[Federal Register Volume 62, Number 89 (Thursday, May 8, 1997)]
[Proposed Rules]
[Pages 25153-25157]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-11846]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 514

[Docket No. 97N-0141]


Adequate and Well-Controlled Studies for Investigational Use and 
Approval of New Animal Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA), as directed by the 
Animal Drug Availability Act of 1996 (ADAA), is publishing 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. Elsewhere in this issue of the Federal 
Register, FDA is reopening docket number 96N-0411 to receive comments 
regarding a concept, ``good study practices,'' that is related to the 
definition of adequate and well-controlled studies.

DATES: Written comments by July 22, 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.

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. 
Section 2(e) of the ADAA directs FDA to issue, within 6 months of its 
enactment, proposed regulations 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. Although FDA believes that the 
definition of adequate and well-controlled is meaningful only when 
considered within the context of the entire set of regulations that 
govern the investigational use and approval of new animal drugs, FDA is 
publishing this proposed definition of adequate and well-controlled 
studies separately because of the statutory timeframe set forth in the 
ADAA. FDA intends to issue proposed revised investigational use new 
animal drug (INAD) regulations followed by proposed revised regulations 
governing new animal drug applications. These proposals, intended to 
further implement the ADAA and the Center for Veterinary Medicine's 
(CVM) commitment to reinvent the animal drug approval process and 
facilitate the approval of new animal drugs, will give context to the 
definition of adequate and well-controlled studies.

II. Adequate and Well-Controlled Studies

    FDA has long considered that the characteristics embodied in 21 CFR 
314.126 and Sec. 514.111(a)(5)(ii) (21 CFR 514.111(a)(5)(ii)) are the 
essentials of an adequate and well-controlled study. Discussions held 
between FDA and members of the Coalition for Animal Health (Coalition) 
prior to enactment of the ADAA and comments from the Animal Health 
Institute in response to the advance notice of proposed rulemaking 
published November 21, 1996 (61 FR 59209), made it clear that some 
members of the regulated industry are concerned that certain scientific 
principles and practices may be difficult to apply in testing new 
animal drugs under field conditions. In response, FDA evaluated the 
extent to which the characteristics in Sec. 514.111(a)(5)(ii) represent 
sound scientific principles essential for adequate and well-controlled 
studies. After careful consideration of the characteristics in light of 
the concerns expressed, FDA believes that the characteristics set forth 
in Sec. 514.111(a)(5)(ii), with minor modifications, remain sound 
scientific principles essential for all adequate and well-controlled 
studies whether conducted under laboratory or field conditions. (See 
definition of substantial evidence, section 512(d)(3) of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(d)(3))). The 
agency is proposing to replace current Sec. 514.111(a)(5)(ii) with new 
proposed Sec. 514.117, which contains minor revisions to the current 
regulation on adequate and well-controlled studies.
    The primary purpose of conducting adequate and well-controlled 
studies is, and has always been, to distinguish the effect of the drug 
from other influences, such as spontaneous change in the

[[Page 25154]]

