[Federal Register Volume 62, Number 214 (Wednesday, November 5, 1997)]
[Proposed Rules]
[Pages 59830-59840]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-29275]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 514
[Docket No. 97N-0435]
Substantial Evidence of Effectiveness of New Animal Drugs
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA), as directed by the
Animal Drug Availability Act of 1996 (ADAA), is proposing to amend its
new animal drug regulations to further define the term ``substantial
evidence.'' The purpose of this proposed regulation is to encourage the
submission of new animal drug applications (NADA's) and supplemental
NADA's for single ingredient and combination new animal drugs. The
proposal also encourages dose range labeling.
DATES: Submit written comments on the proposed rule by February 3,
1998. Submit written comments on the information collection
requirements by December 5, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857. Submit written comments on the information
collection requirements to the Office of Management and Budget (OMB),
New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC
20503, Attn.: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Herman M. Schoenemann, Center for
Veterinary Medicine (HFV-126), Food and Drug Administration, 7500
Standish Pl., Rockville, MD 20855, 301-594-1638.
SUPPLEMENTARY INFORMATION:
I. Background
Congress enacted the ADAA (Pub. L. 104-250) on October 9, 1996. The
purpose of the ADAA is to facilitate the approval and marketing of new
animal drugs and medicated feeds. In furtherance of this purpose,
section 2(a) of the ADAA amended section 512(d)(3) of the Federal Food,
Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(d)(3)) to revise the
definition of ``substantial evidence.'' Section 2(e) of the ADAA
directs FDA to issue proposed regulations to further define the term
``substantial evidence'' in a manner that encourages the submission of
NADA's and supplemental NADA's. Section 2(e) also directs FDA to issue
proposed regulations to encourage dose range labeling. This proposed
regulation further defines substantial evidence and encourages dose
range labeling.
Before FDA can approve a new animal drug, FDA must find, among
other things, that there is substantial evidence that the new animal
drug is effective. The demonstration of effectiveness represents a
significant component of drug development time and cost such that the
amount and nature of the evidence needed can be an important
determinant of whether and when new animal drugs become available to
the public. The availability of certain approved new animal drugs for
use in livestock, poultry, pets, and other animals is vital to
protecting the health of animals and the health of humans who consume
the products of food producing animals. The availability of other
approved new animal drugs is vital to increasing the efficiency of food
production in the United States. Thus, animal and human health and food
production are best served by the development of substantial evidence
of effectiveness in an efficient manner. The changes made to the
definition of ``substantial evidence'' by the ADAA and by the further
definition of that term in this proposed rule give FDA greater
flexibility to make case-specific scientific determinations regarding
the number and types of adequate and well-controlled studies that will
provide, in an efficient manner, substantial evidence that a new animal
drug is effective.
II. The Statutory Definition of Substantial Evidence
The term ``substantial evidence'' as defined in section 512(d)(3)
of the act refers to the number and types of adequate and well-
controlled studies needed for a new animal drug to be determined to be
effective for the intended uses under the conditions of use prescribed,
recommended, or suggested (hereinafter suggested) in its labeling or
proposed labeling.
[[Page 59831]]
Prior to the enactment of the ADAA, section 512(d)(3) of the act
defined substantial evidence as:
[e]vidence consisting of adequate and well-controlled
investigations, including field investigation, by experts qualified
by scientific training and experience to evaluate the effectiveness
of the drug involved, on the basis of which it could fairly and
reasonably be concluded by such experts that the 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.
Under section 512(d)(3), as amended by the ADAA, substantial
evidence is defined as:
[e]vidence consisting of one or more adequate and well-
controlled investigations, such as,
(A) a study in a target species;
(B) a study in laboratory animals;
(C) any field investigation that may be required under this
section and that meets the requirements of [section 512 (b)(3) of
the act] if a presubmission conference is requested by the
applicant;
(D) a bioequivalence study; or
(E) an in vitro study;
by experts qualified by scientific training and experience to
evaluate the effectiveness of the drug involved on the basis of
which it could fairly and reasonably be concluded by such experts
that the 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.
Under the old definition, at least two adequate and well-controlled
studies were necessary to demonstrate by substantial evidence the
effectiveness of a new animal drug and at least one of those adequate
and well-controlled studies was required to be a field study. Under the
revised definition of substantial evidence it is possible that a
minimum of one adequate and well-controlled study \1\ may provide
substantial evidence of the effectiveness of a new animal drug for its
intended uses and associated conditions of use.
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\1\ The ADAA requires FDA to issue a proposed regulation to
further define the term ``adequate and well-controlled'' to require
that field investigations be designed and conducted in a
scientifically sound manner, taking into account practical
conditions in the field and differences between field conditions and
laboratory conditions. FDA published a proposed regulation further
defining the term ``adequate and well-controlled'' in the Federal
Register of May 8, 1997 (62 FR 25153).
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Furthermore, the statutory requirement for a field study has been
eliminated, but FDA continues to have the authority to require field
studies when necessary (H. Rept. 104-823, at 13 (1996)). Elimination of
the requirement for a field study recognizes that while a field study
(because it assesses the effectiveness of a new animal drug under
conditions of use that approximate actual use conditions) remains an
important element of many new animal drug approvals, there will be some
instances in which a field study would yield no more useful information
with regard to the new animal drugs effectiveness than can be obtained
through laboratory studies. Thus, the new definition of substantial
evidence specifically identifies types of adequate and well-controlled
studies that may be used in lieu of, or in addition to, field studies
to provide evidence of the effectiveness of a new animal drug.
III. Description of the Proposed Rule
FDA is proposing to amend part 514 (21 CFR part 514) by adding
Sec. 514.4 Substantial evidence to further define substantial evidence.
Proposed Sec. 514.4 describes the characteristics of substantial
evidence that permit qualified experts to fairly and reasonably
conclude that the drug will have the effect it purports or is
represented to have under the conditions of use suggested in the
proposed labeling. The proposed regulation would give FDA flexibility
to determine, in light of the current state of relevant scientific
knowledge, the minimum number of adequate and well-controlled studies
needed, dependent upon the quality and persuasiveness of such studies,
to permit qualified experts to conclude that a new animal drug is
effective. Substantial evidence must include a sufficient number of
studies of sufficient quality to permit experts qualified by scientific
training and experience to fairly and reasonably conclude that the new
animal drug is effective for each of the intended uses and associated
conditions of use suggested in the proposed labeling.
