[Federal Register Volume 63, Number 43 (Thursday, March 5, 1998)]
[Rules and Regulations]
[Pages 10765-10772]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 98-5675]


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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: 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 
regulations governing new animal drug applications to further define 
the term ``adequate and well-controlled studies.'' The purpose of this 
final rule is to further define ``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.

DATES: The regulations are effective on April 6, 1998.

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 18 months of its 
enactment, final 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. In an advance notice of proposed 
rulemaking that published in the Federal Register of November 21, 1996 
(61 FR 59209), FDA solicited comments from interested parties on how to 
further define ``adequate and well controlled as it relates to field 
studies.'' \1\ Docket No. 96N-0411 was created for comments responding 
to this notice.
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    \1\ The terms field investigation and field study are used 
interchangeably in this final rule.
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    In the Federal Register of May 8, 1997 (62 FR 25153), FDA proposed 
to amend its regulations in part 514 (21 CFR part 514) to further 
define the term ``adequate and well-controlled studies.'' FDA provided 
75 days for public comment on the proposed rule. Docket No. 97N-0141 
was created for comments regarding this proposed rule. As proposed, one 
of the characteristics of an adequate and well-controlled study is that 
such a study, when conducted in target animals, be conducted in 
compliance with ``good study practices'' (GSP's). Elsewhere in the 
Federal Register of May 8, 1997 (62 FR 25152), FDA reopened Docket No. 
96N-0411 and gave interested parties 30 days to comment on GSP's.
    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 course of 
disease and biased observation, so that it can be determined whether 
the drug is effective. This final rule defines the essential 
characteristics of adequate and well-controlled studies and explicitly 
addresses differences between field and laboratory studies.

II. Comments on the Proposed Rule

    FDA received two letters, one from the Animal Health Institute 
(AHI) and one from the Coalition for Animal Health (the Coalition), 
commenting on the proposed definition of ``adequate and well-controlled 
studies.'' FDA also received three letters in response to its reopening 
Docket No. 96N-0411 for comments specifically on GSP's. Comments 
relating to GSP's can be found in that docket. FDA met with 
representatives of the Coalition on June 11, 1997, and July 11, 1997, 
to discuss the proposed rule and GSP's. Those discussions were recorded 
in memoranda of meeting that have been placed in the docket for the 
proposed rule, Docket No. 97N-0141, and in Docket No. 96N-0411.
    In general, the comments agreed that the characteristics of an 
adequate and well-controlled study set forth in the proposed regulation 
represent sound scientific principles essential for adequate and well-
controlled studies. However, the comments criticized FDA's failure to 
address more explicitly in the proposed regulation the differences 
between field and laboratory studies and objected to FDA's reference to 
GSP's.

A. Section 514.117(a)

    1. AHI recommended that FDA clarify in proposed Sec. 514.117(a) 
that reports of adequate and well-controlled studies refer to reports 
of adequate and well-controlled ``effectiveness'' studies. Based on the 
following discussion, FDA does not find it necessary to make such a 
clarification.
    Under section 512(d)(1)(E) of the Federal Food, Drug, and Cosmetic 
Act (the act) (21 U.S.C. 360b(d)(1)(E)), FDA must refuse to approve a 
new animal drug application if there is a lack of substantial evidence 
that the drug will have the effect it is purported or represented to 
have under the conditions of use prescribed, recommended, or suggested 
in the proposed labeling. By definition, substantial evidence consists 
of one or more adequate and well-controlled studies on the basis of 
which experts qualified by scientific training and experience to 
evaluate the effectiveness of the drug could fairly and reasonably 
conclude that the drug will have the effect it purports or is 
represented to have under the conditions of use prescribed, 
recommended, or suggested in its proposed labeling (section 512(d)(3) 
of the act). Thus, it is clear and well established that adequate and 
well-

