[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 ``http://www.fda.gov/cber/
cberftp.html''.
The text of the draft guideline follows:
Ethnic Factors in the Acceptability of Foreign Clinical Data
1.0 Introduction
1.1 Objectives
1.2 Background
1.3 Scope
2.0 Assessment of the Clinical Data Package Including Foreign
Clinical Data for Its Fulfillment of Regulatory Requirements in the
New Region
2.1 Additional Studies to Meet the New Region's Regulatory
Requirements
3.0 Assessment of the Foreign Clinical Data Package for
Extrapolation to the New Region
3.1 Characterization of the Drug's Sensitivity to Ethnic Factors
3.2 Bridging Data Package
3.2.1 Definition of Bridging Study and Bridging Data Package
3.2.2 Nature and Extent of the Bridging Study
3.2.3 Bridging Studies for Efficacy
3.2.4 Bridging Studies for Safety
4.0 Developmental Strategies for Global Development
5.0 Summary
Glossary
Appendix A: Classification of Intrinsic and Extrinsic Ethnic Factors
Appendix B: Assessment of the Clinical Data Package (CDP) for
Acceptability
Appendix C: Pharmacokinetic, Pharmacodynamic, and Dose-Response
Considerations
Appendix D: A Drug's Sensitivity to Ethnic Factors
(Italicized words and terms in the text of the guideline are
defined or explained in the glossary.)
1.0 Introduction
The purpose of this guidance is to facilitate the registration
of medicines among ICH regions by recommending a framework for
evaluating the impact of ethnic factors on a drug's effect, i.e.,
its efficacy and safety at a particular dosage and dose regimen. It
provides guidance with respect to regulatory and development
strategies that will permit adequate evaluation of the influence of
ethnic factors while minimizing duplication of clinical studies and
supplying medicines expeditiously to patients for their benefit. For
the purposes of this document, ethnic factors are defined as those
factors relating to the genetic and physiologic (intrinsic) and the
cultural and environmental (extrinsic) characteristics of a
population (Appendix A).
1.1 Objectives
To describe the characteristics of foreign clinical
data that will facilitate their extrapolation to different
populations and support their acceptance as a basis for drug
registration in a new region.
To describe regulatory strategies that minimize
duplication of clinical data and facilitate acceptance of foreign
clinical data in the new region.
To describe the use of bridging studies, when
necessary, to allow extrapolation of foreign clinical data to a new
region.
To describe development strategies capable of
characterizing ethnic factor influences on safety, efficacy, dosage,
and dose regimen.
1.2 Background
All regions acknowledge the desirability of utilizing foreign
clinical data that meet the regulatory standards and clinical trial
practices acceptable to the region considering the application for
registration.
However, concern that ethnic differences may affect the
medication's safety, efficacy, dosage, and dose regimen in the new
region has limited the willingness to rely on foreign clinical data.
Historically, therefore, this has been one of the reasons the
regulatory authority in the new region has often requested that all,
or much, of the foreign clinical data in support of registration be
duplicated in the new region. Although ethnic differences among
populations may cause differences in a drug's safety, efficacy,
dosage, or dose regimen, many drugs have comparable characteristics
and effects across regions. Requirements for extensive duplication
of clinical evaluation for every compound can delay the availability
of new therapies and unnecessarily waste valuable drug development
resources.
1.3 Scope
This guidance is based on the premise that it is not necessary
to repeat the entire clinical drug development program in the new
region and is intended to recommend strategies for accepting foreign
clinical data as full or partial support for approval of an
application in a new region. It is critical to appreciate that this
guidance is not intended to alter the data requirements in the new
region; it does seek to recommend when these data requirements may
be satisfied with foreign clinical data. All data in the clinical
data package, including foreign data, should meet the standards of
the new region with respect to its study design and conduct, and the
available data should be complete to the satisfaction of the new
region. Additional studies conducted in any region may be required
by the new region to complete the clinical data package.
Once a clinical data package is complete in its fulfillment of
the regulatory requirements of the new region, the only remaining
issue with respect to the acceptance of the foreign clinical data is
its ability to be extrapolated to the population of the new region.
When the regulatory authority or the sponsor is concerned that
differences in ethnic factors could alter the efficacy or safety of
the drug in the population in the new region, the sponsor may need
to generate a limited amount of clinical data in the new region in
order to extrapolate or ``bridge'' the clinical data between the two
regions.
