[Federal Register Volume 64, Number 144 (Wednesday, July 28, 1999)]
[Rules and Regulations]
[Pages 40746-40757]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-19193]


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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: Final rule.

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SUMMARY: The Food and Drug Administration (FDA), as directed by the 
Animal Drug Availability Act of 1996 (ADAA), is amending its new animal 
drug regulations to further define the term ``substantial evidence.'' 
The purpose of this final rule is to encourage the submission of new 
animal drug applications (NADA's) and supplemental NADA's for single

[[Page 40747]]

ingredient and combination new animal drugs. The final rule also 
encourages dose range labeling.

EFFECTIVE DATE: August 27, 1999.

FOR FURTHER INFORMATION CONTACT: Herman M. Schoenemann, Center for 
Veterinary Medicine (HFV-126), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-827-0220.

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 parts 
of the definition of ``substantial evidence.'' Section 2(e) of the ADAA 
directs FDA to issue proposed regulations and final regulations to 
further define ``substantial evidence'' and to encourage dose range 
labeling. In the Federal Register of November 5, 1997 (62 FR 59830), 
FDA proposed to amend its regulations in part 514 (21 CFR part 514) to 
further define ``substantial evidence'' and to encourage dose range 
labeling. FDA provided 90 days for public comment on the proposed rule.
    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 for its intended uses under the conditions of use 
prescribed, recommended, or suggested in the proposed labeling. The 
changes made to the definition of ``substantial evidence'' by the ADAA 
and by the further definition of that term in this final 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. Comments on the Proposed Rule

    FDA received nine letters, primarily from trade associations and 
manufacturers, commenting on the proposed definition of ``substantial 
evidence.'' One comment stated a belief that the proposed definition of 
substantial evidence, particularly the provisions that allow FDA to 
exercise more flexibility in determining the most efficient and cost 
effective number and types of studies required and the provision that 
encourages dose range labeling, will benefit sponsors by reducing some 
costs to gain approvals of animal drugs, for both major and minor 
species. In general, however, the comments objected to the tone of the 
preamble to the proposed regulation. The comments raised specific 
objections to FDA's statement that a single adequate and well-
controlled study frequently will not suffice to establish the 
effectiveness of a new animal drug, the definition of an antibacterial, 
and the perceived prejudice expressed by FDA against the use of 
published and foreign studies.

A. Substantial Evidence (Sec. 514.4)

    1. Several comments objected to the tone of the preamble to the 
proposed rule. One comment noted that while the proposed language of 
the regulation seemingly is consistent with the flexibility envisioned 
by the ADAA, the preamble provides content and meaning, which appear to 
be inconsistent with the spirit of the ADAA and its legislative 
history. Specifically, the comment stated that the real focus of FDA's 
oversight should be to ensure that new animal drugs are safe and the 
effectiveness study(ies) is of sufficient quality to demonstrate 
substantial evidence of effectiveness. The comment alleged that the 
preamble departs from the notion that flexibility was intended to be 
utilized in a way that would minimize the burden on sponsors. The 
comment suggested the elimination of Sec. 514.4(b)(3)(i) relating to 
the number of studies and the addition of the following sentence to 
proposed Sec. 514.4(b)(3)(ii) relating to types of studies: ``Every 
effort will be made to require the least burdensome type of study.''
    The definition of substantial evidence as revised by Congress 
continues to require a sponsor to submit substantial evidence of 
effectiveness, such that qualified experts can fairly and reasonably 
conclude that a new animal drug will have the effect it purports to 
have under the conditions of use prescribed, recommended, or suggested 
(hereinafter suggested) in the proposed labeling. As a comment notes, 
the proposed language of the regulation is consistent with the ADAA. 
The proposed regulation gives FDA the 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. It is FDA's 
intent to work with sponsors to identify the least burdensome 
appropriate means for demonstrating that a new animal drug is safe and 
effective. The number and types of adequate and well-controlled studies 
needed to demonstrate by substantial evidence that a new animal drug is 
effective will need to be sufficient to lead qualified experts to 
conclude that the new animal drug is effective. Thus, as proposed 
Sec. 514.4(a) already states, ``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.'' Addition of the language suggested by the 
comment is not necessary.
    In the preamble to the proposed rule, the discussion regarding the 
number of studies focused on two sound scientific principles: 
Independent substantiation and inferential value. The goal of 
independent substantiation is to provide adequate assurance that an 
experimental finding is not the result of unanticipated, undetected, 
systematic biases or chance. Inferential value of data 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. FDA anticipates and welcomes 
further discussion of implementation of the regulation. The principles 
of independent substantiation and inferential value form a sound 
scientific basis upon which these discussions can proceed.

B. Intended Uses and Conditions of Use (Sec. 514.4(b)(2))

    2. One comment suggested that FDA introduced in its discussion of 
dose range labeling the concept of risk-assessment. The comment 
criticized FDA's failure to further explain that term and suggests that 
FDA is making a safety assessment within the context of the substantial 
evidence determination. The comment further noted that with the 
elimination of the requirement for dose optimization it is unclear the 
extent to which FDA is requesting dose response information.
    Proposed Sec. 514.4(b)(2) requires that a sponsor demonstrate that 
a new animal drug is effective for each proposed intended use and 
associated conditions of use, including the dose or dose range. Before 
enactment of the ADAA, FDA could not approve a new animal drug for use 
at a particular dose or over a dose range that exceeded the dose 
reasonably required to accomplish the physical or other technical 
effect for

[[Page 40748]]