[[Page 10766]]

controlled studies are studies intended to determine whether or not a 
drug is effective.
    Because it is adequate and well-controlled studies and not just 
reports of adequate and well-controlled studies that provide a basis 
for determining whether a new animal drug is effective, and in some 
instances support a claim of target animal safety, FDA is deleting 
``Reports of'' in the second to last sentence in proposed 
Sec. 514.117(a).
    In that same sentence, FDA is also clarifying that adequate and 
well-controlled studies may be relied upon to support target animal 
safety but are not necessary to support claims of target animal safety. 
Studies intended to demonstrate safety need not be adequate and well-
controlled studies (see section 512(d)(1) of the act, which states that 
in order to secure approval of a new animal drug, a sponsor must 
conduct adequate tests by all methods reasonably applicable to show 
whether or not such drug is safe). In proposed Sec. 514.117(a), FDA 
intended only to note that adequate and well-controlled studies 
intended to demonstrate whether a new animal drug is effective may be 
designed in a manner that also permits sponsors to simultaneously 
collect target animal safety data. If a sponsor needs to demonstrate 
through a field study that a new animal drug is safe for use in the 
target animal, the sponsor may do so by adequate tests by methods that 
are reasonably applicable or as part of an adequate and well-controlled 
study that is designed to determine the effectiveness of the new animal 
drug. Accordingly the second to last sentence in Sec. 514.117(a) will 
now provide that 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.

B. Section 514.117(b)(2)

    Proposed Sec. 514.117(b)(2) would require that adequate and well-
controlled studies conducted in target animals be conducted in 
compliance with GSP's. In comments to Docket Nos. 96N-0411 and 97N-
0141, both the Coalition and AHI strongly opposed the inclusion by 
reference of GSP's and proposed that a specific provision addressing 
the differences between field and laboratory studies be added.
1. Objections to GSP's
    2. Although the Coalition is not opposed in concept to the 
development of a standard of conduct of studies in target animals, the 
Coalition believes that reference to ``good study practices'' should be 
removed from the further definition of adequate and well controlled and 
questions whether the standard of conduct must be codified into 
regulations or whether a guidance may be sufficient. In a submission to 
Docket No. 96N-0411 stating its objections to the inclusion of GSP's in 
the definition of adequate and well-controlled studies, AHI cited four 
concerns as follows: (1) GSP regulations are outside of the scope of 
the legislation; (2) establishing GSP's will improperly interfere with 
prompt implementation of the ADAA; (3) discussion of GSP's should be 
deferred until FDA and industry have adequate experience in using 
Guidance Document 58, ``Guidance for Industry for Good Target Animal 
Study Practices: Clinical Investigators and Monitors,'' issued by FDA's 
Center for Veterinary Medicine (CVM) in May 1997; and (4) GSP's could 
have a serious negative impact on current and future international 
harmonization efforts.
    AHI and the Coalition consider GSP's to be outside the scope of the 
ADAA because there is no requirement in the ADAA for GSP's, and because 
GSP's would apply to any study in the target animal. A study in the 
target animal may be conducted to evaluate the safety or the 
effectiveness of a new animal drug. The purpose of the ADAA was to 
responsibly streamline effectiveness requirements. It was not the 
intention of the ADAA to modify the standard for determining whether a 
new animal drug is safe. Thus, it is perceived by AHI and the Coalition 
that FDA acted outside the directives of the ADAA.
    FDA believed that it was in fact being responsive to the directives 
of the ADAA when it proposed GSP's as a new characteristic of adequate 
and well-controlled studies. As FDA explained in the preamble to the 
proposed regulation, the characteristics of an adequate and well-
controlled study listed in current Sec. 514.111(a)(5)(ii) remain sound 
scientific principles essential for all adequate and well-controlled 
studies. These principles, including use of an appropriate control and 
procedures to minimize bias, relate primarily to the design of an 
adequate and well-controlled study. At the same time, FDA acknowledged 
that the practices that apply to the testing of new animal drugs under 
field conditions may need to differ from the practices applied to the 
testing of new animal drugs under laboratory conditions. Good study 
practices was intended to be the standard of conduct specifically 
designed for field studies.
    The primary purpose of any adequate and well-controlled study is to 
distinguish, by comparison with appropriate controls, the effect of the 
new animal drug from other influences so that it can be determined 
whether or not the new animal drug is effective. A further purpose of 
an adequate and well-controlled field study is to observe the new 
animal drug's effects under conditions which closely approximate the 
conditions under which the new animal drug will be applied or 
administered. Thus, as discussed in the legislative history of the ADAA 
(H. Rept. 104-823, at 13 (1996)) and as FDA has repeatedly stated in 
discussions with the Coalition (see, e.g., Memorandum of July 11, 1997, 
meeting with the Coalition for Animal Health, Docket No. 97N-0141), it 
is not expected that sponsors need to or should control all 
environmental factors, husbandry practices, and other such factors in 
studies conducted under field conditions. Adequate and well-controlled 
field studies should balance the need to control the environment and 
other factors with the need to observe the drug's effects 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. Nonetheless, it is critical 
that the study documentation completely and accurately reflect the 
conditions under which the new animal drug was tested so that the 
sponsor and FDA can properly evaluate the study results.
    The purpose of requiring compliance with GSP's as a characteristic 
of an adequate and well-controlled study in the proposed rule was to 
make it clear that it was not FDA's expectation that the standard of 
conduct for laboratory studies applied to the conduct of studies under 
field conditions. By virtue of its inclusion in the definition of 
adequate and well controlled, the applicability of the standard was 
limited to any study in the target animal intended to demonstrate the 
effectiveness of the new animal drug. FDA did not provide further 
definition of GSP's as part of the definition of adequate and well 
controlled because FDA believes, as the Coalition notes in its July 22, 
1997, comments to Docket No. 97N-0141, that GSP's represent a 
significant new regulatory concept that requires serious consideration 
and discussion. Thus, FDA reopened Docket No. 96N-0411 to receive 
comments from interested parties.
    In response to comments opposing the inclusion of GSP's in the 
definition of adequate and well-controlled studies, FDA is removing the 
reference in Sec. 514.117(b)(2) to GSP's and replacing it

