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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 514

[Docket No. 97N-0141]

Adequate and Well-Controlled Studies for Investigational Use and

Approval of New Animal Drugs

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA), as directed by the

Animal Drug Availability Act of 1996 (ADAA), is publishing a proposed

regulation to further define the term ``adequate and well-controlled''

to require that field investigations be designed and conducted in a

scientifically sound manner. Elsewhere in this issue of the Federal

Register, FDA is reopening docket number 96N-0411 to receive comments

regarding a concept, ``good study practices,'' that is related to the

definition of adequate and well-controlled studies.

DATES: Written comments by July 22, 1997.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Herman M. Schoenemann, Center for

Veterinary Medicine (HFV-126), Food and Drug Administration, 7500

Standish Pl., Rockville, MD 20855, 301-594-1638.

SUPPLEMENTARY INFORMATION:

I. Background

Congress enacted the ADAA (Pub. L. 104-250) on October 9, 1996.

Section 2(e) of the ADAA directs FDA to issue, within 6 months of its

enactment, proposed regulations to further define the term ``adequate

and well-controlled'' to require that field investigations be designed

and conducted in a scientifically sound manner, taking into account

practical conditions in the field and differences between field

conditions and laboratory conditions. Although FDA believes that the

definition of adequate and well-controlled is meaningful only when

considered within the context of the entire set of regulations that

govern the investigational use and approval of new animal drugs, FDA is

publishing this proposed definition of adequate and well-controlled

studies separately because of the statutory timeframe set forth in the

ADAA. FDA intends to issue proposed revised investigational use new

animal drug (INAD) regulations followed by proposed revised regulations

governing new animal drug applications. These proposals, intended to

further implement the ADAA and the Center for Veterinary Medicine's

(CVM) commitment to reinvent the animal drug approval process and

facilitate the approval of new animal drugs, will give context to the

definition of adequate and well-controlled studies.

II. Adequate and Well-Controlled Studies

FDA has long considered that the characteristics embodied in 21 CFR

314.126 and Sec. 514.111(a)(5)(ii) (21 CFR 514.111(a)(5)(ii)) are the

essentials of an adequate and well-controlled study. Discussions held

between FDA and members of the Coalition for Animal Health (Coalition)

prior to enactment of the ADAA and comments from the Animal Health

Institute in response to the advance notice of proposed rulemaking

published November 21, 1996 (61 FR 59209), made it clear that some

members of the regulated industry are concerned that certain scientific

principles and practices may be difficult to apply in testing new

animal drugs under field conditions. In response, FDA evaluated the

extent to which the characteristics in Sec. 514.111(a)(5)(ii) represent

sound scientific principles essential for adequate and well-controlled

studies. After careful consideration of the characteristics in light of

the concerns expressed, FDA believes that the characteristics set forth

in Sec. 514.111(a)(5)(ii), with minor modifications, remain sound

scientific principles essential for all adequate and well-controlled

studies whether conducted under laboratory or field conditions. (See

definition of substantial evidence, section 512(d)(3) of the Federal

Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b(d)(3))). The

agency is proposing to replace current Sec. 514.111(a)(5)(ii) with new

proposed Sec. 514.117, which contains minor revisions to the current

regulation on adequate and well-controlled studies.

The primary purpose of conducting adequate and well-controlled

studies is, and has always been, to distinguish the effect of the drug

from other influences, such as spontaneous change in the

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course of disease and biased observation, so that a determination can

be made whether the drug is effective. Thus, FDA's objectives in

defining adequate and well-controlled studies remain unchanged. In the

Federal Register of February 22, 1985 (50 FR 7452), FDA stated that the

regulation defining adequate and well-controlled studies has two

primary objectives: ``(1) to allow the agency to assess methods for

minimizing bias; and (2) to assure a sufficiently detailed description

of the study to allow scientific assessment and interpretation of it.''

These principles continue to apply whether a study is conducted on a

drug intended for use in animals or humans or whether the study is

conducted under laboratory or field conditions.

To satisfy the objective of minimizing bias, the use of appropriate

controls in a study design is of critical importance. Therefore,

proposed Sec. 514.117(b)(4) lists the acceptable types of controls that

may be used when conducting adequate and well-controlled studies. FDA

has listed the types of controls in descending order--roughly in

accordance with the ease of interpretation of associated studies. FDA

believes that there may be good reasons for using different types of

controls in study designs for particular situations and that the

regulation is sufficiently flexible to accommodate the needs of

sponsors in this respect. As a matter of past practice, FDA has

approved products whose effectiveness was established on the basis of

studies utilizing each of the controls listed in the proposed

definition of adequate and well-controlled studies.

