[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
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periodically reviewed, and, where appropriate, the guidance will be
amended. The public will be notified of any such amendments through a
notice in the Federal Register.
Interested persons may, at any time, submit written comments on the
guidance to the Dockets Management Branch (address above). Two copies
of any comments are to be submitted, except that individuals may submit
one copy. Comments are to be identified with the docket number found in
brackets in the heading of this document. The guidance and received
comments may be seen in the office above between 9 a.m. and 4 p.m.,
Monday through Friday. An electronic version of this guidance is
available on the Internet at ``http://www.fda.gov/cder/guidance/
index.htm'' or at CBER's World Wide Webb site at ``http://www.fda.gov/
cber/publications.htm''.
The text of the guidance follows:
E5 Ethnic Factors in the Acceptability of Foreign Clinical 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.
To describe regulatory strategies that minimize
duplication of clinical data and facilitate acceptance of foreign
clinical data in the new region.
To describe the use of bridging studies, when
necessary, to allow extrapolation of foreign clinical data to a new
region.
To describe development strategies capable of
characterizing ethnic factor influences on safety, efficacy, dosage,
and dose regimen.
1.2 Background
All of the ICH regions acknowledge the desirability of
utilizing foreign clinical data that meet the regulatory standards
and clinical trial practices acceptable to the region considering
the application for registration.
However, concern that ethnic differences may affect the
medication's safety, efficacy, dosage, and dose regimen in the new
region has limited the willingness to rely on foreign clinical data.
Historically, this has been one of the reasons, therefore, the
regulatory authority in the new region has often requested that all,
or much of, the foreign clinical data in support of registration be
duplicated in the new region. Although ethnic differences among
populations may cause differences in a medicine's safety, efficacy,
dosage, or dose regimen, many medicines have comparable
characteristics and effects across regions. Requirements for
extensive duplication of clinical evaluation for every compound can
delay the availability of new therapies and unnecessarily waste drug
development resources.
1.3 Scope
This guidance is based on the premise that it is not necessary
to repeat the entire clinical drug development program in the new
region and is intended to recommend strategies for accepting foreign
clinical data as full or partial support for approval of an
application in a new region. It is critical to appreciate that this
guidance is not intended to alter the data requirements for
registration in the new region; it seeks to recommend when these
data requirements may be satisfied with foreign clinical data. All
data in the clinical data package, including foreign data, should
meet the standards of the new region with respect to study design
and conduct, and the available data should satisfy the regulatory
requirements in the new region. Additional studies conducted in any
region may be required by the new region to complete the clinical
data package.
Once a clinical data package fulfills the regulatory
requirements of the new region, the only remaining issue with
respect to the acceptance of the foreign clinical data is its
ability to be extrapolated to the population of the new region. When
the regulatory authority or the sponsor is concerned that
differences in ethnic factors could alter the efficacy or safety of
the medicine in the population in the new region, the sponsor may
need to generate a limited amount of clinical data in the new region
in order to extrapolate or ``bridge'' the clinical data between the
two regions. If a sponsor needs to obtain additional clinical data
to fulfill the regulatory requirements of the new region, it is
possible that these clinical trials can be designed to also serve as
the bridging studies.
Thus, the sponsor and the regional regulatory authority of the
new region would assess an application for registration for:
(1) Its completeness with respect to the regulatory requirements
of the new region, and
(2) The ability to extrapolate to the new region those parts of
the application (which could be most or all of the application)
based on studies from the foreign region (Appendix B).
2.0 Assessment of the Clinical Data Package Including Foreign Clinical
Data for Its Fulfillment of Regulatory Requirements in the New Region
The regional regulatory authority would assess the clinical
data package, including the foreign data, as to whether or not it
meets all of the regulatory standards regarding the nature and
quality of the data, irrespective of its geographic origin, i.e.,
data generated either totally in a foreign region (or regions) or
data from studies conducted both in a foreign and the new region to
which the application is being made. A clinical data package that
meets all of these regional regulatory requirements is defined as a
``complete'' clinical data package for submission and potential
approval. The acceptability of the foreign clinical data component
of the complete data package depends then upon whether it can be
extrapolated to the population of the new region.
Before extrapolation can be considered, the complete clinical
data package, including foreign clinical data, submitted to the new
region should contain:
Adequate characterization of pharmacokinetics,
pharmacodynamics, dose response, efficacy, and safety in the
population of the foreign region(s).