If a sponsor needs to obtain additional clinical data to fulfill
the regulatory requirements of the new region, it is possible that
these clinical trials can be designed to also serve as the bridging
studies. Thus, the sponsor and the regional regulatory authority of
the new region would assess an application for:
(1) Completeness with respect to the regulatory requirements of
the new region, and
(2) The ability to extrapolate to the new region those parts of
the application (which could be most or all of the application)
based on studies from the foreign region (Appendix B).
2.0 Assessment of the Clinical Data Package Including Foreign
Clinical Data for Its Fulfillment of Regulatory Requirements in the
New Region
The regional regulatory authority would assess the clinical data
package, including the foreign data, as to whether or not it meets
all of the regulatory standards regarding the nature and quality of
the data, irrespective of its geographic origin. A data package that
meets all of these regional regulatory requirements would be
considered complete for submission and potential approval. The
acceptability of the foreign clinical data component of the complete
data package depends then upon whether it can be extrapolated to the
population of the new region.
[[Page 41056]]
Before extrapolation can be considered, the clinical data
package, including foreign clinical data, submitted to the new
region should contain:
Adequate characterization of pharmacokinetics,
pharmacodynamics, dose response, efficacy, and safety in the
population of the foreign region(s).
Characterization of pharmacokinetics, and where
possible, pharmacodynamics and dose response for pharmacodynamic
endpoints in a population relevant to the new region of interest.
This characterization need not be performed in the new region but
could be performed in the foreign region in a population
representative of the new region.
Clinical trials establishing dose response, efficacy
and safety. These trials should:
--Be designed and conducted according to regulatory standards in
the new region, e.g., choice of controls, and should be conducted
according to good clinical practice (GCP),
--Be adequate and well-controlled,
--Utilize endpoints that are considered appropriate for
assessment of treatment,
--Evaluate clinical disorders using medical and diagnostic
definitions that are acceptable to the new region.
Several ICH guidelines address aspects with respect to: GCP's
(E6), evaluation of dose response (E4), adequacy of safety data (E1
and E2), conduct of studies in the elderly (E7), reporting of study
results (E3), general considerations for clinical trials (E8), and
statistical considerations (E9). A guideline on the clinical study
design question of choice of control group (E10) is under
development.
2.1 Additional Studies to Meet the New Region's Regulatory Requirements
When the foreign clinical data do not meet the new region's
regulatory requirements, the regulatory authority may require
additional clinical trials, such as:
Clinical trials in different subsets of the
population,
Clinical trials using different comparators at the new
region's approved dosage and dose regimen,
Drug-drug interaction studies,
Pharmacokinetic studies in a population representative
of the new region.
3.0 Assessment of the Foreign Clinical Data Package for
Extrapolation to the New Region
3.1 Characterization of the Drug's Sensitivity to Ethnic Factors
To assess a drug's sensitivity to ethnic factors, it is
important that there be knowledge of its pharmacokinetic and
pharmacodynamic properties and the translation of those properties
to clinical effectiveness and safety. A reasonable evaluation is
described in Appendix C. Some properties of a drug (chemical class,
metabolic pathway, pharmacologic class) make it more or less likely
to be affected by ethnic factors (Appendix D). Characterization of a
drug as ``ethnically insensitive,'' i.e., unlikely to behave
differently in different populations, usually would make it easier
to extrapolate data from one region to another and need less
bridging data.
Factors that make a drug ethnically sensitive or insensitive
will become better understood and documented as effects in different
regions are compared. It is clear at present, however, that such
characteristics as clearance by an enzyme showing genetic
polymorphism and a steep dose-response curve will make ethnic
differences more likely. Conversely, a lack of metabolism or active
excretion, a wide therapeutic dose range, and a flat dose-response
curve will make ethnic differences less likely. The clinical
experience with other members of the drug class in the new region
will also contribute to the assessment of the drug's sensitivity to
ethnic factors. It may be easier to conclude that the
pharmacodynamic and clinical behavior of a drug will be similar in
the foreign and new regions if other members of the pharmacologic
class have been studied and approved in the new region with dosing
regimens similar to those used in the foreign region.
3.2 Bridging Data Package
3.2.1 Definition of Bridging Study and Bridging Data Package
A bridging study is defined as a study performed in the new
region to provide pharmacodynamic or clinical data on efficacy,
safety, dosage, and dose regimen in the new region that will allow
extrapolation of the foreign clinical data package to the population
in the new region. Such studies could include further
pharmacokinetic information.
