31790 Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices
period of 5 years. Any person with an region while allowing for the influence Pharmaceutical Industries Associations,
approved or pending drug product of ethnic factors. the Japanese Ministry of Health and
application who knowingly uses the DATES: Effective June 10, 1998. Submit Welfare, the Japanese Pharmaceutical
services of Mr. Feuer in any in any written comments at any time. Manufacturers Association, the Centers
capacity during his period of debarment ADDRESSES: Submit written comments for Drug Evaluation and Research and
will be subject to civil money penalties on the guidance to the Dockets Biologics Evaluation and Research,
(section 307(a)(6) of the act (21 U.S.C. Management Branch (HFA305), Food FDA, and the Pharmaceutical Research
335b(a)(6))). If Mr. Feuer, during his and Drug Administration, 12420 and Manufacturers of America. The ICH
period of debarment, provides services Parklawn Dr., rm. 123, Rockville, MD Secretariat, which coordinates the
in any capacity to a person with an 20857. Copies of the guidance are preparation of documentation, is
approved or pending drug product available from the Drug Information provided by the International
application, he will be subject to civil Federation of Pharmaceutical
Branch (HFD210), Center for Drug
money penalties (section 307(a)(7) of the Manufacturers Associations (IFPMA).
Evaluation and Research, Food and
act). In addition, FDA will not accept or The ICH Steering Committee includes
Drug Administration, 5600 Fishers
review any abbreviated new drug representatives from each of the ICH
Lane, Rockville, MD 20857, 301827
applications or abbreviated antibiotic sponsors and the IFPMA, as well as
4573. Single copies of the guidance may
drug applications submitted by or with observers from the World Health
be obtained by mail from the Office of
the assistance of Mr. Feuer during his Organization, the Canadian Health
Communication, Training and
period of debarment. Protection Branch, and the European
Manufacturers Assistance (HFM40),
Any application by Mr. Feuer for Free Trade Area.
Center for Biologics Evaluation and
termination of debarment under section In the Federal Register of July 31,
Research (CBER), or by calling the CBER
306(d)(4) of the act should be identified 1997 (62 FR 41054), FDA published a
Voice Information System at 1800
with Docket No. 98N0131 and sent to draft tripartite guideline entitled
8354709 or 3018271800. Copies may
the Dockets Management Branch Ethnic Factors in the Acceptability of
be obtained from CBERs FAX
(address above). All such submissions Foreign Clinical Data (E5). The notice
Information System at 1888CBER
are to be filed in four copies. The public gave interested persons an opportunity
FAX or 3018273844.
availability of information in these to submit comments by October 29,
submissions is governed by 21 CFR FORFURTHERINFORMATIONCONTACT: 1997.
10.20(j). Publicly available submissions Regarding the guidance: Barbara G. After consideration of the comments
may be seen in the Dockets Management Matthews, Center for Biologics received and revisions to the guidance,
Branch between 9 a.m. and 4 p.m., Evaluation and Research (HFM a final draft of the guidance was
Monday through Friday. 570), Food and Drug submitted to the ICH Steering
Administration, 1401 Rockville Committee and endorsed by the three
Dated: May 18, 1998. Pike, Rockville, MD 20852, 301 participating regulatory agencies on
Janet Woodcock, 8275094. February 5, 1998.
Director, Center for Drug Evaluation and Regarding ICH: Janet J. Showalter, In accordance with FDAs good
Research. Office of Health Affairs (HFY20), guidance practices (62 FR 8961,
[FR Doc. 9815482 Filed 6998; 8:45 am] Food and Drug Administration, February 27, 1997), this document has
BILLING CODE 416001F 5600 Fishers Lane, Rockville, MD been designated a guidance, rather than
20857, 3018270864. a guideline.