A. Characteristics of Substantial Evidence (Sec. 514.4(b))
1. Intended Uses and Conditions of Use (Sec. 514.4(b)(2))
Proposed Sec. 514.4(b)(2) requires that the sponsor demonstrate
that a new animal drug is effective for each proposed intended use and
associated conditions of use. A critical step in deciding the number
and types of adequate and well-controlled studies needed to demonstrate
effectiveness is to clearly define the intended uses and the associated
conditions of use. Intended use refers to the structure or function of
the body to be affected or the disease or condition to be treated,
prevented, mitigated, or cured. Conditions of use that may be suggested
in the proposed labeling for each intended use include, but are not
limited to: The dose or dose range, frequency, duration, timing (e.g.,
in relation to the onset of clinical signs), and route of
administration or application of the new animal drug; the withdrawal
period (if any); the preparation of the new animal drug for use; the
species, age, gender, class, and breed of animal for which the new
animal drug is intended for use; and, restriction to use under the
supervision of a licensed veterinarian.
The specific number and types of adequate and well-controlled
studies needed to provide substantial evidence of effectiveness of a
new animal drug will vary depending upon the number of intended uses,
how narrowly or broadly each intended use is defined, and, further,
upon the conditions of use associated with each intended use suggested
in the proposed labeling. Intended uses are the determining factors in
selecting the parameters to be measured under the conditions of use
proposed for the new animal drug. Because a new animal drug must be
shown to be effective for each intended use under the conditions of use
suggested in the proposed labeling, the greater the number of intended
uses and the more varied the associated conditions of use, the less
likely it is that a single study can be designed and conducted to
measure all relevant parameters. Likewise, the broader an intended use,
e.g., the new animal drug is intended to treat a disease with multiple
clinical presentations, the more likely it is that multiple studies
will be needed.
One of the most important conditions of use for any new animal drug
is the dosage. Dosage includes the dose or dose range, dosing
frequency, and the dosing duration. Thus, a sponsor must demonstrate by
substantial evidence that a new animal drug is effective for its
intended use at the dose or dose range and the associated conditions of
use suggested in the proposed labeling for that intended use. The
studies needed to make such a demonstration will depend, in part, upon
whether the new animal drug is labeled for use at a single fixed dose
or over a dose range.
The substantial evidence necessary to support a dose range will
further vary with the nature of the new animal drug and its intended
uses. Proposed Sec. 514.4(b)(2) provides that 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 at least one intended
use at the lower dose limit
[[Page 59832]]
prescribed in the proposed labeling and will be effective for each
intended use at the dose suggested in the proposed labeling for that
intended use. The proposed regulation also provides that substantial
evidence to support a dose range for a new animal drug intended to
affect the structure or function of the body of an animal for the
purpose of enhancing production 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 each intended use at all the doses within the range
prescribed for the intended use. In either instance, the upper limit of
a dose range for any new animal drug will be set based on safety, both
to the the target animal and to humans consuming products from animals
treated with the new animal drug, as well as practicality, e.g., volume
of injection or length of withdrawal period.
The agency notes that a conclusion that a new animal drug is
effective for its intended uses no longer requires dose optimization.
Prior to enactment of the ADAA in 1996, FDA was required under section
512(d)(1)(F) of the act to refuse to approve a new animal drug if, on
the basis of any information before FDA, the tolerance limitation
proposed, if any, exceeded that reasonably required to accomplish the
physical or other technical effect for which the new animal drug is
intended. In order to demonstrate by substantial evidence the minimal
amount of a new animal drug reasonably required to accomplish the
physical or technical effect, dose optimization, typically supported by
adequate and well-controlled dose titration studies that characterize
the critical aspects of the dose response relationship, was required.
This characterization of the dose-response relationship permitted FDA
to make a risk-benefit assessment of the new animal drug. That is, FDA
could determine whether the effectiveness of a new animal drug
outweighed the risks to the target animal at the dose or over the dose
range prescribed in the proposed labeling.
With the enactment of the ADAA, the requirement for dose
optimization has been eliminated. It is no longer necessary that the
dose or dose range prescribed in the proposed labeling of a new animal
drug be limited to that required to accomplish the physical or other
technical effect. Therefore, a sponsor is now required to demonstrate
by substantial evidence that a new animal drug is effective for each
intended use at the associated dose or over the associated dose range
prescribed in the proposed labeling. And, the sponsor must demonstrate
that such dose or dose range is safe for the target animal and, at the
labeled withdrawal time(s), does not result in a residue of such drug
in excess of a tolerance found by FDA to be safe.
Although the requirement for dose optimization has been eliminated,
sponsors will still need to characterize the critical aspects of the
dose response relationship so that qualified experts can make an
informed risk-benefit assessment of the new animal drug and assure that
the proposed labeling is not false or misleading in any particular.
Thus, a sponsor must characterize for an intended use and associated
conditions of use the critical aspects of the dose-response
relationship relevant to the dose or dose range selected. For example,
for new animal drugs intended to affect the structure or function of
the body of an animal for the purpose of enhancing production,
generally a sponsor should characterize whether the dose or dose range
prescribed in the proposed labeling for the new animal drug falls on
the part of the dose-response curve at which there is increasing
effectiveness or on the part of the dose-response curve at which
effectiveness is essentially static, i.e., the plateau. This
characterization does not, however, have to be demonstrated by
substantial evidence.
FDA encourages the use of dose range labeling. The use of dose
range labeling, particularly professional flexible labeling, enhances
the ability of users to safely, effectively, and economically treat
animals without using the new animal drug in an extra-label manner. As
discussed previously, the critical aspects of the dose-response
relationship must generally be characterized to support labeling,
including dose range labeling. Although many drugs have increasing
effectiveness over a definable dose range, most reach a point at which
effectiveness is not measurably improved by increased dosing. Without a
sufficient characterization of the dose-response relationship,
qualified experts cannot determine whether dose range labeling is false
or misleading in any particular and the user cannot be adequately
informed regarding the appropriate use of the new animal drug.
