Substantial Evidence of Effectiveness of New Animal Drugs

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 514

[Docket No. 97N-0435]

Substantial Evidence of Effectiveness 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 proposing to amend its

new animal drug regulations to further define the term ``substantial

evidence.'' The purpose of this proposed regulation is to encourage the

submission of new animal drug applications (NADA's) and supplemental

NADA's for single ingredient and combination new animal drugs. The

proposal also encourages dose range labeling.

DATES: Submit written comments on the proposed rule by February 3,

1998. Submit written comments on the information collection

requirements by December 5, 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. Submit written comments on the information

collection requirements to the Office of Management and Budget (OMB),

New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC

20503, Attn.: Desk Officer for FDA.

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. The

purpose of the ADAA is to facilitate the approval and marketing of new

animal drugs and medicated feeds. In furtherance of this purpose,

section 2(a) of the ADAA amended section 512(d)(3) of the Federal Food,

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

definition of ``substantial evidence.'' Section 2(e) of the ADAA

directs FDA to issue proposed regulations to further define the term

``substantial evidence'' in a manner that encourages the submission of

NADA's and supplemental NADA's. Section 2(e) also directs FDA to issue

proposed regulations to encourage dose range labeling. This proposed

regulation further defines substantial evidence and encourages dose

range labeling.

Before FDA can approve a new animal drug, FDA must find, among

other things, that there is substantial evidence that the new animal

drug is effective. The demonstration of effectiveness represents a

significant component of drug development time and cost such that the

amount and nature of the evidence needed can be an important

determinant of whether and when new animal drugs become available to

the public. The availability of certain approved new animal drugs for

use in livestock, poultry, pets, and other animals is vital to

protecting the health of animals and the health of humans who consume

the products of food producing animals. The availability of other

approved new animal drugs is vital to increasing the efficiency of food

production in the United States. Thus, animal and human health and food

production are best served by the development of substantial evidence

of effectiveness in an efficient manner. The changes made to the

definition of ``substantial evidence'' by the ADAA and by the further

definition of that term in this proposed rule give FDA greater

flexibility to make case-specific scientific determinations regarding

the number and types of adequate and well-controlled studies that will

provide, in an efficient manner, substantial evidence that a new animal

drug is effective.

II. The Statutory Definition of Substantial Evidence

The term ``substantial evidence'' as defined in section 512(d)(3)

of the act refers to the number and types of adequate and well-

controlled studies needed for a new animal drug to be determined to be

effective for the intended uses under the conditions of use prescribed,

recommended, or suggested (hereinafter suggested) in its labeling or

proposed labeling.

[[Page 59831]]

Prior to the enactment of the ADAA, section 512(d)(3) of the act

defined substantial evidence as:

[e]vidence consisting of adequate and well-controlled

investigations, including field investigation, 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.

Under section 512(d)(3), as amended by the ADAA, substantial

evidence is defined as:

[e]vidence consisting of one or more adequate and well-

controlled investigations, such as,

(A) a study in a target species;

(B) a study in laboratory animals;

(C) any field investigation that may be required under this

section and that meets the requirements of [section 512 (b)(3) of

the act] if a presubmission conference is requested by the

applicant;

(D) a bioequivalence study; or

(E) an in vitro study;

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.

Under the old definition, at least two adequate and well-controlled

studies were necessary to demonstrate by substantial evidence the

effectiveness of a new animal drug and at least one of those adequate

and well-controlled studies was required to be a field study. Under the

revised definition of substantial evidence it is possible that a

minimum of one adequate and well-controlled study \1\ may provide

substantial evidence of the effectiveness of a new animal drug for its

intended uses and associated conditions of use.

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\1\ The ADAA requires FDA to issue 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, taking into account practical

conditions in the field and differences between field conditions and

laboratory conditions. FDA published a proposed regulation further

defining the term ``adequate and well-controlled'' in the Federal

Register of May 8, 1997 (62 FR 25153).

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Furthermore, the statutory requirement for a field study has been

eliminated, but FDA continues to have the authority to require field

studies when necessary (H. Rept. 104-823, at 13 (1996)). Elimination of

the requirement for a field study recognizes that while a field study

(because it assesses the effectiveness of a new animal drug under

conditions of use that approximate actual use conditions) remains an

important element of many new animal drug approvals, there will be some

instances in which a field study would yield no more useful information

with regard to the new animal drugs effectiveness than can be obtained

through laboratory studies. Thus, the new definition of substantial

evidence specifically identifies types of adequate and well-controlled

studies that may be used in lieu of, or in addition to, field studies

to provide evidence of the effectiveness of a new animal drug.

III. Description of the Proposed Rule

FDA is proposing to amend part 514 (21 CFR part 514) by adding

Sec. 514.4 Substantial evidence to further define substantial evidence.

Proposed Sec. 514.4 describes the characteristics of substantial

evidence that permit qualified experts to fairly and reasonably

conclude that the drug will have the effect it purports or is

represented to have under the conditions of use suggested in the

proposed labeling. The proposed regulation would give FDA flexibility

to determine, in light of the current state of relevant scientific

knowledge, the minimum number of adequate and well-controlled studies

needed, dependent upon the quality and persuasiveness of such studies,

to permit qualified experts to conclude that a new animal drug is

effective. Substantial evidence must include a sufficient number of

studies of sufficient quality to permit experts qualified by scientific

training and experience to fairly and reasonably conclude that the new

animal drug is effective for each of the intended uses and associated

conditions of use suggested in the proposed labeling.

A. Characteristics of Substantial Evidence (Sec. 514.4(b))

1. Intended Uses and Conditions of Use (Sec. 514.4(b)(2))

Proposed Sec. 514.4(b)(2) requires that the sponsor demonstrate

that a new animal drug is effective for each proposed intended use and

associated conditions of use. A critical step in deciding the number

and types of adequate and well-controlled studies needed to demonstrate

effectiveness is to clearly define the intended uses and the associated

conditions of use. Intended use refers to the structure or function of

the body to be affected or the disease or condition to be treated,

prevented, mitigated, or cured. Conditions of use that may be suggested

in the proposed labeling for each intended use include, but are not

limited to: The dose or dose range, frequency, duration, timing (e.g.,

in relation to the onset of clinical signs), and route of

administration or application of the new animal drug; the withdrawal

period (if any); the preparation of the new animal drug for use; the

species, age, gender, class, and breed of animal for which the new

animal drug is intended for use; and, restriction to use under the

supervision of a licensed veterinarian.