SUPPLEMENTARYINFORMATION: In recent The guidance is intended to facilitate
DEPARTMENT OF HEALTH AND
years, many important initiatives have the registration of drugs and biologics
HUMAN SERVICES
been undertaken by regulatory among ICH regions by recommending a
authorities and industry associations to framework for evaluating the impact of
Food and Drug Administration
promote international harmonization of ethnic factors on a drugs effect, i.e., its
[Docket No. 97D0299] regulatory requirements. FDA has efficacy and safety at a particular dosage
participated in many meetings designed and dose regimen. The guidance
International Conference on
to enhance harmonization and is recommends regulatory and
Harmonisation; Guidance on Ethnic
committed to seeking scientifically development strategies that will permit
Factors in the Acceptability of Foreign
based harmonized technical procedures adequate evaluation of the influence of
Clinical Data; Availability
for pharmaceutical development. One of ethnic factors, minimize duplication of
AGENCY: Food and Drug Administration, the goals of harmonization is to identify clinical studies, and expedite the drug
HHS. and then reduce differences in technical approval process.
ACTION: Notice. requirements for drug development This guidance represents the agencys
among regulatory agencies. current thinking on ethnic factors in the
SUMMARY: The Food and Drug ICH was organized to provide an acceptability of foreign clinical data for
Administration (FDA) is publishing a opportunity for tripartite harmonization approval of both drugs and biologics. It
guidance entitled E5 Ethnic Factors in initiatives to be developed with input does not create or confer any rights for
the Acceptability of Foreign Clinical from both regulatory and industry or on any person and does not operate
Data. The guidance was prepared representatives. FDA also seeks input to bind FDA or the public. An
under the auspices of the International from consumer representatives and alternative approach may be used if
Conference on Harmonisation of others. ICH is concerned with such approach satisfies the
Technical Requirements for Registration harmonization of technical requirements of the applicable statute,
of Pharmaceuticals for Human Use requirements for the registration of regulations, or both.
(ICH). The guidance recommends pharmaceutical products among three As with all of FDAs guidances, the
regulatory and development strategies to regions: The European Union, Japan, public is encouraged to submit written
permit clinical data collected in one and the United States. The six ICH comments with new data or other new
region to be used for the support of drug sponsors are the European Commission, information pertinent to this guidance.
and biologic registrations in another the European Federation of The comments in the docket will be Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices 31791
periodically reviewed, and, where 1.0 Introduction that this guidance is not intended to alter the
appropriate, the guidance will be The purpose of this guidance is to facilitate data requirements for registration in the new
amended. The public will be notified of the registration of medicines among ICH region; it seeks to recommend when these
data requirements may be satisfied with
any such amendments through a notice regions (see Glossary) by recommending a
foreign clinical data. All data in the clinical
in the Federal Register. framework for evaluating the impact of
data package, including foreign data, should
ethnic factors upon a medicines effect, i.e.,
Interested persons may, at any time, its efficacy and safety at a particular dosage meet the standards of the new region with
submit written comments on the and dose regimen. It provides guidance with respect to study design and conduct, and the
guidance to the Dockets Management respect to regulatory and development available data should satisfy the regulatory
requirements in the new region. Additional
Branch (address above). Two copies of strategies that will permit adequate
studies conducted in any region may be
any comments are to be submitted, evaluation of the influence of ethnic factors
except that individuals may submit one while minimizing duplication of clinical required by the new region to complete the
studies and supplying medicines clinical data package.
copy. Comments are to be identified expeditiously to patients for their benefit. Once a clinical data package fulfills the
with the docket number found in This guidance should be implemented in regulatory requirements of the new region,
brackets in the heading of this context with other ICH guidances. For the the only remaining issue with respect to the
document. The guidance and received purposes of this document, ethnic factors are acceptance of the foreign clinical data is its
comments may be seen in the office defined as those factors relating to the genetic ability to be extrapolated to the population of
above between 9 a.m. and 4 p.m., and physiologic (intrinsic) and the cultural the new region. When the regulatory
Monday through Friday. An electronic and environmental (extrinsic) characteristics authority or the sponsor is concerned that
version of this guidance is available on of a population (Appendix A). differences in ethnic factors could alter the
efficacy or safety of the medicine in the
the Internet at http://www.fda.gov/ 1.1 Objectives population in the new region, the sponsor
cder/guidance/index.htm or at CBERs To describe the characteristics of foreign may need to generate a limited amount of
World Wide Webb site at http:// clinical data that will facilitate their clinical data in the new region in order to
www.fda.gov/cber/publications.htm. extrapolation to different populations and extrapolate or bridge the clinical data
The text of the guidance follows: support their acceptance as a basis for between the two regions. If a sponsor needs
registration of a medicine in a new region. to obtain additional clinical data to fulfill the
E5 Ethnic Factors in the Acceptability of  To describe regulatory strategies that regulatory requirements of the new region, it
Foreign Clinical Data1 minimize duplication of clinical data and is possible that these clinical trials can be
facilitate acceptance of foreign clinical data designed to also serve as the bridging studies.