which the new animal drug was intended, the optimum dose. This required 
that sponsors conduct adequate and well-controlled dose titration 
studies to characterize the critical aspects of the dose-response 
relationship. As part of the approval process, FDA used this 
information regarding effectiveness and weighed it against safety 
information to make a risk-benefit assessment of a new animal drug. 
Thus, the concept of a risk-benefit assessment is not new.
    As explained in the preamble to the proposed rule, a risk-benefit 
assessment is a determination whether the effectiveness of a new animal 
drug outweighs the risks to the target animal at the dose or over the 
dose range prescribed in the proposed labeling. Thus, it is more 
accurately termed a risk-effect assessment. The application of a risk-
effect assessment has always been a part of FDA's decision whether to 
approve a new animal drug. The risk-effect assessment is not made 
within the context of the substantial evidence determination but is 
made within the context of the approval decision.
    While the ADAA modified the definition of substantial evidence and 
eliminated the requirement for dose titration, the other provisions of 
the act relating to approval of a new animal drug continue to be 
applicable. The act provides that FDA will refuse to approve an NADA or 
a supplemental NADA if, based on a fair evaluation of all material 
facts, the labeling for the new animal drug is false or misleading. 
Because before enactment of the ADAA, FDA could only approve a new 
animal drug at or below the optimum dose or over a dose range, the 
upper limit of which is at or below the optimum dose, there came to be 
the expectation that the dose suggested on a label is the optimum dose 
or that there is increasing effectiveness over the dose range 
suggested. Even though the requirement for dose optimization has been 
eliminated, there is still a need to sufficiently characterize the 
dose-response relationship so that the labeling is not false or 
misleading.
    Sponsors should justify the dosage (i.e., dose or dose range, 
dosing frequency, and the dosing duration) and characterize for each 
intended use and associated conditions of use the critical aspects of 
the dose-response relationship relevant to the dose or dose range 
selected. While the sponsor must demonstrate by substantial evidence 
that the new animal drug is effective at the dose or over the dose 
range selected, the justification of the dosage and characterization of 
the dose-response relationship need not be demonstrated by substantial 
evidence. Nonetheless, a sponsor may in the interest of minimizing the 
number of studies conduct a single adequate and well-controlled study 
that both demonstrates that a new animal drug is effective at the dose 
or over the dose range recommended in the label and characterizes the 
dose-response relationship under the proposed conditions of use.
    3. One comment expressed concern that FDA may use its general 
authority to prevent false and misleading labeling as a pretext for 
requiring more studies even as the definition of substantial evidence 
has become more flexible.
    It is not FDA's intent to use the false and misleading provision to 
circumvent the spirit of the ADAA and require more than the number and 
types of studies needed by FDA to fairly and reasonably conclude that a 
new animal drug is effective. Nonetheless, one of the criteria for 
approval is that FDA find, based on a fair evaluation of all material 
facts, that the labeling for the new animal drug is not false or 
misleading (21 U.S.C. 512(d)(1)(H)). Therefore, as discussed in comment 
2 of section II.B of this document, some studies may be necessary to 
justify the dosage and characterize the dose-response relationship so 
that a new animal drug can be labeled properly to inform the user about 
the effectiveness of the new animal drug at the suggested dose or over 
the suggested dose range. There may be other instances in which no 
additional studies are needed but FDA or the sponsor has knowledge 
about the effectiveness of the new animal drug that must be addressed 
in the labeling for the drug so that it is not false and misleading. 
For example, FDA or the sponsor may be aware that even though a 
combination new animal drug is approvable under 21 U.S.C. 512(d)(4), 
one active ingredient or animal drug in the combination may interfere 
with the effectiveness of another active ingredient or drug in the 
combination. In such an instance, the labeling for the combination new 
animal drug should indicate that the active ingredient or drug may be 
less effective for its intended use when used in combination than if it 
were applied or administered separately.
    4. One comment suggested that Sec. 514.4(b) (characteristics of 
substantial evidence) be revised. The comment suggested that the first 
word, ``Studies,'' in Sec. 514.4(b)(1) and (b)(2) be changed to ``A 
study or studies.'' The comment also suggested that the sentence, 
``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.'' 
be changed to read as follows: ``Sponsors should, at their discretion 
and 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.''
    Because substantial evidence can consist of one or more adequate 
and well-controlled studies, Sec. 514.4(b)(1) has been changed in this 
final rule to read ``Any study that is intended to be part of 
substantial evidence of the effectiveness * * *.'' Upon further 
consideration, FDA also has revised Sec. 514.4(b)(2) to read as 
follows: ``Substantial evidence of effectiveness of a new animal drug 
shall demonstrate that the new animal drug is effective for each 
intended use and associated conditions of use for, and under, which 
approval is sought.'' This revision clarifies the point that proposed 
Sec. 514.4(b)(2) was intended to convey, whether one study or multiple 
studies are submitted as substantial evidence of effectiveness, FDA 
must be able to determine by substantial evidence that the new animal 
drug is effective for each of its intended uses and conditions of use.
    FDA has not changed Sec. 514.4(b)(2)(i) to add ``at [the sponsor's] 
discretion and.'' Section 514.4(b)(2)(i) already states that dose range 
labeling should be utilized to the ``extent possible.'' Dose range 
labeling always is at the discretion of the sponsor. Approval of new 
animal drugs for use over a dose range, however, gives the users 
greater flexibility and, therefore, increases the utility of new animal 
drugs. Thus, in the spirit of the ADAA and as directed by section 
2(e)(2)(C) of the ADAA, this final regulation implies sponsor 
discretion as well as encourages the use of dose range labeling.
    FDA has revised proposed Sec. 514.4(b)(2)(i) to clarify that this 
section states the requirements that generally apply to demonstrating 
the effectiveness of a new animal drug over a dose range and to address 
dose range labeling by specific intended use to make it consistent with 
the other provisions of the regulation. Generally, substantial evidence 
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 that intended use at the lowest dose 
of the dose range suggested in the proposed labeling for that

[[Page 40749]]

intended use. In many instances, there is a well-established scientific 
basis on which experts can conclude that effectiveness of a new animal 
drug, particularly those intended for use in the diagnosis, cure, 
mitigation, treatment or prevention of disease caused by bacteria or 
other pathogenic organisms, will not decrease as the dose increases. In 
such instances, qualified experts can fairly and reasonably conclude 
that if a new animal drug is effective for an intended use at the 
lowest dose in the suggested dose range, the new animal drug will be 
effective over the entire suggested dose range for the intended use, 
the upper limit of which will generally be established based upon 
target animal safety, human food safety, or practicality. For new 
animal drugs intended to affect the structure or function of the body 
of an animal, scientific evidence does not generally exist to permit 
experts to conclude that the effectiveness of such a new animal drug 
will not decrease as the dose increases. In this case, substantial 
evidence to support the dose range for the intended use 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 such intended use at all the doses 
within the dose range suggested on the proposed labeling. Similarly, 
for certain new animal drugs intended for use in the diagnosis, cure, 
mitigation, treatment, or prevention of disease other than that caused 
by bacteria or other pathogenic organisms, substantial evidence may 
need to 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 such intended 
use at all the doses within the dose range suggested on the proposed 
labeling. FDA intends to issue further guidance regarding the 
substantial evidence needed to demonstrate the effectiveness of new 
animal drugs over dose ranges.