A bridging data package consists of: (1) Information from the
foreign clinical data package that is relevant to the population of
the new region, including pharmacokinetic data, and any preliminary
pharmacodynamic and dose-response data and, if needed, (2) a
bridging study to extrapolate the foreign efficacy data and/or
safety data to the new region.
3.2.2 Nature and Extent of the Bridging Study
This guidance proposes that when the regulatory authority of the
new region is presented with a clinical data package that fulfills
its regulatory requirements, the authority should request only those
additional data necessary to assess the ability to extrapolate data
from the package to the new region. The sensitivity of the medicine
to ethnic factors will help determine the amount of such data. In
most cases, a single trial that successfully provides these data in
the new region and confirms the ability to extrapolate data from the
original region should suffice and should not need further
replication. Note that even though a single study should be
sufficient to ``bridge'' efficacy data, a sponsor may find it
practical to obtain the necessary data by conducting more than one
study. For example, a single clinical endpoint, fixed dose, dose-
response study may be the only one needed to bridge the foreign
data, but a short-term pharmacologic endpoint study might help
choose the doses for the large study.
When the regulatory authority requests, or the sponsor decides
to conduct, a bridging study, discussion between the regional
regulatory authority and sponsor is encouraged, when possible, to
determine what kind of bridging study will be needed. The relative
ethnic sensitivity will help determine the need for and the nature
of the bridging study. For regions with little experience with
registration based on foreign clinical data, the regulatory
authorities may still request a bridging study for approval, even
for compounds insensitive to ethnic factors. As experience with
interregional acceptance increases, there will be a better
understanding of situations in which bridging studies are needed. It
is hoped that with experience, the need for bridging data will
lessen.
The following is general guidance about the ability to
extrapolate data generated from a bridging study:
If the bridging study shows that dose response,
safety, and efficacy in the new region are similar, the study is
readily interpreted as capable of ``bridging'' the foreign data.
If a bridging study, properly executed, indicates that
a different dose in the new region results in a safety and efficacy
profile that is not substantially different from that derived in the
foreign region, it will often be possible to extrapolate the foreign
data to the new region, with appropriate dose adjustment, if this
can be adequately justified (e.g., by pharmacokinetic and/or
pharmacodynamic data).
If the bridging study designed to extrapolate the
foreign data is not of sufficient size to confirm adequately the
extrapolation of the adverse event profile to the new population,
additional safety data may be necessary (section 3.2.4).
If the bridging study fails to verify safety and
efficacy, additional clinical data (e.g., confirmatory clinical
trials) would be necessary.
3.2.3 Bridging Studies for Efficacy
Generally, for drugs characterized as insensitive to ethnic
factors, the type of bridging study needed (if needed) will depend
upon the likelihood that extrinsic ethnic factors (including design
and conduct of clinical trials) could affect the drug's safety,
efficacy, and dose response and upon experience with the drug class.
For drugs that are ethnically sensitive, a bridging study may often
be needed if the patient populations in the two regions are
different. The following examples illustrate types of bridging
studies for consideration in different situations:
No bridging study
In some situations, extrapolation of clinical data may be
feasible without a bridging study:
(1) If the drug is ethnically insensitive and extrinsic factors
such as medical practice and conduct of clinical trials in the two
regions are generally similar.
(2) If the drug is ethnically sensitive but the two regions are
ethnically similar and there is sufficient clinical experience with
pharmacologically related compounds to provide reassurance that the
class behaves similarly in patients in the two regions with respect
to efficacy, safety, dosage, and dose regimen. This might be the
case for well-established classes of drugs known to be administered
similarly, but not necessarily identically, in the two regions.
Bridging studies using pharmacologic endpoints
If the regions are ethnically dissimilar and the drug is
ethnically sensitive but extrinsic factors are generally similar
(e.g., medical
[[Page 41057]]
practice, design and conduct of clinical trials) and the drug class
is a familiar one in the new region, a controlled pharmacodynamic
study in the new region, using a pharmacologic endpoint that is
thought to reflect relevant drug activity (which could be a well-
established surrogate endpoint) could provide assurance that the
efficacy, safety, dose, and dose regimen data developed in the
foreign region are applicable to the new region. Simultaneous
pharmacokinetic (i.e., blood concentration) measurements may make
such studies more interpretable.
Controlled clinical trials
It will usually be necessary to carry out a controlled clinical
trial, often a randomized, fixed dose, dose-response study, in the
new region when:
(1) There are doubts about the choice of dose,
(2) There is little or no experience with acceptance of
controlled clinical trials carried out in the foreign region,
(3) Medical practice (e.g., use of concomitant medications and
design and/or conduct of clinical trials) are different, or
(4) The drug class is not a familiar one in the new region.