1.0 Introduction
in the new region. Thus, the sponsor and the regional
1.1 Objectives
 To describe the use of bridging studies, regulatory authority of the new region would
1.2 Background
when necessary, to allow extrapolation of assess an application for registration for:
1.3 Scope
foreign clinical data to a new region. (1) Its completeness with respect to the
2.0 Assessment of the Clinical Data Package  To describe development strategies regulatory requirements of the new region,
Including Foreign Clinical Data for Its
capable of characterizing ethnic factor and
Fulfillment of Regulatory Requirements in
influences on safety, efficacy, dosage, and (2) The ability to extrapolate to the new
the New Region dose regimen. region those parts of the application (which
2.1 Additional Studies to Meet the New could be most or all of the application) based
Regions Regulatory Requirements 1.2 Background on studies from the foreign region (Appendix
3.0 Assessment of the Foreign Clinical Data All of the ICH regions acknowledge the B).
for Extrapolation to the New Region desirability of utilizing foreign clinical data
3.1 Characterization of the Medicines that meet the regulatory standards and 2.0 Assessment of the Clinical Data Package
Sensitivity to Ethnic Factors clinical trial practices acceptable to the Including Foreign Clinical Data for Its
3.2 Bridging Data Package region considering the application for Fulfillment of Regulatory Requirements in
the New Region
3.2.1 Definition of Bridging Data Package registration.
and Bridging Study However, concern that ethnic differences The regional regulatory authority would
3.2.2 Nature and Extent of the Bridging may affect the medications safety, efficacy, assess the clinical data package, including
Study dosage, and dose regimen in the new region the foreign data, as to whether or not it meets
3.2.3 Bridging Studies for Efficacy has limited the willingness to rely on foreign all of the regulatory standards regarding the
3.2.4 Bridging Studies for Safety clinical data. Historically, this has been one nature and quality of the data, irrespective of
4.0 Developmental Strategies for Global of the reasons, therefore, the regulatory its geographic origin, i.e., data generated
Development authority in the new region has often either totally in a foreign region (or regions)
5.0 Summary requested that all, or much of, the foreign or data from studies conducted both in a
Glossary (Italicized words and terms in the clinical data in support of registration be foreign and the new region to which the
text of the guidance are defined or explained duplicated in the new region. Although application is being made. A clinical data
in the glossary.) ethnic differences among populations may package that meets all of these regional
Appendix A: Classification of intrinsic and cause differences in a medicines safety, regulatory requirements is defined as a
extrinsic ethnic factors efficacy, dosage, or dose regimen, many complete clinical data package for
Appendix B: Assessment of the clinical data medicines have comparable characteristics submission and potential approval. The
package (CDP) for acceptability and effects across regions. Requirements for acceptability of the foreign clinical data
Appendix C: Pharmacokinetic, extensive duplication of clinical evaluation component of the complete data package
pharmacodynamic, and dose-response for every compound can delay the depends then upon whether it can be
considerations availability of new therapies and extrapolated to the population of the new
Appendix D: A medicines sensitivity to unnecessarily waste drug development region.
resources. Before extrapolation can be considered, the
ethnic factors
complete clinical data package, including
1.3 Scope foreign clinical data, submitted to the new
1This guidance represents the agencys current This guidance is based on the premise that region should contain:
thinking on ethnic factors in the acceptability of it is not necessary to repeat the entire clinical  Adequate characterization of
foreign clinical data for approval of both drugs and
drug development program in the new region pharmacokinetics, pharmacodynamics, dose
biologics. It does not create or confer any rights for
and is intended to recommend strategies for response, efficacy, and safety in the
or on any person and does not operate to bind FDA
or the public. An alternative approach may be used accepting foreign clinical data as full or population of the foreign region(s).
