41054 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices

DATES: Written comments on the

petitioner’s environmental assessment

by September 2, 1997.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA-305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: Vir

D. Anand, Center for Food Safety and

Applied Nutrition (HFS-216), Food and

Drug Administration, 200 C St. SW.,

Washington, DC 20204, 202-418-3081.

SUPPLEMENTARY INFORMATION: Under the

Federal Food, Drug, and Cosmetic Act

(sec. 409(b)(5) (21 U.S.C. 348(b)(5))),

notice is given that a food additive

petition (FAP 7B4550) has been filed by

Goldschmidt Chemical Corp., c/o Keller

and Heckman, 1001 G St., NW., suite

500 West, Washington, DC 20001. The

petition proposes to amend the food

additive regulations in § 178.3725

Pigment dispersants (21 CFR 178.3725)

to provide for the expanded safe use of

siloxanes and silicones; cetylmethyl,

dimethyl, methyl 11-methoxy-11-

oxoundecyl as a pigment dispersant in

all pigmented polymers intended for use

in contact with food.

The potential environmental impact

of this action is being reviewed. To

encourage public participation

consistent with regulations promulgated

under the National Environmental

Policy Act (40 CFR 1501.4(b)), the

agency is placing the environmental

assessment submitted with the petition

that is the subject of this notice on

public display at the Dockets

Management Branch (address above) for

public review and comment. Interested

persons may, on or before September 2,

1997, submit to the Dockets

Management Branch (address above)

written comments. 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. Received

comments may be seen in the office

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

Monday through Friday. FDA will also

place on public display any

amendments to, or comments on, the

petitioner’s environmental assessment

without further announcement in the

Federal Register. If, based on its review,

the agency finds that an environmental

impact statement is not required and

this petition results in a regulation, the

notice of availability of the agency’s

finding of no significant impact and the

evidence supporting that finding will be

published with the regulation in the

Federal Register in accordance with 21

CFR 25.40(c).

Dated: July 11, 1997.

Laura M. Tarantino,

Acting Director, Office of Premarket

Approval, Center for Food Safety and Applied

Nutrition.

[FR Doc. 97–20079 Filed 7-30-97; 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; Draft Guideline 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

draft guideline entitled ‘‘Ethnic Factors

in the Acceptability of Foreign Clinical

Data.’’ The draft guideline was prepared

under the auspices of the International

Conference on Harmonisation of

Technical Requirements for Registration

of Pharmaceuticals for Human Use

(ICH). The draft guideline provides

guidance on 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: Written comments by October

29, 1997.

ADDRESSES: Submit written comments

on the draft guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857. Copies of the draft guideline 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 guideline may

be obtained by mail from the Office of

Communication, Training and

Manufacturers Assistance (HFM–40),

Center for Biologics Evaluation and

Research (CBER), 1401 Rockville Pike,

Rockville, MD 20852–1448, 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 guideline: 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 the 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 March 1997, the ICH Steering

Committee agreed that a draft guideline

entitled ‘‘Ethnic Factors in the

Acceptability of Foreign Clinical Data’’

should be made available for public

comment. The draft guideline is the

product of the Efficacy Expert Working

Group of the ICH. Comments about this
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41055

draft will be considered by FDA and the

Efficacy Expert Working Group.

The draft guideline is intended to

facilitate the registration of drugs and

biologics among the 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 draft guideline provides

guidance on regulatory and

development strategies that will permit

adequate evaluation of the influence of

ethnic factors while minimizing

duplication of clinical studies, and

expediting the drug approval process.

This draft guideline 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.

Interested persons may, on or before

Ocotber 29, 1997, submit to the Dockets

Management Branch (address above)

written comments on the draft

guideline. 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 draft

guideline 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

guideline is available via Internet using

the World Wide Web (WWW) at ‘‘http:/

/www.fda.gov/cder/guidance.htm’’. To

connect to CBER’s WWW site, type

‘‘http://www.fda.gov/cber/

cberftp.html’’.

The text of the draft guideline follows:

Ethnic Factors in the Acceptability of

Foreign Clinical Data

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

Package for Extrapolation to the New Region

3.1 Characterization of the Drug’s

Sensitivity to Ethnic Factors

3.2 Bridging Data Package

3.2.1 Definition of Bridging Study and

Bridging Data Package

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

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 Drug’s Sensitivity to Ethnic

Factors

(Italicized words and terms in the text of the

guideline are defined or explained in the

glossary.)