Depending on the situation, the trial could replicate the
foreign study or could utilize a standard clinical endpoint in a
study of shorter duration than the foreign studies or utilize a
validated surrogate endpoint, e.g., blood pressure or cholesterol
(longer studies and other endpoints may have been used in the
foreign phase III clinical trials).
If pharmacodynamic data suggest that there are interregional
differences in response, it will generally be necessary to carry out
a controlled trial with clinical endpoints in the new region.
Pharmacokinetic differences may not always create that necessity, as
dosage adjustments in some cases might be made without new trials.
However, any substantial difference in metabolic pattern may often
indicate a need for a controlled clinical trial.
When the practice of medicine differs significantly in the use
of concomitant medications, or adjunct therapy could alter the
drug's efficacy or safety, the bridging study should be a controlled
clinical trial.
3.2.4 Bridging Studies for Safety
Even though the foreign clinical data package demonstrates
efficacy and safety in the foreign region, there may occasionally
remain a safety concern in the new region. Safety concerns could
include the accurate determination of the rates of relatively common
adverse events in the new region and the detection of serious
adverse events (in the 1 percent range and generally needing about
300 patients to assess). Depending upon the nature of the safety
concern, safety data could be obtained in the following situations:
A bridging study to assess efficacy, such as a dose-
response study, could be powered to address the rates of common
adverse events and could also allow identification of serious
adverse events that occur more commonly in the new region. Close
monitoring of such a trial would allow recognition of such serious
events before an unnecessarily large number of patients in the new
region is exposed. Alternatively, a small safety study could precede
the bridging study to provide assurance that serious adverse effects
were not occurring at a high rate.
If there is no efficacy bridging study needed or if
the efficacy bridging study is too small or of insufficient duration
to provide adequate safety information, a separate safety study may
be needed. This could occur where there is:
--A known index case of a serious adverse event in a foreign
clinical data package,
--A concern about differences in reporting adverse events in the
foreign region,
--Only limited safety data in the new region arising from an
efficacy bridging study, inadequate to extrapolate important aspects
of the safety profile, such as rates of common adverse events or of
more serious adverse events.
4.0 Developmental Strategies for Global Development
Definition of not only pharmacokinetics but also of
pharmacodynamics and dose response early in the development program
may facilitate the determination of the need for, and nature of, any
requisite bridging data. Any candidate drug for global development
should be characterized as ethnically sensitive or insensitive
(Appendix D). Ideally, this characterization should be conducted
during the early clinical phases of drug development, i.e., human
pharmacology and therapeutic exploratory studies. For global
development, studies should include populations representative of
the regions where the drug is to be registered and should be
conducted according to ICH guidelines.
A sponsor may wish to leave the assessment of pharmacokinetics,
pharmacodynamics, dosage, and dose regimens in populations relevant
to the new region until later in the drug development program.
Pharmacokinetic assessment could be accomplished by formal
pharmacokinetic studies or a pharmacokinetic screen conducted either
in a population relevant to the new region or in the new region.
5.0 Summary
This guidance describes how a sponsor developing a drug for a
new region can deal with the possibility that ethnic factors could
influence the effects (safety and efficacy) of drugs and the risk/
benefit assessment in different populations. Results from the
foreign clinical trials could comprise most, or in some cases, all
of the clinical data package for approval in the new region, so long
as they are carried out according to the requirements of the new
region. Acceptance in the new region of such a foreign clinical data
package may be achieved by generating ``bridging'' data to link the
safety and effectiveness data in the foreign region(s) to the
population in the new region.
Glossary
Bridging data package: Information from the foreign clinical
data package that is relevant to the population of the new region,
including pharmacokinetic data, and any preliminary pharmacodynamic
and 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.
Extrinsic ethnic factors: Extrinsic ethnic factors are
factors associated with the environment and culture in which the
patient resides. Extrinsic factors tend to be less genetically and
more culturally and behaviorally determined. Examples of extrinsic
factors include the social and cultural aspects of a region, such as
medical practice, diet, use of tobacco, use of alcohol, exposure to
pollution and sunshine, socioeconomic status, compliance with
prescribed medications, and, particularly important to the reliance
on studies in a new region, practices in clinical trial design and
conduct.