if such approach satisfies the requirements of the partial support for approval of an application  Clinical trials establishing dose response,
applicable statute, regulations, or both. in a new region. It is critical to appreciate efficacy and safety. These trials should: 31792 Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices
Be designed and conducted according to active excretion, a wide therapeutic dose determine the need for and the nature of the
regulatory standards in the new region, e.g., range, and a flat dose-response curve will bridging study. For regions with little
choice of controls, and should be conducted make ethnic differences less likely. The experience with registration based on foreign
according to good clinical practice (GCP), clinical experience with other members of clinical data, the regulatory authorities may
Be adequate and well-controlled, the drug class in the new region will also still request a bridging study for approval
Utilize endpoints that are considered contribute to the assessment of the even for compounds insensitive to ethnic
appropriate for assessment of treatment, medicines sensitivity to ethnic factors. It factors. As experience with interregional
Evaluate clinical disorders using medical may be easier to conclude that the acceptance increases, there will be a better
and diagnostic definitions that are acceptable pharmacodynamic and clinical behavior of a understanding of situations in which
to the new region. medicine will be similar in the foreign and bridging studies are needed. It is hoped that
 Characterization in a population relevant new regions if other members of the with experience, the need for bridging data
to the new region of the pharmacokinetics, pharmacologic class have been studied and will lessen.
and where possible, pharmacodynamics and approved in the new region with dosing The following is general guidance about
dose response for pharmacodynamic regimens similar to those used in the original the ability to extrapolate data generated from
endpoints. This characterization could be region. a bridging study:
performed in the foreign region in a  If the bridging study shows that dose
population representative of the new region 3.2 Bridging Data Package response, safety, and efficacy in the new
or in the new region. 3.2.1 Definition of Bridging Data Package and region are similar, then the study is readily
Several ICH guidances that address aspects Bridging Study interpreted as capable of bridging the
of design, conduct, analysis, and reporting of foreign data.
clinical trials will help implement the A bridging data package consists of: (1)  If a bridging study, properly executed,
concepts of the complete clinical data Selected information from the complete indicates that a different dose in the new
package. These guidances include GCPs (E6), clinical data package that is relevant to the region results in a safety and efficacy profile
evaluation of dose response (E4), adequacy of population of the new region, including that is not substantially different from that
safety data (E1 and E2), conduct of studies in pharmacokinetic data, and any preliminary derived in the original region, it will often be
the elderly (E7), reporting of study results pharmacodynamic and dose-response data possible to extrapolate the foreign data to the
(E3), general considerations for clinical trials and, if needed, (2) a bridging study to new region, with appropriate dose
(E8), and statistical considerations (E9). A extrapolate the foreign efficacy data and/or adjustment, if this can be adequately justified
guidance on the choice of control group in safety data to the new region. (e.g., by pharmacokinetic and/or
clinical study design (E10) is under A bridging study is defined as a study pharmacodynamic data).
development. performed in the new region to provide  If the bridging study designed to
pharmacodynamic or clinical data on extrapolate the foreign data is not of
2.1 Additional Studies to Meet the New efficacy, safety, dosage, and dose regimen in sufficient size to confirm adequately the
Regions Regulatory Requirements the new region that will allow extrapolation extrapolation of the adverse event profile to
When the foreign clinical data do not meet of the foreign clinical data to the population the new population, additional safety data
the regional regulatory requirements, the in the new region. A bridging study for may be necessary (section 3.2.4).
regulatory authority may require additional efficacy could provide additional  If the bridging study fails to verify safety
clinical trials such as: pharmacokinetic information in the and efficacy, additional clinical data (e.g.,
 Clinical trials in different subsets of the population of the new region. When no confirmatory clinical trials) would be
population, such as patients with renal bridging study is needed to provide clinical necessary.
data for efficacy, a pharmacokinetic study in
insufficiency, patients with hepatic the new region may be considered as a 3.2.3 Bridging Studies for Efficacy
dysfunction, etc.,
 Clinical trials using different comparators bridging study. Generally, for medicines characterized as
at the new regions approved dosage and 3.2.2 Nature and Extent of the Bridging Study insensitive to ethnic factors, the type of
dose regimen, bridging study needed (if needed) will
 Drug-drug interaction studies. This guidance proposes that when the depend upon experience with the drug class
regulatory authority of the new region is and upon the likelihood that extrinsic ethnic
3.0 Assessment of the Foreign Clinical Data presented with a clinical data package that factors (including design and conduct of
for Extrapolation to the New Region fulfills its regulatory requirements, the clinical trials) could affect the medicines
authority should request only those safety, efficacy, and dose-response. For
3.1 Characterization of the Medicines additional data necessary to assess the ability medicines that are ethnically sensitive, a
Sensitivity to Ethnic Factors to extrapolate foreign data from the complete bridging study may often be needed if the
To assess a medicines sensitivity to ethnic clinical data package to the new region. The populations in the two regions are different.
