[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