31790 Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices

period of 5 years. Any person with an

approved or pending drug product

application who knowingly uses the

services of Mr. Feuer in any in any

capacity during his period of debarment

will be subject to civil money penalties

(section 307(a)(6) of the act (21 U.S.C.

335b(a)(6))). If Mr. Feuer, during his

period of debarment, provides services

in any capacity to a person with an

approved or pending drug product

application, he will be subject to civil

money penalties (section 307(a)(7) of the

act). In addition, FDA will not accept or

review any abbreviated new drug

applications or abbreviated antibiotic

drug applications submitted by or with

the assistance of Mr. Feuer during his

period of debarment.

Any application by Mr. Feuer for

termination of debarment under section

306(d)(4) of the act should be identified

with Docket No. 98N–0131 and sent to

the Dockets Management Branch

(address above). All such submissions

are to be filed in four copies. The public

availability of information in these

submissions is governed by 21 CFR

10.20(j). Publicly available submissions

may be seen in the Dockets Management

Branch between 9 a.m. and 4 p.m.,

Monday through Friday.

Dated: May 18, 1998.

Janet Woodcock,

Director, Center for Drug Evaluation and

Research.

[FR Doc. 98–15482 Filed 6–9–98; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97D–0299]

International Conference on

Harmonisation; Guidance on Ethnic

Factors in the Acceptability of Foreign

Clinical Data; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

guidance entitled ‘‘E5 Ethnic Factors in

the Acceptability of Foreign Clinical

Data.’’ The guidance was prepared

under the auspices of the International

Conference on Harmonisation of

Technical Requirements for Registration

of Pharmaceuticals for Human Use

(ICH). The guidance recommends

regulatory and development strategies to

permit clinical data collected in one

region to be used for the support of drug

and biologic registrations in another

region while allowing for the influence

of ethnic factors.

DATES: Effective June 10, 1998. Submit

written comments at any time.

ADDRESSES: Submit written comments

on the guidance to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the guidance are

available from the Drug Information

Branch (HFD–210), Center for Drug

Evaluation and Research, Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–827–

4573. Single copies of the guidance may

be obtained by mail from the Office of

Communication, Training and

Manufacturers Assistance (HFM–40),

Center for Biologics Evaluation and

Research (CBER), or by calling the CBER

Voice Information System at 1–800–

835–4709 or 301–827–1800. Copies may

be obtained from CBER’s FAX

Information System at 1–888–CBER–

FAX or 301–827–3844.

FOR FURTHER INFORMATION CONTACT:

Regarding the guidance: Barbara G.

Matthews, Center for Biologics

Evaluation and Research (HFM–

570), Food and Drug

Administration, 1401 Rockville

Pike, Rockville, MD 20852, 301–

827–5094.

Regarding ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–827–0864.

SUPPLEMENTARY INFORMATION: In recent

years, many important initiatives have

been undertaken by regulatory

authorities and industry associations to

promote international harmonization of

regulatory requirements. FDA has

participated in many meetings designed

to enhance harmonization and is

committed to seeking scientifically

based harmonized technical procedures

for pharmaceutical development. One of

the goals of harmonization is to identify

and then reduce differences in technical

requirements for drug development

among regulatory agencies.

ICH was organized to provide an

opportunity for tripartite harmonization

initiatives to be developed with input

from both regulatory and industry

representatives. FDA also seeks input

from consumer representatives and

others. ICH is concerned with

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. The six ICH

sponsors are the European Commission,

the European Federation of

Pharmaceutical Industries Associations,

the Japanese Ministry of Health and

Welfare, the Japanese Pharmaceutical

Manufacturers Association, the Centers

for Drug Evaluation and Research and

Biologics Evaluation and Research,

FDA, and the Pharmaceutical Research

and Manufacturers of America. The ICH

Secretariat, which coordinates the

preparation of documentation, is

provided by the International

Federation of Pharmaceutical

Manufacturers Associations (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and the IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

In the Federal Register of July 31,

1997 (62 FR 41054), FDA published a

draft tripartite guideline entitled

‘‘Ethnic Factors in the Acceptability of

Foreign Clinical Data’’ (E5). The notice

gave interested persons an opportunity

to submit comments by October 29,

1997.

After consideration of the comments

received and revisions to the guidance,

a final draft of the guidance was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies on

February 5, 1998.

In accordance with FDA’s good

guidance practices (62 FR 8961,

February 27, 1997), this document has

been designated a guidance, rather than

a guideline.

The guidance is intended to facilitate

the registration of drugs and biologics

among ICH regions by recommending a

framework for evaluating the impact of

ethnic factors on a drug’s effect, i.e., its

efficacy and safety at a particular dosage

and dose regimen. The guidance

recommends regulatory and

development strategies that will permit

adequate evaluation of the influence of

ethnic factors, minimize duplication of

clinical studies, and expedite the drug

approval process.