factors, it is important that there be sensitivity of the medicine to ethnic factors The following examples illustrate types of
knowledge of its pharmacokinetic and will help determine the amount of such data. bridging studies for consideration in different
pharmacodynamic properties and the In most cases, a single trial that successfully situations:
translation of those properties to clinical provides these data in the new region and  No bridging study
effectiveness and safety. A reasonable confirms the ability to extrapolate data from In some situations, extrapolation of clinical
evaluation is described in Appendix C. Some the original region should suffice and should data may be feasible without a bridging
properties of a medicine (chemical class, not need further replication. Note that even study:
metabolic pathway, pharmacologic class) though a single study should be sufficient to (1) If the medicine is ethnically insensitive
make it more or less likely to be affected by bridge efficacy data, a sponsor may find it and extrinsic factors such as medical practice
ethnic factors (Appendix D). Characterization practical to obtain the necessary data by and conduct of clinical trials in the two
of a medicine as ethnically insensitive, i.e., conducting more than one study. For regions are generally similar.
unlikely to behave differently in different example, where it is intended that a fixed (2) If the medicine is ethnically sensitive
populations, would usually make it easier to dose, dose-response study using a clinical but the two regions are ethnically similar and
extrapolate data from one region to another endpoint is needed as the bridging study, a there is sufficient clinical experience with
and need less bridging data. short-term pharmacologic endpoint study pharmacologically related compounds to
Factors that make a medicine ethnically may be used to choose the dose(s) for the provide reassurance that the class behaves
sensitive or insensitive will become better larger (clinical endpoint) study. similarly in patients in the two regions with
understood and documented as effects in When the regulatory authority requests, or respect to efficacy, safety, dosage, and dose
different regions are compared. It is clear at the sponsor decides to conduct, a bridging regimen. This might be the case for well-
present, however, that such characteristics as study, discussion between the regional established classes of drugs known to be
clearance by an enzyme showing genetic regulatory authority and sponsor is administered similarly, but not necessarily
polymorphism and a steep dose-response encouraged, when possible, to determine identically, in the two regions.
curve will make ethnic differences more what kind of bridging study will be needed.  Bridging studies using pharmacologic
likely. Conversely, a lack of metabolism or The relative ethnic sensitivity will help endpoints Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices 31793
If the regions are ethnically dissimilar and monitoring of such a trial would allow generating bridging data in order to
the medicine is ethnically sensitive but recognition of such serious events before an extrapolate the safety and efficacy data from
extrinsic factors are generally similar (e.g., unnecessarily large number of patients in the the population in the foreign region(s) to the
medical practice, design and conduct of new region are exposed. Alternatively, a population in the new region.
clinical trials) and the drug class is a familiar small safety study could precede the bridging
Glossary
one in the new region, a controlled study to provide assurance that serious
pharmacodynamic study in the new region, adverse effects were not occurring at a high Adequate and well-controlled trial: An
using a pharmacologic endpoint that is rate. adequate and well controlled trial has the
thought to reflect relevant drug activity  If there is no efficacy bridging study following characteristics:
(which could be a well-established surrogate needed or if the efficacy bridging study is too  A design that permits a valid comparison
endpoint), could provide assurance that the small or of insufficient duration to provide with a control to provide a quantitative
efficacy, safety, dose and dose regimen data adequate safety information, a separate safety assessment of treatment effect;
developed in the first region are applicable study may be needed. This could occur  The use of methods to minimize bias in
to the new region. Simultaneous where there is: the allocation of patients to treatment groups
pharmacokinetic (i.e., blood concentration) An index case of a serious adverse event and in the measurement and assessment of
measurements may make such studies more in the foreign clinical data, response to treatment; and
interpretable. A concern about differences in reporting  An analysis of the study results
 Controlled clinical trials adverse events in the foreign region, appropriate to the design to assess the effects
It will usually be necessary to carry out a Only limited safety data in the new of the treatment.
