59830 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

provide other means of verification

satisfactory to the Secretaries in these

situations.

The proposed rule does not contain

policies with Federalism implications

sufficient to warrant preparation of a

Federalism assessment under Executive

Order 12612.

Regulatory Flexibility Act. In

accordance with the Regulatory

Flexibility Act, 5 U.S.C. 601 et seq., the

Assistant General Counsel for

Legislation and Regulation has certified

to the Chief Counsel, Small Business

Administration, that the proposed rule

will not have a significant economic

impact on a substantial number of small

entities. This is because the rulemaking

is primarily to make technical changes.

Paperwork Reduction Act. This

rulemaking involves information

collection activities subject to the

Paperwork Reduction Act of 1980, 44

U.S.C. 3501 et seq. which is currently

approved by the Office of Management

and Budget under control number 0625–

0134. The amendments would have no

effect on the information burden on the

public.

Notwithstanding any other provision

of the law, no person is required to

respond to, nor shall any person be

subject to a penalty for failure to comply

with a collection of information unless

it displays a currently valid OMB

Control Number.

It has been determined that the

proposed rulemaking is not significant

for purposes of Executive Order 12866.

List of Subjects in 15 CFR Part 303

Administrative practice and

procedure, American Samoa, Customs

duties and inspection, Guam, Imports,

Marketing quotas, Northern Mariana

Islands, Reporting and recordkeeping

requirements, Virgin Islands, Watches

and jewelry.

For reasons set forth above, we

propose to amend 15 CFR Part 303 as

follows:

PART 303—[AMENDED]

§ 303.6 [Amended]

1. Section 303.6(a) is amended by

adding to the second to last sentence ‘‘,

or verified by other means satisfactory

to the Secretaries,’’ after the words U.S.

Customs Service.

§ 303.14 [Amended]

2. Section 303.14(e) is amended by

removing ‘‘3,100,000’’ and adding

‘‘2,600,000’’ in its place.

Robert S. LaRussa,

Assistant Secretary for Import

Administration.

Allen Stayman,

Director, Office of Insular Affairs.

[FR Doc. 97–29198 Filed 11–4–97; 8:45 am]

BILLING CODE 3510–DS–M and 4310–93–M

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.

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 wellcontrolled 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.
Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules 59831

1The 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).

Prior to the enactment of the ADAA,

section 512(d)(3) of the act defined

substantial evidence as:

[e]vidence consisting of adequate and wellcontrolled 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 wellcontrolled study 1 may provide

substantial evidence of the effectiveness

of a new animal drug for its intended

uses and associated conditions of use.

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 § 514.4

Substantial evidence to further define

substantial evidence. Proposed § 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 wellcontrolled 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 (§ 514.4(b))

1. Intended Uses and Conditions of Use

(§ 514.4(b)(2))

Proposed § 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

§ 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
59832 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

2Target 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.

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 doseresponse 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 doseresponse 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 doseresponse 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 (§ 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

§ 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.

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 § 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

(§ 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 (§ 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
Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules 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 wellcontrolled 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

§ 514.111(a)(5)(ii) (proposed § 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

(§ 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

(§ 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 (§ 514.4(b)(3)(ii))

Proposed § 514.4(b)(3)(ii) specifies

that the types of adequate and wellcontrolled 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 (§ 514.111;

proposed § 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
59834 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

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 peerreviewed 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 wellcontrolled 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 onstudy 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 peerreviewed 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

(§ 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 § 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
Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules 59835

3Use 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.

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 (§ 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.

To implement these statutory

provisions, proposed § 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 § 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 § 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
59836 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

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 § 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 § 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 § 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 § 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
Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules 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

§§ 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 wellcontrolled 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 doseresponse 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
59838 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

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,

§ 514.4(a), gives FDA greater flexibility

to make case-specific scientific

determinations regarding the number

and types of adequate and wellcontrolled 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

21 CFR No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

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:

§ 514.1 Applications.

* * * * *

(b) * * *

(8) * * *

(ii) An application may be refused

unless it includes substantial evidence
Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules 59839

of the effectiveness of the new animal

drug as defined in § 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 § 514.4.