C. Number of Studies (Sec. 514.4(b)(3)(i))

    5. One comment suggested that Sec. 514.4(b)(3)(i) (number of 
studies) be removed. No basis for the proposal to remove this section 
was provided.
    Section 514.4(b)(3)(i) provides objective criteria for determining 
how many adequate and well-controlled studies are needed to demonstrate 
by substantial evidence that a new animal drug is effective for its 
intended uses under the conditions of use suggested in the proposed 
labeling. FDA believes these scientifically-based criteria provide 
sponsors considerable flexibility to work with FDA to design an 
approvable application. Therefore, FDA is not removing 
Sec. 514.4(b)(3)(i). FDA is, however, changing ``an intended use'' to 
``each intended use'' to make it clear that a sponsor must demonstrate 
that a new animal drug is effective for each proposed intended use and 
associated conditions of use.
    6. Several comments objected to language in the preamble to the 
proposed rule that indicates that FDA believes that there will be 
limited instances in which it can rely on a single adequate and well-
controlled study to determine the effectiveness of a new animal drug. 
Comments interpreted this language to mean that a drug sponsor's burden 
with respect to new animal drug development will not be lessened at all 
by the regulations implementing the ADAA and, therefore, believe such 
language is contrary to the spirit of the ADAA. The comments also 
referred to the discussion in the preamble that indicates that FDA is 
more likely to rely on a single adequate and well-controlled study if 
it is a multicenter study. Comments questioned the meaning of the term 
multicenter study. One comment urged FDA to retract the language in the 
preamble stating where only one study is to be accepted as substantial 
evidence of effectiveness, it would generally need to be a multicenter 
study. The comment also urged FDA to provide in the final rule and 
other appropriate guidance documents a detailed explanation of the 
underlying principles that should guide the design of a study.
    When Congress made changes to the definition of substantial 
evidence under the ADAA, Congress did not change the standard that 
evidence must meet to constitute substantial evidence. The definition 
of substantial evidence, both before and after the ADAA, requires that 
the evidence provided must be such that qualified experts can fairly 
and reasonably conclude that the new animal drug would be effective for 
the intended uses and conditions of use suggested in the proposed 
labeling. Thus as amended by the ADAA, the act permits FDA to rely on a 
single adequate and well-controlled study if FDA can fairly and 
reasonably conclude from such a study that the new animal drug is 
effective. As discussed in the preamble to the proposed regulation, any 
study(ies) that supports a determination that a new animal drug is 
effective must provide independent substantiation that experimental 
findings of effectiveness are not the result of: unanticipated, 
undetected, or systematic biases or chance. As the preamble notes, 
independent substantiation can be achieved by conducting multiple 
adequate and well-controlled studies that corroborate the results of 
one another. However, the preamble also suggests characteristics of a 
single adequate and well-controlled study the presence of which can 
provide independent substantiation: The study involves prospective 
randomized stratifications or identified analytic subsets that each 
show a significant effect; the study includes multiple endpoints 
involving different events; the study provides highly reliable and 
statistically strong evidence of effectiveness; or 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. A multicenter 
study is a study of a design in which a single study protocol, with 
allowance for minor site-specific modifications, is followed at 
multiple locations.
    Experts must be able to fairly and reasonably conclude by 
substantial evidence that a new animal drug is effective for all the 
conditions of use prescribed, recommended or suggested in the proposed 
labeling. Thus, the second scientific principle enunciated in the 
proposed regulation is that the study(ies) that constitute substantial 
evidence must have sufficient inferential value. If the proposed 
conditions of use for a new animal drug vary widely (e.g., geographic 
conditions, husbandry practices, animal genetics), one adequate and 
well-controlled study conducted at a single location may not provide 
representative conditions of use from which experts can conclude that 
the new animal drug is effective for all of the conditions of use 
suggested in the proposed labeling. However, if a single adequate and 
well-controlled study can be designed which is representative of varied 
conditions of use, such a study may provide adequate inferential value 
upon which experts can determine whether there is substantial evidence 
that the drug is effective.
    As FDA stated in the preamble to the proposed regulation, the 
number and types of studies needed to demonstrate that a new animal 
drug is effective will depend upon how narrowly or broadly the intended 
uses and conditions of use for the new animal drug are defined as well 
as existing knowledge about the new animal drug, similar compounds, or 
the disease to be treated or structure or function to be affected. It 
should not be assumed that a drug sponsor's burden with respect to new 
animal drug development will not be lessened at all

[[Page 40750]]

by the regulations implementing the ADAA when FDA determines that a 
single adequate and well-controlled study will not suffice to establish 
the effectiveness of a new animal drug. In addition to giving FDA 
greater flexibility regarding the number of studies that are needed to 
demonstrate that a new animal drug is effective, the ADAA eliminated 
the requirement for a field study in some instances and listed many 
types of adequate and well-controlled studies that can be submitted to 
support a determination by FDA that a new animal drug is effective. 
Whether the burden on sponsors is lessened will be a function of the 
types of studies as well as the number of studies conducted. FDA 
reiterates that it is FDA's intent to work with sponsors to identify 
the least burdensome appropriate means for demonstrating that a new 
animal drug is safe and effective.
    With the further explanation given in this response, FDA does not 
believe it necessary to retract its statement that where only one 
adequate and well-controlled study is to be accepted as substantial 
evidence of effectiveness, that single study should provide sufficient 
inferential value and independent substantiation of the results of the 
study to permit qualified experts to determine whether the new animal 
drug is effective. The underlying principles that govern the design of 
a study intended to demonstrate effectiveness are already set forth in 
the further definition of adequate and well-controlled study that 
published in the Federal Register of March 5, 1998 (63 FR 10765). FDA 
will, subject to public input, issue further guidance on how to 
determine the number and types of studies necessary to demonstrate by 
substantial evidence that a new animal drug is effective. FDA will 
consider various public forums, including workshops, for discussing the 
number and types of studies necessary to demonstrate by substantial 
evidence that a new animal drug, production or therapeutic, is 
effective. Use of single studies as substantial evidence of the 
effectiveness of a new animal drug intended for production purposes, 
among other issues, will be further discussed in a public forum.
    7. Another comment expressed concern regarding how the presumption 
that for one study to be accepted as substantial evidence it would 
generally need to be a multicenter study applies to field studies. The 
comment noted that the specific intent of Congress in redefining 
substantial evidence was to eliminate the requirement that a field 
study be conducted in all instances to prove effectiveness and further 
that FDA move away from the longstanding notion that, where one or more 
field investigations are required, there must be three investigations 
in geographically distinct regions of the country. The comment also 
noted that there is no meaningful difference between multiple field 
studies and a single field study with multiple study centers and, 
therefore, FDA should have to justify requesting multiple sites just as 
it is required to justify a requirement for more than one field study.
    As discussed in comment 6 of section II.C of this document, 
substantial evidence is predicated on the principles of independent 
substantiation and inferential value to meet the statutory requirement 
that the studies must be sufficient such that experts can fairly and 
reasonably conclude the drug is effective for the intended uses and 
conditions of use suggested in the proposed labeling. Studies conducted 
at more than one site provide a basis for satisfying these criteria, 
but FDA will consider alternative approaches. These underlying 
principles apply equally to laboratory and field studies. Whether a 
field study is needed to demonstrate effectiveness depends upon the new 
animal drug and the nature of its intended uses. The legislative 
history of the ADAA recognized this fact. ``Assessing the safety and 
effectiveness of new animal drugs under conditions of use which closely 
approximate actual field use conditions will remain an important 
element of many new animal drug approvals.'' H. Rept. 104-823 at 15. 
However, there are situations, e.g., approval of anthelmintics, in 
which the effectiveness of the new animal drug can be demonstrated 
without a field study.
    The act, as amended by the ADAA, entitles any person intending to 
file a request for investigational use of a new animal drug, an NADA, 
or a supplemental NADA to request one or more presubmission 
conferences. If it is decided during a presubmission conference that 
more than one field study is needed to demonstrate effectiveness, FDA 
is statutorily required to provide a written order setting forth a 
scientific justification for requiring more than one field study. In 
those instances in which FDA requires more than one field study, FDA 
will provide written scientific justification for such a requirement. 
One study can be a study at a single location or a study in which data 
are collected from multiple locations, and FDA agrees with the comments 
that the need for a multilocation field study falls within the spirit 
of the justification provision of the ADAA. Therefore, if FDA requires 
a field study to be conducted at multiple locations, FDA will provide a 
scientific justification for requiring the study to be conducted at 
multiple locations.
    FDA plans to issue guidance or regulations to describe how to 
request a presubmission conference and to describe the procedures for 
the conduct of the presubmission conference. FDA also intends to issue 
guidance regarding the circumstances under which more than one field 
study may be necessary to demonstrate effectiveness. For example, FDA 
would require more than one field study when a single field study, 
although adequate and well-controlled, would not provide results from 
which valid inferences can be drawn regarding whether the new animal 
drug is effective under actual conditions of use for the intended uses 
suggested in the proposed labeling. In developing guidance on this 
issue, FDA will solicit public input.
    8. Several comments criticized FDA's introduction of the terms 
``persuasiveness'' and ``sufficient quality'' to describe the required 
characteristics of effectiveness studies. The comments noted that the 
statute requires that effectiveness studies be adequate and well-
controlled.
    Substantial evidence as defined in the act is evidence consisting 
of one or more adequate and well-controlled studies by experts 
qualified by scientific training and experience to evaluate the 
effectiveness of the drug, 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 proposed labeling. 
Thus, to maintain that the statute requires that effectiveness studies 
be adequate and well-controlled is to acknowledge only half of the 
statutory requirement. As stated earlier in this preamble, Congress did 
not change the standard that evidence must meet to be substantial 
evidence. Not only must the study(ies) that constitute substantial 
evidence be adequate and well-controlled, the study(ies) must also 
provide a basis upon which qualified experts can fairly and reasonably 
conclude that a new animal drug is effective.
    FDA has by regulation further defined the characteristics of 
adequate and well-controlled studies (63 FR 10765); these 
characteristics relate primarily to the design of an adequate and well-
controlled study. The terms ``sufficient quality'' and 
``persuasiveness'' relate respectively to the conduct and results of 
the study.