The sponsor's choice of the type of control used in a study should

be based on the scientific, ethical, and practical circumstances

associated with that particular study. This decision should integrate,

among other considerations, information such as the claim being made

for the drug, the nature of the new animal drug, the animal population

for which the animal drug is intended, and the number of animals

necessary to demonstrate effectiveness. As long as the sponsor's choice

is scientifically justifiable and the studies are properly designed and

conducted, the approvability of the application will not be affected by

the choice of control. Nothing in the proposed regulation prohibits an

animal from serving as its own control under such circumstances.

Sponsors are encouraged to discuss the choice of control and other

aspects of study design with CVM during the development of the

protocol.

In proposed Sec. 514.117(b)(4)(iii), FDA has modified the

description of the active treatment concurrent control in the current

Sec. 514.111(a)(5)(i)(a)(4)(iii) to make it consistent with such

descriptions used elsewhere in the regulations. A demonstration of

effectiveness by means of showing similarity of the new animal drug to

an active control drug is an indirect demonstration of effectiveness

because the active control treatment serves as an intermediary in the

comparison between the new animal drug and the placebo. That is, it is

presumed, without actually measuring it, that the active control would

have been superior to the placebo if there had been a comparison

between the active control and placebo. Under this study design,

similarity of the new animal drug and active control drug can mean

either that both were effective or that neither was effective.

Therefore, FDA has specified that the analysis of the study must

explain why the active control drug should be considered to have been

effective in the completed study, for example, by reference to previous

placebo-controlled studies of the active control drug. Although the

active treatment concurrent control may be useful in studies where

humane considerations are presumed paramount, a sponsor needs to

carefully consider, based on the particular circumstances associated

with a study, whether the use of an active treatment concurrent control

(due to the greater number of animals often necessary to demonstrate

effectiveness in an active control study) may be less humane than other

controls. For example, use of an active control may require inducing a

disease or condition in a greater number of animals than would be

necessary with other types of controls and animals in the test (or

control) group may suffer if the new animal drug (or control article)

proves to be unsafe or ineffective.

Consistent with the objective of the regulation on adequate and

well-controlled studies to assure that there is a sufficiently detailed

description of studies to allow proper scientific assessment and

interpretation, the proposed definition of adequate and well-controlled

studies states in Sec. 514.117(b)(2) that good study practices are to

be followed in conducting such studies in the target animal species. An

application for a new animal drug approval will, with respect to each

study conducted in the target animal species, need to include a

statement that the study was conducted in compliance with good study

practices. Minor, inconsequential deviations from good study practices

would not lead to the conclusion that the study did not comply with

good study practices; rather, substantial compliance with good study

practices would be considered compliance. FDA intends to establish this

set of study standards when the agency proposes revisions to its INAD

regulations; until regulations defining good study practices are

finalized, the study report for an adequate and well-controlled study

need not contain a statement describing adherence to good study

practices. FDA intends to publish, as soon as possible, the revised

INAD regulations, including the requirements of good study practices.

The agency published in the Federal Register an advance notice of

proposed rulemaking soliciting comments regarding proposed revisions to

the INAD regulations and specifically requesting comments on defining

``adequate and well-controlled'' (61 FR 59209). FDA is reopening

elsewhere in this issue of the Federal Register docket number 96N-0411

to receive comments specifically related to defining good study

practices. The agency encourages interested parties to submit comments

regarding good study practices to that docket and is considering

additional forums in which interested parties can provide comments and

discuss with FDA the general concepts of these regulations. In the

interim, the clear reference in the proposed definition of adequate and

well-controlled studies to a standard of conduct specifically designed

for target animal studies, good study practices, should clear up any

confusion that sponsors may have regarding the need to apply good

laboratory practices to the conduct of field studies. It is the

agency's intent that the referenced standard of conduct should be

applied with sound scientific judgment. A study that is designed and

conducted in a manner that is consistent with sound scientific

principles and practices would generally not be rejected because of

minor, inconsequential deviations from good study practices.

Proposed Sec. 514.117 continues to anticipate that there may be

limited circumstances in which a scientifically sound evaluation of a

particular study is not precluded by certain flaws in the protocol for,

or execution of, the study and provides for a procedure to seek a

waiver from particular characteristics enumerated in the definition.

However, because FDA believes that the agency's description of adequate

and well-controlled studies has served satisfactorily as a basis for

approval over time and contains the essential characteristics of such

studies, FDA

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concludes that any request for a waiver must be well-justified.