The specific number and types of adequate and well-controlled

studies needed to provide substantial evidence of effectiveness of a

new animal drug will vary depending upon the number of intended uses,

how narrowly or broadly each intended use is defined, and, further,

upon the conditions of use associated with each intended use suggested

in the proposed labeling. Intended uses are the determining factors in

selecting the parameters to be measured under the conditions of use

proposed for the new animal drug. Because a new animal drug must be

shown to be effective for each intended use under the conditions of use

suggested in the proposed labeling, the greater the number of intended

uses and the more varied the associated conditions of use, the less

likely it is that a single study can be designed and conducted to

measure all relevant parameters. Likewise, the broader an intended use,

e.g., the new animal drug is intended to treat a disease with multiple

clinical presentations, the more likely it is that multiple studies

will be needed.

One of the most important conditions of use for any new animal drug

is the dosage. Dosage includes the dose or dose range, dosing

frequency, and the dosing duration. Thus, a sponsor must demonstrate by

substantial evidence that a new animal drug is effective for its

intended use at the dose or dose range and the associated conditions of

use suggested in the proposed labeling for that intended use. The

studies needed to make such a demonstration will depend, in part, upon

whether the new animal drug is labeled for use at a single fixed dose

or over a dose range.

The substantial evidence necessary to support a dose range will

further vary with the nature of the new animal drug and its intended

uses. Proposed Sec. 514.4(b)(2) provides that substantial evidence to

support dose range labeling for a new animal drug intended for use in

the diagnosis, cure, mitigation, treatment, or prevention of disease

must consist of at least one adequate and well-controlled study on the

basis of which qualified experts could fairly and reasonably conclude

that the new animal drug will be effective for at least one intended

use at the lower dose limit

[[Page 59832]]

prescribed in the proposed labeling and will be effective for each

intended use at the dose suggested in the proposed labeling for that

intended use. The proposed regulation also provides that substantial

evidence to support a dose range for a new animal drug intended to

affect the structure or function of the body of an animal for the

purpose of enhancing production must consist of at least one adequate

and well-controlled study on the basis of which qualified experts could

fairly and reasonably conclude that the new animal drug will be

effective for each intended use at all the doses within the range

prescribed for the intended use. In either instance, the upper limit of

a dose range for any new animal drug will be set based on safety, both

to the the target animal and to humans consuming products from animals

treated with the new animal drug, as well as practicality, e.g., volume

of injection or length of withdrawal period.

The agency notes that a conclusion that a new animal drug is

effective for its intended uses no longer requires dose optimization.

Prior to enactment of the ADAA in 1996, FDA was required under section

512(d)(1)(F) of the act to refuse to approve a new animal drug if, on

the basis of any information before FDA, the tolerance limitation

proposed, if any, exceeded that reasonably required to accomplish the

physical or other technical effect for which the new animal drug is

intended. In order to demonstrate by substantial evidence the minimal

amount of a new animal drug reasonably required to accomplish the

physical or technical effect, dose optimization, typically supported by

adequate and well-controlled dose titration studies that characterize

the critical aspects of the dose response relationship, was required.

This characterization of the dose-response relationship permitted FDA

to make a risk-benefit assessment of the new animal drug. That is, FDA

could determine whether the effectiveness of a new animal drug

outweighed the risks to the target animal at the dose or over the dose

range prescribed in the proposed labeling.

With the enactment of the ADAA, the requirement for dose

optimization has been eliminated. It is no longer necessary that the

dose or dose range prescribed in the proposed labeling of a new animal

drug be limited to that required to accomplish the physical or other

technical effect. Therefore, a sponsor is now required to demonstrate

by substantial evidence that a new animal drug is effective for each

intended use at the associated dose or over the associated dose range

prescribed in the proposed labeling. And, the sponsor must demonstrate

that such dose or dose range is safe for the target animal and, at the

labeled withdrawal time(s), does not result in a residue of such drug

in excess of a tolerance found by FDA to be safe.

Although the requirement for dose optimization has been eliminated,

sponsors will still need to characterize the critical aspects of the

dose response relationship so that qualified experts can make an

informed risk-benefit assessment of the new animal drug and assure that

the proposed labeling is not false or misleading in any particular.

Thus, a sponsor must characterize for an intended use and associated

conditions of use the critical aspects of the dose-response

relationship relevant to the dose or dose range selected. For example,

for new animal drugs intended to affect the structure or function of

the body of an animal for the purpose of enhancing production,

generally a sponsor should characterize whether the dose or dose range

prescribed in the proposed labeling for the new animal drug falls on

the part of the dose-response curve at which there is increasing

effectiveness or on the part of the dose-response curve at which

effectiveness is essentially static, i.e., the plateau. This

characterization does not, however, have to be demonstrated by

substantial evidence.

FDA encourages the use of dose range labeling. The use of dose

range labeling, particularly professional flexible labeling, enhances

the ability of users to safely, effectively, and economically treat

animals without using the new animal drug in an extra-label manner. As

discussed previously, the critical aspects of the dose-response

relationship must generally be characterized to support labeling,

including dose range labeling. Although many drugs have increasing

effectiveness over a definable dose range, most reach a point at which

effectiveness is not measurably improved by increased dosing. Without a

sufficient characterization of the dose-response relationship,

qualified experts cannot determine whether dose range labeling is false

or misleading in any particular and the user cannot be adequately

informed regarding the appropriate use of the new animal drug.

2. Number of Studies (Sec. 514.4(b)(3)(i))

Whether substantial evidence for a particular new animal drug

consists of a single adequate and well-controlled study of sufficient

quality or one adequate and well-controlled study corroborated by

additional adequate and well-controlled studies will depend on the new

animal drug involved. Proposed Sec. 514.4(b)(3)(i) provides that

studies intended to provide substantial evidence of effectiveness shall

consist of a sufficient number of studies of sufficient quality and

persuasiveness to permit qualified experts in determining that the

parameters reflect the effectiveness of the new animal drug; that the

results obtained are likely to be repeatable, and that valid inferences

can be drawn to the target animal \2\ population; and, that the new

animal drug is effective for the intended use at the dose or dose range

and associated conditions of use suggested in the proposed labeling.

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\2\ Target animal and target animal population as used

throughout this document refer to the animal or animal population

for which the new animal drug is intended for use.

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For each study that is part of substantial evidence, the critical

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

form of the new animal drug used must be sufficiently documented to

permit meaningful evaluation of the study and comparison with other

studies conducted with the new animal drug (proposed Sec. 514.117(b)(3)

(62 FR 25153, May 8, 1997)).