[[Page 40751]]

    The fact that a study is an adequate and well-controlled study does 
not mean that the results of such a study will support a finding that a 
new animal drug is effective. Whether experts can reasonably conclude 
from adequate and well-controlled studies that a new animal drug is 
effective will depend upon the quality of the studies, i.e., whether 
the study was actually conducted in accordance with the study design as 
described in the study protocol and in accordance with reasonable 
scientific practices for the conduct of studies. Whether experts can 
conclude that a new animal drug is effective will further depend upon 
whether the results of adequate and well-controlled studies persuade 
experts that the new animal drug is effective for its intended uses 
under the conditions of use suggested in the proposed labeling. Results 
of a study are likely to be persuasive if the parameters selected for 
measurement and the measured responses reliably reflect the 
effectiveness of the new animal drug, the results are likely to be 
repeatable, and valid inferences can be drawn to the target animal 
population.
    Persuasiveness and sufficient quality are adjectives that describe 
those adequate and well-controlled studies that will lead qualified 
experts to conclude that a new animal drug is effective. Thus, 
Sec. 514.4(b)(3)(i) continues to include reference to those terms.
    9. Another comment asserted that effectiveness need not be 
demonstrated for all conceivable variations of genetic and 
environmental conditions because it is the intent of the ADAA to 
encourage the submission of NADA's and supplemental NADA's.
    The purpose of the ADAA was to build needed flexibility into FDA's 
animal drug review processes to enable more efficient approval and more 
expeditious marketing of safe and effective animal drugs. The ADAA did 
not eliminate the requirement that sponsors demonstrate that a new 
animal drug has the effect it purports or is represented to have under 
the conditions of use suggested in the proposed labeling. FDA agrees 
that substantial evidence need not consist of a direct demonstration 
that a new animal drug is effective under all conceivable genetic and 
environmental conditions. However, a sponsor does need to demonstrate 
that a new animal drug is effective under genetic and environmental 
conditions sufficiently representative of the conditions of use 
suggested in the proposed labeling so that qualified experts can fairly 
and reasonably conclude that the new animal drug will be effective 
under those proposed conditions of use. If experts cannot so conclude, 
the evidence does not meet the statutory definition of substantial 
evidence.
    10. One comment opposed FDA's proposal to consider how time may 
affect the inferential value of a particular set of data citing the 
fact that currently approved animal drugs in wide use today were 
approved on what could now be considered ``aged data.'' Another comment 
questioned how FDA will evaluate whether data are sufficiently 
``current'' for purposes of submitting an NADA.
    Approval decisions are made at a specific point in time and FDA 
must be able to fairly and reasonably conclude from the data available 
at the time it makes its approval decision whether the new animal drug 
is effective. The act does, however, provide that if on the basis of 
new information, evaluated together with the evidence available at the 
time the application was approved there is a lack of substantial 
evidence that a new animal drug is effective, FDA must take steps to 
withdraw the approval. Therefore, the currency of data is relevant even 
with respect to approved new animal drugs.
    FDA only stated that time may affect the inferential value of data. 
FDA recognizes that not all data are equally sensitive to time. FDA 
will need to make determinations regarding the currency of data on a 
case-by-case basis. FDA agrees with the comment that the test is 
whether the data provide a basis on which qualified experts could 
fairly and reasonably conclude that the new animal drug is effective. 
Currency is particularly meaningful in terms of the inferences that can 
be drawn from data. Therefore, there may be instances in which the age 
of the data limit or invalidate the usefulness of data in determining 
the effectiveness of a new animal drug just as the discovery of new 
data may give FDA reason to consider withdrawing an approval.
    11. One comment objected to any intent of FDA to require a 
demonstration of effectiveness in multiple geographic locations or 
under multiple management practices.
    As stated previously, the act provides that in order to meet the 
definition of substantial evidence, the evidence provided must be such 
that qualified experts can fairly and reasonably conclude that the new 
animal drug is effective for its intended uses under the conditions of 
use suggested in the proposed labeling. While a sponsor generally need 
not demonstrate effectiveness under every condition of use suggested in 
the proposed labeling, a sponsor will need to demonstrate that the new 
animal drug is effective under conditions such that FDA will be able to 
fairly and reasonably conclude that the new animal drug will be 
effective for its intended uses under the conditions of use suggested 
in the proposed labeling. If a single adequate and well-controlled 
study can be designed, which is representative of varied conditions of 
use, such as varied geographic conditions and management practices, 
such a study would provide adequate inferential value such that experts 
can fairly and reasonably conclude that the drug will be effective. FDA 
will develop guidance on this issue, soliciting public input, and will 
discuss this issue on a case-by-case basis with a sponsor during a 
presubmission conference.
    12. One comment asserted that while effectiveness must be 
demonstrated for each intended use, substantial evidence should not 
require conducting studies in every conceivable subdivision of species 
of animals.
    FDA agrees. Adequate and well-controlled studies need only be 
conducted in species and subspecies that are representative of the 
species for which the new animal drug is intended such that qualified 
experts can fairly and reasonably conclude by that the new animal drug 
is effective for its intended uses under the conditions of use 
suggested in the proposed labeling. It is reasonable to expect that 
studies in many different subspecies or breeds will not be needed if 
there is a scientific basis to conclude that there will be no 
difference in response or safety between subspecies or breeds 
respectively.