course of disease and biased observation, so that a determination can 
be made whether the drug is effective. Thus, FDA's objectives in 
defining adequate and well-controlled studies remain unchanged. In the 
Federal Register of February 22, 1985 (50 FR 7452), FDA stated that the 
regulation defining adequate and well-controlled studies has two 
primary objectives: ``(1) to allow the agency to assess methods for 
minimizing bias; and (2) to assure a sufficiently detailed description 
of the study to allow scientific assessment and interpretation of it.'' 
These principles continue to apply whether a study is conducted on a 
drug intended for use in animals or humans or whether the study is 
conducted under laboratory or field conditions.
    To satisfy the objective of minimizing bias, the use of appropriate 
controls in a study design is of critical importance. Therefore, 
proposed Sec. 514.117(b)(4) lists the acceptable types of controls that 
may be used when conducting adequate and well-controlled studies. FDA 
has listed the types of controls in descending order--roughly in 
accordance with the ease of interpretation of associated studies. FDA 
believes that there may be good reasons for using different types of 
controls in study designs for particular situations and that the 
regulation is sufficiently flexible to accommodate the needs of 
sponsors in this respect. As a matter of past practice, FDA has 
approved products whose effectiveness was established on the basis of 
studies utilizing each of the controls listed in the proposed 
definition of adequate and well-controlled studies.
    The sponsor's choice of the type of control used in a study should 
be based on the scientific, ethical, and practical circumstances 
associated with that particular study. This decision should integrate, 
among other considerations, information such as the claim being made 
for the drug, the nature of the new animal drug, the animal population 
for which the animal drug is intended, and the number of animals 
necessary to demonstrate effectiveness. As long as the sponsor's choice 
is scientifically justifiable and the studies are properly designed and 
conducted, the approvability of the application will not be affected by 
the choice of control. Nothing in the proposed regulation prohibits an 
animal from serving as its own control under such circumstances. 
Sponsors are encouraged to discuss the choice of control and other 
aspects of study design with CVM during the development of the 
protocol.
    In proposed Sec. 514.117(b)(4)(iii), FDA has modified the 
description of the active treatment concurrent control in the current 
Sec. 514.111(a)(5)(i)(a)(4)(iii) to make it consistent with such 
descriptions used elsewhere in the regulations. A demonstration of 
effectiveness by means of showing similarity of the new animal drug to 
an active control drug is an indirect demonstration of effectiveness 
because the active control treatment serves as an intermediary in the 
comparison between the new animal drug and the placebo. That is, it is 
presumed, without actually measuring it, that the active control would 
have been superior to the placebo if there had been a comparison 
between the active control and placebo. Under this study design, 
similarity of the new animal drug and active control drug can mean 
either that both were effective or that neither was effective. 
Therefore, FDA has specified that the analysis of the study must 
explain why the active control drug should be considered to have been 
effective in the completed study, for example, by reference to previous 
placebo-controlled studies of the active control drug. Although the 
active treatment concurrent control may be useful in studies where 
humane considerations are presumed paramount, a sponsor needs to 
carefully consider, based on the particular circumstances associated 
with a study, whether the use of an active treatment concurrent control 
(due to the greater number of animals often necessary to demonstrate 
effectiveness in an active control study) may be less humane than other 
controls. For example, use of an active control may require inducing a 
disease or condition in a greater number of animals than would be 
necessary with other types of controls and animals in the test (or 
control) group may suffer if the new animal drug (or control article) 
proves to be unsafe or ineffective.
    Consistent with the objective of the regulation on adequate and 
well-controlled studies to assure that there is a sufficiently detailed 
description of studies to allow proper scientific assessment and 
interpretation, the proposed definition of adequate and well-controlled 
studies states in Sec. 514.117(b)(2) that good study practices are to 
be followed in conducting such studies in the target animal species. An 
application for a new animal drug approval will, with respect to each 
study conducted in the target animal species, need to include a 
statement that the study was conducted in compliance with good study 
practices. Minor, inconsequential deviations from good study practices 
would not lead to the conclusion that the study did not comply with 
good study practices; rather, substantial compliance with good study 
practices would be considered compliance. FDA intends to establish this 
set of study standards when the agency proposes revisions to its INAD 
regulations; until regulations defining good study practices are 
finalized, the study report for an adequate and well-controlled study 
need not contain a statement describing adherence to good study 
practices. FDA intends to publish, as soon as possible, the revised 
INAD regulations, including the requirements of good study practices. 
The agency published in the Federal Register an advance notice of 
proposed rulemaking soliciting comments regarding proposed revisions to 
the INAD regulations and specifically requesting comments on defining 
``adequate and well-controlled'' (61 FR 59209). FDA is reopening 
elsewhere in this issue of the Federal Register docket number 96N-0411 
to receive comments specifically related to defining good study 
practices. The agency encourages interested parties to submit comments 
regarding good study practices to that docket and is considering 
additional forums in which interested parties can provide comments and 
discuss with FDA the general concepts of these regulations. In the 
interim, the clear reference in the proposed definition of adequate and 
well-controlled studies to a standard of conduct specifically designed 
for target animal studies, good study practices, should clear up any 
confusion that sponsors may have regarding the need to apply good 
laboratory practices to the conduct of field studies. It is the 
agency's intent that the referenced standard of conduct should be 
applied with sound scientific judgment. A study that is designed and 
conducted in a manner that is consistent with sound scientific 
principles and practices would generally not be rejected because of 
minor, inconsequential deviations from good study practices.
    Proposed Sec. 514.117 continues to anticipate that there may be 
limited circumstances in which a scientifically sound evaluation of a 
particular study is not precluded by certain flaws in the protocol for, 
or execution of, the study and provides for a procedure to seek a 
waiver from particular characteristics enumerated in the definition. 
However, because FDA believes that the agency's description of adequate 
and well-controlled studies has served satisfactorily as a basis for 
approval over time and contains the essential characteristics of such 
studies, FDA

