pertaining to new animal drug applications shall be served:
(a) In person by any officer or employee of the Department
designated by the Commissioner; or
(b) By mailing the order by certified mail addressed to the
applicant or respondent at his last known address in the records of the
Food and Drug Administration.
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.200]
[Page 81-82]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart C--Hearing Procedures
Sec. 514.200 Contents of notice of opportunity for a hearing.
(a) The notice to the applicant of opportunity for a hearing on a
proposal by the Commissioner to refuse to approve an application or to
withdraw
[[Page 82]]
the approval of an application will specify the grounds upon which he
proposes to issue his order. On request of the applicant, the
Commissioner will explain the reasons for his action. The notice of
opportunity for a hearing will be published in the Federal Register and
will specify that the applicant has 30 days after issuance of the notice
within which he is required to file a written appearance electing
whether:
(1) To avail himself of the opportunity for a hearing; or
(2) Not to avail himself of the opportunity for a hearing.
(b) If the applicant fails to file a written appearance in answer to
the notice of opportunity for hearing, his failure will be construed as
an election not to avail himself of the opportunity for the hearing, and
the Commissioner without further notice may enter a final order.
(c) If the applicant elects to avail himself of the opportunity for
a hearing, he is required to file a written appearance requesting the
hearing within 30 days after the publication of the notice, giving the
reason why the application should not be refused or should not be
withdrawn, together with a well-organized and full-factual analysis of
the clinical and other investigational data he is prepared to prove in
support of his opposition to the Commissioner's proposal. A request for
a hearing may not rest upon mere allegations or denials, but must set
forth specific facts showing there is a genuine and substantial issue of
fact that requires a hearing. When it clearly appears from the data in
the application and from the reasons and a factual analysis in the
request for the hearing that no genuine and substantial issue of fact
precludes the refusal to approve the application or the withdrawal of
approval of the application (for example, no adequate and well-
controlled clinical investigations to support the claims of
effectiveness have been identified), the Commissioner will enter an
order on this data, stating his findings and conclusions. If a hearing
is requested and is justified by the applicant's response to the notice
of opportunity for a hearing, the issues will be defined, an
Administrative Law Judge will be named, and he shall issue a written
notice of the time and place at which the hearing will commence. In the
case of denial of approval, such time shall be not more than 90 days
after the expiration of such 30 days unless the Administrative Law Judge
and the applicant otherwise agree; and, in the case of withdrawal of
approval, such time shall be as soon as practicable.
(d) The hearing will be open to the public; however, if the
Commissioner finds that portions of the application which serve as a
basis for the hearing contain information concerning a method or process
entitled to protection as a trade secret, the part of the hearing
involving such portions will not be public, unless the respondent so
specifies in his appearance.
[40 FR 13825, Mar. 27, 1975, as amended at 43 FR 1941, Jan. 13, 1978]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.201]
[Page 82]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart C--Hearing Procedures
Sec. 514.201 Procedures for hearings.
Hearings relating to new animal drugs under section 512(d) and (e)
of the act shall be governed by part 12 of this chapter.
[64 FR 63204, Nov. 19, 1999]
Subparts D-E [Reserved]
[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of April 1, 2001]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.235]
[Page 82]
TITLE 21--FOOD AND DRUGS
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES--(Continued)
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
Subpart F--Judicial Review
Sec. 514.235 Judicial review.
(a) The transcript and record shall be certified by the
Commissioner. In any case in which the Commissioner enters an order
without a hearing pursuant to Sec. 314.200(g) of this chapter, the
request(s) for hearing together with the data and information submitted
and the Commissioner's findings and conclusions shall be included in the
record certified by the Commissioner.
(b) Judicial review of an order withdrawing approval of a new drug
application, whether or not a hearing has been held, may be sought by a
manufacturer or distributor of an identical, related, or similar drug
product, as defined in Sec. 310.6 of this chapter, in a United States
court of appeals pursuant to section 505(h) of the act.
[42 FR 4717, Jan. 25, 1977]
[[Page 83]]
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