This guidance represents the agency’s

current thinking on ethnic factors in the

acceptability of foreign clinical data for

approval of both drugs and biologics. It

does not create or confer any rights for

or on any person and does not operate

to bind FDA or the public. An

alternative approach may be used if

such approach satisfies the

requirements of the applicable statute,

regulations, or both.

As with all of FDA’s guidances, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guidance.

The comments in the docket will be
Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices 31791

1This guidance represents the agency’s current

thinking on ethnic factors in the acceptability of

foreign clinical data for approval of both drugs and

biologics. It does not create or confer any rights for

or on any person and does not operate to bind FDA

or the public. An alternative approach may be used

if such approach satisfies the requirements of the

applicable statute, regulations, or both.

periodically reviewed, and, where

appropriate, the guidance will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

guidance to the Dockets Management

Branch (address above). Two copies of

any comments are to be submitted,

except that individuals may submit one

copy. Comments are to be identified

with the docket number found in

brackets in the heading of this

document. The guidance and received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday. An electronic

version of this guidance is available on

the Internet at ‘‘http://www.fda.gov/

cder/guidance/index.htm’’ or at CBER’s

World Wide Webb site at ‘‘http://

www.fda.gov/cber/publications.htm’’.

The text of the guidance follows:

E5 Ethnic Factors in the Acceptability of

Foreign Clinical Data1

1.0 Introduction

1.1 Objectives

1.2 Background

1.3 Scope

2.0 Assessment of the Clinical Data Package

Including Foreign Clinical Data for Its

Fulfillment of Regulatory Requirements in

the New Region

2.1 Additional Studies to Meet the New

Region’s Regulatory Requirements

3.0 Assessment of the Foreign Clinical Data

for Extrapolation to the New Region

3.1 Characterization of the Medicine’s

Sensitivity to Ethnic Factors

3.2 Bridging Data Package

3.2.1 Definition of Bridging Data Package

and Bridging Study

3.2.2 Nature and Extent of the Bridging

Study

3.2.3 Bridging Studies for Efficacy

3.2.4 Bridging Studies for Safety

4.0 Developmental Strategies for Global

Development

5.0 Summary

Glossary (Italicized words and terms in the

text of the guidance are defined or explained

in the glossary.)

Appendix A: Classification of intrinsic and

extrinsic ethnic factors

Appendix B: Assessment of the clinical data

package (CDP) for acceptability

Appendix C: Pharmacokinetic,

pharmacodynamic, and dose-response

considerations

Appendix D: A medicine’s sensitivity to

ethnic factors

1.0 Introduction

The purpose of this guidance is to facilitate

the registration of medicines among ICH

regions (see Glossary) by recommending a

framework for evaluating the impact of

ethnic factors upon a medicine’s effect, i.e.,

its efficacy and safety at a particular dosage

and dose regimen. It provides guidance with

respect to regulatory and development

strategies that will permit adequate

evaluation of the influence of ethnic factors

while minimizing duplication of clinical

studies and supplying medicines

expeditiously to patients for their benefit.

This guidance should be implemented in

context with other ICH guidances. For the

purposes of this document, ethnic factors are

defined as those factors relating to the genetic

and physiologic (intrinsic) and the cultural

and environmental (extrinsic) characteristics

of a population (Appendix A).

1.1 Objectives

To describe the characteristics of foreign

clinical data that will facilitate their

extrapolation to different populations and

support their acceptance as a basis for

registration of a medicine in a new region.

• To describe regulatory strategies that

minimize duplication of clinical data and

facilitate acceptance of foreign clinical data

in the new region.

• To describe the use of bridging studies,

when necessary, to allow extrapolation of

foreign clinical data to a new region.

• To describe development strategies

capable of characterizing ethnic factor

influences on safety, efficacy, dosage, and

dose regimen.

1.2 Background

All of the ICH regions acknowledge the

desirability of utilizing foreign clinical data

that meet the regulatory standards and

clinical trial practices acceptable to the

region considering the application for

registration.

However, concern that ethnic differences

may affect the medication’s safety, efficacy,

dosage, and dose regimen in the new region

has limited the willingness to rely on foreign

clinical data. Historically, this has been one

of the reasons, therefore, the regulatory

authority in the new region has often

requested that all, or much of, the foreign

clinical data in support of registration be

duplicated in the new region. Although

ethnic differences among populations may

cause differences in a medicine’s safety,

efficacy, dosage, or dose regimen, many

medicines have comparable characteristics

and effects across regions. Requirements for

extensive duplication of clinical evaluation

for every compound can delay the

availability of new therapies and

unnecessarily waste drug development

resources.