* * * * *

3. Section 514.4 is added to subpart

A to read as follows:

§ 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 wellcontrolled 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
59840 Federal Register / Vol. 62, No. 214 / Wednesday, November 5, 1997 / Proposed Rules

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:

§ 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 § 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

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 58

[AD–FRL–5903–6]

RIN 2060–AF71

Ambient Air Quality Surveillance for

Lead

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: Lead air pollution levels

measured near the Nation’s roadways

have decreased 97 percent between

1976 and 1995 with the elimination of

lead in gasoline used by on-road mobile

sources. Because of this historic

decrease, EPA is shifting its ambient air

monitoring focus from measuring lead

air pollutant concentrations emanating

from mobile source emissions toward a

focus on stationary point sources of lead

air pollution. Today’s action proposes to

revise the part 58 lead air monitoring

regulations to allow many lead

monitoring stations to be discontinued

while maintaining a core lead

monitoring network in urban areas to

track continued compliance with the

lead National Ambient Air Quality

Standards (NAAQS). This action also

requires lead ambient air monitoring

around lead stationary sources. This

action is being taken at the direct

request of numerous State and local

agencies whose on-road mobile sourceoriented lead monitors have been

reporting peak lead air pollution values

that are many times less than the

quarterly lead NAAQS of 1.5μg/m3 for

many years. Approximately 70 of the

National Air Monitoring Stations

(NAMS) and a number of the State and

Local Air Monitoring Stations (SLAMS)

could be discontinued with this action,

thus making more resources available to

those State and local agencies to deploy

lead air quality monitors around

heretofore unmonitored lead stationary

sources.

DATES: Comments must be submitted on

or before December 5, 1997.

ADDRESSES: Comments should be

submitted (in duplicate, if possible) to:

Air Docket (LE–131), US Environmental

Protection Agency, Attn. Docket No. A–

91–22, 401 M Street, SW, Washington,

D.C. 20460.

FOR FURTHER INFORMATION CONTACT:

Brenda Millar, Emissions, Monitoring,

and Analysis Division (MD–14), Office

of Air Quality Planning and Standards,

U.S. Environmental Protection Agency,

Research Triangle Park, North Carolina

27711, Telephone: (919) 541–4036, email:millar.brenda@email.epa.gov.

SUPPLEMENTARY INFORMATION:

I. Authority

Sections 110, 301(a), and 319 of the

Clean Air Act as amended 42 U.S.C.

7410, 7601(a), 7619.

II. Background

The current ambient air monitoring

regulations that pertain to lead air

sampling were written in the 1970’s

when lead emissions from on-road

mobile sources (e.g., automobiles,

trucks) were the predominant lead air

emission source affecting our

communities. As such, the current lead

monitoring requirements focus

primarily upon the idea of determining

the air quality impacts from major

roadways and urban traffic arterial

highways. Since the 1970’s, lead has

been removed from gasoline sources for

on-road vehicles (on-oad vehicles now

account for less than 1 percent of total

lead emissions), and a 97 percent

decrease in lead air pollution levels

measured in our neighborhoods and

near roadways has occurred nationwide.

Because of this historic decrease, EPA is

reducing its requirements for measuring

lead air pollutant concentrations near

major highways, and is focusing on

stationary point sources and their

impacts on neighboring populations.

The current lead air monitoring

regulations require that each urbanized

area with a population of 500,000 or

more operate at least two lead NAMS,

one of which must be a roadwayoriented site and the second must be a

neighborhood site with nearby traffic

arteries or other major roadways. There

are approximately 85 NAMS in

operation and reporting data for 1996.

This action would reduce this NAMS

requirement to include one NAMS site

in one of the two largest Metropolitan

Statistical Areas (MSA/CMSA) within

each of the ten EPA Regions, and one

NAMS population-oriented site in each

populated area (either a MSA/CMSA,

town, or county) where lead violations

have been measured over the most

recent 8 calendar quarters. This latter

requirement is designed to provide

information to citizens living in areas

that have one or more lead stationary

sources that are causing recent air

quality violations. At present, the MSA/

CMSAs, cities, or counties that have one

or more quarterly Pb NAAQS violations

that would be subject to this

requirement include:

TABLE 1.—CMSA/MSA’S OR COUNTIES WITH ONE OR MORE LEAD NAAQS VIOLATIONS IN 1995–1996

CMSA/MSA or county Contributing lead source(s)

Philadelphia-Wilmington-Atlantic City CMSA ........................................... Franklin Smelter in Philadelphia County, PA.

Tampa-St. Petersburg-Clearwater MSA ................................................... Gulf Coast Lead in Hillsborough County, FL.

Memphis MSA .......................................................................................... Refined Metals in Shelby County, TN.

Nashville MSA .......................................................................................... General Smelting in Williamson County, TN.

St. Louis MSA ........................................................................................... Chemetco in Madison County, IL, and Doe Run in Jefferson County,

MO.

Cleveland-Akron CMSA ............................................................................ Master Metals in Cuyahoga County, OH.

Iron County, MO ....................................................................................... ASARCO in/near Hogan, MO.