[[Page 10767]]

with a reference to ``an appropriate standard.'' By referencing an 
appropriate standard, Sec. 514.117(b)(2) allows the application of Good 
Laboratory Practices (GLP's) to adequate and well-controlled laboratory 
studies and the application of an as yet to be defined standard of 
conduct to adequate and well-controlled field studies. Until a guidance 
or regulations defining the appropriate standard of conduct for 
conducting adequate and well-controlled studies under field conditions 
are finalized, FDA will, on its own initiative, waive the requirement 
for compliance with an appropriate standard of conduct for field 
studies (Sec. 514.117(d)) and the study report for an adequate and 
well-controlled study need not contain a statement describing adherence 
to an appropriate standard. In the meantime, sponsors can continue to 
refer to FDA's guidance, ``Good Target Animal Study Practices: Clinical 
Investigators and Monitors,'' for guidance regarding the 
responsibilities of investigators and monitors who conduct clinical 
studies.
    Issues to be resolved regarding the development of an appropriate 
standard of conduct include: (1) What the standard of conduct for field 
studies should be, (2) whether the standard of conduct should be 
defined in guidance or by regulation, and (3) whether the standard of 
conduct should be applied to field studies intended to demonstrate the 
safety of the new animal drug as well as to adequate and well-
controlled field studies intended to demonstrate the effectiveness of 
the new animal drug.
    Although the definition of adequate and well-controlled studies 
only applies to studies intended to demonstrate the effectiveness of a 
new animal drug, FDA believes that it is logical that there should be 
one standard for the conduct of all field studies. The agency believes 
this to be true because it is the fact that a field study is conducted 
under field conditions--and not whether the field study is intended to 
demonstrate safety or effectiveness--that gives rise to the need for a 
different standard.
    In a Federal Register notice dated May 8, 1997, that reopened the 
comment period for Docket No. 96N-0411 and in meetings with the 
Coalition, FDA asked interested parties to provide FDA with specific 
examples of how field studies and laboratory studies differ so that FDA 
can develop a reasonable and appropriate standard of conduct for field 
studies. No such examples have been provided by any interested parties. 
FDA intends to continue its efforts to obtain relevant information from 
interested parties.
    As FDA considers further the development of a standard of conduct 
for field studies, FDA will evaluate its experience in implementing the 
guidance ``Good Target Animal Study Practices: Clinical Investigators 
and Monitors.'' However, FDA contemplates that the standard of conduct 
for field studies will also address issues such as facilities and 
equipment in addition to those issues addressed in the guidance. 
Because FDA recognizes the importance of efforts to achieve 
international harmonization, FDA will also take into consideration the 
work of the International Cooperation on Harmonisation of Technical 
Requirements for Registration of Veterinary Medicinal Products (VICH), 
the body responsible for the harmonization of technical requirements 
for the registration of veterinary medicinal products, relating to the 
development of standards of conduct for field studies.
2. Explicit Provision to Address Differences Between Field and 
Laboratory Studies
    3. AHI and the Coalition maintain that the further definition of 
adequate and well controlled should more explicitly take into account 
practical conditions in the field and the differences between field and 
laboratory conditions. In its July 22, 1997, comment to Docket No. 97N-
0141, the Coalition, on behalf of its member national trade 
associations including AHI, proposed for inclusion in Sec. 514.117 a 
paragraph to address the differences between adequate and well-