1.3 Scope

This guidance is based on the premise that

it is not necessary to repeat the entire clinical

drug development program in the new region

and is intended to recommend strategies for

accepting foreign clinical data as full or

partial support for approval of an application

in a new region. It is critical to appreciate

that this guidance is not intended to alter the

data requirements for registration in the new

region; it seeks to recommend when these

data requirements may be satisfied with

foreign clinical data. All data in the clinical

data package, including foreign data, should

meet the standards of the new region with

respect to study design and conduct, and the

available data should satisfy the regulatory

requirements in the new region. Additional

studies conducted in any region may be

required by the new region to complete the

clinical data package.

Once a clinical data package fulfills the

regulatory requirements of the new region,

the only remaining issue with respect to the

acceptance of the foreign clinical data is its

ability to be extrapolated to the population of

the new region. When the regulatory

authority or the sponsor is concerned that

differences in ethnic factors could alter the

efficacy or safety of the medicine in the

population in the new region, the sponsor

may need to generate a limited amount of

clinical data in the new region in order to

extrapolate or ‘‘bridge’’ the clinical data

between the two regions. If a sponsor needs

to obtain additional clinical data to fulfill the

regulatory requirements of the new region, it

is possible that these clinical trials can be

designed to also serve as the bridging studies.

Thus, the sponsor and the regional

regulatory authority of the new region would

assess an application for registration for:

(1) Its completeness with respect to the

regulatory requirements of the new region,

and

(2) The ability to extrapolate to the new

region those parts of the application (which

could be most or all of the application) based

on studies from the foreign region (Appendix

B).

2.0 Assessment of the Clinical Data Package

Including Foreign Clinical Data for Its

Fulfillment of Regulatory Requirements in

the New Region

The regional regulatory authority would

assess the clinical data package, including

the foreign data, as to whether or not it meets

all of the regulatory standards regarding the

nature and quality of the data, irrespective of

its geographic origin, i.e., data generated

either totally in a foreign region (or regions)

or data from studies conducted both in a

foreign and the new region to which the

application is being made. A clinical data

package that meets all of these regional

regulatory requirements is defined as a

‘‘complete’’ clinical data package for

submission and potential approval. The

acceptability of the foreign clinical data

component of the complete data package

depends then upon whether it can be

extrapolated to the population of the new

region.

Before extrapolation can be considered, the

complete clinical data package, including

foreign clinical data, submitted to the new

region should contain:

• Adequate characterization of

pharmacokinetics, pharmacodynamics, dose

response, efficacy, and safety in the

population of the foreign region(s).

• Clinical trials establishing dose response,

efficacy and safety. These trials should:
31792 Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices

—Be designed and conducted according to

regulatory standards in the new region, e.g.,

choice of controls, and should be conducted

according to good clinical practice (GCP),

—Be adequate and well-controlled,

—Utilize endpoints that are considered

appropriate for assessment of treatment,

—Evaluate clinical disorders using medical

and diagnostic definitions that are acceptable

to the new region.

• Characterization in a population relevant

to the new region of the pharmacokinetics,

and where possible, pharmacodynamics and

dose response for pharmacodynamic

endpoints. This characterization could be

performed in the foreign region in a

population representative of the new region

or in the new region.

Several ICH guidances that address aspects

of design, conduct, analysis, and reporting of

clinical trials will help implement the

concepts of the complete clinical data

package. These guidances include GCP’s (E6),

evaluation of dose response (E4), adequacy of

safety data (E1 and E2), conduct of studies in

the elderly (E7), reporting of study results

(E3), general considerations for clinical trials

(E8), and statistical considerations (E9). A

guidance on the choice of control group in

clinical study design (E10) is under

development.

2.1 Additional Studies to Meet the New

Region’s Regulatory Requirements

When the foreign clinical data do not meet

the regional regulatory requirements, the

regulatory authority may require additional

clinical trials such as:

• Clinical trials in different subsets of the

population, such as patients with renal

insufficiency, patients with hepatic

dysfunction, etc.,

• Clinical trials using different comparators

at the new region’s approved dosage and

dose regimen,

• Drug-drug interaction studies.

3.0 Assessment of the Foreign Clinical Data

for Extrapolation to the New Region

3.1 Characterization of the Medicine’s

Sensitivity to Ethnic Factors

To assess a medicine’s sensitivity to ethnic

factors, it is important that there be

knowledge of its pharmacokinetic and

pharmacodynamic properties and the

translation of those properties to clinical

effectiveness and safety. A reasonable

evaluation is described in Appendix C. Some

properties of a medicine (chemical class,

metabolic pathway, pharmacologic class)

make it more or less likely to be affected by

ethnic factors (Appendix D). Characterization

of a medicine as ‘‘ethnically insensitive,’’ i.e.,

unlikely to behave differently in different

populations, would usually make it easier to

extrapolate data from one region to another

and need less bridging data.