D. Types of Studies (Sec. 514.4(b)(3)(ii))

    13. Comments strongly disagreed with FDA's comments in the preamble 
regarding the value of published studies, peer-reviewed studies, and 
foreign studies. Comments asserted that such studies are useful and 
that the preamble to the proposed rule reflects prejudice against the 
use of such studies as a basis of establishing efficacy. One comment 
acknowledged that there may be differences in animal genetics and 
husbandry represented in foreign studies that may justify FDA's 
requiring that foreign data be confirmed but also notes that such 
differences may have no impact on animals' response to a drug. Another 
comment suggested that FDA establish guidance relating to each of these 
types of studies.
    In the preamble to the proposed regulation, FDA clearly stated that 
a published study, foreign study, or a study using a model may provide 
substantial evidence of effectiveness if it is an adequate and well-
controlled

[[Page 40752]]

study. Nonetheless, the utility of published studies, foreign studies, 
and studies using models, like studies conducted by or on behalf of 
sponsors, may vary because of the nature of the study. It was FDA's 
intent to provide in the preamble direction regarding the use of 
published studies, foreign studies, and studies using models.
    With regard to foreign studies, the preamble noted that differences 
such as animal breeds, genetic composition within a breed, diseases, 
nutrition, and husbandry practices need to be addressed sufficiently. 
FDA did not preclude the use of foreign studies. Furthermore, FDA 
agrees that where these differences have no impact on an animal's 
response to a new animal drug, adequate and well-controlled foreign 
studies may support a finding by substantial evidence that a new animal 
drug is effective. FDA is willing and available to discuss with 
sponsors what information, if any, relating to foreign data is needed 
to address these kinds of differences. FDA anticipates issuing, subject 
to public input, guidance regarding this issue as expeditiously as 
resources permit.
    14. One comment questioned why sponsors must disclose the source of 
funding for published studies asserting that the source of funding is 
irrelevant to the evaluation of the study.
    FDA disagrees with the assertion that the source of funding is 
irrelevant to the evaluation of a published study. Knowledge regarding 
the funding of the study allows FDA to determine whether a sponsor 
owns, and can provide FDA access to, the study protocol, study 
documentation, and study data for purposes of evaluating the study. 
Additionally, if current and/or future funding depend upon the outcome 
of the study, there is a potential for bias and FDA will want to have 
available the study protocol, study documentation, and study data to 
scrutinize more closely.
    Who funds the study and their purpose in sponsoring the study are 
also relevant because it may affect which studies are ultimately 
published with the result that published studies may represent a skewed 
subset of available information. That is, if a sponsor funds a study 
that supports their research, the sponsor may attempt to get the study 
published. But, if the study does not support their research, the 
sponsor may not pursue publication of the study. Thus, a search of the 
published literature may not accurately reflect the body of knowledge 
that actually exists.
    15. One comment suggested that the definition of combination drugs 
should acknowledge that some combination drugs may be topical 
antibacterials which, under aquaculture conditions, might be applied in 
the water in which fish are raised.
    Increasingly there are concerns that overuse or improper use of 
antibacterials may contribute unnecessarily to the development of 
antibacterial resistance. It is for this reason that the ADAA requires 
that applicants establish that nontopical antibacterials contribute to 
the effectiveness of a combination new animal drug. When used in 
aquaculture, antibacterials are applied or administered not 
``topically'' in the sense that they are applied or administered to 
individual fish but they are applied or administered in a body of water 
through which fish swim. Because of the nature of the products and 
because of the added potential for the development and transfer of 
resistance in the bodies of water in which antibacterials are applied, 
FDA will for purposes of the application of Sec. 514.4(c) consider 
aquaculture drugs administered in water to be nontopical 
antibacterials.
    FDA has worked with the aquaculture industry to facilitate the 
approval of new animal drugs for use in aquaculture and recognizes that 
there is a vital need for the approval of more aquaculture drugs. FDA 
anticipates that proposals being made to facilitate the approval of new 
animal drugs intended for minor uses or use in minor species will 
provide additional tools to facilitate the approval of new animal drugs 
for use in aquaculture.
    16. Comments relating to substantial evidence for combination drugs 
focused primarily on the definition of ``antibacterial.'' The comments 
claimed that by defining ``antibacterial'' in a way that includes 
classes of drugs such as anticoccidials, ionophores, and arsenicals, 
FDA has rendered the streamlined approval provision for certain 
combination drugs meaningless. The comments stated that the intent of 
the streamlined combination approval provision was to speed up approval 
of feed use combination drugs and virtually all of the economically and 
medicinally important combinations of drugs for food animal feeds 
involve an ionophore and/or arsenical and an antibacterial. Therefore, 
the comments urged FDA to define ``antibacterial'' in a way that 
ensures the exemption of anticoccidials, ionophores, and arsenicals. 
One comment suggested that FDA can accomplish this by exempting from 
the definition of ``antibacterial'' any drug use which: (1) Has been 
determined by FDA to have met the criteria of Sec. 558.15 (21 CFR 
558.15), or (2) was exempted by FDA from compliance with Sec. 558.15. 
The comment asserted that the term ``antibacterial'' should not include 
chemicals that have some antibiotic activity but which are not known or 
speculated to contribute to the development of resistance by bacterial 
pathogens to antibiotics in human medicine. Another comment attempted 
to provide justification for excluding the ionophore class of animal 
drugs from the general classification of ``antibacterial'' claiming 
ionophores are unlikely to contribute to the development of 
antibacterial resistance of importance to human or veterinary medicine.
    The combination new animal drug provision of section 512(d)(4) the 
act, added by the ADAA treats antibacterial ingredients and drugs 
differently from other active ingredients and animal drugs intended for 
use in combination because increasingly there are concerns that overuse 
or improper use may contribute unnecessarily to the development of 
antibacterial resistance. The term antibacterial does not include any 
new animal drug that is intended for use only to kill or suppress 
organisms other than bacteria. For example, the term antibacterial does 
not include a new animal drug which is intended to kill or suppress 
coccidia unless such animal drug also has an approved use in the 
particular species that is attributable to its antibacterial 
properties. Therefore, new animal drugs approved solely as 
anticoccidials will not fall within the definition of antibacterial.
    As enacted, the ADAA did not address how specific classes of animal 
drugs such as arsenicals and ionophores should fit within the term 
antibacterial. Drugs that achieve their effect by killing or 
suppressing the replication of bacteria are considered to be 
antibacterials. If an active ingredient or animal drug intended for use 
in combination can be shown to act through some other mechanism to 
achieve its intended effect in a particular species it will not be 
considered an antibacterial.
    On October 21, 1998, Congress, as part of the agriculture 
appropriations in Pub. L. 105-277, amended the act to exclude 
ionophores and arsenicals from the definition of antibacterial for 
purposes of determining whether combination new animal drugs intended 
for use in drinking water or animal feed qualify for the modified 
combination drug approval process set forth in 21 U.S.C. 512(d)(4). 
Therefore, FDA is revising proposed Sec. 514.4(c)(1)(ii), final 21 CFR 
514.4(c)(1)(iii), to add at the end the following: ``But, antibacterial 
does