2. Number of Studies (Sec. 514.4(b)(3)(i))
Whether substantial evidence for a particular new animal drug
consists of a single adequate and well-controlled study of sufficient
quality or one adequate and well-controlled study corroborated by
additional adequate and well-controlled studies will depend on the new
animal drug involved. Proposed Sec. 514.4(b)(3)(i) provides that
studies intended to provide substantial evidence of effectiveness shall
consist of a sufficient number of studies of sufficient quality and
persuasiveness to permit qualified experts in determining that the
parameters reflect the effectiveness of the new animal drug; that the
results obtained are likely to be repeatable, and that valid inferences
can be drawn to the target animal \2\ population; and, that the new
animal drug is effective for the intended use at the dose or dose range
and associated conditions of use suggested in the proposed labeling.
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\2\ Target animal and target animal population as used
throughout this document refer to the animal or animal population
for which the new animal drug is intended for use.
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For each study that is part of substantial evidence, the critical
characteristics of identity, strength, quality, purity, and physical
form of the new animal drug used must be sufficiently documented to
permit meaningful evaluation of the study and comparison with other
studies conducted with the new animal drug (proposed Sec. 514.117(b)(3)
(62 FR 25153, May 8, 1997)).
For qualified experts to fairly and reasonably conclude that a new
animal drug is effective for an intended use under the conditions of
use suggested in the proposed labeling for the new animal drug, the
study parameters selected for measurement must reliably reflect the
effectiveness of the new animal drug for the intended use (selection of
study parameters (Sec. 514.117(b)(3)(i)(A))). A new animal drug cannot
be shown to be effective for an intended use without eliciting a
measurable response with respect to parameters highly correlated to
that intended use of the drug. Generally, a sponsor should evaluate
parameters that provide direct evidence of effectiveness with respect
to the intended use, but, where appropriate, a sponsor may measure
effects on an established surrogate endpoint.
The studies that provide substantial evidence must provide
reasonable assurance that the results obtained from the use of the new
animal drug are repeatable when the new animal drug is applied or
administered under conditions of use suggested in the proposed labeling
(repeatability of study results (Sec. 514.4(b)(3)(i)(B)). The
definition of substantial evidence in section 512 of the act prior to
its amendment by the ADAA and its requirement for more than one
adequate and well-controlled study were based
[[Page 59833]]
on the principle of independent substantiation. The goal of independent
substantiation of experimental results is to ensure that an
experimental finding of effectiveness is not the result of:
Unanticipated, undetected, or systematic biases; study site-or
investigator-specific factors that prevent generalization of the
finding to the intended target animal population; or chance.
Independent substantiation also provides a safeguard against those rare
instances in which the results of a study are the product of fraudulent
reporting of scientific studies. Independent substantiation continues
to be a primary scientific principle upon which qualified experts can
make a determination whether a new animal drug is effective.
Historically, the need for independent substantiation was
frequently equated with the need for replication, i.e., replication of
an identical study. While replication is usually a highly reliable way
to independently substantiate experimental results, it is not the only
way. Results obtained from studies that are different in design or
execution or both may provide support for a conclusion of effectiveness
that is at least as convincing as a repeat of the same study. Under the
revised definition of substantial evidence, substantial evidence
supporting the effectiveness of a new animal drug for an intended use
may be achieved by carefully and properly designing and conducting a
single adequate and well-controlled study or by conducting multiple
adequate and well-controlled studies that need not replicate one
another.
The number of studies needed to provide independent substantiation
and support a finding by qualified experts that a new animal drug is
effective will depend upon the quality of the studies and the
inferential value of the studies. Whatever scientific evidence is
needed to demonstrate the effectiveness of a new animal drug, the
quality of that scientific evidence is of comparable importance to its
quantity. Quality of a study includes factors such as the rigor, power,
and scope of the design and conduct of a study, and the sufficiency of
the study documentation. As the quality of an effectiveness study
improves, the study's reliability, inferential value, and capacity to
substantiate effectiveness improves.
Even when intended uses and conditions of use are narrowly defined
and there is relevant scientific knowledge to inform qualified experts
about the chemical entity, the disease or condition to be treated, or
the structure or function to be affected, a single adequate and well-
controlled study frequently will not suffice to establish the
effectiveness of a new animal drug without the corroboration
(independent substantiation) provided by other adequate and well-
controlled studies. When considering whether to rely on a single
adequate and well-controlled study, it is critical that the possibility
of an incorrect outcome be considered and that all available data be
examined for their potential to either support or undercut reliance on
a single study. In those limited instances in which reliance is placed
on a single adequate and well-controlled study that has the
characteristics described in Sec. 514.111(a)(5)(ii) (proposed
Sec. 514.117 (62 FR 25153, May 8, 1997)), such a study will need to be
of sufficient quality, as well as persuasiveness in outcome, to enable
qualified experts to make valid inferences from study results to the
target animal population. The presence of the following characteristics
in a study can contribute to a conclusion by qualified experts that a
single adequate and well-controlled study provides substantial evidence
of effectiveness: The study is a multicenter study in which no single
study site provides an unusually large fraction of the target animals
and no single investigator or site is disproportionately responsible
for the effects seen; the study involves prospective randomized
stratifications or identified analytic subsets that each show a
significant effect; the study includes multiple endpoints involving
different events; and, the study provides highly reliable and
statistically strong evidence of effectiveness. The likelihood that
qualified experts can rely on a single adequate and well-controlled
study as establishing the effectiveness of a new animal drug increases
with the number of these and similar characteristics displayed in the
single study.
Inferential value of data (sometimes referred to as
generalizability) relates to the confidence with which the data
relating to effectiveness of a new animal drug for an intended use
under the conditions tested can be used to conclude that the new animal
drug will be effective in the target animal population for the intended
use and associated conditions of use suggested in the proposed labeling
(Sec. 514.4(b)(3)(i)(B)) . The inferential value of data may depend
upon, among other things, how closely the test animals approximate the
characteristics of the target animal population. Time, how recently a
particular set of data has been collected, may also affect its
inferential value. Animal research data has an effective life span
during which time-dependent factors such as genetics of the target
animal and the target organism, husbandry practices, and diets remain
sufficiently static to assure the continued relevance of the data.
Beyond this period, changes in target animal genetics, target organism
genetics, husbandry practices, and diets may affect the ability of the
new animal drug to achieve the effect demonstrated under prevailing
conditions at the time of testing. Time is particularly meaningful in
terms of the inferences that can be drawn from data relating to
therapeutic uses of antimicrobial animal drugs because of the
development of resistant microbes.