Factors that make a medicine ethnically

sensitive or insensitive will become better

understood and documented as effects in

different regions are compared. It is clear at

present, however, that such characteristics as

clearance by an enzyme showing genetic

polymorphism and a steep dose-response

curve will make ethnic differences more

likely. Conversely, a lack of metabolism or

active excretion, a wide therapeutic dose

range, and a flat dose-response curve will

make ethnic differences less likely. The

clinical experience with other members of

the drug class in the new region will also

contribute to the assessment of the

medicine’s sensitivity to ethnic factors. It

may be easier to conclude that the

pharmacodynamic and clinical behavior of a

medicine will be similar in the foreign and

new regions if other members of the

pharmacologic class have been studied and

approved in the new region with dosing

regimens similar to those used in the original

region.

3.2 Bridging Data Package

3.2.1 Definition of Bridging Data Package and

Bridging Study

A bridging data package consists of: (1)

Selected information from the complete

clinical data package that is relevant to the

population of the new region, including

pharmacokinetic data, and any preliminary

pharmacodynamic and dose-response data

and, if needed, (2) a bridging study to

extrapolate the foreign efficacy data and/or

safety data to the new region.

A bridging study is defined as a study

performed in the new region to provide

pharmacodynamic or clinical data on

efficacy, safety, dosage, and dose regimen in

the new region that will allow extrapolation

of the foreign clinical data to the population

in the new region. A bridging study for

efficacy could provide additional

pharmacokinetic information in the

population of the new region. When no

bridging study is needed to provide clinical

data for efficacy, a pharmacokinetic study in

the new region may be considered as a

bridging study.

3.2.2 Nature and Extent of the Bridging Study

This guidance proposes that when the

regulatory authority of the new region is

presented with a clinical data package that

fulfills its regulatory requirements, the

authority should request only those

additional data necessary to assess the ability

to extrapolate foreign data from the complete

clinical data package to the new region. The

sensitivity of the medicine to ethnic factors

will help determine the amount of such data.

In most cases, a single trial that successfully

provides these data in the new region and

confirms the ability to extrapolate data from

the original region should suffice and should

not need further replication. Note that even

though a single study should be sufficient to

‘‘bridge’’ efficacy data, a sponsor may find it

practical to obtain the necessary data by

conducting more than one study. For

example, where it is intended that a fixed

dose, dose-response study using a clinical

endpoint is needed as the bridging study, a

short-term pharmacologic endpoint study

may be used to choose the dose(s) for the

larger (clinical endpoint) study.

When the regulatory authority requests, or

the sponsor decides to conduct, a bridging

study, discussion between the regional

regulatory authority and sponsor is

encouraged, when possible, to determine

what kind of bridging study will be needed.

The relative ethnic sensitivity will help

determine the need for and the nature of the

bridging study. For regions with little

experience with registration based on foreign

clinical data, the regulatory authorities may

still request a bridging study for approval

even for compounds insensitive to ethnic

factors. As experience with interregional

acceptance increases, there will be a better

understanding of situations in which

bridging studies are needed. It is hoped that

with experience, the need for bridging data

will lessen.

The following is general guidance about

the ability to extrapolate data generated from

a bridging study:

• If the bridging study shows that dose

response, safety, and efficacy in the new

region are similar, then the study is readily

interpreted as capable of ‘‘bridging’’ the

foreign data.

• If a bridging study, properly executed,

indicates that a different dose in the new

region results in a safety and efficacy profile

that is not substantially different from that

derived in the original region, it will often be

possible to extrapolate the foreign data to the

new region, with appropriate dose

adjustment, if this can be adequately justified

(e.g., by pharmacokinetic and/or

pharmacodynamic data).

• If the bridging study designed to

extrapolate the foreign data is not of

sufficient size to confirm adequately the

extrapolation of the adverse event profile to

the new population, additional safety data

may be necessary (section 3.2.4).

• If the bridging study fails to verify safety

and efficacy, additional clinical data (e.g.,

confirmatory clinical trials) would be

necessary.

3.2.3 Bridging Studies for Efficacy

Generally, for medicines characterized as

insensitive to ethnic factors, the type of

bridging study needed (if needed) will

depend upon experience with the drug class

and upon the likelihood that extrinsic ethnic

factors (including design and conduct of

clinical trials) could affect the medicine’s

safety, efficacy, and dose-response. For

medicines that are ethnically sensitive, a

bridging study may often be needed if the

populations in the two regions are different.