Intrinsic ethnic factors: Intrinsic ethnic factors are
characteristics associated with the drug recipient. These are
factors that help to define and identify a subpopulation and may
influence the ability to extrapolate clinical data between regions.
Examples of intrinsic factors include genetic polymorphism, age,
gender, height, weight, lean body mass, body composition, and organ
dysfunction.
Extrapolation of foreign clinical data: The ability to apply the
safety, efficacy, and 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
[[Page 41059]]
[GRAPHIC] [TIFF OMITTED] TN31JY97.003
[[Page 41060]]
[GRAPHIC] [TIFF OMITTED] TN31JY97.004
BILLING CODE 4160-01-C
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Appendix C: Pharmacokinetic, Pharmacodynamic, and Dose-Response
Considerations
Evaluation of the pharmacokinetics and pharmacodynamics, and
their comparability, in the three major racial groups (Asian, Black,
and Caucasian) is critical to the registration of drugs in the ICH
regions. Basic pharmacokinetic evaluation should characterize
absorption, distribution, metabolism, excretion (ADME), and where
appropriate, food-drug and drug-drug interactions.
A sound pharmacokinetic comparison in the foreign and new
regions allows rational consideration of what kinds of further
pharmacodynamic and clinical studies (bridging studies) are needed
in the new region. In contrast to a medicine's pharmacokinetics,
where differences between populations may be attributed primarily to
intrinsic ethnic factors and are readily identified, a medicine's
pharmacodynamic response (clinical effectiveness, safety, and dose
response) may be influenced by both intrinsic and extrinsic ethnic
factors and this may be difficult to identify except by conducting
clinical studies in the new region.
The ICH E4 guideline describes various approaches to dose-
response evaluation. In general, dose response (or concentration
response) should be evaluated for both pharmacologic effect (where
one is considered pertinent) and clinical endpoints in the foreign
region. The pharmacologic effect, including dose response, may also
be evaluated in the foreign region in a population representative of
the new region. Depending on the situation, data on clinical
efficacy and dose response in the new region may or may not be
needed, e.g., if the drug class is familiar and the pharmacologic
effect is closely linked to clinical effectiveness and dose
response, these foreign pharmacodynamic data may be a sufficient
basis for approval and clinical endpoint and dose-response data may
not be needed in the new region. The pharmacodynamic evaluation, and
possible clinical evaluation (including dose response) is important
because of the possibility that the response curve may be shifted in
a new population. Examples of this are well-documented, e.g., the
decreased response in blood pressure of blacks to angiotensin-
converting enzyme inhibitors.
Appendix D: A Drug's Sensitivity to Ethnic Factors
Characterization of a drug according to the potential impact of
ethnic factors upon its pharmacokinetics, pharmacodynamics, and
therapeutic effects may be useful in determining what sort of
bridging study is needed in the new region. The impact of ethnic
factors upon a drug's effect will vary depending upon the drug's
pharmacologic class and indication and the age and gender of the
patient. No one property of the drug is predictive of the compound's
relative sensitivity to ethnic factors. The type of bridging study
needed is ultimately a matter of judgment, but assessment of
sensitivity to ethnic factors may help in that judgment.
The following properties of a compound make it less likely to be
sensitive to ethnic factors:
Linear pharmacokinetics (PK).
A flat pharmacodynamic (PD) (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).
A wide therapeutic dose range (again, possibly an
indicator of good tolerability).
Minimal metabolism or metabolism distributed among
multiple pathways.
High bioavailability, thus less susceptibility to
dietary absorption effects.
Low potential for protein binding.
Little potential for drug-drug, drug-diet, and drug-
disease interactions.
Nonsystemic mode of action.
Little potential for abuse.
The following properties of a compound make it more likely to be
sensitive to ethnic factors:
Nonlinear pharmacokinetics.
A steep pharmacodynamic curve for both efficacy and
safety (a small change in dose results in a large change in effect)
in the range of the recommended dosage and dose regimen.
A narrow therapeutic dose range.
Highly metabolized, especially through a single
pathway, thereby increasing the potential for drug-drug interaction.
Metabolism by enzymes known to show genetic
polymorphism.
Administration as a prodrug, with the potential for
ethnically variable enzymatic conversion.
High intersubject variation in bioavailability.
Low bioavailability, thus more susceptible to dietary
absorption effects.
High likelihood of use in a setting of multiple co-
medications.
High potential for abuse.
Dated: July 25, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 97-20246 Filed 7-30-97; 8:45 am]
BILLING CODE 4160-01-F