Clinical trials establishing dose response, efficacy
and safety. These trials should:
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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.
Characterization in a population relevant to the new
region of the pharmacokinetics, and where possible, pharmacodynamics
and dose response for pharmacodynamic endpoints. This
characterization could be performed in the foreign region in a
population representative of the new region or in the new region.
Several ICH guidances that address aspects of design, conduct,
analysis, and reporting of clinical trials will help implement the
concepts of the complete clinical data package. These guidances
include GCP's (E6), evaluation of dose response (E4), adequacy of
safety data (E1 and E2), conduct of studies in the elderly (E7),
reporting of study results (E3), general considerations for clinical
trials (E8), and statistical considerations (E9). A guidance on the
choice of control group in clinical study design (E10) is under
development.
2.1 Additional Studies to Meet the New Region's Regulatory
Requirements
When the foreign clinical data do not meet the regional
regulatory requirements, the regulatory authority may require
additional clinical trials such as:
Clinical trials in different subsets of the population,
such as patients with renal insufficiency, patients with hepatic
dysfunction, etc.,
Clinical trials using different comparators at the new
region's approved dosage and dose regimen,
Drug-drug interaction studies.
3.0 Assessment of the Foreign Clinical Data for Extrapolation to the
New Region
3.1 Characterization of the Medicine's Sensitivity to Ethnic
Factors
To assess a medicine's sensitivity to ethnic factors, it is
important that there be knowledge of its pharmacokinetic and
pharmacodynamic properties and the translation of those properties
to clinical effectiveness and safety. A reasonable evaluation is
described in Appendix C. Some properties of a medicine (chemical
class, metabolic pathway, pharmacologic class) make it more or less
likely to be affected by ethnic factors (Appendix D).
Characterization of a medicine as ``ethnically insensitive,'' i.e.,
unlikely to behave differently in different populations, would
usually make it easier to extrapolate data from one region to
another and need less bridging data.
Factors that make a medicine ethnically sensitive or insensitive
will become better understood and documented as effects in different
regions are compared. It is clear at present, however, that such
characteristics as clearance by an enzyme showing genetic
polymorphism and a steep dose-response curve will make ethnic
differences more likely. Conversely, a lack of metabolism or active
excretion, a wide therapeutic dose range, and a flat dose-response
curve will make ethnic differences less likely. The clinical
experience with other members of the drug class in the new region
will also contribute to the assessment of the medicine's sensitivity
to ethnic factors. It may be easier to conclude that the
pharmacodynamic and clinical behavior of a medicine will be similar
in the foreign and new regions if other members of the pharmacologic
class have been studied and approved in the new region with dosing
regimens similar to those used in the original region.
3.2 Bridging Data Package
3.2.1 Definition of Bridging Data Package and Bridging Study
A bridging data package consists of: (1) Selected information
from the complete clinical data package that is relevant to the
population of the new region, including pharmacokinetic data, and
any preliminary pharmacodynamic and dose-response data and, if
needed, (2) a bridging study to extrapolate the foreign efficacy
data and/or safety data to the new region.
A bridging study is defined as a study performed in the new
region to provide pharmacodynamic or clinical data on efficacy,
safety, dosage, and dose regimen in the new region that will allow
extrapolation of the foreign clinical data to the population in the
new region. A bridging study for efficacy could provide additional
pharmacokinetic information in the population of the new region.
When no bridging study is needed to provide clinical data for
efficacy, a pharmacokinetic study in the new region may be
considered as a bridging study.
3.2.2 Nature and Extent of the Bridging Study
This guidance proposes that when the regulatory authority of the
new region is presented with a clinical data package that fulfills
its regulatory requirements, the authority should request only those
additional data necessary to assess the ability to extrapolate
foreign data from the complete clinical data package to the new
region. The sensitivity of the medicine to ethnic factors will help
determine the amount of such data. In most cases, a single trial
that successfully provides these data in the new region and confirms
the ability to extrapolate data from the original region should
suffice and should not need further replication. Note that even
though a single study should be sufficient to ``bridge'' efficacy
data, a sponsor may find it practical to obtain the necessary data
by conducting more than one study. For example, where it is intended
that a fixed dose, dose-response study using a clinical endpoint is
needed as the bridging study, a short-term pharmacologic endpoint
study may be used to choose the dose(s) for the larger (clinical
endpoint) study.