The following examples illustrate types of

bridging studies for consideration in different

situations:

• No bridging study

In some situations, extrapolation of clinical

data may be feasible without a bridging

study:

(1) If the medicine is ethnically insensitive

and extrinsic factors such as medical practice

and conduct of clinical trials in the two

regions are generally similar.

(2) If the medicine is ethnically sensitive

but the two regions are ethnically similar and

there is sufficient clinical experience with

pharmacologically related compounds to

provide reassurance that the class behaves

similarly in patients in the two regions with

respect to efficacy, safety, dosage, and dose

regimen. This might be the case for wellestablished classes of drugs known to be

administered similarly, but not necessarily

identically, in the two regions.

• Bridging studies using pharmacologic

endpoints
Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices 31793

If the regions are ethnically dissimilar and

the medicine is ethnically sensitive but

extrinsic factors are generally similar (e.g.,

medical practice, design and conduct of

clinical trials) and the drug class is a familiar

one in the new region, a controlled

pharmacodynamic study in the new region,

using a pharmacologic endpoint that is

thought to reflect relevant drug activity

(which could be a well-established surrogate

endpoint), could provide assurance that the

efficacy, safety, dose and dose regimen data

developed in the first region are applicable

to the new region. Simultaneous

pharmacokinetic (i.e., blood concentration)

measurements may make such studies more

interpretable.

• Controlled clinical trials

It will usually be necessary to carry out a

controlled clinical trial, often a randomized,

fixed dose, dose-response study, in the new

region when:

(1) There are doubts about the choice of

dose,

(2) There is little or no experience with

acceptance of controlled clinical trials

carried out in the foreign region,

(3) Medical practice (e.g., use of

concomitant medications and design and/or

conduct of clinical trials) is different, or

(4) The drug class is not a familiar one in

the new region.

Depending on the situation, the trial could

replicate the foreign study or could utilize a

standard clinical endpoint in a study of

shorter duration than the foreign studies or

utilize a validated surrogate endpoint, e.g.,

blood pressure or cholesterol (longer studies

and other endpoints may have been used in

the foreign phase III clinical trials).

If pharmacodynamic data suggest that there

are interregional differences in response, it

will generally be necessary to carry out a

controlled trial with clinical endpoints in the

new region. Pharmacokinetic differences may

not always create that necessity, as dosage

adjustments in some cases might be made

without new trials. However, any substantial

difference in metabolic pattern may often

indicate a need for a controlled clinical trial.

When the practice of medicine differs

significantly in the use of concomitant

medications, or adjunct therapy could alter

the medicine’s efficacy or safety, the bridging

study should be a controlled clinical trial.

3.2.4 Bridging Studies for Safety

Even though the foreign clinical data

demonstrate efficacy and safety in the foreign

region, there may occasionally remain a

safety concern in the new region. Safety

concerns could include the accurate

determination of the rates of relatively

common adverse events in the new region

and the detection of serious adverse events

(in the 1 percent range and generally needing

about 300 patients to assess). Depending

upon the nature of the safety concern, safety

data could be obtained in the following

situations:

• A bridging study to assess efficacy, such

as a dose-response study, could be powered

to address the rates of common adverse

events and could also allow identification of

serious adverse events that occur more

commonly in the new region. Close

monitoring of such a trial would allow

recognition of such serious events before an

unnecessarily large number of patients in the

new region are exposed. Alternatively, a

small safety study could precede the bridging

study to provide assurance that serious

adverse effects were not occurring at a high

rate.

• If there is no efficacy bridging study

needed or if the efficacy bridging study is too

small or of insufficient duration to provide

adequate safety information, a separate safety

study may be needed. This could occur

where there is:

—An index case of a serious adverse event

in the foreign clinical data,

—A concern about differences in reporting

adverse events in the foreign region,

—Only limited safety data in the new

region arising from an efficacy bridging

study, inadequate to extrapolate important

aspects of the safety profile, such as rates of

common adverse events or of more serious

adverse events.

4.0 Developmental Strategies for Global

Development

Definition of not only pharmacokinetics

but also pharmacodynamics and dose

response early in the development program

may facilitate the determination of the need

for, and nature of, any requisite bridging

data. Any candidate medicine for global

development should be characterized as

ethnically sensitive or insensitive (Appendix

D). Ideally, this characterization should be

conducted during the early clinical phases of

drug development, i.e., human pharmacology

and therapeutic exploratory studies. In some

cases, it may be useful to discuss bridging

study designs with regulatory agencies prior

to completion of the clinical data package.

However, analysis of the data within the

complete clinical data package will

determine the need for, and type of bridging

study. For global development, studies

should include populations representative of

the regions where the medicine is to be

registered and should be conducted

according to ICH guidelines.