[[Page 25155]]

concludes that any request for a waiver must be well-justified.
    All studies intended by the sponsor to be used to support an 
approval, including adequate and well-controlled studies to demonstrate 
effectiveness, must be designed, conducted, and reported in a manner 
which provides assurance that the study report and the underlying data 
are reliable and can be appropriately reviewed. Without such reliable 
data and information the agency cannot make the safety, effectiveness, 
and labeling determinations required for approval under the statue (See 
21 U.S.C. 360b(d).) FDA believes that generation of reliable data and 
information can best be accomplished by conducting adequate and well-
controlled studies under a documented program of quality assurance.
    The primary purpose of adequate and well-controlled studies is to 
determine whether the animal drug is effective. Therefore, adequate and 
well-controlled field studies must balance the need to control 
environmental and other factors with the need to observe the effects of 
the animal drug under closely approximated use conditions so that the 
true effect of the animal drug can be measured and an appropriate 
inference can be drawn regarding the effect of the animal drug in 
actual use. In general, as long as a study reflects a considered 
judgment regarding the study's appropriateness relative to particular 
scientific, ethical, and practical circumstances and the study is 
properly designed and conducted (e.g., it uses an appropriate control 
group, minimizes bias, and assures a sufficiently detailed description 
of the study to allow the application of a documented quality assurance 
process and subsequent scientific assessment and interpretation), the 
study will be considered by FDA in support of approval of an 
application.

III. Environmental Impact

    FDA has carefully considered the potential environmental impacts of 
this proposed rule. The agency has determined under 21 CFR 25.24(a)(8) 
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.

IV. Analysis of 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). The agency 
believes that this proposed rule is consistent with the regulatory 
philosophy and principles identified in the Executive Order. In 
addition, the proposed rule is not a significant regulatory action as 
defined by the Executive Order and so is not subject to review under 
the Executive Order.
    Section 2(e) of the ADAA requires FDA 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. Discussions between FDA and 
regulated industry during the development of the ADAA made it clear 
that the regulated industry is concerned that certain scientific 
principles and practices may be difficult to apply in testing new 
animal drugs under actual field conditions. FDA reviewed the essentials 
of adequate and well-controlled studies currently identified in 
Sec. 514.111(a)(5)(ii) and determined that these essentials continue to 
represent scientifically sound principles governing the conduct of 
adequate and well-controlled studies, whether conducted under 
laboratory or field conditions. However, FDA does agree that the 
practices followed in the conduct of adequate and well-controlled 
studies in the target animal under field conditions may need to be more 
flexible in some regards than the practices followed under laboratory 
conditions. Thus, the primary change in FDA's proposed definition of 
adequate and well-controlled studies is the definitions requirement 
that an adequate and well-control study conducted in the target animal 
be conducted in compliance with good study practices.
    The definition of adequate and well-controlled studies in proposed 
Sec. 514.117 has significance only within the context of the 
regulations governing investigational use and approval of new animal 
drugs. Because FDA has not issued revised INAD regulations to fully 
define good study practices and has not issued revised new animal drug 
application regulations, there will be little or no effect from this 
proposed rule on the level of effort currently expended by industry in 
testing the effectiveness of new animal drugs as part of the drug 
approval process. A thorough economic analysis will be conducted on the 
impact of proposed changes to the regulations governing INAD's, 
including provisions defining good study practices, and on the impact 
of proposed changes to the new animal drug application regulations in 
future proposals.
    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 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 
Commissioner of Food and Drugs 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.

V. 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.

Lists 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 
the 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: Secs. 501, 502, 512, 701, 721, 801 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 352, 360b, 371, 379e, 
381).