[[Page 40753]]

not include ionophores or arsenicals intended for use in combination in 
animal feed or drinking water.''
    17. Comments objected to the requirement in the proposed regulation 
that conditions treated by a combination new animal drug occur 
simultaneously with sufficient frequency in the intended target animal 
population. The comments argue that the objective of the ADAA is drug 
availability and, therefore, the frequency of conditions should not be 
considered. One comment suggested that drugs or active ingredients to 
be used in combination should be approved as long as there is credible 
medical evidence that the conditions to be treated do occur 
simultaneously.
    As the comment suggests, the important principle that needs to be 
met in determining whether there is appropriate concurrent use is that 
there be evidence that any conditions to be treated or physiological 
effects intended to be achieved can occur simultaneously. Thus, FDA 
will find that appropriate concurrent use exists if there is credible 
evidence that the conditions for which the combination is intended can 
occur simultaneously. FDA has added a definition of appropriate 
concurrent use at Sec. 514.4(c)(1)(iv) of these final rules. Because 
combination new animal drugs may contain animal drugs intended for 
therapeutic and/or production use, the definition does not adopt the 
comment's suggestion that there be credible ``medical'' evidence.
    18. Comments objected to the provision in the proposed regulation 
that requires that sponsors demonstrate bioavailability as a mechanism 
to determine the physical compatibility and the compatibility of dosing 
regimens of separately approved animal drugs when used in combination. 
Comments assert that the ADAA clearly places the burden on FDA to make 
a scientifically based initial conclusion that there is reason to 
believe that incompatibility exists, rather than for sponsors to 
continue to demonstrate compatibility.
    FDA has reconsidered the statutory basis for the proposed 
requirement that applicants demonstrate comparable bioavailability for 
some classes of combination new animal drugs. FDA agrees that 
bioavailability and compatibility are not completely correlative. 
However, just as the requirement to demonstrate compatibility is a 
recognition that under some circumstances use of an active ingredient 
or animal drug in a combination new animal drug may affect the 
effectiveness of that (or another) active ingredient or animal drug, 
the proposed requirement to demonstrate comparable bioavailability is a 
recognition that under some circumstances use of an active ingredient 
or animal drug in a combination new animal drug may affect the safety 
of that (or another) active ingredient or animal drug. Furthermore, the 
ADAA recognizes that this concern varies by class of combination new 
animal drug with dosage form new animal drugs, other than for use in 
drinking water, having the greatest potential to affect the 
effectiveness of the new animal drugs being combined, and animal drugs 
for use in feed having the least (see 21 U.S.C. 360b(d)(4)(C) and 
(d)(4)(D)). FDA believes similarly that combining dosage form new 
animal drugs, other than for use in drinking water, has the greatest 
potential to affect the safety of the new animal drugs being combined 
because many of these dosage form new animal drugs are indicated for 
serious or life-threatening conditions, have relatively narrow margins 
of safety, and/or have complex formulations.
    Under the act, FDA may refuse to approve a combination new animal 
drug if there is a substantiated scientific issue specific to one or 
more of the animal drugs in the combination that cannot adequately be 
evaluated based on information in the application for the combination 
or there is a scientific issue raised by target animal observations 
contained in studies submitted to FDA as part of the application for 
the combination (21 U.S.C. 360b(d)(4)(B)). It is a well-accepted 
scientific principle that changes in formulation can affect the 
bioavailability and, thus, the safety and effectiveness of a new animal 
drug. FDA currently requires a demonstration of comparable 
bioavailability when a sponsor proposes to make significant formulation 
changes to a single active ingredient new animal drug and when a 
sponsor proposes to market a generic formulation of a new animal drug. 
In the latter case, comparable bioavailability is more formally defined 
as bioequivalence. Formulation changes necessitated by combining dosage 
form new animal drugs other than those intended for use in drinking 
water are considered to be significant changes that may similarly 
affect bioavailability and, thus, the safety of a combination new 
animal drug. Thus, FDA believes it is appropriate and in keeping with 
the spirit of the ADAA for FDA to determine that in the specific case 
of dosage form animal drugs intended for use in combination other than 
in drinking water there is a substantiated scientific issue relating to 
the formulation changes necessitated to combine such animal drugs that 
warrants the requirement for additional target animal safety data. FDA 
plans to issue a guidance or regulations setting forth further 
discussion on this issue.
    Because the proposed requirement to demonstrate comparable 
bioavailability relates primarily to safety, FDA is eliminating 
proposed Sec. 514.4(c)(2)(iv) and (c)(2)(v). New Sec. 514.4(c)(2)(i)(C) 
and (c)(2)(ii)(D) will reflect that as part of demonstrating the 
effectiveness of certain combination new animal drugs, sponsors need 
only demonstrate that active ingredients or animal drugs intended for 
use in combination are physically compatible and/or do not have 
disparate dosing regimens where FDA, based on scientific information, 
has reason to believe there is a lack of physical compatibility or the 
dosing regimens are disparate.
    19. One comment interpreted the preamble to the proposed regulation 
to require that entirely new studies with a combination new animal drug 
be conducted when an additional claim is added to a previously 
separately approved individual active ingredient or animal drug that is 
part of the combination new animal drug. The comment opposed such a 
requirement and suggested that label extensions for the combination new 
animal drug should be pursued at the discretion of the sponsor.
    When an additional claim is approved for a single ingredient new 
animal drug that is part of a combination new animal drug that has been 
approved under the modified combination approval process provided by 
section 512(d)(4) of the act, the additional claim may not 
automatically become a claim for the combination new animal drug. A 
supplemental application may need to be submitted for the combination 
new animal drug. Otherwise, an applicant could attempt to circumvent 
effectiveness requirements for a combination new animal drug that 
qualifies for approval under the modified combination approval process 
by choosing to seek approval of certain claims for one of the single 
ingredient new animal drugs after the combination new animal drug 
containing it has been approved.
    For example, assume that drug A is approved for indication X and 
drug B is approved for indication Y, and the combination new animal 
drug containing drug A and drug B qualifies for approval under the 
modified combination approval process. Because each new animal drug is 
intended for at least one use that is different from the

[[Page 40754]]

other new animal drug in the combination, the application for the 
combination new animal drug would primarily need to include a 
demonstration that combination new animal drug AB represents 
appropriate concurrent use to establish that the combination is 
effective. If drug A had been approved for indications X and Y, the 
application would have had to include a demonstration that drug B 
contributed to the labeled effectiveness of the combination new animal 
drug with respect to indication Y. Therefore, if drug A is subsequently 
approved for indication Y after the combination new animal drug AB is 
approved, a supplemental application is needed to demonstrate that drug 
B contributes to the labeled effectiveness of the combination new 
animal drug. In no case will FDA require any more than FDA would have 
required had the applicant originally sought approval of a combination 
new animal drug that includes the animal drug with the additional 
claim.
    20. One comment requested confirmation regarding the application of 
the combination new animal drug provision of the proposed regulation. 
In particular, the comment sought confirmation that sponsors need only 
show that each antibacterial in a combination new animal drug makes a 
contribution to a combination's effectiveness. The comment further 
sought confirmation that the contribution of nonantibacterials that 
have no overlapping claims need not be demonstrated.
    Section 514.3(c) specifies the requirements for demonstrating that 
a combination new animal drug is effective. Because increasingly there 
are concerns that overuse or improper use of antibacterials may 
contribute unnecessarily to the development of antibacterial 
resistance, there are additional, specific requirements that relate to 
combination new animal drugs that contain antibacterial ingredients or 
animal drugs.
    For those combinations that contain antibacterials and qualify for 
the modified combination approval process provided under section 512(d) 
of the act, a sponsor will need to show more than that each 
antibacterial makes a contribution to the combination's effectiveness. 
The sponsor will also have to demonstrate: (1) That each 
nonantibacterial active ingredient or animal drug that is intended only 
for the same use as another active ingredient or animal drug makes a 
contribution to effectiveness and (2) each antibacterial and 
nonantibacterial active ingredient or animal drug with a unique claim 
provides appropriate concurrent use. Furthermore, the sponsor may, 
under certain circumstances, need to demonstrate that the active 
ingredients or animal drugs are physically compatible and/or do not 
have disparate dosing regimens.
    If each of the active ingredients or animal drugs intended for use 
in a combination that qualifies for the modified approval process has a 
unique claim, the sponsor must demonstrate that each active ingredient 
or animal drug provides appropriate concurrent use. The sponsor may, 
under certain circumstances, also need to demonstrate that the active 
ingredients or animal drugs are physically compatible and/or do not 
have disparate dosing regimens.
    21. One comment criticized the length and complexity of proposed 
Sec. 514.4(c)(2), which describes the substantial evidence required for 
the evaluation of combination new animal drugs with active ingredients 
or animal drugs that have previously been separately approved.
    FDA has made some revisions to proposed Sec. 514.4(c)(2) in an 
attempt to make the provision more understandable. Unfortunately the 
combination new animal drug provision of the act, section 512(d)(4), is 
complex. One of the revisions includes defining ``dosage form 
combination new animal drug'' at Sec. 514.4(c)(1)(ii). FDA has also 
tried to simplify the provision, by describing in list form for dosage 
form combination new animal drugs and combination new animal drugs 
intended for use in animal feed or drinking water separately, what 
substantial evidence is needed to demonstrate that a combination of 
previously separately approved active ingredients or animal drugs is 
effective. The preamble to the proposed rule provides further 
explanation of the substantial evidence needed to demonstrate that a 
combination new animal drug is effective. FDA intends to issue guidance 
to further assist sponsors and interested parties in interpreting this 
very complex provision.