A sponsor may wish to leave the

assessment of pharmacokinetics,

pharmacodynamics, dosage, and dose

regimens in populations relevant to the new

region until later in the drug development

program. Pharmacokinetic assessment could

be accomplished by formal pharmacokinetic

studies or by applying population

pharmacokinetic methods to clinical trials

conducted either in a population relevant to

the new region or in the new region.

5.0 Summary

This guidance describes how a sponsor

developing a medicine for a new region can

deal with the possibility that ethnic factors

could influence the effects (safety and

efficacy) of medicines and the risk/benefit

assessment in different populations. Results

from the foreign clinical trials could

comprise most, or in some cases, all of the

clinical data package for approval in the new

region, so long as they are carried out

according to the requirements of the new

region. Acceptance in the new region of such

foreign clinical data may be achieved by

generating ‘‘bridging’’ data in order to

extrapolate the safety and efficacy data from

the population in the foreign region(s) to the

population in the new region.

Glossary

Adequate and well-controlled trial: An

adequate and well controlled trial has the

following characteristics:

• A design that permits a valid comparison

with a control to provide a quantitative

assessment of treatment effect;

• The use of methods to minimize bias in

the allocation of patients to treatment groups

and in the measurement and assessment of

response to treatment; and

• An analysis of the study results

appropriate to the design to assess the effects

of the treatment.

Bridging data package: Selected

information from the complete clinical data

package that is relevant to the population of

the new region, including pharmacokinetic

data, and any preliminary pharmacodynamic

and dose-response data and, if needed,

supplemental data obtained from a bridging

study in the new region that will allow

extrapolation of the foreign safety and

efficacy data to the population of the new

region.

Bridging study: A bridging study is defined

as a supplemental study performed in the

new region to provide pharmacodynamic or

clinical data on efficacy, safety, dosage, and

dose regimen in the new region that will

allow extrapolation of the foreign clinical

data to the new region. Such studies could

include additional pharmacokinetic

information.

Complete clinical data package: A clinical

data package intended for registration

containing clinical data that fulfill the

regulatory requirements of the new region

and containing pharmacokinetic data

relevant to the population in the new region.

Compound insensitive to ethnic factors: A

compound whose characteristics suggest

minimal potential for clinically significant

impact by ethnic factors on safety, efficacy,

or dose response.

Compound sensitive to ethnic factors: A

compound whose pharmacokinetic,

pharmacodynamic, or other characteristics

suggest the potential for clinically significant

impact by intrinsic and/or extrinsic ethnic

factors on safety, efficacy, or dose response.

Dosage: The quantity of a medicine given

per administration, or per day.

Dose regimen: The route, frequency and

duration of administration of the dose of a

medicine over a period of time.

Ethnic factors: The word ethnicity is

derived from the Greek word ‘‘ethnos,’’

meaning nation or people. Ethnic factors are

factors relating to races or large populations

grouped according to common traits and

customs. Note that this definition gives

ethnicity, by virtue of its cultural as well as

genetic implications, a broader meaning than

racial. Ethnic factors may be classified as

either intrinsic or extrinsic. (Appendix A)

• Extrinsic ethnic factors: Extrinsic ethnic

factors are factors associated with the

environment and culture in which a person

resides. Extrinsic factors tend to be less

genetically and more culturally and
31794 Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices

behaviorally determined. Examples of

extrinsic factors include the social and

cultural aspects of a region such as medical

practice, diet, use of tobacco, use of alcohol,

exposure to pollution and sunshine,

socioeconomic status, compliance with

prescribed medications, and, particularly

important to the reliance on studies from a

different region, practices in clinical trial

design and conduct.

• Intrinsic ethnic factors: Intrinsic ethnic

factors are factors that help to define and

identify a subpopulation and may influence

the ability to extrapolate clinical data

between regions. Examples of intrinsic

factors include genetic polymorphism, age,

gender, height, weight, lean body mass, body

composition, and organ dysfunction.

Extrapolation of foreign clinical data: The

generalization and application of the safety,

efficacy, and dose-response data generated in

a population of a foreign region to the

population of the new region.

Foreign clinical data: Foreign clinical data

is defined as clinical data generated outside

of the new region (i.e., in the foreign region).

ICH regions: European Union, Japan, the

United States of America.

New region: The region where product

registration is sought.

• Population representative of the new

region: A population that includes the major

racial groups within the new region.

Pharmacokinetic study: A study of how a

medicine is handled by the body, usually

involving measurement of blood

concentrations of drug and its metabolite(s)

(sometimes concentrations in urine or

tissues) as a function of time.

Pharmacokinetic studies are used to

characterize absorption, distribution,

metabolism, and excretion of a drug, either

in blood or in other pertinent locations.

When combined with pharmacodynamic

measures (a PK/PD study) it can characterize

the relation of blood concentrations to the

extent and timing of pharmacodynamic

effects.

