[Federal Register Volume 63, Number 111 (Wednesday, June 10, 1998)]
[Notices]
[Pages 31790-31796]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-15408]


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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.

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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

[[Page 31791]]

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 ``<a href="http://www.fda.gov/cder/guidance/
index.htm">http://www.fda.gov/cder/guidance/
index.htm</a>'' or at CBER's World Wide Webb site at ``<a href="http://www.fda.gov/
cber/publications.htm">http://www.fda.gov/
cber/publications.htm</a>''.
     The text of the guidance follows:

E5 Ethnic Factors in the Acceptability of Foreign Clinical Data\1\
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    \1\ 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.
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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.
    <bullet> To describe regulatory strategies that minimize 
duplication of clinical data and facilitate acceptance of foreign 
clinical data in the new region.
    <bullet> To describe the use of bridging studies, when 
necessary, to allow extrapolation of foreign clinical data to a new 
region.
    <bullet> 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:
    <bullet> Adequate characterization of pharmacokinetics, 
pharmacodynamics, dose response, efficacy, and safety in the 
population of the foreign region(s).
    <bullet> Clinical trials establishing dose response, efficacy 
and safety. These trials should:

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    --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.
    <bullet> 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:
    <bullet> Clinical trials in different subsets of the population, 
such as patients with renal insufficiency, patients with hepatic 
dysfunction, etc.,
    <bullet> Clinical trials using different comparators at the new 
region's approved dosage and dose regimen,
    <bullet> 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:
    <bullet> 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.
    <bullet> 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).
    <bullet> 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).
    <bullet> 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:
    <bullet> 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 well-established classes of drugs known to be 
administered similarly, but not necessarily identically, in the two 
regions.
    <bullet> Bridging studies using pharmacologic endpoints

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    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.
    <bullet> 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:
    <bullet> 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.
    <bullet> 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:
    <bullet> A design that permits a valid comparison with a control 
to provide a quantitative assessment of treatment effect;
    <bullet> 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
    <bullet> 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)
    <bullet> 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

[[Page 31794]]

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.
    <bullet> 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.
    <bullet> 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
[GRAPHIC] [TIFF OMITTED] TN10JN98.000


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Appendix B: Assessment of the clinical data package (CDP) for 
acceptability
[GRAPHIC] [TIFF OMITTED] TN10JN98.001

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 drug-drug 
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:
    <bullet> Linear pharmacokinetics (PK).
    <bullet> A flat pharmacodynamic (PD) (effect-concentration) 
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).
    <bullet> A wide therapeutic dose range (again, possibly an 
indicator of good tolerability).

[[Page 31796]]

    <bullet> Minimal metabolism or metabolism distributed among 
multiple pathways.
    <bullet> High bioavailability, thus less susceptibility to 
dietary absorption effects.
    <bullet> Low potential for protein binding.
    <bullet> Little potential for drug-drug, drug-diet, and drug-
disease interactions.
    <bullet> Nonsystemic mode of action.
    <bullet> Little potential for inappropriate use.
    The following properties of a compound make it more likely to be 
sensitive to ethnic factors:
    <bullet> Nonlinear pharmacokinetics.
    <bullet> 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.
    <bullet> A narrow therapeutic dose range.
    <bullet> Highly metabolized, especially through a single 
pathway, thereby increasing the potential for drug-drug interaction.
    <bullet> Metabolism by enzymes known to show genetic 
polymorphism.
    <bullet> Administration as a prodrug, with the potential for 
ethnically variable enzymatic conversion.
    <bullet> High intersubject variation in bioavailability.
    <bullet> Low bioavailability, thus more susceptible to dietary 
absorption effects.
    <bullet> High likelihood of use in a setting of multiple co-
medications.
    <bullet> 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