controlled field and laboratory studies. The proposed paragraph read:
    Field Investigation. It is recognized that under field 
conditions, there may be less opportunity for blinding or other 
traditional non-field controls, such as concurrent placebo or 
untreated groups. The nature of field trials may preclude the use of 
a concurrent control group; thus the animal may serve as its own 
control in selected situations. While the general principles in 
subparagraph (1) are applicable to a field investigation, conditions 
on farms, ranches, other animal husbandry operations, and veterinary 
private practices are such that the same degree of precision with 
regard to environmental management and documentation of all 
variables cannot be maintained, as when the trials are conducted on 
sponsor-owned premises. Controls and documentation must be 
sufficient to evaluate the investigation, permit the application of 
statistical methods of evaluation and permit the documentation to be 
audited.
    In response to comments requesting the inclusion of a more explicit 
provision to address the differences between field and laboratory 
studies, FDA is revising Sec. 514.117 by redesignating paragraphs (c) 
and (d) as paragraphs (d) and (e), respectively, and is adding a new 
paragraph (c). As revised, Sec. 514.117(c) more explicitly addresses 
the differences between field and laboratory studies.
    Unlike the Coalition's suggested language, FDA's provision 
describing field studies does not discuss at length the use of controls 
in field studies but instead requires the use of an appropriate 
control. As discussed in the preamble to the proposed rule (62 FR 25153 
at 25154), 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. Section 514.117(b)(6) already 
states that when the effect of 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 other therapy 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. Consistent with the discussion in the 
preamble to the proposed rule (62 FR 25153 at 25155) and the American 
Veterinary Medical Association's comments submitted to Docket No. 96N-
0411, FDA's provision reflects the need for field studies to balance 
the need to control the environment and other factors with the need to 
observe the drug's performance under actual conditions of use.

C. Section 514.117(b)(3)

    4. AHI questioned why the requirements of current 
Sec. 514.111(a)(3) were changed and greatly expanded by proposed 
Sec. 514.117(b)(3).
    Current Sec. 514.111(a)(3) lists one of the grounds on which FDA 
may refuse to approve a new animal drug application. Specifically, FDA 
may refuse to approve a new animal drug application if the methods used 
in and the facilities and controls used for the manufacture, 
processing, and packaging of such drug are inadequate to preserve its 
identity, strength, quality, and purity. Proposed Sec. 514.117(b)(3) 
does not expand upon the requirements of this section.
    Proposed Sec. 514.117(b)(3) describes a characteristic of an 
adequate and well-controlled study and was intended to correspond to 
current Sec. 514.111(a)(5)(ii)(b) which provides that the test drug 
must be standardized in order for a study to be considered adequate. 
FDA did not provide an explanation of this section because it believed 
the provision to be clear on its face. The identity, strength, quality, 
and purity of a new animal drug being tested

[[Page 10768]]

in a particular study must be known and be reproducible. Knowledge of 
this information permits meaningful evaluation of the effectiveness of 
the new animal drug and allows the appropriate comparison of 
effectiveness studies in which different formulations of the new animal 
drug are used. Furthermore, the sponsor of the new animal drug must be 
able to demonstrate the equivalency of the formulation of the new 
animal drug proposed for marketing to the formulations used in the 
study or studies supporting effectiveness and safety. Therefore, FDA 
has finalized Sec. 514.117(b)(3) as proposed.