Substantial evidence must permit qualified experts to conclude that
a new animal drug will have the effect it purports or is represented to
have under the conditions of use suggested in the proposed labeling
(concluding a new animal drug is effective (Sec. 514.4(b)(3)(i)(C)).
Section 512 of the act requires that FDA issue an order refusing to
approve an NADA if there is a lack of substantial evidence that the new
animal drug will have the effect it purports or is represented to have
under the conditions of use suggested in the proposed labeling.
Similarly, the statute requires that FDA issue an order refusing to
approve an NADA if, based on a fair evaluation of all the material
facts, the proposed labeling is false or misleading in any particular,
including as it relates to the demonstrated effectiveness of the new
animal drug for its intended uses under associated conditions of use.
Thus, sponsors should remember that it may be necessary to provide, in
addition to or as part of substantial evidence, evidence that explicit
or implicit claims relating to effectiveness made on the label of a new
animal drug are neither false nor misleading.
3. Types of Studies (Sec. 514.4(b)(3)(ii))
Proposed Sec. 514.4(b)(3)(ii) specifies that the types of adequate
and well-controlled studies needed to provide substantial evidence may
include, but are not limited to, published studies, foreign studies,
studies using models, and studies conducted by or on behalf of the
sponsor. Isolated case reports, random experience, and reports lacking
the details which permit scientific evaluation will not be considered
as part of substantial evidence (Sec. 514.111; proposed Sec. 514.117
(62 FR 25153, May 8, 1997)), and will not contribute to the current
state of scientific knowledge that informs qualified experts.
The utility of published studies, foreign studies, and studies
using
[[Page 59834]]
models as adequate and well-controlled studies to support a finding of
effectiveness may vary. The use of published studies raises at least
two questions: (1) How reliable are the data? and, (2) do the data
represent a skewed subset of information?
Published literature, even in peer-reviewed journals, may not be
free from error, omission, misinterpretation, or even outright fraud.
Peer reviewers of articles submitted for publication in journals vary
in the relevant experience and expertise they may have to review
particular journal articles and, typically, only have access to a
limited data set and analyses. As noted by Dr. Richard Horton, editor
of The Lancet, an international biomedical journal, ``* * * the review
process will only rarely detect misconduct and it may well miss
critical flaws in a research article'' (Ref. 1). Dr. Horton further
noted that in instances where legitimate questions are raised about the
validity of research methods and data analyses, ``[i]t is possible that
the only way to settle the dispute is to provide access to raw data or
to invite the institution where the research was conducted to assist in
the ongoing investigations'' (Ref. 1). In many instances, published
literature is intended to advance science by stimulating further
analysis and interpretation. In that sense, some amount of error is not
necessarily bad; disputes over analyses and interpretation can drive
scientific research and progress (Ref. 1). However, if a sponsor of a
new animal drug uses a published study to provide evidence that a new
animal drug is effective, use of invalid research methods or invalid
data analyses in the study will make the study unacceptable.
FDA's ability to rely on a published study as an adequate and well-
controlled study that is part of substantial evidence is enhanced, and
in many cases is only possible, if FDA can obtain additional critical
study details. The level of scrutiny for such a published study should
not be less rigorous than that given to studies conducted by or on
behalf of the sponsor that are intended to be adequate and well-
controlled studies to support a determination of effectiveness.
Providing as much of the following types of information about a
study, in conjunction with the published report, can increase the
likelihood that the study can be relied upon as an adequate and well-
controlled study: A statement describing the extent, if any, to which
the study was funded or supported by the sponsor; the qualifications of
the expert who conducted the study; a copy of the protocol, as amended,
used for the study, of sufficient detail to permit the study to be
reconstructed or repeated; access to written documentation describing
the practices followed in the conduct of the study (including
identification of animals omitted from analysis, and an analysis of
results using all subjects with on-study data); the prospective
statistical analysis plan and any changes from the original plan that
occurred during or after the study; a full accounting of all
investigational animals; an adequate characterization of the new animal
drug used in the study; assay data for the new animal drug; and,
complete study records including pertinent baseline characteristics for
each animal or experimental unit of animals.
In addition to the public debate concerning the reliability of
peer-reviewed published data, there has been expressed in recent years
concern that published studies represent a skewed subset of all
existing information available on a particular subject. While it may
not be possible to determine the extent to which the published studies
represent a skewed subset of all existing information, the likelihood
of reliance on published literature is increased not only by full
knowledge about how the studies were conducted but by the availability
of a balanced discussion of the published studies listed in the
bibliography that both support and raise questions relating to the
safety and effectiveness of the new animal drug. The current
regulations already require a sponsor to provide as part of its NADA a
complete bibliography and a summary of each published study relevant to
the intended uses of the new animal drug for which approval is sought
(Sec. 514.1(b)(7)(iv)).
An adequate and well-controlled foreign study may also be relied
upon to support a finding by substantial evidence that a new animal
drug is effective. The utility of such studies depends upon whether the
potential differences such as animal breeds, genetic composition within
a breed, diseases, nutrition, and husbandry practices between the
foreign country and the United States are sufficiently addressed. There
will be instances in which such differences will scientifically limit
the applicability of results of foreign studies.
In some instances, model study designs may be appropriate for use
in proving the effectiveness of a new animal drug. In order for a model
study to be an adequate and well-controlled study that supports a
finding that a new animal drug is effective, the model must be
validated to establish an adequate relationship of parameters measured
and effects observed in the model with one or more significant effects
of treatment in the target animal population under actual conditions of
use. Proposed Sec. 514.4(b)(3)(ii) requires such validation. If the
correlation of parameters measured and effects observed in the model
with one or more significant effects of treatment has not been
established as part of general scientific knowledge, such correlation
must be established scientifically.