All studies intended by the sponsor to be used to support an

approval, including adequate and well-controlled studies to demonstrate

effectiveness, must be designed, conducted, and reported in a manner

which provides assurance that the study report and the underlying data

are reliable and can be appropriately reviewed. Without such reliable

data and information the agency cannot make the safety, effectiveness,

and labeling determinations required for approval under the statue (See

21 U.S.C. 360b(d).) FDA believes that generation of reliable data and

information can best be accomplished by conducting adequate and well-

controlled studies under a documented program of quality assurance.

The primary purpose of adequate and well-controlled studies is to

determine whether the animal drug is effective. Therefore, adequate and

well-controlled field studies must balance the need to control

environmental and other factors with the need to observe the effects of

the animal drug under closely approximated use conditions so that the

true effect of the animal drug can be measured and an appropriate

inference can be drawn regarding the effect of the animal drug in

actual use. In general, as long as a study reflects a considered

judgment regarding the study's appropriateness relative to particular

scientific, ethical, and practical circumstances and the study is

properly designed and conducted (e.g., it uses an appropriate control

group, minimizes bias, and assures a sufficiently detailed description

of the study to allow the application of a documented quality assurance

process and subsequent scientific assessment and interpretation), the

study will be considered by FDA in support of approval of an

application.

III. Environmental Impact

FDA has carefully considered the potential environmental impacts of

this proposed rule. The agency has determined under 21 CFR 25.24(a)(8)

that this action is of a type that does not individually or

cumulatively have a significant effect on the human environment.

Therefore, neither an environmental assessment nor an environmental

impact statement is required.

IV. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and under the Regulatory Flexibility Act (5 U.S.C. 601-

612). Executive Order 12866 directs agencies to assess all costs and

benefits of available regulatory alternatives and, when regulation is

necessary, to select regulatory approaches that maximize net benefits

(including potential economic, environmental, public health and safety,

and other advantages; distributive impacts; and equity). The agency

believes that this proposed rule is consistent with the regulatory

philosophy and principles identified in the Executive Order. In

addition, the proposed rule is not a significant regulatory action as

defined by the Executive Order and so is not subject to review under

the Executive Order.

Section 2(e) of the ADAA requires FDA to further define the term

``adequate and well-controlled'' to require that field investigations

be designed and conducted in a scientifically sound manner, taking into

account practical conditions in the field and differences between field

conditions and laboratory conditions. Discussions between FDA and

regulated industry during the development of the ADAA made it clear

that the regulated industry is concerned that certain scientific

principles and practices may be difficult to apply in testing new

animal drugs under actual field conditions. FDA reviewed the essentials

of adequate and well-controlled studies currently identified in

Sec. 514.111(a)(5)(ii) and determined that these essentials continue to

represent scientifically sound principles governing the conduct of

adequate and well-controlled studies, whether conducted under

laboratory or field conditions. However, FDA does agree that the

practices followed in the conduct of adequate and well-controlled

studies in the target animal under field conditions may need to be more

flexible in some regards than the practices followed under laboratory

conditions. Thus, the primary change in FDA's proposed definition of

adequate and well-controlled studies is the definitions requirement

that an adequate and well-control study conducted in the target animal

be conducted in compliance with good study practices.

The definition of adequate and well-controlled studies in proposed

Sec. 514.117 has significance only within the context of the

regulations governing investigational use and approval of new animal

drugs. Because FDA has not issued revised INAD regulations to fully

define good study practices and has not issued revised new animal drug

application regulations, there will be little or no effect from this

proposed rule on the level of effort currently expended by industry in

testing the effectiveness of new animal drugs as part of the drug

approval process. A thorough economic analysis will be conducted on the

impact of proposed changes to the regulations governing INAD's,

including provisions defining good study practices, and on the impact

of proposed changes to the new animal drug application regulations in

future proposals.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities unless the rule is not expected to have a significant

economic impact on a substantial number of small entities. As this

proposed regulation will not impose significant new costs on any firms,

under the Regulatory Flexibility Act (5 U.S.C. 605(b)), the

Commissioner of Food and Drugs certifies that the final rule will not

have a significant impact on a substantial number of small entities.

Therefore, under the Regulatory Flexibility Act, no further analysis is

required.