For qualified experts to fairly and reasonably conclude that a new

animal drug is effective for an intended use under the conditions of

use suggested in the proposed labeling for the new animal drug, the

study parameters selected for measurement must reliably reflect the

effectiveness of the new animal drug for the intended use (selection of

study parameters (Sec. 514.117(b)(3)(i)(A))). A new animal drug cannot

be shown to be effective for an intended use without eliciting a

measurable response with respect to parameters highly correlated to

that intended use of the drug. Generally, a sponsor should evaluate

parameters that provide direct evidence of effectiveness with respect

to the intended use, but, where appropriate, a sponsor may measure

effects on an established surrogate endpoint.

The studies that provide substantial evidence must provide

reasonable assurance that the results obtained from the use of the new

animal drug are repeatable when the new animal drug is applied or

administered under conditions of use suggested in the proposed labeling

(repeatability of study results (Sec. 514.4(b)(3)(i)(B)). The

definition of substantial evidence in section 512 of the act prior to

its amendment by the ADAA and its requirement for more than one

adequate and well-controlled study were based

[[Page 59833]]

on the principle of independent substantiation. The goal of independent

substantiation of experimental results is to ensure that an

experimental finding of effectiveness is not the result of:

Unanticipated, undetected, or systematic biases; study site-or

investigator-specific factors that prevent generalization of the

finding to the intended target animal population; or chance.

Independent substantiation also provides a safeguard against those rare

instances in which the results of a study are the product of fraudulent

reporting of scientific studies. Independent substantiation continues

to be a primary scientific principle upon which qualified experts can

make a determination whether a new animal drug is effective.

Historically, the need for independent substantiation was

frequently equated with the need for replication, i.e., replication of

an identical study. While replication is usually a highly reliable way

to independently substantiate experimental results, it is not the only

way. Results obtained from studies that are different in design or

execution or both may provide support for a conclusion of effectiveness

that is at least as convincing as a repeat of the same study. Under the

revised definition of substantial evidence, substantial evidence

supporting the effectiveness of a new animal drug for an intended use

may be achieved by carefully and properly designing and conducting a

single adequate and well-controlled study or by conducting multiple

adequate and well-controlled studies that need not replicate one

another.

The number of studies needed to provide independent substantiation

and support a finding by qualified experts that a new animal drug is

effective will depend upon the quality of the studies and the

inferential value of the studies. Whatever scientific evidence is

needed to demonstrate the effectiveness of a new animal drug, the

quality of that scientific evidence is of comparable importance to its

quantity. Quality of a study includes factors such as the rigor, power,

and scope of the design and conduct of a study, and the sufficiency of

the study documentation. As the quality of an effectiveness study

improves, the study's reliability, inferential value, and capacity to

substantiate effectiveness improves.

Even when intended uses and conditions of use are narrowly defined

and there is relevant scientific knowledge to inform qualified experts

about the chemical entity, the disease or condition to be treated, or

the structure or function to be affected, a single adequate and well-

controlled study frequently will not suffice to establish the

effectiveness of a new animal drug without the corroboration

(independent substantiation) provided by other adequate and well-

controlled studies. When considering whether to rely on a single

adequate and well-controlled study, it is critical that the possibility

of an incorrect outcome be considered and that all available data be

examined for their potential to either support or undercut reliance on

a single study. In those limited instances in which reliance is placed

on a single adequate and well-controlled study that has the

characteristics described in Sec. 514.111(a)(5)(ii) (proposed

Sec. 514.117 (62 FR 25153, May 8, 1997)), such a study will need to be

of sufficient quality, as well as persuasiveness in outcome, to enable

qualified experts to make valid inferences from study results to the

target animal population. The presence of the following characteristics

in a study can contribute to a conclusion by qualified experts that a

single adequate and well-controlled study provides substantial evidence

of effectiveness: The study is a multicenter study in which no single

study site provides an unusually large fraction of the target animals

and no single investigator or site is disproportionately responsible

for the effects seen; the study involves prospective randomized

stratifications or identified analytic subsets that each show a

significant effect; the study includes multiple endpoints involving

different events; and, the study provides highly reliable and

statistically strong evidence of effectiveness. The likelihood that

qualified experts can rely on a single adequate and well-controlled

study as establishing the effectiveness of a new animal drug increases

with the number of these and similar characteristics displayed in the

single study.

Inferential value of data (sometimes referred to as

generalizability) relates to the confidence with which the data

relating to effectiveness of a new animal drug for an intended use

under the conditions tested can be used to conclude that the new animal

drug will be effective in the target animal population for the intended

use and associated conditions of use suggested in the proposed labeling

(Sec. 514.4(b)(3)(i)(B)) . The inferential value of data may depend

upon, among other things, how closely the test animals approximate the

characteristics of the target animal population. Time, how recently a

particular set of data has been collected, may also affect its

inferential value. Animal research data has an effective life span

during which time-dependent factors such as genetics of the target

animal and the target organism, husbandry practices, and diets remain

sufficiently static to assure the continued relevance of the data.

Beyond this period, changes in target animal genetics, target organism

genetics, husbandry practices, and diets may affect the ability of the

new animal drug to achieve the effect demonstrated under prevailing

conditions at the time of testing. Time is particularly meaningful in

terms of the inferences that can be drawn from data relating to

therapeutic uses of antimicrobial animal drugs because of the

development of resistant microbes.

Substantial evidence must permit qualified experts to conclude that

a new animal drug will have the effect it purports or is represented to

have under the conditions of use suggested in the proposed labeling

(concluding a new animal drug is effective (Sec. 514.4(b)(3)(i)(C)).

Section 512 of the act requires that FDA issue an order refusing to

approve an NADA if there is a lack of substantial evidence that the new

animal drug will have the effect it purports or is represented to have

under the conditions of use suggested in the proposed labeling.

Similarly, the statute requires that FDA issue an order refusing to

approve an NADA if, based on a fair evaluation of all the material

facts, the proposed labeling is false or misleading in any particular,

including as it relates to the demonstrated effectiveness of the new

animal drug for its intended uses under associated conditions of use.

Thus, sponsors should remember that it may be necessary to provide, in

addition to or as part of substantial evidence, evidence that explicit

or implicit claims relating to effectiveness made on the label of a new

animal drug are neither false nor misleading.

3. Types of Studies (Sec. 514.4(b)(3)(ii))

Proposed Sec. 514.4(b)(3)(ii) specifies that the types of adequate

and well-controlled studies needed to provide substantial evidence may

include, but are not limited to, published studies, foreign studies,

studies using models, and studies conducted by or on behalf of the

sponsor. Isolated case reports, random experience, and reports lacking

the details which permit scientific evaluation will not be considered

as part of substantial evidence (Sec. 514.111; proposed Sec. 514.117

(62 FR 25153, May 8, 1997)), and will not contribute to the current

state of scientific knowledge that informs qualified experts.

