[Federal Register Volume 62, Number 147 (Thursday, July 31, 1997)]
[Notices]
[Pages 41054-41061]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-20246]


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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.

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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

[[Page 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 ``<a href="http://www.fda.gov/cber/
cberftp.html">http://www.fda.gov/cber/
cberftp.html</a>''.
    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

    <bullet>  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.
    <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 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.

[[Page 41056]]

    Before extrapolation can be considered, the 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>  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.
    <bullet>  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:
    <bullet>  Clinical trials in different subsets of the 
population,
    <bullet>  Clinical trials using different comparators at the new 
region's approved dosage and dose regimen,
    <bullet>  Drug-drug interaction studies,
    <bullet>  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:
    <bullet>  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.
    <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 
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).
    <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 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:
    <bullet>  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 well-established classes of drugs known to be administered 
similarly, but not necessarily identically, in the two regions.
    <bullet>  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

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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.
    <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) 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:
    <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 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.
    <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:
    --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 dose-response 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.
    <bullet>  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.
    <bullet>  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 dose-response 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.

[[Page 41058]]

    Pharmacokinetic screen: A pharmacokinetic screen is 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. 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

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[GRAPHIC] [TIFF OMITTED] TN31JY97.003



[[Page 41060]]

[GRAPHIC] [TIFF OMITTED] TN31JY97.004



BILLING CODE 4160-01-C

[[Page 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:
    <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 drug is well-
tolerated).
    <bullet>  A wide therapeutic dose range (again, possibly an 
indicator of good tolerability).
    <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 abuse.
    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 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