[Code of Federal Regulations]
[Title 21, Volume 6]
[Revised as of January 1, 2003]
From the U.S. Government Printing Office via GPO Access
[CITE: 21CFR514.117]

[Page 85-87]
 
                        TITLE 21--FOOD AND DRUGS
 
CHAPTER I--FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN 
                          SERVICES (CONTINUED)
 
PART 514--NEW ANIMAL DRUG APPLICATIONS--Table of Contents
 
            Subpart B--Administrative Actions on Applications
 
Sec.  514.117  Adequate and well-controlled studies.

    (a)  Purpose. The primary purpose of conducting adequate and well-
controlled studies of a new animal drug is to distinguish the effect of 
the new animal drug from other influences, such as spontaneous change in 
the course of the disease, normal animal production performance, or 
biased observation. One or more adequate and well-controlled studies are 
required to establish, by substantial evidence, that a new animal drug 
is effective. The characteristics described in paragraph (b) of this 
section have been developed over a period of years and are generally 
recognized as the essentials of an adequate and well-controlled study. 
Well controlled, as used in the phrase adequate and well controlled, 
emphasizes an important aspect of adequacy. The Food and Drug 
Administration (FDA) considers these characteristics in determining 
whether a study is adequate and well controlled for purposes of section 
512 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 
360b). Adequate and well-controlled studies, in addition to providing a 
basis for determining whether a new animal drug is effective, may also 
be relied upon to support target animal safety. The report of an 
adequate and well-controlled study should provide sufficient details of 
study design, conduct, and analysis to allow critical evaluation and a 
determination of whether the characteristics of an adequate and well-
controlled study are present.
    (b) Characteristics. An adequate and well-controlled study has the 
following characteristics:
    (1) The protocol for the study (protocol) and the report of the 
study results (study report) must include a clear statement of the study 
objective(s).
    (2) The study is conducted in accordance with an appropriate 
standard of conduct that addresses, among other issues, study conduct, 
study personnel, study facilities, and study documentation. The protocol 
contains a statement acknowledging the applicability of, and intention 
to follow, a standard of conduct acceptable to FDA. The study report 
contains a statement describing adherence to the standard.
    (3) The study is conducted with a new animal drug that is produced 
in accordance with appropriate manufacturing practices, which include, 
but are not necessarily limited to, the manufacture, processing, 
packaging, holding, and labeling of the new animal drug such that the 
critical characteristics of identity, strength, quality, purity, and 
physical form of the new animal drug are known, recorded, and 
reproducible, to permit meaningful evaluations of and comparisons with 
other studies conducted with the new animal drug. The physical form of a 
new animal drug includes the formulation and physical characterization 
(including delivery systems thereof, if any) of the new animal drug as 
presented to the animal. The protocol and study report must include an 
identification number which can be correlated with the specific 
formulation and production process used to manufacture the new animal 
drug used in the study.
    (4) The study uses a design that permits a valid comparison with one 
or more controls to provide a quantitative evaluation of drug effects. 
The protocol and the study report must describe the precise nature of 
the study design, e.g., duration of treatment periods, whether 
treatments are parallel, sequential, or crossover, and the determination 
of sample size. Within the broad range of studies conducted to support a 
determination of the effectiveness of a new animal drug, certain of the 
controls listed below would be appropriate and preferred depending on 
the study conducted:
    (i) Placebo concurrent control. The new animal drug is compared with 
an inactive preparation designed to resemble the new animal drug as far 
as possible.
    (ii) Untreated concurrent control. The new animal drug is compared 
with the absence of any treatment. The use of this control may be 
appropriate when 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