The utility of published studies, foreign studies, and studies

using

[[Page 59834]]

models as adequate and well-controlled studies to support a finding of

effectiveness may vary. The use of published studies raises at least

two questions: (1) How reliable are the data? and, (2) do the data

represent a skewed subset of information?

Published literature, even in peer-reviewed journals, may not be

free from error, omission, misinterpretation, or even outright fraud.

Peer reviewers of articles submitted for publication in journals vary

in the relevant experience and expertise they may have to review

particular journal articles and, typically, only have access to a

limited data set and analyses. As noted by Dr. Richard Horton, editor

of The Lancet, an international biomedical journal, ``* * * the review

process will only rarely detect misconduct and it may well miss

critical flaws in a research article'' (Ref. 1). Dr. Horton further

noted that in instances where legitimate questions are raised about the

validity of research methods and data analyses, ``[i]t is possible that

the only way to settle the dispute is to provide access to raw data or

to invite the institution where the research was conducted to assist in

the ongoing investigations'' (Ref. 1). In many instances, published

literature is intended to advance science by stimulating further

analysis and interpretation. In that sense, some amount of error is not

necessarily bad; disputes over analyses and interpretation can drive

scientific research and progress (Ref. 1). However, if a sponsor of a

new animal drug uses a published study to provide evidence that a new

animal drug is effective, use of invalid research methods or invalid

data analyses in the study will make the study unacceptable.

FDA's ability to rely on a published study as an adequate and well-

controlled study that is part of substantial evidence is enhanced, and

in many cases is only possible, if FDA can obtain additional critical

study details. The level of scrutiny for such a published study should

not be less rigorous than that given to studies conducted by or on

behalf of the sponsor that are intended to be adequate and well-

controlled studies to support a determination of effectiveness.

Providing as much of the following types of information about a

study, in conjunction with the published report, can increase the

likelihood that the study can be relied upon as an adequate and well-

controlled study: A statement describing the extent, if any, to which

the study was funded or supported by the sponsor; the qualifications of

the expert who conducted the study; a copy of the protocol, as amended,

used for the study, of sufficient detail to permit the study to be

reconstructed or repeated; access to written documentation describing

the practices followed in the conduct of the study (including

identification of animals omitted from analysis, and an analysis of

results using all subjects with on-study data); the prospective

statistical analysis plan and any changes from the original plan that

occurred during or after the study; a full accounting of all

investigational animals; an adequate characterization of the new animal

drug used in the study; assay data for the new animal drug; and,

complete study records including pertinent baseline characteristics for

each animal or experimental unit of animals.

In addition to the public debate concerning the reliability of

peer-reviewed published data, there has been expressed in recent years

concern that published studies represent a skewed subset of all

existing information available on a particular subject. While it may

not be possible to determine the extent to which the published studies

represent a skewed subset of all existing information, the likelihood

of reliance on published literature is increased not only by full

knowledge about how the studies were conducted but by the availability

of a balanced discussion of the published studies listed in the

bibliography that both support and raise questions relating to the

safety and effectiveness of the new animal drug. The current

regulations already require a sponsor to provide as part of its NADA a

complete bibliography and a summary of each published study relevant to

the intended uses of the new animal drug for which approval is sought

(Sec. 514.1(b)(7)(iv)).

An adequate and well-controlled foreign study may also be relied

upon to support a finding by substantial evidence that a new animal

drug is effective. The utility of such studies depends upon whether the

potential differences such as animal breeds, genetic composition within

a breed, diseases, nutrition, and husbandry practices between the

foreign country and the United States are sufficiently addressed. There

will be instances in which such differences will scientifically limit

the applicability of results of foreign studies.

In some instances, model study designs may be appropriate for use

in proving the effectiveness of a new animal drug. In order for a model

study to be an adequate and well-controlled study that supports a

finding that a new animal drug is effective, the model must be

validated to establish an adequate relationship of parameters measured

and effects observed in the model with one or more significant effects

of treatment in the target animal population under actual conditions of

use. Proposed Sec. 514.4(b)(3)(ii) requires such validation. If the

correlation of parameters measured and effects observed in the model

with one or more significant effects of treatment has not been

established as part of general scientific knowledge, such correlation

must be established scientifically.

The number and types of new studies that need to be conducted by or

on behalf of a sponsor to demonstrate by substantial evidence the

effectiveness of a new animal drug for a particular intended use will

depend upon factors such as: the availability (either publicly or

through right of reference) of information about the drug or the active

ingredient, and, in some cases, the chemical class to which it belongs,

information derived from studies of other approved or unapproved uses

of the active ingredient or drug, and information derived from foreign

studies if applicable to the proposed use and the target animal

population in the United States; whether the nature of the new animal

drug or active ingredient, or the proposed claims, makes the new animal

drug conducive to in vitro testing or data extrapolation via

pharmacokinetic studies; the availability of published studies

involving the new animal drug (as discussed previously); and, concern

for animal welfare. The science and practice of drug research and

development have significantly evolved since the effectiveness

requirement for drugs was established in 1962, and this evolution has

implications for the number and type of data needed to demonstrate

effectiveness of a particular new animal drug. Today, for many disease

conditions, there is a greater understanding of pathogenesis, disease

stages, treatment modalities and their characteristics, and,

frequently, an increased general understanding regarding the activity

of a particular chemical entity or related chemical entities in humans

or other animals.

Thus, if there is a significant amount of existing relevant

scientific knowledge available to inform qualified experts about a

chemical entity, such as the effectiveness of a chemical entity in a

condition closely related to that for which the new animal drug is

intended, about the pathogenesis and stages of the disease or condition

to be treated, or the production function (e.g., weight gain or feed

efficiency) to be affected, by the chemical entity, fewer new studies

may need to be conducted to support FDA's determination of the

effectiveness of the

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drug for its intended use. Conversely, the less information known about

the nature of the chemical entity or about the disease or condition to

be treated or the production effect to be achieved, the greater the

need for new studies to support a determination of the effectiveness of

the new animal drug. If new studies need to be conducted, existing

relevant scientific knowledge may, at least, be helpful in designing

studies which provide highly reliable and statistically strong evidence

of effectiveness.