The number and types of new studies that need to be conducted by or
on behalf of a sponsor to demonstrate by substantial evidence the
effectiveness of a new animal drug for a particular intended use will
depend upon factors such as: the availability (either publicly or
through right of reference) of information about the drug or the active
ingredient, and, in some cases, the chemical class to which it belongs,
information derived from studies of other approved or unapproved uses
of the active ingredient or drug, and information derived from foreign
studies if applicable to the proposed use and the target animal
population in the United States; whether the nature of the new animal
drug or active ingredient, or the proposed claims, makes the new animal
drug conducive to in vitro testing or data extrapolation via
pharmacokinetic studies; the availability of published studies
involving the new animal drug (as discussed previously); and, concern
for animal welfare. The science and practice of drug research and
development have significantly evolved since the effectiveness
requirement for drugs was established in 1962, and this evolution has
implications for the number and type of data needed to demonstrate
effectiveness of a particular new animal drug. Today, for many disease
conditions, there is a greater understanding of pathogenesis, disease
stages, treatment modalities and their characteristics, and,
frequently, an increased general understanding regarding the activity
of a particular chemical entity or related chemical entities in humans
or other animals.
Thus, if there is a significant amount of existing relevant
scientific knowledge available to inform qualified experts about a
chemical entity, such as the effectiveness of a chemical entity in a
condition closely related to that for which the new animal drug is
intended, about the pathogenesis and stages of the disease or condition
to be treated, or the production function (e.g., weight gain or feed
efficiency) to be affected, by the chemical entity, fewer new studies
may need to be conducted to support FDA's determination of the
effectiveness of the
[[Page 59835]]
drug for its intended use. Conversely, the less information known about
the nature of the chemical entity or about the disease or condition to
be treated or the production effect to be achieved, the greater the
need for new studies to support a determination of the effectiveness of
the new animal drug. If new studies need to be conducted, existing
relevant scientific knowledge may, at least, be helpful in designing
studies which provide highly reliable and statistically strong evidence
of effectiveness.
B. Substantial Evidence for Combination New Animal Drugs
(Sec. 514.4(c))
Under the ADAA, a streamlined approval process was established for
certain combination new animal drugs. Section 512(d)(4) of the act
provides that, except in the case of a combination new animal drug that
is intended for use other than in animal feed or drinking water
(hereinafter referred to as ``dosage form combination new animal
drugs'') \3\ and contains a nontopical antibacterial ingredient or
animal drug, FDA will not refuse to approve an application for a dosage
form combination new animal drug that contains active ingredients or
animal drugs that have previously been separately approved on grounds
that there is a lack of evidence of effectiveness if the sponsor: (1)
Demonstrates by substantial evidence that each 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
effectiveness, and (2) demonstrates (a) 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 (b) if FDA has a scientific basis to believe the active
ingredients or animal drugs may be incompatible or have disparate
dosing regimens, that the active ingredients or animal drugs are
physically compatible and do not have disparate dosing regimens
(section 512(d)(4)(C) of the act). FDA will not refuse to approve an
application for a combination new animal drug that is intended for use
in animal feed or drinking water and contains active ingredients or
animal drugs that have previously been separately approved on grounds
that there is a lack of evidence of effectiveness if the sponsor: (1)
Demonstrates by substantial evidence that each active ingredient or
animal drug intended only for the same use as another active ingredient
or animal drug in the combination, and, if there is more than one than
one antibacterial ingredient or animal drug, each antibacterial
ingredient or animal drug, makes a contribution to labeled
effectiveness, and (2) demonstrates (a) that each active ingredient or
animal drug that is intended for at least one use that is different
from all other active ingredients or animal drugs in the combination
provides appropriate concurrent use for the intended target animal
population, and (b) if FDA has a scientific basis to believe the active
ingredients or animal drugs intended for use in drinking water may be
incompatible, that the active ingredients or animal drugs are
physically compatible (section 512(d)(4)(D) of the act). For all other
combination new animal drugs, FDA will not refuse to approve an
application on the grounds that there is a lack of evidence of
effectiveness if the sponsor demonstrates by substantial evidence that
the combination new animal drug will have the effect it purports or is
represented to have under the conditions of use suggested in the
proposed labeling for the combination new animal drug and that each
active ingredient or animal drug contributes to the effectiveness of
the combination new animal drug.
---------------------------------------------------------------------------
\3\ Use of the phrase ``dosage form combination new animal
drugs'' as used in this preamble is a shorthand reference to
combination new animal drugs ``intended for use other than in animal
feed or drinking water,'' the purpose of which is to make the
complex preamble discussion relating to combination new animal drugs
more readable. The term ``dosage form,'' outside of the discussion
in this preamble relating to the combination new animal drug
provisions of the act, includes and will continue to include new
animal drugs intended for use in drinking water.
---------------------------------------------------------------------------
To implement these statutory provisions, proposed
Sec. 514.4(c)(1)(i) defines a combination new animal drug as 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. The
substantial evidence necessary to support a conclusion by qualified
experts that a combination new animal drug is effective will vary
depending upon the active ingredients or animal drugs used in the
combination.
Proposed Sec. 514.4(c)(2) provides that for combination new animal
drugs that contain 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
(hereinafter ``previously been separately approved''), except in the
case of a combination new animal drug that is intended for use other
than in animal feed or drinking water that contains a nontopical
antibacterial ingredient or animal drug, a sponsor must demonstrate by
substantial evidence, as defined in section 512(d)(3) of the act and
this proposed regulation, 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. For combination new animal drugs that
contain active ingredients or animal drugs that have previously been
separately approved for use in animal feed or drinking water and
contain more than one antibacterial ingredient or animal drug, the
sponsor must also demonstrate by substantial evidence, as defined in
section 512(d)(3) of the act and this proposed regulation, that each
antibacterial makes a contribution to labeled effectiveness.
Proposed Sec. 514.4(c)(3) provides that for all other combination
new animal drugs ( i.e., those that contain active ingredients or
animal drugs that have not previously been separately approved and
those that are dosage form combination new animal drugs that contain an
active ingredient or animal drug that is a nontopical antibacterial),
the sponsor must demonstrate by substantial evidence, as defined in
section 512(d)(3) of the act and this proposed regulation, that: (1)
The combination new animal drug will have the effect it purports or is
represented to have under the conditions of use suggested in the
proposed labeling, and (2) each active ingredient or animal drug
contributes to the effectiveness of the combination new animal drug.