V. Unfunded Mandates Act of 1995

The Unfunded Mandates Act of 1995 (2 U.S.C. 1532) requires that

agencies prepare an assessment of the anticipated costs and benefits

before proposing any rule that may result in annual expenditure by

State, local, and tribal governments, in the aggregate, or by the

private sector, of $100,000,000 or more (adjusted annually for

inflation). This proposed rule does not impose any mandates on State,

local, or tribal governments, or the private sector that will result in

an annual expenditure of $100,000,000 or more.

Lists of Subjects in 21 CFR part 514

Administrative practice and procedure, Animal drugs, Confidential

business information, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

the authority delegated to the Commissioner of Food and Drugs, 21 CFR

part 514 is amended as follows:

PART 514--NEW ANIMAL DRUG APPLICATIONS

1. The authority citation for 21 CFR part 514 continues to read as

follows:

Authority: Secs. 501, 502, 512, 701, 721, 801 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 351, 352, 360b, 371, 379e,

381).

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

as follows:

Sec. 514.111 Refusal to approve an application.

(a) * * *

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(5) Evaluated on the basis of information submitted as part of the

application and any other information before the Food and Drug

Administration with respect to such drug, there is lack of substantial

evidence consisting of one or more adequate and well-controlled studies

by experts qualified by scientific training and experience to evaluate

the effectiveness of the drug involved, on the basis of which it could

fairly and reasonably be concluded by such experts that the drug will

have the effect it purports or is represented to have under the

conditions of use prescribed, recommended, or suggested in the labeling

or proposed labeling thereof.

* * * * *

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

Sec. 514.117 Adequate and well-controlled studies.

(a) Purpose. The primary purpose of conducting adequate and well-

controlled studies of a new animal drug is to distinguish the effect of

the new animal drug from other influences, such as spontaneous change

in the course of the disease, normal animal production performance, or

biased observation. One or more adequate and well-controlled studies

are required to establish, by substantial evidence, that a new animal

drug is effective. The characteristics described in paragraph (b) of

this section have been developed over a period of years and are

generally recognized as the essentials of an adequate and well-

controlled study. Well-controlled, as used in the phrase adequate and

well-controlled, emphasizes an important aspect of adequacy. FDA

considers these characteristics in determining whether a study is

adequate and well-controlled for purposes of section 512 of the Federal

Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360b). Reports of

adequate and well-controlled studies, in addition to providing a basis

for determining whether a new animal drug is effective, may also be

needed to support claims of target animal safety. The report of an

adequate and well-controlled study should provide sufficient details of

study design, conduct, and analysis to allow critical evaluation and a

determination of whether the characteristics of an adequate and well-

controlled study are present.

(b) Characteristics. An adequate and well-controlled study has the

following characteristics:

(1) The protocol for the study (protocol) and the report of the

study results (study report) must include a clear statement of the

study objective(s).

(2) Any study conducted in the target animal shall be conducted in

compliance with the good study practices. The protocol contains a

statement acknowledging the applicability of, and intention to follow,

the good study practices for the conduct of the study. The study report

contains a statement describing adherence to the good study practices.

(3) The study is conducted with a new animal drug that is produced

in accordance with appropriate manufacturing practices, which include,

but are not necessarily limited to, the manufacture, processing,

packaging, holding, and labeling of the new animal drug such that the

critical characteristics of identity, strength, quality, purity, and

physical form of the new animal drug are known, recorded, and

reproducible, to permit meaningful evaluations of and comparisons with

other studies conducted with the new animal drug. The physical form of

a new animal drug includes the formulation and physical

characterization (including delivery systems thereof, if any) of the

new animal drug as presented to the animal. The protocol and study

report must include an identification number which can be correlated

with the specific formulation and production process used to

manufacture the new animal drug used in the study.

(4) The study uses a design that permits a valid comparison with

one or more controls to provide a quantitative evaluation of drug

effects. The protocol and the study report must describe the precise

nature of the study design, e.g., duration of treatment periods,

whether treatments are parallel, sequential, or crossover, and the

determination of sample size. Within the broad range of studies

conducted to support a determination of the effectiveness of a new

animal drug, certain of the controls listed below would be appropriate

and preferred depending on the study conducted:

(i) Placebo concurrent control. The new animal drug is compared

with an inactive preparation designed to resemble the new animal drug

as far as possible.

(ii) Untreated concurrent control. The new animal drug is compared

with the absence of any treatment. The use of this control may be

appropriate when objective measurements of effectiveness, not subject

to observer bias, are available.