B. Substantial Evidence for Combination New Animal Drugs

(Sec. 514.4(c))

Under the ADAA, a streamlined approval process was established for

certain combination new animal drugs. Section 512(d)(4) of the act

provides that, except in the case of a combination new animal drug that

is intended for use other than in animal feed or drinking water

(hereinafter referred to as ``dosage form combination new animal

drugs'') \3\ and contains a nontopical antibacterial ingredient or

animal drug, FDA will not refuse to approve an application for a dosage

form combination new animal drug that contains active ingredients or

animal drugs that have previously been separately approved on grounds

that there is a lack of evidence of effectiveness if the sponsor: (1)

Demonstrates by substantial evidence that each active ingredient or

animal drug intended only for the same use as another active ingredient

or animal drug in the combination makes a contribution to

effectiveness, and (2) demonstrates (a) that each active ingredient or

animal drug intended for at least one use that is different from all

other active ingredients or animal drugs used in the combination

provides appropriate concurrent use for the intended target animal

population, and (b) if FDA has a scientific basis to believe the active

ingredients or animal drugs may be incompatible or have disparate

dosing regimens, that the active ingredients or animal drugs are

physically compatible and do not have disparate dosing regimens

(section 512(d)(4)(C) of the act). FDA will not refuse to approve an

application for a combination new animal drug that is intended for use

in animal feed or drinking water and contains active ingredients or

animal drugs that have previously been separately approved on grounds

that there is a lack of evidence of effectiveness if the sponsor: (1)

Demonstrates by substantial evidence that each active ingredient or

animal drug intended only for the same use as another active ingredient

or animal drug in the combination, and, if there is more than one than

one antibacterial ingredient or animal drug, each antibacterial

ingredient or animal drug, makes a contribution to labeled

effectiveness, and (2) demonstrates (a) that each active ingredient or

animal drug that is intended for at least one use that is different

from all other active ingredients or animal drugs in the combination

provides appropriate concurrent use for the intended target animal

population, and (b) if FDA has a scientific basis to believe the active

ingredients or animal drugs intended for use in drinking water may be

incompatible, that the active ingredients or animal drugs are

physically compatible (section 512(d)(4)(D) of the act). For all other

combination new animal drugs, FDA will not refuse to approve an

application on the grounds that there is a lack of evidence of

effectiveness if the sponsor demonstrates by substantial evidence that

the combination new animal drug will have the effect it purports or is

represented to have under the conditions of use suggested in the

proposed labeling for the combination new animal drug and that each

active ingredient or animal drug contributes to the effectiveness of

the combination new animal drug.

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

\3\ Use of the phrase ``dosage form combination new animal

drugs'' as used in this preamble is a shorthand reference to

combination new animal drugs ``intended for use other than in animal

feed or drinking water,'' the purpose of which is to make the

complex preamble discussion relating to combination new animal drugs

more readable. The term ``dosage form,'' outside of the discussion

in this preamble relating to the combination new animal drug

provisions of the act, includes and will continue to include new

animal drugs intended for use in drinking water.

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

To implement these statutory provisions, proposed

Sec. 514.4(c)(1)(i) defines a combination new animal drug as a new

animal drug that contains more than one active ingredient or animal

drug that is applied or administered simultaneously in a single dosage

form or simultaneously in or on animal feed or drinking water. The

substantial evidence necessary to support a conclusion by qualified

experts that a combination new animal drug is effective will vary

depending upon the active ingredients or animal drugs used in the

combination.

Proposed Sec. 514.4(c)(2) provides that for combination new animal

drugs that contain active ingredients or animal drugs that have

previously been separately approved for the particular uses and

conditions of use for which they are intended in combination

(hereinafter ``previously been separately approved''), except in the

case of a combination new animal drug that is intended for use other

than in animal feed or drinking water that contains a nontopical

antibacterial ingredient or animal drug, a sponsor must demonstrate by

substantial evidence, as defined in section 512(d)(3) of the act and

this proposed regulation, that any active ingredient or animal drug

intended only for the same use as another active ingredient or animal

drug in the combination makes a contribution to the effectiveness of

the combination new animal drug. For combination new animal drugs that

contain active ingredients or animal drugs that have previously been

separately approved for use in animal feed or drinking water and

contain more than one antibacterial ingredient or animal drug, the

sponsor must also demonstrate by substantial evidence, as defined in

section 512(d)(3) of the act and this proposed regulation, that each

antibacterial makes a contribution to labeled effectiveness.

Proposed Sec. 514.4(c)(3) provides that for all other combination

new animal drugs ( i.e., those that contain active ingredients or

animal drugs that have not previously been separately approved and

those that are dosage form combination new animal drugs that contain an

active ingredient or animal drug that is a nontopical antibacterial),

the sponsor must demonstrate by substantial evidence, as defined in

section 512(d)(3) of the act and this proposed regulation, that: (1)

The combination new animal drug will have the effect it purports or is

represented to have under the conditions of use suggested in the

proposed labeling, and (2) each active ingredient or animal drug

contributes to the effectiveness of the combination new animal drug.

On occasion, FDA may have a substantiated scientific basis for

believing that the use in combination of active ingredients or animal

drugs that have previously been separately approved will result in a

decrease in the effectiveness of one or more of the active ingredients

or animal drugs. Although section 512(d)(4) of the act generally

provides for a modified approval process for combination new animal

drugs containing active ingredients or animal drugs that have

previously been separately approved, FDA will, to the extent necessary,

require additional testing to characterize the effectiveness of such a

combination new animal drug to assure that the labeling will not be

false or misleading in any particular, consistent with section

512(d)(1)(H) of the act.

For purposes of determining the substantial evidence necessary to

demonstrate the effectiveness of a combination of animal drugs that

have

[[Page 59836]]

previously been separately approved, each animal drug brings with it to

the combination each intended use for which it was previously

separately approved under the conditions of use proposed for the

combination new animal drug. If an active ingredient or animal drug has

previously been separately approved as a prescription animal drug or a

veterinary feed directive drug for any of the intended uses and

conditions of use suggested in the proposed labeling for the

combination new animal drug, the combination new animal drug, if

approved, would usually need to be approved as a prescription animal

drug or veterinary feed directive drug, respectively.

1. Antibacterial Active Ingredient or Animal Drug

The approval process provided by section 512(d)(4) of the act does

not apply to dosage form combination new animal drugs if any of the

active ingredients or animal drugs is a nontopical antibacterial. And,

for combination new animal drugs intended for use in animal feed and

drinking water that contain more than one antibacterial and qualify for

approval under the process provided by section 512(d)(4), a sponsor

must demonstrate by substantial evidence that each antibacterial

ingredient or animal drug contributes to the effectiveness of the

combination new animal drug. The act, as amended by the ADAA, treats

antibacterial ingredients and animal drugs differently from other

active ingredients and animal drugs because increasingly there are

concerns that overuse or improper use of antibacterials may contribute

unnecessarily to the development of antibacterial resistance.