When the regulatory authority requests, or the sponsor decides
to conduct, a bridging study, discussion between the regional
regulatory authority and sponsor is encouraged, when possible, to
determine what kind of bridging study will be needed. The relative
ethnic sensitivity will help determine the need for and the nature
of the bridging study. For regions with little experience with
registration based on foreign clinical data, the regulatory
authorities may still request a bridging study for approval even for
compounds insensitive to ethnic factors. As experience with
interregional acceptance increases, there will be a better
understanding of situations in which bridging studies are needed. It
is hoped that with experience, the need for bridging data will
lessen.
The following is general guidance about the ability to
extrapolate data generated from a bridging study:
If the bridging study shows that dose response, safety,
and efficacy in the new region are similar, then the study is
readily interpreted as capable of ``bridging'' the foreign data.
If a bridging study, properly executed, indicates that
a different dose in the new region results in a safety and efficacy
profile that is not substantially different from that derived in the
original region, it will often be possible to extrapolate the
foreign data to the new region, with appropriate dose adjustment, if
this can be adequately justified (e.g., by pharmacokinetic and/or
pharmacodynamic data).
If the bridging study designed to extrapolate the
foreign data is not of sufficient size to confirm adequately the
extrapolation of the adverse event profile to the new population,
additional safety data may be necessary (section 3.2.4).
If the bridging study fails to verify safety and
efficacy, additional clinical data (e.g., confirmatory clinical
trials) would be necessary.
3.2.3 Bridging Studies for Efficacy
Generally, for medicines characterized as insensitive to ethnic
factors, the type of bridging study needed (if needed) will depend
upon experience with the drug class and upon the likelihood that
extrinsic ethnic factors (including design and conduct of clinical
trials) could affect the medicine's safety, efficacy, and dose-
response. For medicines that are ethnically sensitive, a bridging
study may often be needed if the populations in the two regions are
different. The following examples illustrate types of bridging
studies for consideration in different situations:
No bridging study
In some situations, extrapolation of clinical data may be
feasible without a bridging study:
(1) If the medicine is ethnically insensitive and extrinsic
factors such as medical practice and conduct of clinical trials in
the two regions are generally similar.
(2) If the medicine is ethnically sensitive but the two regions
are ethnically similar and there is sufficient clinical experience
with pharmacologically related compounds to provide reassurance that
the class behaves similarly in patients in the two regions with
respect to efficacy, safety, dosage, and dose regimen. This might be
the case for well-established classes of drugs known to be
administered similarly, but not necessarily identically, in the two
regions.
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.
Controlled clinical trials
It will usually be necessary to carry out a controlled clinical
trial, often a randomized, fixed dose, dose-response study, in the
new region when:
(1) There are doubts about the choice of dose,
(2) There is little or no experience with acceptance of
controlled clinical trials carried out in the foreign region,
(3) Medical practice (e.g., use of concomitant medications and
design and/or conduct of clinical trials) is different, or
(4) The drug class is not a familiar one in the new region.
Depending on the situation, the trial could replicate the
foreign study or could utilize a standard clinical endpoint in a
study of shorter duration than the foreign studies or utilize a
validated surrogate endpoint, e.g., blood pressure or cholesterol
(longer studies and other endpoints may have been used in the
foreign phase III clinical trials).
If pharmacodynamic data suggest that there are interregional
differences in response, it will generally be necessary to carry out
a controlled trial with clinical endpoints in the new region.
Pharmacokinetic differences may not always create that necessity, as
dosage adjustments in some cases might be made without new trials.
However, any substantial difference in metabolic pattern may often
indicate a need for a controlled clinical trial.
When the practice of medicine differs significantly in the use
of concomitant medications, or adjunct therapy could alter the
medicine's efficacy or safety, the bridging study should be a
controlled clinical trial.
3.2.4 Bridging Studies for Safety
Even though the foreign clinical data demonstrate efficacy and
safety in the foreign region, there may occasionally remain a safety
concern in the new region. Safety concerns could include the
accurate determination of the rates of relatively common adverse
events in the new region and the detection of serious adverse events
(in the 1 percent range and generally needing about 300 patients to
assess). Depending upon the nature of the safety concern, safety
data could be obtained in the following situations:
A bridging study to assess efficacy, such as a dose-
response study, could be powered to address the rates of common
adverse events and could also allow identification of serious
adverse events that occur more commonly in the new region. Close
monitoring of such a trial would allow recognition of such serious
events before an unnecessarily large number of patients in the new
region are exposed. Alternatively, a small safety study could
precede the bridging study to provide assurance that serious adverse
effects were not occurring at a high rate.