D. Section 514.117(b)(4)

    5. AHI commented that the list of acceptable study controls should 
not be ranked and the controls used should be ``appropriate to the 
scientific objectives of the study.'' AHI believes that justification 
for the use of each type of control is preferable to a ranking system 
that may erroneously give the impression that one type of control is 
always preferred over others.
    FDA lists the acceptable types of controls in descending order, 
roughly in accordance with the ease of interpretation of the associated 
studies. Sponsors should not ascribe unintended meaning to the order in 
which the controls are listed. As discussed in the preamble to the 
proposed rule (62 FR 25153 at 25154), FDA believes that there may be 
good reasons for using different types of controls in study designs for 
particular situations and that the sponsor's choice of the type of 
control used in a particular study should be based on the scientific, 
ethical, and practical circumstances associated with that particular 
study. Therefore, the selection of the proper control is best addressed 
in discussions between FDA and the sponsor during protocol development.
    6. AHI objected to FDA's inclusion in the preamble to the proposed 
rule of examples of when a specific type of control may not be 
appropriate. AHI asserted that humane considerations are always taken 
into account by the sponsor during the design phase of the study.
    FDA did not include in the preamble examples of when specific types 
of controls may not be appropriate, rather FDA identified circumstances 
to be considered when choosing the type of control to be used in any 
particular study. An important consideration in choosing the type of 
control to be used is the humane treatment of the investigational 
animals, including control animals. FDA wanted to remind sponsors and 
the owners of investigational animals that considerations relating to 
the humane treatment of investigational animals require more than 
considering treatment versus no treatment. Notably, the use of an 
active control sometimes requires inducing a disease or condition in a 
greater number of animals than would be necessary with other types of 
controls, thus, a greater number of animals may suffer if the new 
animal drug proves to be unsafe or ineffective.
    7. AHI believes that the proposed rule unfairly biases the value of 
active treatment controls. AHI noted that it is difficult, if not 
impossible, to find clinicians or owners who will allow studies 
conducted on an owner's animals with a placebo or no treatment. AHI 
noted further that the proposed rule implies that the only active 
controls that may be used are those drugs that have been tested in 
placebo-controlled studies. AHI objected to any limitation on the use 
of an approved drug as an active control, regardless of how it was 
approved, i.e., without data from a study with a placebo control.
    It is not FDA's intent to express a bias against studies using 
active treatment controls. The overriding principle to be followed in 
selecting a type of control is to select a control that is appropriate 
to the scientific, ethical, and practical circumstances associated with 
the particular study. However, from a scientific standpoint, 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 and necessarily involves making assumptions that do 
not need to be made in studies with controls that permit a direct 
demonstration of effectiveness. For example, it must be presumed that 
the active control would have been superior to a placebo if there had 
been a comparison. Thus, if the particular circumstances of a study do 
not dictate a need for an active control, it is usually easier to 
interpret the results of studies using placebo or untreated controls.
    It is understandable that clinicians and owners of investigational 
animals, including control animals, may be reluctant to participate in 
studies using placebo or untreated controls when a new animal drug is 
intended to cure, mitigate, treat, or prevent disease. Nonetheless, it 
is up to the sponsor to select, based on the particular circumstances 
of the study, the appropriate control and to obtain the informed 
consent of each owner who authorizes the use of their animal in the 
study.
    In those instances in which a new animal drug is intended to affect 
the structure or function of the animal's body by increasing feed 
efficiency or weight gain (production animal drugs), it is much less 
clear why clinicians or owners would object to the participation of 
animals in studies using placebo or untreated controls, because there 
is no potential for animal suffering if the new animal drug is not 
administered or applied to the particular animal. In fact, the health 
of an animal could be compromised by the administration or application 
of the new animal drug if there are side effects from the 
investigational use of the new animal drug. Furthermore, because the 
effects of production animal drugs are generally small, they are more 
difficult to measure, and it can be expected that even active drugs 
will not prove effective in all studies. Studies involving placebo or 
untreated controls may be the only way to evaluate such treatments.
    Use of active treatment controls in studies to evaluate the 
effectiveness of a production animal drug are likely to require the 
participation of a very large number of animals if, indeed, such 
controls are credible at all. In any instance in which a sponsor 
chooses to use an active treatment control, the sponsor should justify 
the need to use such a control.
    Because comparison with an active treatment control establishes 
only that the new animal drug is more or less effective than, or as 
effective as, the active control, before FDA can evaluate the study FDA 
must know that the active treatment control is effective. One way, but 
not the only way, to provide information to FDA about the effectiveness 
of the active treatment control is to reference previous placebo-
controlled studies of the active control drug. When such studies are 
not available, a sponsor should justify the choice of active treatment 
control and explain how it can be known that the active control drug 
was effective in the study.