Proposed Sec. 514.4(c)(1)(ii) defines an ``antibacterial'' with

respect to a particular target animal species as an active ingredient

or animal drug: (1) That is approved for use in that species for the

diagnosis, cure, mitigation, treatment, or prevention of bacterial

disease; or (2) that is approved in that species for any other use that

is attributable to its antibacterial properties.

2. Appropriate Concurrent Use and Compatibility

Section 512(d)(4)(C) and (d)(4)(D) of the act requires that in

certain cases appropriate concurrent use and compatibility must be

demonstrated. The demonstration need not be by substantial evidence but

sponsors must provide a scientifically sound basis for qualified

experts to reach these conclusions. Proposed Sec. 514.4(c)(2)(iii) sets

out the requirement for sponsors to establish appropriate concurrent

use for the target species in cases in which each active ingredient or

animal drug is intended for at least one use that is different from all

the other active ingredients or animal drugs in the combination. To

determine whether a combination new animal drug provides ``appropriate

concurrent use'' the agency will consider factors such as whether the

conditions to be treated by the combination are likely to occur

simultaneously with sufficient frequency in the intended target animal

population.

Proposed Sec. 514.4(c)(2)(iv) and (c)(2)(v) sets out the

requirements in section 512(d)(4)(C)(iii) and (d)(4)(D)(iv) of the act

regarding compatibility. These requirements apply where, based on

scientific information, FDA has reason to believe that for dosage form

combination new animal drugs the active ingredients or animal drugs may

be physically incompatible or have disparate dosing regimens or that

for active ingredients or animal drugs intended for use in drinking

water the active ingredients or animal drugs may be physically

incompatible. The legislative history of ADAA describes the purpose of

these provisions as ``authoriz[ing] FDA to deny approval of a

combination animal drug if the physical compatibility or compatibility

of the dosing regimens may affect the effectiveness of the combination

animal drug and such compatibility is not demonstrated'' (H. Rept. 104-

823 at 14 (1996)).

Scientific information exists that gives FDA reason to believe that

dosage form combinations and combinations intended for use in drinking

water may be physically incompatible and/or have disparate dosing

regimens. With the enactment of the Generic Animal Drug Patent Term

Restoration Act of 1988 (GADPTRA), it was well-recognized that, based

on scientific information, the bioavailability of active ingredients

may be affected by changes relating to the formulation or manufacture

of a generic new animal drug and, therefore, the statute, rather than

assuming bioequivalence based on the use of the same active ingredient,

requires a demonstration of bioequivalence. Similarly, the

bioavailability of an active ingredient or animal drug as part of a

combination new animal drug may be affected by changes relating to the

formulation or manufacture of the active ingredient or animal drug for

use in the combination or to the formulation and manufacture of the

combination new animal drug. Thus, FDA has scientific information that

gives it reason to generally believe that active ingredients or animal

drugs intended for use in a dosage form combination new animal drug may

not be physically compatible and may have disparate dosing regimens or

that for active ingredients or animal drugs intended for use in

drinking water the active ingredients or animal drugs may not be

physically compatible. Therefore, proposed Sec. 514.4(c)(2)(iv) and

(c)(2)(v) requires the sponsor to demonstrate the comparable

bioavailability of the active ingredients or animal drugs in

combination relative to the active ingredients or animal drugs singly.

However, as with FDA's implementation of GADPTRA, certain classes of

products are recognized to be of less concern with respect to potential

differences in bioavailability, e.g., true solutions, inhalant

anesthetics and some topicals. In such cases, some or all of the

demonstration of comparable in vivo bioavailability may be waived. The

proposed rule provides for such waivers where appropriate.

C. Conclusion

The basic premise underlying the modified requirement for

demonstrating the effectiveness of particular combination new animal

drugs is that there exists knowledge about the individual active

ingredients or animal drugs contained in that combination. This

knowledge exists in the approved applications in the form of

substantial evidence of effectiveness of the individual active

ingredients or animal drugs. The substantial evidence supporting the

effectiveness of an approved active ingredient or animal drug generally

is not publicly available but is usually owned by the sponsor of the

approved application for the active ingredient or animal drug. Thus,

the sponsor submitting an application for a combination new animal drug

must either own the underlying applications or obtain a right of

reference from the owners of such applications if FDA is to rely upon

the substantial evidence contained in those applications.

Sponsors may submit supplemental NADA's and receive supplemental

approval of new animal drugs for new intended uses. The approval of a

new intended use for a single active ingredient new animal drug that

has already been approved for use in a combination new animal drug may

necessitate the submission of a new or supplemental application for the

combination new animal drug. Such new or supplemental NADA for the

combination new animal drug must contain substantial evidence of

effectiveness in accordance with this

[[Page 59837]]

proposed regulation. Sponsors cannot circumvent approval requirements

relating to the effectiveness of a combination new animal drug by

adding or deleting intended uses to or from any of the new animal drugs

approved for use in the combination subsequent to the approval of the

combination new animal drug. Section 512(e)(1)(F) of the act would

require withdrawal of an existing approval for the combination new

animal drug unless the sponsor submits and FDA approves a supplement to

the combination NADA that provides adequate information supporting any

changes affecting its safety or effectiveness beyond the variations

provided for in the approved application.

FDA recognizes that the requirements for obtaining approval of

combination new animal drugs are complex. Following the Good Guidance

Practices established in the Federal Register of February 27, 1997 (62

FR 869691), FDA's Center for Veterinary Medicine (CVM) intends to

develop, for public comment, one or more draft guidance documents

representing the agency's current thinking on what information should

be included in NADA's to support combination new animal drugs.

In all instances, FDA encourages sponsors to meet with CVM to

discuss the development of evidence of safety and effectiveness to

support approval of an NADA for single ingredient or combination new

animal drugs. In considering the number and types of the adequate and

well-controlled studies needed to demonstrate the effectiveness of a

new animal drug, the sponsor may also want to discuss with FDA any

possible later expansion or extension of the claims for the new animal

drug so that the studies conducted in support of the initially proposed

intended uses will, to the extent possible, facilitate later approvals.