Pharmacodynamic study: A study of a

pharmacological or clinical effect of the

medicine in individuals to describe the

relation of the effect to dose or drug

concentration. A pharmacodynamic effect

can be a potentially adverse effect

(anticholinergic effect with a tricyclic), a

measure of activity thought related to clinical

benefit (various measures of beta-blockade,

effect on ECG (electrocardiogram) intervals,

inhibition of ACE (angiotensin converting

enzyme) or of angiotensin I or II response),

a short-term desired effect, often a surrogate

endpoint (blood pressure, cholesterol), or the

ultimate intended clinical benefit (effects on

pain, depression, sudden death).

Population pharmacokinetic methods:

Population pharmacokinetic methods are a

population-based evaluation of

measurements of systemic drug

concentrations, usually two or more per

patient under steady state conditions, from

all, or a defined subset of, patients who

participate in clinical trials.

Therapeutic dose range: The difference

between the lowest effective dose and the

highest dose that gives further benefit.

Appendix A: Classification of intrinsic and extrinsic ethnic factors
Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices 31795

Appendix B: Assessment of the clinical data package (CDP) for acceptability

Appendix C: Pharmacokinetic,

pharmacodynamic, and dose-response

considerations

Evaluation of the pharmacokinetics and

pharmacodynamics, and their comparability,

in the three major racial groups in the ICH

regions (Asian, Black, and Caucasian) is

critical to the registration of medicines in the

ICH regions. Basic pharmacokinetic

evaluation should characterize absorption,

distribution, metabolism, excretion (ADME),

and where appropriate, food-drug and drugdrug interactions.

Adequate pharmacokinetic comparison

between populations of the two regions

allows rational consideration of what kinds

of further pharmacodynamic and clinical

studies (bridging studies) are needed in the

new region. In contrast to the

pharmacokinetics of a medication, where

differences between populations may be

attributed primarily to intrinsic ethnic factors

and are readily identified, the

pharmacodynamic response (clinical

effectiveness, safety, and dose response) may

be influenced by both intrinsic and extrinsic

ethnic factors and this may be difficult to

identify except by conducting clinical studies

in the new region.

The ICH E4 document describes various

approaches to dose-response evaluation. In

general, dose response (or concentration

response) should be evaluated for both

pharmacologic effect (where one is

considered pertinent) and clinical endpoints

in the foreign region. The pharmacologic

effect, including dose response, may also be

evaluated in the foreign region in a

population representative of the new region.

Depending on the situation, data on clinical

efficacy and dose response in the new region

may or may not be needed, e.g., if the drug

class is familiar and the pharmacologic effect

is closely linked to clinical effectiveness and

dose response, these foreign

pharmacodynamic data may be a sufficient

basis for approval and clinical endpoint and

dose-response data may not be needed in the

new region. The pharmacodynamic

evaluation, and possible clinical evaluation

(including dose response) is important

because of the possibility that the response

curve may be shifted in a new population.

Examples of this are well-documented, e.g.,

the decreased response in blood pressure of

blacks to angiotensin converting enzyme

inhibitors.

Appendix D: A medicine’s sensitivity to

ethnic factors

Characterization of a medicine according to

the potential impact of ethnic factors upon its

pharmacokinetics, pharmacodynamics, and

therapeutic effects may be useful in

determining what sort of bridging study is

needed in the new region. The impact of

ethnic factors upon a medicine’s effect will

vary depending upon the drug’s

pharmacologic class and indication and the

age and gender of the patient. No one

property of the medicine is predictive of the

compound’s relative sensitivity to ethnic

factors. The type of bridging study needed is

ultimately a matter of judgment, but

assessment of sensitivity to ethnic factors

may help in that judgment.

The following properties of a compound

make it less likely to be sensitive to ethnic

factors:

• Linear pharmacokinetics (PK).

• A flat pharmacodynamic (PD) (effectconcentration) curve for both efficacy and

safety in the range of the recommended

dosage and dose regimen (this may mean that

the medicine is well-tolerated).

• A wide therapeutic dose range (again,

possibly an indicator of good tolerability).
31796 Federal Register / Vol. 63, No. 111 /Wednesday, June 10, 1998 / Notices

• Minimal metabolism or metabolism

distributed among multiple pathways.

• High bioavailability, thus less

susceptibility to dietary absorption effects.

• Low potential for protein binding.

• Little potential for drug-drug, drug-diet,

and drug-disease interactions.

• Nonsystemic mode of action.

• Little potential for inappropriate use.

The following properties of a compound

make it more likely to be sensitive to ethnic

factors:

• Nonlinear pharmacokinetics.

• A steep pharmacodynamic curve for both

efficacy and safety (a small change in dose

results in a large change in effect) in the

range of the recommended dosage and dose

regimen.

