[Federal Register Volume 63, Number 43 (Thursday, March 5, 1998)]
[Rules and Regulations]
[Pages 10765-10772]
From the Federal Register Online via the Government Publishing 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