FDA has chosen to define substantial evidence, consistent with the

spirit of the ADAA, in a manner that permits the maximum flexibility in

determining what studies are necessary to demonstrate by substantial

evidence that a new animal drug is effective. While specificity brings

with it consistency and predictability, the spirit of the ADAA is

flexibility, efficiency, and greater animal drug availability. FDA

believes that consistency and predictability can be maintained by the

application of sound science.

IV. Conforming Changes

This proposed rule would make necessary conforming changes to

Secs. 514.1(b)(8) and 514.111 of the current regulations.

V. Environmental Impact

FDA has carefully considered the potential environmental impacts of

this proposed rule. 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.

VI. Analysis of Economic 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). FDA believes

that this proposed rule is consistent with the regulatory philosophy

and principles identified in the Executive Order. The proposed rule is

not a significant regulatory action as defined by the Executive Order.

FDA, as directed by the ADAA, is further defining ``substantial

evidence,'' the standard by which a new animal drug is determined to be

effective for its intended uses under the conditions of use represented

in its proposed labeling. The purpose of the proposed rule further

defining substantial evidence is to encourage the submission of NADA's,

the submission of supplemental NADA's, and the use of dose range

labeling. Accordingly, the proposed definition of substantial evidence,

while not changing the standard of effectiveness, recognizes that

``substantial evidence,'' as redefined under the ADAA, gives FDA

greater flexibility to determine the number and types of studies that

FDA would find demonstrate the effectiveness of any particular new

animal drug. For example, under the new statutory definition, sponsor

companies are no longer required, in every instance, to submit a field

study to establish the effectiveness of a new animal drug under

investigation. Because the new definition gives FDA greater flexibility

to work with sponsors to tailor the evidence needed to demonstrate

effectiveness, this proposed rule is not expected to impose any new

marginal costs on the industry. Furthermore, because sponsors will have

more options under this revised definition to design and conduct

studies to demonstrate effectiveness, and because sponsors can be

expected to choose the most efficient and cost effective option, the

net effect of this provision is expected to be a small benefit to

sponsors.

Further, the revised definition allows for the submission of as few

as one adequate and well-controlled study, whereas the previous

statutory language required at least two studies. While FDA expects

that the instances in which a single study will be sufficient to

demonstrate effectiveness will be limited, those sponsors who are able

to demonstrate effectiveness by a single adequate and well-controlled

study are likely to realize lower drug development costs.

The proposed rule also provides for the submission and review of

NADA's for new animal drugs intended for use over a dose range. The

ADAA eliminated the statutory requirement to limit the use of a new

animal drug to an amount no greater than that reasonably required to

accomplish the physical or other technical effect of the drug for its

intended use; the act, as amended by the ADAA, permits the use of a new

animal drug at any level that is safe for the target animal, effective,

and will not result in a residue of such drug in excess of a tolerance

found to be safe. Because dose optimization is no longer required,

sponsors are no longer required to conduct adequate and well-controlled

in vivo dose titration studies, but need only conduct such studies as

may be needed to characterize the dose or dose range so that FDA can

make a risk-benefit assessment and assure that the labeling for a new

animal drug is not false or misleading. Because there will be greater

flexibility in determining the studies needed to characterize the dose-

response relationship, sponsors are expected to realize a small cost

savings.

Finally, the proposed rule further defines substantial evidence as

it relates to combination new animal drugs. For certain combination new

animal drugs that contain active ingredients or animal drugs that have

previously been separately approved, sponsors will not be required to

conduct additional studies to demonstrate that the combination new

animal drug is effective. This change is expected to provide a cost

savings to the sponsors of NADA's that meet the criteria for the

streamlined approval process.

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

[[Page 59838]]

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 agency certifies that

the proposed 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.

VII. 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.

VIII. Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that

are subject to review by the Office of Management and Budget (OMB)

under the Paperwork Reduction Act of 1995 (PRA of 1995) (44 U.S.C.

3501-3520). A description of the information collection provisions and

an estimate of the annual collection of information burden follow.

FDA invites comments on: (1) Whether the proposed collection of

information is necessary for the proper performance of FDA's functions,

including whether the information will have practical utility; (2) the

accuracy of the agency's estimate of the burden of the proposed

collection of information including the validity of the methodology and

assumptions used; (3) ways to enhance the quality, utility, and clarity

of the information to be collected; and (4) ways to minimize the burden

of the collection of information on respondents, including the validity

of the methodology and assumptions used.

Title: Substantial Evidence of Effectiveness of New Animal Drugs.

Description: As directed by the ADAA, FDA is publishing a proposed

regulation to further define substantial evidence in a manner that

encourages the submission of NADA's and supplemental NADA's and

encourages dose range labeling. The proposed regulation implements the

definition of ``substantial evidence'' in 21 U.S.C. 360b(d)(3) as

amended by the ADAA. Substantial evidence is the standard that a

sponsor must meet to demonstrate the effectiveness of a new animal drug

for its intended uses under the conditions of use suggested in its

proposed labeling. The proposed regulation, Sec. 514.4(a), gives FDA

greater flexibility to make case-specific scientific determinations

regarding the number and types of adequate and well-controlled studies

that will provide, in an efficient manner, substantial evidence that a

new animal drug is effective. The proposed regulation will reduce the

number of adequate and well-controlled studies necessary to demonstrate

the effectiveness of certain combination new animal drugs, will

eliminate the need for an adequate and well-controlled dose titration

study, and may, in limited instances, reduce or eliminate the number of

adequate and well-controlled field investigations necessary to

demonstrate by substantial evidence the effectiveness of a new animal

drug.

Table 1 below represents the estimated burden of meeting the new

substantial evidence standard. The numbers in the chart are based on

recent consultation with several of the major research and development

firms that conduct the majority of studies submitted to establish

substantial evidence of effectiveness of new animal drugs. Because of

the more flexible requirements for demonstrating substantial evidence

of effectiveness, FDA estimates that the proposed regulation would

reduce by approximately 10 percent the total annual burden associated

with demonstrating the effectiveness of a new animal drug as part of an

NADA or supplemental NADA submission.

Description of Respondents: Persons and businesses, including small

businesses.

Table 1.--Estimated Annual Reporting Burden

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

Annual

21 CFR No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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

514.4(a) 190 4.5 860 632.6 544,036

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

There are no capital costs or operating and maintenance costs associated with this collection.

In compliance with section 3507(d) of the PRA of 1995, the agency

has submitted the information collection provisions of this proposed

rule to OMB for review. Interested persons are requested to send

comments regarding information collection by December 5, 1997 to the

Office of Information and Regulatory Affairs, Office of Management and

Budget, New Executive Office Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn.: Desk Officer for FDA.