1.0 Introduction

The purpose of this guidance is to facilitate

the registration of medicines 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. 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. 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 drug

registration 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 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, therefore, this has

been one of the reasons 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 drug’s safety, efficacy,

dosage, or dose regimen, many drugs 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 valuable

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 in the new region; it does

seek 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 its study design and conduct, and the

available data should be complete to the

satisfaction of 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 is complete in

its fulfillment of 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 drug

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:

(1) 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. A data package that

meets all of these regional regulatory

requirements would be considered complete

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.
41056 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices

Before extrapolation can be considered, the

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).

• Characterization of pharmacokinetics,

and where possible, pharmacodynamics and

dose response for pharmacodynamic

endpoints in a population relevant to the

new region of interest. This characterization

need not be performed in the new region but

could be performed in the foreign region in

a population representative of the new

region.

• Clinical trials establishing dose

response, efficacy and safety. These trials

should:

—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.

Several ICH guidelines address aspects

with respect to: 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 guideline on

the clinical study design question of choice

of control group (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 new region’s regulatory requirements, the

regulatory authority may require additional

clinical trials, such as:

• Clinical trials in different subsets of the

population,

• Clinical trials using different

comparators at the new region’s approved

dosage and dose regimen,

• Drug-drug interaction studies,

• Pharmacokinetic studies in a

population representative of the new region.

3.0 Assessment of the Foreign Clinical Data

Package for Extrapolation to the New Region

3.1 Characterization of the Drug’s Sensitivity

to Ethnic Factors

To assess a drug’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 drug (chemical class,

metabolic pathway, pharmacologic class)

make it more or less likely to be affected by

ethnic factors (Appendix D). Characterization

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

unlikely to behave differently in different

populations, usually would make it easier to

extrapolate data from one region to another

and need less bridging data.

Factors that make a drug 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 drug’s

sensitivity to ethnic factors. It may be easier

to conclude that the pharmacodynamic and

clinical behavior of a drug 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 foreign

region.

3.2 Bridging Data Package

3.2.1 Definition of Bridging Study and

Bridging Data Package

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 package to the

population in the new region. Such studies

could include further pharmacokinetic

information.

A bridging data package consists of: (1)

Information from the foreign 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.

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 data from the 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, a single

clinical endpoint, fixed dose, dose-response

study may be the only one needed to bridge

the foreign data, but a short-term

pharmacologic endpoint study might help

choose the doses for the large 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, 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 foreign 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 drugs characterized as

insensitive to ethnic factors, the type of

bridging study needed (if needed) will

depend upon the likelihood that extrinsic

ethnic factors (including design and conduct

of clinical trials) could affect the drug’s

safety, efficacy, and dose response and upon

experience with the drug class. For drugs that

are ethnically sensitive, a bridging study may

often be needed if the patient 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 drug 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 drug 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

If the regions are ethnically dissimilar and

the drug is ethnically sensitive but extrinsic

factors are generally similar (e.g., medical
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41057

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 foreign 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) are 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 drug’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

package demonstrates 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 is 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:

—A known index case of a serious adverse

event in a foreign clinical data package,

—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 of 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 drug 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. For

global development, studies should include

populations representative of the regions

where the drug 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 a pharmacokinetic screen

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 drug for a new region can deal

with the possibility that ethnic factors could

influence the effects (safety and efficacy) of

drugs 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 a foreign clinical

data package may be achieved by generating

‘‘bridging’’ data to link the safety and

effectiveness data in the foreign region(s) to

the population in the new region.

Glossary

Bridging data package: Information from

the foreign clinical data package that is

relevant to the population of the new region,

including pharmacokinetic data, and any

preliminary pharmacodynamic and doseresponse data and, if needed, supplemental

data obtained in the new region that will

allow extrapolation of the safety and efficacy

data in the foreign clinical data package 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 package to the new region. Such studies

could include further 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.

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 groups of

people classed 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.

• Extrinsic ethnic factors: Extrinsic ethnic

factors are factors associated with the

environment and culture in which the

patient resides. Extrinsic factors tend to be

less genetically and more culturally and

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 in a new

region, practices in clinical trial design and

conduct.

• Intrinsic ethnic factors: Intrinsic ethnic

factors are characteristics associated with the

drug recipient. These 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

ability to apply the safety, efficacy, and doseresponse data from the foreign clinical data

package to the population of the new region.

Foreign clinical data: Foreign clinical data

is defined as clinical data generated outside

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

ICH regions: The European Union, Japan,

the United States of America.

New region: The region where product

registration is sought.
41058 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices

Pharmacokinetic screen: A

pharmacokinetic screen is a populationbased 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. In

order for these data to be useful in the

evaluation of the relationships between

pharmacokinetics and intrinsic ethnic and

other factors, it is important that there be a

prospective protocol for the collection of

samples for drug concentration

measurements and that the timing of samples

relative to dosing be known precisely. While

these analyses may be less precise than those

from formal pharmacokinetic studies, the

numbers of patients studied is greater and a

much greater variety of factors that could

influence pharmacokinetics, including

unexpected influences, can be evaluated.