E. Responses to Remaining Comments

    22. One comment urged FDA to make animal testing illegal.
    The act requires that manufacturers of new animal drugs demonstrate 
prior to marketing that a new animal drug is safe to the animals 
administered the drug, safe to humans who may consume food derived from 
animals administered the drug, and effective. This final rule describes 
the numbers and types of studies needed to demonstrate that a new 
animal drug is effective. Depending upon the nature of the intended 
uses, which may include the alleviation of animal pain and suffering, 
and conditions of use of the new animal drug, substantial evidence of 
effectiveness may consist of one or more studies in the target animal, 
studies in laboratory animals, field studies, bioequivalence studies, 
or in vitro studies.
    As stated repeatedly, FDA intends to work with sponsors to identify 
the least burdensome appropriate means for demonstrating that a new 
animal drug is safe and effective. With technological advances, the use 
of animals in testing has been in decline and FDA fully supports the 
use of alternative methodologies where appropriate. FDA balances the 
need for live animal testing of new animal drugs with the need to 
protect the welfare of the animals that would receive the new animal 
drug if it is approved. To the extent animal testing is used, there are 
in effect laws and regulations that provide for the humane care and use 
of animals in research, testing, and teaching environments. FDA 
advocates full observance of all applicable animal welfare laws, 
regulations, and guidelines.
    23. Several comments referred to the efforts of the Center for 
Veterinary Medicine's ADAA Minor Use/Minor Species Working Group to 
propose regulatory and statutory changes to facilitate the approval of 
new animal drugs for minor uses or for use in minor species.
    Section 2(f) of the ADAA required the Secretary of Health and Human 
Services to consider and announce legislative and regulatory options 
for facilitating the approval under section 512 of the act of animal 
drugs intended for minor species and for minor uses. Although the 
redefinition of substantial evidence by the ADAA and FDA's further 
definition of substantial evidence may have the indirect effect of 
facilitating approval of animal drugs intended for minor species and 
for minor uses, the charge from Congress to announce proposals for 
regulatory and statutory changes was not specifically addressed by FDA 
in redefining substantial evidence. Comments relating to proposals for 
facilitating the approval of animal drugs for minor use or minor 
species were addressed in the context of FDA's proposal for regulatory 
and statutory changes (63 FR 58056, October 29, 1998).

III. Conforming Changes

    FDA has made conforming changes to Secs. 514.1(b)(8) and 514.111.

[[Page 40755]]

IV. Environmental Impact

    FDA has carefully considered the potential environmental impacts of 
this final rule. The agency has determined that this action is of a 
type that does not individually or cumulatively have a significant 
effect on the human environment (21 CFR 25.30(h)). Therefore, neither 
an environmental assessment nor an environmental impact statement is 
required.

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and 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). The agency believes that 
this final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. The Office of Management 
and Budget (OMB) has determined that this final rule is a significant 
regulatory action subject to review under the Executive Order.
    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 
impact on a substantial number of small entities. Because this final 
rule 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 final 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.
    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 labeling. The purpose of the final rule is to encourage the 
submission of NADA's, the submission of supplemental NADA's, and the 
use of dose range labeling. Accordingly, the final 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 adequately demonstrate the effectiveness of any particular 
new animal drug. For example, under the new 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 final rule is not expected to impose any new 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 will be a benefit to sponsors.
    The final rule also applies to 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 will no longer be required, 
sponsors are no longer required to conduct adequate and well-controlled 
in vivo dose titration studies, but will need only to conduct such 
studies as may be needed to justify the dosage and characterize the 
critical aspects of the dose-response relationship relevant to the dose 
or dose range selected so that FDA can make a risk-effect assessment 
and ensure 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 justify dosage and characterize the dose-response 
relationship, sponsors will realize a small cost savings.
    Finally, the final 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. These changes will provide further cost 
savings to the sponsors of NADA's that meet the criteria for the 
streamlined approval process. Based on comments to the proposal, FDA 
has reconsidered and subsequently removed the requirement in this 
provision that would have required applicants to demonstrate comparable 
bioavailability as a mechanism for determining the physical 
compatibility and compatibility of dosing regimens of active 
ingredients or animal drugs intended for use in combination.

VI. 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 expenditure by State, 
local, and tribal governments, in the aggregate, or by the private 
sector, of $100 million or more (adjusted annually for inflation) in 
any one year. This final rule does not impose any mandates on State, 
local, or tribal governments, or the private sector that will result in 
an expenditure of $100 million or more in any one year.

VII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are 
subject to review by OMB under the Paperwork Reduction Act of 1995 (44 
U.S.C. 3501-3520). A description of these provisions is given below. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed and completing and reviewing each collection of information.
    Title: Substantial Evidence of Effectiveness of New Animal Drugs.
    Description: As directed by the ADAA, FDA is publishing a final 
rule 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 final 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 final regulation, Sec. 514.4, 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. FDA estimated 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.

[[Page 40756]]

    Description of Respondents: Persons and businesses, including small 
businesses. In the Federal Register of November 5, 1997 (62 FR 59830), 
FDA requested comments on the proposed collection of information annual 
reporting burden estimate. As a result of comments received on the 
proposed regulation (see comment 18 in section II.D of this document), 
the requirement in the proposed regulation that sponsors demonstrate 
comparable bioavailability as a mechanism to determine the physical 
compatibility and the compatibility of dosing regimens of separately 
approved animal drugs intended for use in a dosage form combination new 
animal drug has been eliminated in the final rule. The final rule 
reflects that as part of demonstrating effectiveness of certain 
combination new animal drugs sponsors need only demonstrate that active 
ingredients or animal drugs intended for use in combination are 
physically compatible and/or do not have disparate dosing regimens 
where FDA, based on scientific information, has reason to believe there 
is a lack of physical compatibility or the dosing regimens are 
disparate. Because combinations that qualify for the modified approval 
process created by the ADAA represent a small portion of all NADA's and 
supplemental NADA's submitted to FDA and the majority of combinations 
that qualify for the modified approval process are expected to be 
combinations intended for use in animal feed, any reduction in 
paperwork burden resulting from the elimination of the requirement to 
demonstrate comparable bioavailability would be negligible. Therefore, 
FDA believes that the annual reporting burden estimate of 544,036 hours 
should remain unchanged.