IX. References

The following information has been placed on display in the Dockets

Management Branch and may be seen by interested persons between 9 a.m.

and 4 p.m., Monday through Friday.

1. Horton, Richard, ``Revising the Research Record,'' The

Lancet, vol. 346, p. 1610-11, 1995.

List 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 514.1 is amended by revising paragraphs (b)(8)(ii) and

(b)(8)(v) to read as follows:

Sec. 514.1 Applications.

* * * * *

(b) * * *

(8) * * *

(ii) An application may be refused unless it includes substantial

evidence

[[Page 59839]]

of the effectiveness of the new animal drug as defined in Sec. 514.4.

* * * * *

(v) If the new animal drug is a combination of active ingredients

or animal drugs, an application may be refused unless it includes

substantial evidence of the effectiveness of the combination new animal

drug as required in Sec. 514.4.

* * * * *

3. Section 514.4 is added to subpart A to read as follows:

Sec. 514.4 Substantial evidence.

(a) Definition of substantial evidence. Substantial evidence means

evidence consisting of one or more adequate and well-controlled

studies, such as a study in a target species, study in laboratory

animals, field study, bioequivalence study, or an in vitro study, on

the basis of which it could fairly and reasonably be concluded by

experts qualified by scientific training and experience to evaluate the

effectiveness of the new animal drug involved that the new animal 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. Substantial evidence shall include such

adequate and well-controlled studies that are, as a matter of sound

scientific judgment, necessary to establish that a new animal drug will

have its intended effect.

(b) Characteristics of substantial evidence--(1) Qualifications of

experts. Studies that are intended to provide substantial evidence of

the effectiveness of a new animal drug shall be conducted by experts

qualified by scientific training and experience.

(2) Intended uses and conditions of use. Studies that are intended

to provide substantial evidence of the effectiveness of a new animal

drug shall demonstrate that the new animal drug is effective for each

intended use and associated conditions of use for and under which

approval is sought. Substantial evidence to support dose range labeling

for a new animal drug intended for use in the diagnosis, cure,

mitigation, treatment, or prevention of disease must consist of at

least one adequate and well-controlled study on the basis of which

qualified experts could fairly and reasonably conclude that the new

animal drug will be effective for at least one intended use at the

lower dose limit prescribed in the proposed labeling and will be

effective for each intended use at the dose suggested in the proposed

labeling for that intended use. Substantial evidence to support a dose

range for a new animal drug intended to affect the structure or

function of the body of an animal for the purpose of enhancing

production must consist of at least one adequate and well-controlled

study on the basis of which qualified experts could fairly and

reasonably conclude that the new animal drug will be effective for each

intended use at all the doses within the range prescribed for the

intended use. Sponsors should, to the extent possible, provide for a

dose range because it increases the utility of the new animal drug by

providing the user flexibility in the selection of a safe and effective

dose.

(3) Studies--(i) Number. Substantial evidence of the effectiveness

of a new animal drug for an intended use and associated conditions of

use shall consist of a sufficient number of current adequate and well-

controlled studies of sufficient quality and persuasiveness to permit

qualified experts:

(A) To determine that the parameters selected for measurement and

the measured responses reliably reflect the effectiveness of the new

animal drug;

(B) To determine that the results obtained are likely to be

repeatable, and that valid inferences can be drawn to the target animal

population; and

(C) To conclude that the new animal drug is effective for the

intended use at the dose or dose range and associated conditions of use

prescribed, recommended, or suggested in the proposed labeling.

(ii) Types. Adequate and well-controlled studies that are intended

to provide substantial evidence of the effectiveness of a new animal

drug may include, but are not limited to, published studies, foreign

studies, studies using models, and studies conducted by or on behalf of

the sponsor. Studies using models shall be validated to establish an

adequate relationship of parameters measured and effects observed in

the model with one or more significant effects of treatment.

(c) Substantial evidence for combination new animal drugs--(1)

Definitions--(i) Combination new animal drug means a new animal drug

that contains more than one active ingredient or animal drug that is

applied or administered simultaneously in a single dosage form or

simultaneously in or on animal feed or drinking water.

(ii) For purposes of this section, antibacterial with respect to a

particular target animal species means an active ingredient or animal

drug:

(A) That is approved in that species for the diagnosis, cure,

mitigation, treatment, or prevention of bacterial disease; or

(B) That is approved for use in that species for any other use that

is attributable to its antibacterial properties.

(2) Combinations with active ingredients or animal drugs that have

previously been separately approved. Except in the case of a

combination new animal drug intended for use other than in animal feed

or drinking water that contains a nontopical antibacterial ingredient

or animal drug, for combination new animal drugs that contain active

ingredients or animal drugs that have previously been separately

approved for the particular uses and conditions of use for which they

are intended in combination, a sponsor shall incorporate into the

application for the combination new animal drug substantial evidence of

the effectiveness of each active ingredient or animal drug previously

approved and shall demonstrate:

(i) By substantial evidence, as defined in this section, that any

active ingredient or animal drug intended only for the same use as

another active ingredient or animal drug in the combination makes a

contribution to the effectiveness of the combination new animal drug;

(ii) For such combination new animal drugs that are intended for

use in animal feed or drinking water and contain more than one

antibacterial ingredient or animal drug, by substantial evidence, as

defined in this section, that each antibacterial makes a contribution

to labeled effectiveness;

(iii) That each active ingredient or animal drug intended for at

least one use that is different from all the other active ingredients

or animal drugs used in the combination provides appropriate concurrent

use for the intended target animal population;

(iv) Unless waived in specific cases, that the active ingredients

or animal drugs intended for use other than in animal feed or drinking

water are physically compatible and do not have disparate dosing

regimens by demonstrating bioavailability of the active ingredients or

animal drugs in combination relative to the bioavailability of active

ingredients or animal drugs singly; and,

(v) Unless waived in specific cases, that the active ingredients or

animal drugs intended for use in drinking water are physically

compatible by demonstrating bioavailability of the active ingredients

or animal drugs in combination relative to the bioavailability of

active ingredients or animal drugs singly;

(3) Other combination new animal drugs. For all other combination

new

[[Page 59840]]

animal drugs, the sponsor shall demonstrate by substantial evidence, as

defined in this section, that the combination new animal drug will have

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

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

and that each active ingredient or animal drug contributes to the

effectiveness of the combination new animal drug.

4. 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 as defined in Sec. 514.4.

* * * * *

Dated: October 30, 1997.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 97-29275 Filed 10-31-97; 2:48 pm]

BILLING CODE 4160-01-F