controlled clinical trial, often a randomized, region arising from an efficacy bridging Bridging data package: Selected
fixed dose, dose-response study, in the new study, inadequate to extrapolate important information from the complete clinical data
region when: aspects of the safety profile, such as rates of package that is relevant to the population of
(1) There are doubts about the choice of common adverse events or of more serious the new region, including pharmacokinetic
dose, adverse events. data, and any preliminary pharmacodynamic
(2) There is little or no experience with and dose-response data and, if needed,
acceptance of controlled clinical trials 4.0 Developmental Strategies for Global supplemental data obtained from a bridging
carried out in the foreign region, Development study in the new region that will allow
(3) Medical practice (e.g., use of Definition of not only pharmacokinetics extrapolation of the foreign safety and
concomitant medications and design and/or but also pharmacodynamics and dose efficacy data to the population of the new
conduct of clinical trials) is different, or response early in the development program region.
(4) The drug class is not a familiar one in may facilitate the determination of the need Bridging study: A bridging study is defined
the new region. for, and nature of, any requisite bridging as a supplemental study performed in the
Depending on the situation, the trial could data. Any candidate medicine for global new region to provide pharmacodynamic or
replicate the foreign study or could utilize a development should be characterized as clinical data on efficacy, safety, dosage, and
standard clinical endpoint in a study of ethnically sensitive or insensitive (Appendix dose regimen in the new region that will
shorter duration than the foreign studies or D). Ideally, this characterization should be allow extrapolation of the foreign clinical
utilize a validated surrogate endpoint, e.g., conducted during the early clinical phases of data to the new region. Such studies could
blood pressure or cholesterol (longer studies drug development, i.e., human pharmacology include additional pharmacokinetic
and other endpoints may have been used in and therapeutic exploratory studies. In some information.
the foreign phase III clinical trials). cases, it may be useful to discuss bridging Complete clinical data package: A clinical
If pharmacodynamic data suggest that there study designs with regulatory agencies prior data package intended for registration
are interregional differences in response, it to completion of the clinical data package. containing clinical data that fulfill the
will generally be necessary to carry out a However, analysis of the data within the regulatory requirements of the new region
controlled trial with clinical endpoints in the complete clinical data package will and containing pharmacokinetic data
new region. Pharmacokinetic differences may determine the need for, and type of bridging relevant to the population in the new region.
not always create that necessity, as dosage study. For global development, studies Compound insensitive to ethnic factors: A
adjustments in some cases might be made should include populations representative of compound whose characteristics suggest
without new trials. However, any substantial the regions where the medicine is to be minimal potential for clinically significant
difference in metabolic pattern may often registered and should be conducted impact by ethnic factors on safety, efficacy,
indicate a need for a controlled clinical trial. according to ICH guidelines. or dose response.
When the practice of medicine differs A sponsor may wish to leave the Compound sensitive to ethnic factors: A
significantly in the use of concomitant assessment of pharmacokinetics, compound whose pharmacokinetic,
medications, or adjunct therapy could alter pharmacodynamics, dosage, and dose pharmacodynamic, or other characteristics
the medicines efficacy or safety, the bridging regimens in populations relevant to the new suggest the potential for clinically significant
study should be a controlled clinical trial. region until later in the drug development impact by intrinsic and/or extrinsic ethnic
program. Pharmacokinetic assessment could factors on safety, efficacy, or dose response.
3.2.4 Bridging Studies for Safety be accomplished by formal pharmacokinetic Dosage: The quantity of a medicine given
Even though the foreign clinical data studies or by applying population per administration, or per day.
demonstrate efficacy and safety in the foreign pharmacokinetic methods to clinical trials Dose regimen: The route, frequency and
region, there may occasionally remain a conducted either in a population relevant to duration of administration of the dose of a
safety concern in the new region. Safety the new region or in the new region. medicine over a period of time.