(iii) Active treatment concurrent control. The new animal drug is

compared with known effective therapy. The use of this control is

appropriate when the use of a placebo control or of an untreated

concurrent control would unreasonably compromise the welfare of the

animals. Similarity of the new animal drug and the active control drug

can mean either that both drugs were effective or that neither was

effective. The study report should assess the ability of the study to

have detected a difference between treatments. The evaluation of the

study should explain why the new animal drugs should be considered

effective in the study, for example, by reference to results in

previous placebo-controlled studies of the active control.

(iv) Historical control. The results of treatment with the new

animal drug are quantitatively compared with experience historically

derived from the adequately documented natural history of the disease

or condition, or with a regimen (therapeutic, diagnostic, prophylactic)

whose effectiveness is established, in comparable animals. Because

historical control populations usually cannot be as well assessed with

respect to pertinent variables as can concurrent control populations,

historical control designs are usually reserved for special

circumstances. Examples include studies in which the effect of the new

animal drug is self-evident or studies of diseases with high and

predictable mortality, or signs and symptoms of predictable duration or

severity, or, in the case of prophylaxis, predictable morbidity.

(5) The study uses a method of selecting animals that provides

adequate assurances that the animals are suitable for the purposes of

the study. For example, the animals can reasonably be expected to have

animal production characteristics typical of the class(es) of animals

for which the new animal drug is intended, there is adequate assurance

that the animals have the disease or condition being studied, or, in

the case of prophylactic agents, evidence of susceptibility and

exposure to the condition against which prophylaxis is desired has been

provided. The protocol and the study report describe the method of

selecting animals for the study.

(6) The study uses a method to assign a treatment or a control to

each experimental unit of animals that is random and minimizes bias.

Experimental units of animals are groups of animals that are comparable

with respect to pertinent variables such as age, sex, class of animal,

severity of disease, duration of disease, dietary regimen, level of

animal production, and use of drugs or therapy other than the new

animal drug. The protocol and the study report describe the method of

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assignment of animals to an experimental unit to account for pertinent

variables and method of assignment of a treatment or a control to the

experimental units. When the effect of such variables is accounted for

by an appropriate design, and when, within the same animal, effects due

to the test drug can be obtained free of the effects of such variables,

the same animal may be used for both the test drug and the control

using the controls set forth in paragraph (b)(4) of this section.

(7) The study uses methods to minimize bias on the part of

observers and analysts of the data that are adequate to prevent undue

influences on the results and interpretation of the study data. The

protocol and study report explain the methods of observation and

recording of the animal response variables and document the methods,

such as ``blinding'' or ``masking,'' used in the study for excluding or

minimizing bias in the observations.

(8) The study uses methods to assess animal response that are well-

defined and reliable. The protocol and study report describe the

methods for conducting the study, including any appropriate analytical

and statistical methods, used to collect and analyze the data resulting

from the conduct of the study, describe the criteria used to assess

response, and, when appropriate, justify the selection of the methods

to assess animal response.

(9) There is an analysis and evaluation of the results of the study

in accord with the protocol adequate to assess the effects of the new

animal drug. The study report evaluates the methods used to conduct,

and presents and evaluates the results of, the study as to their

adequacy to assess the effects of the new animal drug. This evaluation

of the results of the study assesses, among other items, the

comparability of treatment and control groups with respect to pertinent

variables and the effects of any interim analyses performed.

(c) Waiver. The Director of the Center for Veterinary Medicine (the

Director) may, on the Director's own initiative or on the petition of

an interested person, waive in whole or in part any of the criteria in

paragraph (b) of this section with respect to a specific study. A

petition for a waiver is required to set forth clearly and concisely

the specific criteria from which waiver is sought, why the criteria are

not reasonably applicable to the particular study, what alternative

procedures, if any, are to be, or have been employed, and what results

have been obtained. The petition is also required to state why the

studies so conducted will yield, or have yielded, substantial evidence

of effectiveness, notwithstanding nonconformance with the criteria for

which waiver is requested.

(d) Uncontrolled studies. Uncontrolled studies or partially

controlled studies, including studies for which the Director has

granted a waiver, under paragraph (c) of this section, of the use of

any necessary control described in paragraph (b)(4) of this section,

are not acceptable as the sole basis for the approval of claims of

effectiveness or target animal safety. Such studies, carefully

conducted and documented, may provide corroborative support of adequate

and well-controlled studies regarding effectiveness and may yield

valuable data regarding safety of the new animal drug. Such studies

will be considered on their merits in the light of the characteristics

listed here. Isolated case reports, random experience, and reports

lacking the details which permit scientific evaluation will not be

considered.

Dated: April 29, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97-11846 Filed 5-7-97; 8:45 am]

BILLING CODE 4160-01-F