    2. Section 514.111 is amended by revising paragraph (a)(5) to read 
as follows:

Sec. 514.111  Refusal to approve an application.

    (a) * * *

[[Page 25156]]

    (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 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 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.
* * * * *
    3. New Sec. 514.117 is added to subpart B to read as follows:

Sec. 514.117  Adequate and well-controlled studies.

    (a) Purpose. The primary purpose of conducting adequate and well-
controlled studies of a new animal drug is to distinguish the effect of 
the new animal drug from other influences, such as spontaneous change 
in the course of the disease, normal animal production performance, or 
biased observation. One or more adequate and well-controlled studies 
are required to establish, by substantial evidence, that a new animal 
drug is effective. The characteristics described in paragraph (b) of 
this section have been developed over a period of years and are 
generally recognized as the essentials of an adequate and well-
controlled study. Well-controlled, as used in the phrase adequate and 
well-controlled, emphasizes an important aspect of adequacy. FDA 
considers these characteristics in determining whether a study is 
adequate and well-controlled for purposes of section 512 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). Reports of 
adequate and well-controlled studies, in addition to providing a basis 
for determining whether a new animal drug is effective, may also be 
needed to support claims of target animal safety. The report of an 
adequate and well-controlled study should provide sufficient details of 
study design, conduct, and analysis to allow critical evaluation and a 
determination of whether the characteristics of an adequate and well-
controlled study are present.
    (b) Characteristics. An adequate and well-controlled study has the 
following characteristics:
    (1) The protocol for the study (protocol) and the report of the 
study results (study report) must include a clear statement of the 
study objective(s).
    (2) Any study conducted in the target animal shall be conducted in 
compliance with the good study practices. The protocol contains a 
statement acknowledging the applicability of, and intention to follow, 
the good study practices for the conduct of the study. The study report 
contains a statement describing adherence to the good study practices.
    (3) The study is conducted with a new animal drug that is produced 
in accordance with appropriate manufacturing practices, which include, 
but are not necessarily limited to, the manufacture, processing, 
packaging, holding, and labeling of the new animal drug such that the 
critical characteristics of identity, strength, quality, purity, and 
physical form of the new animal drug are known, recorded, and 
reproducible, to permit meaningful evaluations of and comparisons with 
other studies conducted with the new animal drug. The physical form of 
a new animal drug includes the formulation and physical 
characterization (including delivery systems thereof, if any) of the 
new animal drug as presented to the animal. The protocol and study 
report must include an identification number which can be correlated 
with the specific formulation and production process used to 
manufacture the new animal drug used in the study.
    (4) The study uses a design that permits a valid comparison with 
one or more controls to provide a quantitative evaluation of drug 
effects. The protocol and the study report must describe the precise 
nature of the study design, e.g., duration of treatment periods, 
whether treatments are parallel, sequential, or crossover, and the 
determination of sample size. Within the broad range of studies 
conducted to support a determination of the effectiveness of a new 
animal drug, certain of the controls listed below would be appropriate 
and preferred depending on the study conducted:
    (i) Placebo concurrent control. The new animal drug is compared 
with an inactive preparation designed to resemble the new animal drug 
as far as possible.
    (ii) Untreated concurrent control. The new animal drug is compared 
with the absence of any treatment. The use of this control may be 
appropriate when objective measurements of effectiveness, not subject 
to observer bias, are available.
    (iii) Active treatment concurrent control. The new animal drug is 
compared with known effective therapy. The use of this control is 
appropriate when the use of a placebo control or of an untreated 
concurrent control would unreasonably compromise the welfare of the 
animals. Similarity of the new animal drug and the active control drug 
can mean either that both drugs were effective or that neither was 
effective. The study report should assess the ability of the study to 
have detected a difference between treatments. The evaluation of the 
study should explain why the new animal drugs should be considered 
effective in the study, for example, by reference to results in 
previous placebo-controlled studies of the active control.
    (iv) Historical control. The results of treatment with the new 
animal drug are quantitatively compared with experience historically 
derived from the adequately documented natural history of the disease 
or condition, or with a regimen (therapeutic, diagnostic, prophylactic) 
whose effectiveness is established, in comparable animals. Because 
historical control populations usually cannot be as well assessed with 
respect to pertinent variables as can concurrent control populations, 
historical control designs are usually reserved for special 
circumstances. Examples include studies in which the effect of the new 
animal drug is self-evident or studies of diseases with high and 
predictable mortality, or signs and symptoms of predictable duration or 
severity, or, in the case of prophylaxis, predictable morbidity.
    (5) The study uses a method of selecting animals that provides 
adequate assurances that the animals are suitable for the purposes of 
the study. For example, the animals can reasonably be expected to have 
animal production characteristics typical of the class(es) of animals 
for which the new animal drug is intended, there is adequate assurance 
that the animals have the disease or condition being studied, or, in 
the case of prophylactic agents, evidence of susceptibility and 
exposure to the condition against which prophylaxis is desired has been 
provided. The protocol and the study report describe the method of 
selecting animals for the study.
    (6) The study uses a method to assign a treatment or a control to 
each experimental unit of animals that is random and minimizes bias. 
Experimental units of animals are groups of animals that are comparable 
with respect to pertinent variables such as age, sex, class of animal, 
severity of disease, duration of disease, dietary regimen, level of 
animal production, and use of drugs or therapy other than the new 
animal drug. The protocol and the study report describe the method of