concerns could include the accurate Ethnic factors: The word ethnicity is
determination of the rates of relatively 5.0 Summary derived from the Greek word ethnos,
common adverse events in the new region This guidance describes how a sponsor meaning nation or people. Ethnic factors are
and the detection of serious adverse events developing a medicine for a new region can factors relating to races or large populations
(in the 1 percent range and generally needing deal with the possibility that ethnic factors grouped according to common traits and
about 300 patients to assess). Depending could influence the effects (safety and customs. Note that this definition gives
upon the nature of the safety concern, safety efficacy) of medicines and the risk/benefit ethnicity, by virtue of its cultural as well as
data could be obtained in the following assessment in different populations. Results genetic implications, a broader meaning than
situations: from the foreign clinical trials could racial. Ethnic factors may be classified as
 A bridging study to assess efficacy, such comprise most, or in some cases, all of the either intrinsic or extrinsic. (Appendix A)
as a dose-response study, could be powered clinical data package for approval in the new  Extrinsic ethnic factors: Extrinsic ethnic
to address the rates of common adverse region, so long as they are carried out factors are factors associated with the
events and could also allow identification of according to the requirements of the new environment and culture in which a person
serious adverse events that occur more region. Acceptance in the new region of such resides. Extrinsic factors tend to be less
commonly in the new region. Close foreign clinical data may be achieved by genetically and more culturally and 31794 Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices
behaviorally determined. Examples of ICH regions: European Union, Japan, the concentration. A pharmacodynamic effect
extrinsic factors include the social and United States of America. can be a potentially adverse effect
cultural aspects of a region such as medical New region: The region where product (anticholinergic effect with a tricyclic), a
practice, diet, use of tobacco, use of alcohol, registration is sought.
measure of activity thought related to clinical
exposure to pollution and sunshine,  Population representative of the new
benefit (various measures of beta-blockade,
socioeconomic status, compliance with region: A population that includes the major
effect on ECG (electrocardiogram) intervals,
prescribed medications, and, particularly racial groups within the new region.
inhibition of ACE (angiotensin converting
important to the reliance on studies from a Pharmacokinetic study: A study of how a
different region, practices in clinical trial medicine is handled by the body, usually enzyme) or of angiotensin I or II response),
design and conduct. involving measurement of blood a short-term desired effect, often a surrogate
 Intrinsic ethnic factors: Intrinsic ethnic concentrations of drug and its metabolite(s) endpoint (blood pressure, cholesterol), or the
factors are factors that help to define and (sometimes concentrations in urine or ultimate intended clinical benefit (effects on
identify a subpopulation and may influence tissues) as a function of time. pain, depression, sudden death).
the ability to extrapolate clinical data Pharmacokinetic studies are used to Population pharmacokinetic methods:
between regions. Examples of intrinsic characterize absorption, distribution,
Population pharmacokinetic methods are a
factors include genetic polymorphism, age, metabolism, and excretion of a drug, either
population-based evaluation of
gender, height, weight, lean body mass, body in blood or in other pertinent locations.
measurements of systemic drug
composition, and organ dysfunction. When combined with pharmacodynamic
Extrapolation of foreign clinical data: The measures (a PK/PD study) it can characterize concentrations, usually two or more per
generalization and application of the safety, the relation of blood concentrations to the patient under steady state conditions, from
efficacy, and dose-response data generated in extent and timing of pharmacodynamic all, or a defined subset of, patients who
a population of a foreign region to the effects. participate in clinical trials.
population of the new region. Pharmacodynamic study: A study of a Therapeutic dose range: The difference
Foreign clinical data: Foreign clinical data pharmacological or clinical effect of the between the lowest effective dose and the
is defined as clinical data generated outside medicine in individuals to describe the
highest dose that gives further benefit.