E. Section 514.117(b)(5)

    8. Proposed Sec. 514.117(b)(5) would require that adequate and 
well-controlled studies use a method of selecting animals that provides 
adequate assurances that the animals are suitable for the purposes of 
the study. AHI believes that examples cited in the characteristic are 
too specific for inclusion in a regulation and should be eliminated. 
AHI notes that criteria for selection should be established on a case-
by-case basis during the protocol review.

[[Page 10769]]

    FDA does not agree that the examples provided in proposed 
Sec. 514.117(b)(5) are too specific. The examples represent generally 
some of the criteria to be considered in selecting animals. The 
examples are drawn from, and clarify FDA's interpretation of, current 
Sec. 514.111(a)(5)(ii)(a)(2)(i). FDA agrees that the criteria for 
selecting animals suitable for a study should be determined on a case-
by-case basis during protocol development and nothing in the examples 
precludes such case-by-case determination.

F. Section 514.117(b)(6)

    9. AHI believes that FDA has expanded the ``pertinent variables'' 
used to judge whether experimental units of animals are comparable and 
that such expansion is unnecessary.
    The only difference in the list of pertinent variables described in 
proposed Sec. 514.117(b)(6) from those variables listed in current 
Sec. 514.111(a)(5)(ii)(a)(2)(iii) is the use of the phrase ``class of 
animal'' in place of the term ``species'' and the listing of ``dietary 
management'' and ``level of animal production'' in place of 
``management practices.'' These substitutions represent a 
clarification, not expansion, of the list of variables. FDA is 
retaining Sec. 514.117(b)(6) as proposed.

G. Section 514.117(b)(7)

    10. AHI has asked for clarification of how FDA is interpreting the 
phrase ``analysts of the data'' under Sec. 514.117(b)(7).
    As used in proposed Sec. 514.117(b)(7), ``observers'' of data 
refers to those individuals who, on behalf of the investigator or 
sponsor, observe, collect, or record data and information as part of 
the conduct of an adequate and well-controlled study. This would 
include individuals who analyze specimens and samples (including the 
new animal drug and animal feed bearing or containing the new animal 
drug) which are collected as part of such a study. In contrast, 
``analysts'' of data refers to those individuals who, on behalf of the 
sponsor or investigator, analyze the data and information collected and 
recorded during the conduct of an adequate and well-controlled study. 
Both observers and analysts of the data would be expected to perform 
their functions in a manner which minimizes bias. For example, 
observers of the data should be ``blinded'' or ``masked'' at all times, 
while analysts of the data should maintain such ``blinding'' or 
``masking'' as long as reasonable or practical.

H. Data Variations

    11. AHI recommended that the definition of adequate and well-
controlled studies include a new subsection entitled ``Data 
variations'' to explain that nonsystematic errors or omissions 
generally will not disqualify a study as being adequate and well 
controlled for purposes of establishing that a drug is effective for 
use as described in the proposed labeling. Data variations would be 
subject to review and would require an explanation.
    FDA does not find it necessary to create a provision to address 
data variations. FDA has not, nor does FDA intend to, disqualify 
studies as not being adequate and well controlled based solely on a 
finding of nonsystematic errors or omissions, i.e., random human error, 
that are explained and do not affect the integrity of the study. 
Furthermore, sponsors may ask the Director of CVM to waive the 
requirement to meet a specific characteristic of an adequate and well-
controlled study with respect to a specific study and still accept that 
study as an adequate and well-controlled study.