[[Page 25157]]

assignment of animals to an experimental unit to account for pertinent 
variables and method of assignment of a treatment or a control to the 
experimental units. When the effect of such variables is accounted for 
by an appropriate design, and when, within the same animal, effects due 
to the test drug can be obtained free of the effects of such variables, 
the same animal may be used for both the test drug and the control 
using the controls set forth in paragraph (b)(4) of this section.
    (7) The study uses methods to minimize bias on the part of 
observers and analysts of the data that are adequate to prevent undue 
influences on the results and interpretation of the study data. The 
protocol and study report explain the methods of observation and 
recording of the animal response variables and document the methods, 
such as ``blinding'' or ``masking,'' used in the study for excluding or 
minimizing bias in the observations.
    (8) The study uses methods to assess animal response that are well-
defined and reliable. The protocol and study report describe the 
methods for conducting the study, including any appropriate analytical 
and statistical methods, used to collect and analyze the data resulting 
from the conduct of the study, describe the criteria used to assess 
response, and, when appropriate, justify the selection of the methods 
to assess animal response.
    (9) There is an analysis and evaluation of the results of the study 
in accord with the protocol adequate to assess the effects of the new 
animal drug. The study report evaluates the methods used to conduct, 
and presents and evaluates the results of, the study as to their 
adequacy to assess the effects of the new animal drug. This evaluation 
of the results of the study assesses, among other items, the 
comparability of treatment and control groups with respect to pertinent 
variables and the effects of any interim analyses performed.
    (c) Waiver. The Director of the Center for Veterinary Medicine (the 
Director) may, on the Director's own initiative or on the petition of 
an interested person, waive in whole or in part any of the criteria in 
paragraph (b) of this section with respect to a specific study. A 
petition for a waiver is required to set forth clearly and concisely 
the specific criteria from which waiver is sought, why the criteria are 
not reasonably applicable to the particular study, what alternative 
procedures, if any, are to be, or have been employed, and what results 
have been obtained. The petition is also required to state why the 
studies so conducted will yield, or have yielded, substantial evidence 
of effectiveness, notwithstanding nonconformance with the criteria for 
which waiver is requested.
    (d) Uncontrolled studies. Uncontrolled studies or partially 
controlled studies, including studies for which the Director has 
granted a waiver, under paragraph (c) of this section, of the use of 
any necessary control described in paragraph (b)(4) of this section, 
are not acceptable as the sole basis for the approval of claims of 
effectiveness or target animal safety. Such studies, carefully 
conducted and documented, may provide corroborative support of adequate 
and well-controlled studies regarding effectiveness and may yield 
valuable data regarding safety of the new animal drug. Such studies 
will be considered on their merits in the light of the characteristics 
listed here. Isolated case reports, random experience, and reports 
lacking the details which permit scientific evaluation will not be 
considered.

    Dated: April 29, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-11846 Filed 5-7-97; 8:45 am]
BILLING CODE 4160-01-F