On occasion, FDA may have a substantiated scientific basis for
believing that the use in combination of active ingredients or animal
drugs that have previously been separately approved will result in a
decrease in the effectiveness of one or more of the active ingredients
or animal drugs. Although section 512(d)(4) of the act generally
provides for a modified approval process for combination new animal
drugs containing active ingredients or animal drugs that have
previously been separately approved, FDA will, to the extent necessary,
require additional testing to characterize the effectiveness of such a
combination new animal drug to assure that the labeling will not be
false or misleading in any particular, consistent with section
512(d)(1)(H) of the act.
For purposes of determining the substantial evidence necessary to
demonstrate the effectiveness of a combination of animal drugs that
have
[[Page 59836]]
previously been separately approved, each animal drug brings with it to
the combination each intended use for which it was previously
separately approved under the conditions of use proposed for the
combination new animal drug. If an active ingredient or animal drug has
previously been separately approved as a prescription animal drug or a
veterinary feed directive drug for any of the intended uses and
conditions of use suggested in the proposed labeling for the
combination new animal drug, the combination new animal drug, if
approved, would usually need to be approved as a prescription animal
drug or veterinary feed directive drug, respectively.
1. Antibacterial Active Ingredient or Animal Drug
The approval process provided by section 512(d)(4) of the act does
not apply to dosage form combination new animal drugs if any of the
active ingredients or animal drugs is a nontopical antibacterial. And,
for combination new animal drugs intended for use in animal feed and
drinking water that contain more than one antibacterial and qualify for
approval under the process provided by section 512(d)(4), a sponsor
must demonstrate by substantial evidence that each antibacterial
ingredient or animal drug contributes to the effectiveness of the
combination new animal drug. The act, as amended by the ADAA, treats
antibacterial ingredients and animal drugs differently from other
active ingredients and animal drugs because increasingly there are
concerns that overuse or improper use of antibacterials may contribute
unnecessarily to the development of antibacterial resistance.
Proposed Sec. 514.4(c)(1)(ii) defines an ``antibacterial'' with
respect to a particular target animal species as an active ingredient
or animal drug: (1) That is approved for use in that species for the
diagnosis, cure, mitigation, treatment, or prevention of bacterial
disease; or (2) that is approved in that species for any other use that
is attributable to its antibacterial properties.
2. Appropriate Concurrent Use and Compatibility
Section 512(d)(4)(C) and (d)(4)(D) of the act requires that in
certain cases appropriate concurrent use and compatibility must be
demonstrated. The demonstration need not be by substantial evidence but
sponsors must provide a scientifically sound basis for qualified
experts to reach these conclusions. Proposed Sec. 514.4(c)(2)(iii) sets
out the requirement for sponsors to establish appropriate concurrent
use for the target species in cases in which each active ingredient or
animal drug is intended for at least one use that is different from all
the other active ingredients or animal drugs in the combination. To
determine whether a combination new animal drug provides ``appropriate
concurrent use'' the agency will consider factors such as whether the
conditions to be treated by the combination are likely to occur
simultaneously with sufficient frequency in the intended target animal
population.
Proposed Sec. 514.4(c)(2)(iv) and (c)(2)(v) sets out the
requirements in section 512(d)(4)(C)(iii) and (d)(4)(D)(iv) of the act
regarding compatibility. These requirements apply where, based on
scientific information, FDA has reason to believe that for dosage form
combination new animal drugs the active ingredients or animal drugs may
be physically incompatible or have disparate dosing regimens or that
for active ingredients or animal drugs intended for use in drinking
water the active ingredients or animal drugs may be physically
incompatible. The legislative history of ADAA describes the purpose of
these provisions as ``authoriz[ing] FDA to deny approval of a
combination animal drug if the physical compatibility or compatibility
of the dosing regimens may affect the effectiveness of the combination
animal drug and such compatibility is not demonstrated'' (H. Rept. 104-
823 at 14 (1996)).
Scientific information exists that gives FDA reason to believe that
dosage form combinations and combinations intended for use in drinking
water may be physically incompatible and/or have disparate dosing
regimens. With the enactment of the Generic Animal Drug Patent Term
Restoration Act of 1988 (GADPTRA), it was well-recognized that, based
on scientific information, the bioavailability of active ingredients
may be affected by changes relating to the formulation or manufacture
of a generic new animal drug and, therefore, the statute, rather than
assuming bioequivalence based on the use of the same active ingredient,
requires a demonstration of bioequivalence. Similarly, the
bioavailability of an active ingredient or animal drug as part of a
combination new animal drug may be affected by changes relating to the
formulation or manufacture of the active ingredient or animal drug for
use in the combination or to the formulation and manufacture of the
combination new animal drug. Thus, FDA has scientific information that
gives it reason to generally believe that active ingredients or animal
drugs intended for use in a dosage form combination new animal drug may
not be physically compatible and may have disparate dosing regimens or
that for active ingredients or animal drugs intended for use in
drinking water the active ingredients or animal drugs may not be
physically compatible. Therefore, proposed Sec. 514.4(c)(2)(iv) and
(c)(2)(v) requires the sponsor to demonstrate the comparable
bioavailability of the active ingredients or animal drugs in
combination relative to the active ingredients or animal drugs singly.
However, as with FDA's implementation of GADPTRA, certain classes of
products are recognized to be of less concern with respect to potential
differences in bioavailability, e.g., true solutions, inhalant
anesthetics and some topicals. In such cases, some or all of the
demonstration of comparable in vivo bioavailability may be waived. The
proposed rule provides for such waivers where appropriate.
C. Conclusion
The basic premise underlying the modified requirement for
demonstrating the effectiveness of particular combination new animal
drugs is that there exists knowledge about the individual active
ingredients or animal drugs contained in that combination. This
knowledge exists in the approved applications in the form of
substantial evidence of effectiveness of the individual active
ingredients or animal drugs. The substantial evidence supporting the
effectiveness of an approved active ingredient or animal drug generally
is not publicly available but is usually owned by the sponsor of the
approved application for the active ingredient or animal drug. Thus,
the sponsor submitting an application for a combination new animal drug
must either own the underlying applications or obtain a right of
reference from the owners of such applications if FDA is to rely upon
the substantial evidence contained in those applications.