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the animals. Similarity of the new animal drug and the active control 
drug can mean either that both drugs were effective or that neither was 
effective. The study report should assess the ability of the study to 
have detected a difference between treatments. The evaluation of the 
study should explain why the new animal drugs should be considered 
effective in the study, for example, by reference to results in previous 
placebo-controlled studies of the active control.
    (iv) Historical control. The results of treatment with the new 
animal drug are quantitatively compared with experience historically 
derived from the adequately documented natural history of the disease or 
condition, or with a regimen (therapeutic, diagnostic, prophylactic) 
whose effectiveness is established, in comparable animals. Because 
historical control populations usually cannot be as well assessed with 
respect to pertinent variables as can concurrent control populations, 
historical control designs are usually reserved for special 
circumstances. Examples include studies in which the effect of the new 
animal drug is self-evident or studies of diseases with high and 
predictable mortality, or signs and symptoms of predictable duration or 
severity, or, in the case of prophylaxis, predictable morbidity.
    (5) The study uses a method of selecting animals that provides 
adequate assurances that the animals are suitable for the purposes of 
the study. For example, the animals can reasonably be expected to have 
animal production characteristics typical of the class(es) of animals 
for which the new animal drug is intended, there is adequate assurance 
that the animals have the disease or condition being studied, or, in the 
case of prophylactic agents, evidence of susceptibility and exposure to 
the condition against which prophylaxis is desired has been provided. 
The protocol and the study report describe the method of selecting 
animals for the study.
    (6) The study uses a method to assign a treatment or a control to 
each experimental unit of animals that is random and minimizes bias. 
Experimental units of animals are groups of animals that are comparable 
with respect to pertinent variables such as age, sex, class of animal, 
severity of disease, duration of disease, dietary regimen, level of 
animal production, and use of drugs or therapy other than the new animal 
drug. The protocol and the study report describe the method of 
assignment of animals to an experimental unit to account for pertinent 
variables and method of assignment of a treatment or a control to the 
experimental units. When the effect of such variables is accounted for 
by an appropriate design, and when, within the same animal, effects due 
to the test drug can be obtained free of the effects of such variables, 
the same animal may be used for both the test drug and the control using 
the controls set forth in paragraph (b)(4) of this section.
    (7) The study uses methods to minimize bias on the part of observers 
and analysts of the data that are adequate to prevent undue influences 
on the results and interpretation of the study data. The protocol and 
study report explain the methods of observation and recording of the 
animal response variables and document the methods, such as ``blinding'' 
or ``masking,'' used in the study for excluding or minimizing bias in 
the observations.
    (8) The study uses methods to assess animal response that are well 
defined and reliable. The protocol and study report describe the methods 
for conducting the study, including any appropriate analytical and 
statistical methods, used to collect and analyze the data resulting from 
the conduct of the study, describe the criteria used to assess response, 
and, when appropriate, justify the selection of the methods to assess 
animal response.
    (9) There is an analysis and evaluation of the results of the study 
in accord with the protocol adequate to assess the effects of the new 
animal drug. 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.

[[Page 87]]

    (c) Field studies. (1) Field conditions as used in this section 
refers to conditions which closely approximate the conditions under 
which the new animal drug, if approved, is intended to be applied or 
administered.
    (2) Studies of a new animal drug conducted under field conditions 
shall, consistent with generally recognized scientific principles and 
procedures, use an appropriate control that permits comparison, employ 
procedures to minimize bias, and have the characteristics generally 
described in paragraph (b) of this section. However, because field 
studies are conducted under field conditions, it is recognized that the 
level of control over some study conditions need not or should not be 
the same as the level of control in laboratory studies. While not all 
conditions relating to a field study need to be or should be controlled, 
observations of the conditions under which the new animal drug is tested 
shall be recorded in sufficient detail to permit evaluation of the 
study. Adequate and well-controlled field studies shall balance the need 
to control study conditions with the need to observe the true effect of 
the new animal drug under closely approximated actual use conditions.
    (d) Waiver. The Director of the Center for Veterinary Medicine (the 
Director) may, on the Director's own initiative or on the petition of an 
interested person, waive in whole or in part any of the criteria in 
paragraph (b) of this section with respect to a specific study. A 
petition for a waiver is required to set forth clearly and concisely the 
specific criteria from which waiver is sought, why the criteria are not 
reasonably applicable to the particular study, what alternative 
procedures, if any, are to be, or have been employed, and what results 
have been obtained. The petition is also required to state why the 
studies so conducted will yield, or have yielded, substantial evidence 
of effectiveness, notwithstanding nonconformance with the criteria for 
which waiver is requested.
    (e) Uncontrolled studies. Uncontrolled studies or partially 
controlled studies are not acceptable as the sole basis for the approval 
of claims of effectiveness or target animal safety. Such studies, 
carefully conducted and documented, may provide corroborative support of 
adequate and well-controlled studies regarding effectiveness and may 
yield valuable data regarding safety of the new animal drug. Such 
studies will be considered on their merits in light of the 
characteristics listed here. Isolated case reports, random experience, 
and reports lacking the details which permit scientific evaluation will 
not be considered.

[63 FR 10770, Mar. 5, 1998]