If there is no efficacy bridging study needed or if the
efficacy bridging study is too small or of insufficient duration to
provide adequate safety information, a separate safety study may be
needed. This could occur where there is:
--An index case of a serious adverse event in the foreign
clinical data,
--A concern about differences in reporting adverse events in the
foreign region,
--Only limited safety data in the new region arising from an
efficacy bridging study, inadequate to extrapolate important aspects
of the safety profile, such as rates of common adverse events or of
more serious adverse events.
4.0 Developmental Strategies for Global Development
Definition of not only pharmacokinetics but also
pharmacodynamics and dose response early in the development program
may facilitate the determination of the need for, and nature of, any
requisite bridging data. Any candidate medicine for global
development should be characterized as ethnically sensitive or
insensitive (Appendix D). Ideally, this characterization should be
conducted during the early clinical phases of drug development,
i.e., human pharmacology and therapeutic exploratory studies. In
some cases, it may be useful to discuss bridging study designs with
regulatory agencies prior to completion of the clinical data
package. However, analysis of the data within the complete clinical
data package will determine the need for, and type of bridging
study. For global development, studies should include populations
representative of the regions where the medicine is to be registered
and should be conducted according to ICH guidelines.
A sponsor may wish to leave the assessment of pharmacokinetics,
pharmacodynamics, dosage, and dose regimens in populations relevant
to the new region until later in the drug development program.
Pharmacokinetic assessment could be accomplished by formal
pharmacokinetic studies or by applying population pharmacokinetic
methods to clinical trials conducted either in a population relevant
to the new region or in the new region.
5.0 Summary
This guidance describes how a sponsor developing a medicine for
a new region can deal with the possibility that ethnic factors could
influence the effects (safety and efficacy) of medicines and the
risk/benefit assessment in different populations. Results from the
foreign clinical trials could comprise most, or in some cases, all
of the clinical data package for approval in the new region, so long
as they are carried out according to the requirements of the new
region. Acceptance in the new region of such foreign clinical data
may be achieved by generating ``bridging'' data in order to
extrapolate the safety and efficacy data from the population in the
foreign region(s) to the population in the new region.
Glossary
Adequate and well-controlled trial: An adequate and well
controlled trial has the following characteristics:
A design that permits a valid comparison with a control
to provide a quantitative assessment of treatment effect;
The use of methods to minimize bias in the allocation
of patients to treatment groups and in the measurement and
assessment of response to treatment; and
An analysis of the study results appropriate to the
design to assess the effects of the treatment.
Bridging data package: Selected information from the complete
clinical data package that is relevant to the population of the new
region, including pharmacokinetic data, and any preliminary
pharmacodynamic and dose-response data and, if needed, supplemental
data obtained from a bridging study in the new region that will
allow extrapolation of the foreign safety and efficacy data to the
population of the new region.
Bridging study: A bridging study is defined as a supplemental
study performed in the new region to provide pharmacodynamic or
clinical data on efficacy, safety, dosage, and dose regimen in the
new region that will allow extrapolation of the foreign clinical
data to the new region. Such studies could include additional
pharmacokinetic information.
Complete clinical data package: A clinical data package intended
for registration containing clinical data that fulfill the
regulatory requirements of the new region and containing
pharmacokinetic data relevant to the population in the new region.
Compound insensitive to ethnic factors: A compound whose
characteristics suggest minimal potential for clinically significant
impact by ethnic factors on safety, efficacy, or dose response.
Compound sensitive to ethnic factors: A compound whose
pharmacokinetic, pharmacodynamic, or other characteristics suggest
the potential for clinically significant impact by intrinsic and/or
extrinsic ethnic factors on safety, efficacy, or dose response.
Dosage: The quantity of a medicine given per administration, or
per day.
Dose regimen: The route, frequency and duration of
administration of the dose of a medicine over a period of time.