• A narrow therapeutic dose range.

• Highly metabolized, especially through a

single pathway, thereby increasing the

potential for drug-drug interaction.

• Metabolism by enzymes known to show

genetic polymorphism.

• Administration as a prodrug, with the

potential for ethnically variable enzymatic

conversion.

• High intersubject variation in

bioavailability.

• Low bioavailability, thus more

susceptible to dietary absorption effects.

• High likelihood of use in a setting of

multiple co-medications.

• High likelihood for inappropriate use ,

e.g., analgesics and tranquilizers.

Dated: May 25, 1998.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 98–15408 Filed 6–9–98; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HOUSING AND

URBAN DEVELOPMENT

[Docket No. FR–4349–N–23]

Submission for OMB Review:

Comment Request

AGENCY: Office of the Assistant

Secretary for Administration, HUD.

ACTION: Notice.

SUMMARY: The proposed information

collection requirement described below

has been submitted to the Office of

Management and Budget (OMB) for

review, as required by the Paperwork

Reduction Act. The Department is

soliciting public comments on the

subject proposal.

DATES: Comments due date: July 10,

1998.

ADDRESSES: Interested persons are

invited to submit comments regarding

this proposal. Comments must be

received within thirty (30) days from the

date of this Notice. Comments should

refer to the proposal by name and/or

OMB approval number and should be

sent to: Joseph F. Lackey, Jr., OMB Desk

Officer, Office of Management and

Budget, Room 10235, New Executive

Office Building, Washington, DC 20503.

FOR FURTHER INFORMATION CONTACT:

Wayne Eddins, Reports Management

Officer, Department of Housing and

Urban Development, 451 7th Street,

Southwest, Washington, DC 20410,

telephone (202) 708–1305. This is not a

toll-free number. Copies of the proposed

forms and other available documents

submitted to OMB may be obtained

from Mr. Eddins.

SUPPLEMENTARY INFORMATION: The

Department has submitted the proposal

for the collection of information, as

described below, to OMB for review, as

required by the Paperwork Reduction

Act (44 U.S.C. Chapter 35).

The Notice lists the following

information: (1) The title of the

information collection proposal; (2) the

office of the agency to collect the

information; (3) the OMB approval

number, if applicable; (4) the

description of the need for the

information and its proposed use; (5)

the agency form number, if applicable;

(6) what members of the public will be

affected by the proposal; (7) how

frequently information submissions will

be required; (8) an estimate of the total

number of hours needed to prepare the

information submission including

number of respondents, frequency of

response, and hours of response; (9)

whether the proposal is new, an

extension, reinstatement, or revision of

an information collection requirement;

and (10) the names and telephone

numbers of an agency official familiar

with the proposal and of the OMB Desk

Officer for the Department.

Authority: Sec. 3507 of the Paperwork

Reduction Act of 1995, 44 U.S.C. 35, as

amended.

Dated: June 4, 1998.

David S. Cristy,

Director, IRM Policy and Management

Division.

Title of Proposal: Public and Indian

Housing: Demolition/Disposition/

Conversion/Taking of Units or Property.

Office: Public and Indian Housing.

OMB Approval Number: 2577–0075.

Description of The Need For The

Information and Its Proposed Use: The

purpose of the Housing Authorities

request is to seek HUD approval of a

change in a public housing development

application from what was originally

authorized under the Annual

Contributions Contract.

Form Number: 52860.

Respondents: State, Local, or Tribal

Governments.

Frequency of Submission:

Recordkeeping and Annually.

Reporting Burden:

Number of

respondents × Frequency ofresponse × Hours perresponse = Burden hours

Application .................................................................................. 120 1 16 1920

Recordkeeping ........................................................................... 120 1 1 120

Total Estimated Burden Hours: 2,040.

Status: Reinstatement, with no

changes.

Contact: Virginia Mathis, HUD, (202)

708–1640; Joseph F. Lackey, Jr., OMB,

(202) 395–7316.

Dated: June 4, 1998.

[FR Doc. 98–15478 Filed 6–9–98; 8:45 am]

BILLING CODE 4210–01–M

DEPARTMENT OF HOUSING AND

URBAN DEVELOPMENT

[Docket No. FR–4181–N–06]

Public and Indian Housing Drug

Elimination Program Announcement of

Funding Awards for FY 1997

AGENCY: Office of the Assistant

Secretary for Public and Indian

Housing, HUD.

ACTION: Announcement of funding

awards.

SUMMARY: In accordance with section

102(a)(4)(C) of the Department of

Housing and Urban Development

Reform Act of 1989, this announcement

notifies the public of funding decisions

made by the department in competition

for funding under the Notice of Funding

Availability (NOFA) for the Public and

Indian Housing Drug Elimination