Moreover, small variations which might be

missed in the clinical setting are likely

unimportant. Large differences detected by

the screen may be definitive or may suggest

the need for further evaluation for safety and

efficacy in the new population.

Pharmacokinetic study: A study of how a

drug is handled by the body, usually

involving measurement of blood

concentrations (sometimes concentrations in

urine or tissues) over time of the drug and

its metabolism. 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 an

effect of the drug on individuals. The effect

measured can be any pharmacologic or

clinical effect of the drug and it is usual to

seek 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).

Therapeutic dose range: The difference

between the lowest useful dose and the

highest dose that gives further benefit.

BILLING CODE 4160–01–F
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41059
41060 Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices

BILLING CODE 4160–01–C
Federal Register / Vol. 62, No. 147 / Thursday, July 31, 1997 / Notices 41061

Appendix C: Pharmacokinetic,

Pharmacodynamic, and Dose-Response

Considerations

Evaluation of the pharmacokinetics and

pharmacodynamics, and their comparability,

in the three major racial groups (Asian,

Black, and Caucasian) is critical to the

registration of drugs in the ICH regions. Basic

pharmacokinetic evaluation should

characterize absorption, distribution,

metabolism, excretion (ADME), and where

appropriate, food-drug and drug-drug

interactions.

A sound pharmacokinetic comparison in

the foreign and new regions allows rational

consideration of what kinds of further

pharmacodynamic and clinical studies

(bridging studies) are needed in the new

region. In contrast to a medicine’s

pharmacokinetics, where differences between

populations may be attributed primarily to

intrinsic ethnic factors and are readily

identified, a medicine’s 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 guideline 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 Drug’s Sensitivity to Ethnic

Factors

Characterization of a drug 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 drug’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 drug

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 drug is well-tolerated).

• A wide therapeutic dose range (again,

possibly an indicator of good tolerability).

• 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 abuse.

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 potential for abuse.

Dated: July 25, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–20246 Filed 7–30–97; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 97N–0289]

Content and Format of Labeling for

Human Prescription Drugs; Pregnancy

Labeling; Public Hearing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of public hearing; request

for comments.

SUMMARY: The Food and Drug

Administration (FDA) is announcing a

public hearing regarding requirements

for the content and format of the

pregnancy subsection of labeling for

human prescription drugs. The public

hearing will focus on the requirement

that each drug product be classified in

one of five pregnancy categories

intended to aid clinicians and patients

with decisions about drug therapy.

Public comments and FDA’s

preliminary review of the pregnancy

category designations for marketed

drugs suggest that the categories may be

misleading and confusing, may not

accurately reflect reproductive and

developmental risk, and may be used

inappropriately by clinicians in making

decisions about drug therapy in

pregnant women and women of

childbearing potential and also in

making decisions about how to respond

to inadvertent fetal exposure. The

hearing is intended to elicit comments

on the practical utility, effects, and

limitations of the current pregnancy

labeling categories in order to help the

agency identify the range of problems

associated with the categories and to

identify and evaluate options that might

address identified problems, and to hear

the views of groups most affected.

DATES: The public hearing will be held

on Friday, September 12, 1997, from 9

a.m. to 5 p.m. Submit written notices of

participation and comments for

consideration at the hearing by August

28, 1997. Written comments will be

accepted after the hearing until

November 12, 1997.

ADDRESSES: The hearing will be held at

the Holiday Inn Bethesda, 8120

Wisconsin Ave.,Versailles I and II,

Bethesda, MD 20814. Submit written

notices of participation and comments

to the Advisors and Consultants Staff,

Center for Drug Evaluation and Research

(HFD–21), ATTN: Pregnancy Labeling

Hearing—Robin M. Spencer or Kimberly

L. Topper, Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, FAX 301–443–

0699. Federal Express deliveries need to

use the following street address: 1901

Chapman Ave., rm. 200, Rockville, MD

20852.

Transcripts of the hearing will be

available from the Freedom of

Information Office (HFI–35), Food and

Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, FAX 301–

443–1726, approximately 15 business

days after the hearing at a cost of 10

cents per page. Requests can also be

made for microfiche or computer disk

copies in place of paper copies.

FOR FURTHER INFORMATION CONTACT: Rose

E. Cunningham, Center for Drug

Evaluation and Research (HFD–6), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

6779, or FAX 301–594–5493; or

Kimberly L. Topper, Advisors and