                                  Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
                                                      Annual
         21 CFR Section               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
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.

    Individuals and organizations may submit comments on this burden 
estimate or on any other aspect of these information collection 
provisions, including suggestions for reducing the burden, and should 
direct them to Herman M. Schoenemann, Center for Veterinary Medicine 
(HFV-126), Food and Drug Administration, 7500 Standish Pl., Rockville, 
MD 20855.
    The information collection provisions in this final rule have been 
approved under OMB control number 0910-0356. This approval expires 
December 31, 2000. An agency may not conduct or sponsor, and a person 
is not required to provide, a collection of information unless it 
displays a currently valid OMB control number.

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 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. Any study that is intended to be part of substantial evidence 
of the effectiveness of a new animal drug shall be conducted by experts 
qualified by scientific training and experience.
    (2) Intended uses and conditions of use. Substantial evidence of 
effectiveness of a new animal drug shall demonstrate that the new 
animal drug is effective for each intended use and associated 
conditions of use for and under which approval is sought.
    (i) Dose range labeling. Sponsors should, to the extent possible, 
provide for a dose range because it increases the utility of the new 
animal drug by providing the user flexibility in the selection of a 
safe and effective dose. In general, substantial evidence to support 
dose range labeling for a new animal drug intended for use in the 
diagnosis, cure, mitigation, treatment, or prevention of disease must 
consist of at least one adequate and well-controlled study on the basis 
of which qualified experts could fairly and reasonably conclude that 
the new animal drug will be effective for the intended use at the 
lowest dose of the dose range suggested in the proposed labeling for 
that intended use. Substantial evidence to support dose range labeling 
for a new animal drug intended to affect the structure or function of 
the body of an animal generally must consist of at least one adequate 
and well-controlled study on the basis of which qualified experts could 
fairly and reasonably conclude

[[Page 40757]]

that the new animal drug will be effective for the intended use at all 
doses within the range suggested in the proposed labeling for the 
intended use.
    (ii) [Reserved]
    (3) Studies--(i) Number. Substantial evidence of the effectiveness 
of a new animal drug for each intended use and associated conditions of 
use shall consist of a sufficient number of current adequate and well-
controlled studies of sufficient quality and persuasiveness to permit 
qualified experts:
    (A) To determine that the parameters selected for measurement and 
the measured responses reliably reflect the effectiveness of the new 
animal drug;
    (B) To determine that the results obtained are likely to be 
repeatable, and that valid inferences can be drawn to the target animal 
population; and
    (C) To conclude that the new animal drug is effective for the 
intended use at the dose or dose range and associated conditions of use 
prescribed, recommended, or suggested in the proposed labeling.
    (ii) Types. Adequate and well-controlled studies that are intended 
to provide substantial evidence of the effectiveness of a new animal 
drug may include, but are not limited to, published studies, foreign 
studies, studies using models, and studies conducted by or on behalf of 
the sponsor. Studies using models shall be validated to establish an 
adequate relationship of parameters measured and effects observed in 
the model with one or more significant effects of treatment.
    (c) Substantial evidence for combination new animal drugs--(1) 
Definitions. The following definitions of terms apply to this section:
    (i) Combination new animal drug means a new animal drug that 
contains more than one active ingredient or animal drug that is applied 
or administered simultaneously in a single dosage form or 
simultaneously in or on animal feed or drinking water.
    (ii) Dosage form combination new animal drug means a combination 
new animal drug intended for use other than in animal feed or drinking 
water.
    (iii) Antibacterial with respect to a particular target animal 
species means an active ingredient or animal drug: That is approved in 
that species for the diagnosis, cure, mitigation, treatment, or 
prevention of bacterial disease; or that is approved for use in that 
species for any other use that is attributable to its antibacterial 
properties. But, antibacterial does not include ionophores or 
arsenicals intended for use in combination in animal feed or drinking 
water.
    (iv) Appropriate concurrent use exists when there is credible 
evidence that the conditions for which the combination new animal drug 
is intended can occur simultaneously.
    (2) Combination new animal drugs that contain only active 
ingredients or animal drugs that have previously been separately 
approved.
    (i) For dosage form combination new animal drugs, except for those 
that contain a nontopical antibacterial, that contain only active 
ingredients or animal drugs that have previously been separately 
approved for the particular uses and conditions of use for which they 
are intended in combination, a sponsor shall demonstrate:
    (A) By substantial evidence, as defined in this section, that any 
active ingredient or animal drug intended only for the same use as 
another active ingredient or animal drug in the combination makes a 
contribution to the effectiveness of the combination new animal drug;
    (B) That each active ingredient or animal drug intended for at 
least one use that is different from all the other active ingredients 
or animal drugs used in the combination provides appropriate concurrent 
use for the intended target animal population; and
    (C) That the active ingredients or animal drugs are physically 
compatible and do not have disparate dosing regimens if FDA, based on 
scientific information, has reason to believe the active ingredients or 
animal drugs are physically incompatible or have disparate dosing 
regimens.
    (ii) For combination new animal drugs intended for use in animal 
feed or drinking water that contain only active ingredients or animal 
drugs that have previously been separately approved for the particular 
uses and conditions of use for which they are intended in combination, 
the sponsor shall demonstrate:
    (A) By substantial evidence, as defined in this section, that any 
active ingredient or animal drug intended only for the same use as 
another active ingredient or animal drug in the combination makes a 
contribution to the effectiveness of the combination new animal drug;
    (B) For such combination new animal drugs that contain more than 
one antibacterial ingredient or animal drug, by substantial evidence, 
as defined in this section, that each antibacterial makes a 
contribution to labeled effectiveness;
    (C) That each active ingredient or animal drug intended for at 
least one use that is different from all other active ingredients or 
animal drugs used in the combination provides appropriate concurrent 
use for the intended target animal population; and
    (D) That the active ingredients or animal drugs intended for use in 
drinking water are physically compatible if FDA, based on scientific 
information, has reason to believe the active ingredients or animal 
drugs are physically incompatible.
    (3) Other combination new animal drugs. For all other combination 
new animal drugs, the sponsor shall demonstrate by substantial 
evidence, as defined in this section, that the combination new animal 
drug will have the effect it purports or is represented to have under 
the conditions of use prescribed, recommended, or suggested in the 
proposed labeling and that each active ingredient or animal drug 
contributes to the effectiveness of the combination new animal drug.
    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: July 21, 1999.
William K. Hubbard,
Senior Associate Commissioner for Policy, Planning and Legislation.
[FR Doc. 99-19193 Filed 7-27-99; 8:45 am]
BILLING CODE 4160-01-F