Ethnic factors: The word ethnicity is derived from the Greek
word ``ethnos,'' meaning nation or people. Ethnic factors are
factors relating to races or large populations grouped according to
common traits and customs. Note that this definition gives
ethnicity, by virtue of its cultural as well as genetic
implications, a broader meaning than racial. Ethnic factors may be
classified as either intrinsic or extrinsic. (Appendix A)
Extrinsic ethnic factors: Extrinsic ethnic factors are
factors associated with the environment and culture in which a
person resides. Extrinsic factors tend to be less genetically and
more culturally and
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behaviorally determined. Examples of extrinsic factors include the
social and cultural aspects of a region such as medical practice,
diet, use of tobacco, use of alcohol, exposure to pollution and
sunshine, socioeconomic status, compliance with prescribed
medications, and, particularly important to the reliance on studies
from a different region, practices in clinical trial design and
conduct.
Intrinsic ethnic factors: Intrinsic ethnic factors are
factors that help to define and identify a subpopulation and may
influence the ability to extrapolate clinical data between regions.
Examples of intrinsic factors include genetic polymorphism, age,
gender, height, weight, lean body mass, body composition, and organ
dysfunction.
Extrapolation of foreign clinical data: The generalization and
application of the safety, efficacy, and dose-response data
generated in a population of a foreign region to the population of
the new region.
Foreign clinical data: Foreign clinical data is defined as
clinical data generated outside of the new region (i.e., in the
foreign region).
ICH regions: European Union, Japan, the United States of
America.
New region: The region where product registration is sought.
Population representative of the new region: A
population that includes the major racial groups within the new
region.
Pharmacokinetic study: A study of how a medicine is handled by
the body, usually involving measurement of blood concentrations of
drug and its metabolite(s) (sometimes concentrations in urine or
tissues) as a function of time. Pharmacokinetic studies are used to
characterize absorption, distribution, metabolism, and excretion of
a drug, either in blood or in other pertinent locations. When
combined with pharmacodynamic measures (a PK/PD study) it can
characterize the relation of blood concentrations to the extent and
timing of pharmacodynamic effects.
Pharmacodynamic study: A study of a pharmacological or clinical
effect of the medicine in individuals to describe the relation of
the effect to dose or drug concentration. A pharmacodynamic effect
can be a potentially adverse effect (anticholinergic effect with a
tricyclic), a measure of activity thought related to clinical
benefit (various measures of beta-blockade, effect on ECG
(electrocardiogram) intervals, inhibition of ACE (angiotensin
converting enzyme) or of angiotensin I or II response), a short-term
desired effect, often a surrogate endpoint (blood pressure,
cholesterol), or the ultimate intended clinical benefit (effects on
pain, depression, sudden death).
Population pharmacokinetic methods: Population pharmacokinetic
methods are a population-based evaluation of measurements of
systemic drug concentrations, usually two or more per patient under
steady state conditions, from all, or a defined subset of, patients
who participate in clinical trials.
Therapeutic dose range: The difference between the lowest
effective dose and the highest dose that gives further benefit.
Appendix A: Classification of intrinsic and extrinsic ethnic factors
[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:
Linear pharmacokinetics (PK).
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).
A wide therapeutic dose range (again, possibly an
indicator of good tolerability).
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Minimal metabolism or metabolism distributed among
multiple pathways.
High bioavailability, thus less susceptibility to
dietary absorption effects.
Low potential for protein binding.
Little potential for drug-drug, drug-diet, and drug-
disease interactions.
Nonsystemic mode of action.
Little potential for inappropriate use.
The following properties of a compound make it more likely to be
sensitive to ethnic factors:
Nonlinear pharmacokinetics.
A steep pharmacodynamic curve for both efficacy and
safety (a small change in dose results in a large change in effect)
in the range of the recommended dosage and dose regimen.
A narrow therapeutic dose range.
Highly metabolized, especially through a single
pathway, thereby increasing the potential for drug-drug interaction.
Metabolism by enzymes known to show genetic
polymorphism.
Administration as a prodrug, with the potential for
ethnically variable enzymatic conversion.
High intersubject variation in bioavailability.
Low bioavailability, thus more susceptible to dietary
absorption effects.
High likelihood of use in a setting of multiple co-
medications.
High likelihood for inappropriate use , e.g.,
analgesics and tranquilizers.
Dated: May 25, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-15408 Filed 6-9-98; 8:45 am]
BILLING CODE 4160-01-F