Sponsors may submit supplemental NADA's and receive supplemental
approval of new animal drugs for new intended uses. The approval of a
new intended use for a single active ingredient new animal drug that
has already been approved for use in a combination new animal drug may
necessitate the submission of a new or supplemental application for the
combination new animal drug. Such new or supplemental NADA for the
combination new animal drug must contain substantial evidence of
effectiveness in accordance with this
[[Page 59837]]
proposed regulation. Sponsors cannot circumvent approval requirements
relating to the effectiveness of a combination new animal drug by
adding or deleting intended uses to or from any of the new animal drugs
approved for use in the combination subsequent to the approval of the
combination new animal drug. Section 512(e)(1)(F) of the act would
require withdrawal of an existing approval for the combination new
animal drug unless the sponsor submits and FDA approves a supplement to
the combination NADA that provides adequate information supporting any
changes affecting its safety or effectiveness beyond the variations
provided for in the approved application.
FDA recognizes that the requirements for obtaining approval of
combination new animal drugs are complex. Following the Good Guidance
Practices established in the Federal Register of February 27, 1997 (62
FR 869691), FDA's Center for Veterinary Medicine (CVM) intends to
develop, for public comment, one or more draft guidance documents
representing the agency's current thinking on what information should
be included in NADA's to support combination new animal drugs.
In all instances, FDA encourages sponsors to meet with CVM to
discuss the development of evidence of safety and effectiveness to
support approval of an NADA for single ingredient or combination new
animal drugs. In considering the number and types of the adequate and
well-controlled studies needed to demonstrate the effectiveness of a
new animal drug, the sponsor may also want to discuss with FDA any
possible later expansion or extension of the claims for the new animal
drug so that the studies conducted in support of the initially proposed
intended uses will, to the extent possible, facilitate later approvals.
FDA has chosen to define substantial evidence, consistent with the
spirit of the ADAA, in a manner that permits the maximum flexibility in
determining what studies are necessary to demonstrate by substantial
evidence that a new animal drug is effective. While specificity brings
with it consistency and predictability, the spirit of the ADAA is
flexibility, efficiency, and greater animal drug availability. FDA
believes that consistency and predictability can be maintained by the
application of sound science.
IV. Conforming Changes
This proposed rule would make necessary conforming changes to
Secs. 514.1(b)(8) and 514.111 of the current regulations.
V. Environmental Impact
FDA has carefully considered the potential environmental impacts of
this proposed rule. The agency has determined under 21 CFR 25.30(h)
that this action is of a type that does not individually or
cumulatively have a significant effect on the human environment.
Therefore, neither an environmental assessment nor an environmental
impact statement is required.
VI. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and under the Regulatory Flexibility Act (5 U.S.C. 601-
612). Executive Order 12866 directs agencies to assess all costs and
benefits of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits
(including potential economic, environmental, public health and safety,
and other advantages; distributive impacts; and equity). FDA believes
that this proposed rule is consistent with the regulatory philosophy
and principles identified in the Executive Order. The proposed rule is
not a significant regulatory action as defined by the Executive Order.
FDA, as directed by the ADAA, is further defining ``substantial
evidence,'' the standard by which a new animal drug is determined to be
effective for its intended uses under the conditions of use represented
in its proposed labeling. The purpose of the proposed rule further
defining substantial evidence is to encourage the submission of NADA's,
the submission of supplemental NADA's, and the use of dose range
labeling. Accordingly, the proposed definition of substantial evidence,
while not changing the standard of effectiveness, recognizes that
``substantial evidence,'' as redefined under the ADAA, gives FDA
greater flexibility to determine the number and types of studies that
FDA would find demonstrate the effectiveness of any particular new
animal drug. For example, under the new statutory definition, sponsor
companies are no longer required, in every instance, to submit a field
study to establish the effectiveness of a new animal drug under
investigation. Because the new definition gives FDA greater flexibility
to work with sponsors to tailor the evidence needed to demonstrate
effectiveness, this proposed rule is not expected to impose any new
marginal costs on the industry. Furthermore, because sponsors will have
more options under this revised definition to design and conduct
studies to demonstrate effectiveness, and because sponsors can be
expected to choose the most efficient and cost effective option, the
net effect of this provision is expected to be a small benefit to
sponsors.
Further, the revised definition allows for the submission of as few
as one adequate and well-controlled study, whereas the previous
statutory language required at least two studies. While FDA expects
that the instances in which a single study will be sufficient to
demonstrate effectiveness will be limited, those sponsors who are able
to demonstrate effectiveness by a single adequate and well-controlled
study are likely to realize lower drug development costs.
The proposed rule also provides for the submission and review of
NADA's for new animal drugs intended for use over a dose range. The
ADAA eliminated the statutory requirement to limit the use of a new
animal drug to an amount no greater than that reasonably required to
accomplish the physical or other technical effect of the drug for its
intended use; the act, as amended by the ADAA, permits the use of a new
animal drug at any level that is safe for the target animal, effective,
and will not result in a residue of such drug in excess of a tolerance
found to be safe. Because dose optimization is no longer required,
sponsors are no longer required to conduct adequate and well-controlled
in vivo dose titration studies, but need only conduct such studies as
may be needed to characterize the dose or dose range so that FDA can
make a risk-benefit assessment and assure that the labeling for a new
animal drug is not false or misleading. Because there will be greater
flexibility in determining the studies needed to characterize the dose-
response relationship, sponsors are expected to realize a small cost
savings.
Finally, the proposed rule further defines substantial evidence as
it relates to combination new animal drugs. For certain combination new
animal drugs that contain active ingredients or animal drugs that have
previously been separately approved, sponsors will not be required to
conduct additional studies to demonstrate that the combination new
animal drug is effective. This change is expected to provide a cost
savings to the sponsors of NADA's that meet the criteria for the
streamlined approval process.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities unless the rule is not expected to have a significant
economic impact
[[Page 59838]]
on a substantial number of small entities. As this proposed regulation
will not impose significant new costs on any firms, under the
Regulatory Flexibility Act (5 U.S.C. 605(b)), the agency certifies that
the proposed rule will not have a significant impact on a substantial
number of small entities. Therefore, under the Regulatory Flexibility
Act, no further analysis is required.
VII. Unfunded Mandates Act of 1995
The Unfunded Mandates Act of 1995 (2 U.S.C. 1532) requires that
agencies prepare an assessment of the anticipated costs and benefits
before proposing any rule that may result in annual expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation). This proposed rule does not impose any mandates on State,
local, or tribal governments, or the private sector that will result in
an annual expenditure of $100,000,000 or more.