I. Uncontrolled Studies

    12.As discussed in section II.B.1 of this document, proposed 
Sec. 514.117(d), which describes how uncontrolled studies would be 
considered by FDA, has been redesignated in this final rule as 
Sec. 514.117(e). FDA and the Coalition agree that regardless of the 
differences between field and laboratory studies, a control group 
(placebo, untreated, active treatment, or historical) is always needed 
for a laboratory or a field study to be an adequate and well-controlled 
study (see Memorandum of July 11, 1997, meeting with the Coalition for 
Animal Health, at 2, Docket No. 97N-0141). Not only is a study without 
a control group not acceptable as the sole basis for the approval of 
claims of effectiveness, such a study does not permit scientific 
evaluation of claims of effectiveness. Accordingly, the phrase 
``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,'' in the first sentence 
in proposed Sec. 514.117(d) was erroneous. FDA is revising 
Sec. 514.117(e) to remove this phrase. Thus, Sec. 514.117(e) is the 
same as current Sec. 514.11(a)(5)(ii)(c).

J. Quality Assurance

    13. AHI inquired whether reference to a ``documented quality 
assurance process or program'' is a reference to a quality assurance 
function and not a specific, defined quality assurance unit as required 
in 21 CFR 58.35.
    In the preamble to the proposed rule (62 FR 25153 at 25155), FDA 
stated that it 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. FDA 
is primarily concerned that sponsors develop and implement a quality 
assurance process that is carried out in accordance with the well-
established principles of quality assurance. A well-established 
principle of quality assurance is that personnel responsible for 
quality assurance should be independent from those personnel 
responsible for the development of new animal drugs, including the 
conduct and monitoring of the study. Personnel responsible for quality 
assurance may or may not function as a ``unit.''

III. Environmental Impact

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

IV. 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 following analysis 
demonstrates that the final rule is not an economically significant 
regulatory action as defined by the Executive Order and is consistent 
with the regulatory philosophy and principles identified in 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

[[Page 10770]]

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 determined 
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 practices followed under 
laboratory conditions.
    In its proposed rule published in the May 8, 1997, Federal 
Register, FDA proposed to amend its regulations in part 514 to further 
define the term ``adequate and well-controlled studies'' to allow for 
more flexibility in the practices followed in the conduct of adequate 
and well-controlled studies in the target animal under field 
conditions. Specifically, FDA proposed to incorporate by reference 
GSP's, that is, the practices to be followed in conducting studies in 
target animals under field conditions.
    FDA received several letters from industry groups commenting on the 
proposed definition of ``adequate and well-controlled studies.'' Some 
of the comments criticized the rule for its failure to explicitly 
address the difference between field and laboratory studies and 
objected to FDA's reference to GSP's. In response to these comments, 
FDA has removed the references to GSP's and added language to the rule 
that will more explicitly address the differences between field and 
laboratory studies.
    The definition of adequate and well-controlled studies has 
significance only within the context of the regulations governing 
investigational use and approval of new animal drugs. Because FDA has 
issued neither revised new animal drugs for investigational use 
regulations nor revised new animal drug applications regulations, there 
will be little or no effect on the level of effort expended by industry 
in testing the effectiveness of new animal drugs as part of the animal 
drug approval process. FDA did not receive any comments on its estimate 
of impacts for the proposal, which reached an identical conclusion. The 
agency notes that a thorough economic analysis will be conducted on the 
impact of proposed changes to the regulations governing investigational 
use new animal drugs and 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 
final regulation will not impose significant new costs on any firms, 
under the Regulatory Flexibility Act (5 U.S.C. 605(b)), the agency 
certifies that the final rule will not have a significant economic 
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 issuing any final 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 final 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 
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 514.111 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 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. 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

[[Page 10771]]

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 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.
    (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

[[Page 10772]]

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.

    Dated: February 25, 1998.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 98-5675 Filed 3-4-98; 8:45 am]
BILLING CODE 4160-01-F