VIII. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (PRA of 1995) (44 U.S.C.
3501-3520). A description of the information collection provisions and
an estimate of the annual collection of information burden follow.
FDA invites comments on: (1) Whether the proposed collection of
information is necessary for the proper performance of FDA's functions,
including whether the information will have practical utility; (2) the
accuracy of the agency's estimate of the burden of the proposed
collection of information including the validity of the methodology and
assumptions used; (3) ways to enhance the quality, utility, and clarity
of the information to be collected; and (4) ways to minimize the burden
of the collection of information on respondents, including the validity
of the methodology and assumptions used.
Title: Substantial Evidence of Effectiveness of New Animal Drugs.
Description: As directed by the ADAA, FDA is publishing a proposed
regulation to further define substantial evidence in a manner that
encourages the submission of NADA's and supplemental NADA's and
encourages dose range labeling. The proposed regulation implements the
definition of ``substantial evidence'' in 21 U.S.C. 360b(d)(3) as
amended by the ADAA. Substantial evidence is the standard that a
sponsor must meet to demonstrate the effectiveness of a new animal drug
for its intended uses under the conditions of use suggested in its
proposed labeling. The proposed regulation, Sec. 514.4(a), gives FDA
greater flexibility to make case-specific scientific determinations
regarding the number and types of adequate and well-controlled studies
that will provide, in an efficient manner, substantial evidence that a
new animal drug is effective. The proposed regulation will reduce the
number of adequate and well-controlled studies necessary to demonstrate
the effectiveness of certain combination new animal drugs, will
eliminate the need for an adequate and well-controlled dose titration
study, and may, in limited instances, reduce or eliminate the number of
adequate and well-controlled field investigations necessary to
demonstrate by substantial evidence the effectiveness of a new animal
drug.
Table 1 below represents the estimated burden of meeting the new
substantial evidence standard. The numbers in the chart are based on
recent consultation with several of the major research and development
firms that conduct the majority of studies submitted to establish
substantial evidence of effectiveness of new animal drugs. Because of
the more flexible requirements for demonstrating substantial evidence
of effectiveness, FDA estimates that the proposed regulation would
reduce by approximately 10 percent the total annual burden associated
with demonstrating the effectiveness of a new animal drug as part of an
NADA or supplemental NADA submission.
Description of Respondents: Persons and businesses, including small
businesses.
Table 1.--Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
514.4(a) 190 4.5 860 632.6 544,036
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection.
In compliance with section 3507(d) of the PRA of 1995, the agency
has submitted the information collection provisions of this proposed
rule to OMB for review. Interested persons are requested to send
comments regarding information collection by December 5, 1997 to the
Office of Information and Regulatory Affairs, Office of Management and
Budget, New Executive Office Bldg., 725 17th St. NW., rm. 10235,
Washington, DC 20503, Attn.: Desk Officer for FDA.
IX. References
The following information has been placed on display in the Dockets
Management Branch and may be seen by interested persons between 9 a.m.
and 4 p.m., Monday through Friday.
1. Horton, Richard, ``Revising the Research Record,'' The
Lancet, vol. 346, p. 1610-11, 1995.
List of Subjects in 21 CFR part 514
Administrative practice and procedure, Animal drugs, Confidential
business information, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
514 is amended as follows:
PART 514--NEW ANIMAL DRUG APPLICATIONS
1. The authority citation for 21 CFR part 514 continues to read as
follows:
Authority: 21 U.S.C. 351, 352, 360b, 371, 379e, 381.
2. Section 514.1 is amended by revising paragraphs (b)(8)(ii) and
(b)(8)(v) to read as follows:
Sec. 514.1 Applications.
* * * * *
(b) * * *
(8) * * *
(ii) An application may be refused unless it includes substantial
evidence
[[Page 59839]]
of the effectiveness of the new animal drug as defined in Sec. 514.4.
* * * * *
(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.
* * * * *
3. Section 514.4 is added to subpart A to read as follows:
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. Studies that are intended to provide 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. Studies that are intended
to provide substantial evidence of the 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. 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 at least one intended use at the
lower dose limit prescribed in the proposed labeling and will be
effective for each intended use at the dose suggested in the proposed
labeling for that intended use. Substantial evidence to support a dose
range for a new animal drug intended to affect the structure or
function of the body of an animal for the purpose of enhancing
production 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 each
intended use at all the doses within the range prescribed for the
intended use. 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.
(3) Studies--(i) Number. Substantial evidence of the effectiveness
of a new animal drug for an 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--(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) For purposes of this section, antibacterial with respect to a
particular target animal species means an active ingredient or animal
drug:
(A) That is approved in that species for the diagnosis, cure,
mitigation, treatment, or prevention of bacterial disease; or
(B) That is approved for use in that species for any other use that
is attributable to its antibacterial properties.
(2) Combinations with active ingredients or animal drugs that have
previously been separately approved. Except in the case of a
combination new animal drug intended for use other than in animal feed
or drinking water that contains a nontopical antibacterial ingredient
or animal drug, for combination new animal drugs that contain 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 incorporate into the
application for the combination new animal drug substantial evidence of
the effectiveness of each active ingredient or animal drug previously
approved and shall demonstrate:
(i) 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;
(ii) For such combination new animal drugs that are intended for
use in animal feed or drinking water and 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;
(iii) 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;
(iv) Unless waived in specific cases, that the active ingredients
or animal drugs intended for use other than in animal feed or drinking
water are physically compatible and do not have disparate dosing
regimens by demonstrating bioavailability of the active ingredients or
animal drugs in combination relative to the bioavailability of active
ingredients or animal drugs singly; and,
(v) Unless waived in specific cases, that the active ingredients or
animal drugs intended for use in drinking water are physically
compatible by demonstrating bioavailability of the active ingredients
or animal drugs in combination relative to the bioavailability of
active ingredients or animal drugs singly;
(3) Other combination new animal drugs. For all other combination
new
[[Page 59840]]
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.
4. Section 514.111 is amended by revising paragraph (a)(5) to read
as follows:
Sec. 514.111 Refusal to approve an application.
(a) * * *
(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.
* * * * *
Dated: October 30, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-29275 Filed 10-31-97; 2:48 pm]
BILLING CODE 4160-01-F