of the new region (i.e., in the foreign region). relation of the effect to dose or drug
Appendix A: Classification of intrinsic and extrinsic ethnic factors Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices 31795
Appendix B: Assessment of the clinical data package (CDP) for acceptability
Appendix C: Pharmacokinetic, The ICH E4 document describes various Appendix D: A medicines sensitivity to
pharmacodynamic, and dose-response approaches to dose-response evaluation. In ethnic factors
considerations general, dose response (or concentration Characterization of a medicine according to
Evaluation of the pharmacokinetics and response) should be evaluated for both the potential impact of ethnic factors upon its
pharmacodynamics, and their comparability, pharmacologic effect (where one is pharmacokinetics, pharmacodynamics, and
in the three major racial groups in the ICH considered pertinent) and clinical endpoints therapeutic effects may be useful in
regions (Asian, Black, and Caucasian) is in the foreign region. The pharmacologic determining what sort of bridging study is
critical to the registration of medicines in the effect, including dose response, may also be needed in the new region. The impact of
ICH regions. Basic pharmacokinetic evaluated in the foreign region in a ethnic factors upon a medicines effect will
evaluation should characterize absorption, population representative of the new region. vary depending upon the drugs
distribution, metabolism, excretion (ADME), Depending on the situation, data on clinical pharmacologic class and indication and the
and where appropriate, food-drug and drug- efficacy and dose response in the new region age and gender of the patient. No one
drug interactions. may or may not be needed, e.g., if the drug property of the medicine is predictive of the
Adequate pharmacokinetic comparison class is familiar and the pharmacologic effect compounds relative sensitivity to ethnic
between populations of the two regions is closely linked to clinical effectiveness and factors. The type of bridging study needed is
allows rational consideration of what kinds ultimately a matter of judgment, but
dose response, these foreign
of further pharmacodynamic and clinical assessment of sensitivity to ethnic factors
pharmacodynamic data may be a sufficient
studies (bridging studies) are needed in the may help in that judgment.
basis for approval and clinical endpoint and
new region. In contrast to the The following properties of a compound
dose-response data may not be needed in the
pharmacokinetics of a medication, where make it less likely to be sensitive to ethnic
new region. The pharmacodynamic
differences between populations may be factors:
attributed primarily to intrinsic ethnic factors evaluation, and possible clinical evaluation  Linear pharmacokinetics (PK).
and are readily identified, the (including dose response) is important  A flat pharmacodynamic (PD) (effect-
because of the possibility that the response
pharmacodynamic response (clinical concentration) curve for both efficacy and
effectiveness, safety, and dose response) may curve may be shifted in a new population. safety in the range of the recommended
be influenced by both intrinsic and extrinsic Examples of this are well-documented, e.g., dosage and dose regimen (this may mean that
ethnic factors and this may be difficult to the decreased response in blood pressure of the medicine is well-tolerated).
identify except by conducting clinical studies blacks to angiotensin converting enzyme  A wide therapeutic dose range (again,
in the new region. inhibitors. possibly an indicator of good tolerability). 31796 Federal Register/Vol. 63, No. 111/Wednesday, June 10, 1998/Notices
 Minimal metabolism or metabolism ACTION: Notice. (6) what members of the public will be
distributed among multiple pathways. affected by the proposal; (7) how
 High bioavailability, thus less SUMMARY: The proposed information
frequently information submissions will
susceptibility to dietary absorption effects. collection requirement described below
 Low potential for protein binding. has been submitted to the Office of be required; (8) an estimate of the total
 Little potential for drug-drug, drug-diet, Management and Budget (OMB) for number of hours needed to prepare the
and drug-disease interactions. information submission including
 Nonsystemic mode of action. review, as required by the Paperwork number of respondents, frequency of
 Little potential for inappropriate use. Reduction Act. The Department is response, and hours of response; (9)
The following properties of a compound soliciting public comments on the
whether the proposal is new, an
make it more likely to be sensitive to ethnic subject proposal.
factors: DATES: Comments due date: July 10, extension, reinstatement, or revision of
 Nonlinear pharmacokinetics. 1998. an information collection requirement;
 A steep pharmacodynamic curve for both and (10) the names and telephone
ADDRESSES: Interested persons are
efficacy and safety (a small change in dose numbers of an agency official familiar
results in a large change in effect) in the invited to submit comments regarding
with the proposal and of the OMB Desk
range of the recommended dosage and dose this proposal. Comments must be
Officer for the Department.
regimen. received within thirty (30) days from the
 A narrow therapeutic dose range. date of this Notice. Comments should Authority: Sec. 3507 of the Paperwork
 Highly metabolized, especially through a refer to the proposal by name and/or Reduction Act of 1995, 44 U.S.C. 35, as
single pathway, thereby increasing the
OMB approval number and should be amended.
potential for drug-drug interaction.
 Metabolism by enzymes known to show sent to: Joseph F. Lackey, Jr., OMB Desk Dated: June 4, 1998.
genetic polymorphism. Officer, Office of Management and David S. Cristy,
 Administration as a prodrug, with the Budget, Room 10235, New Executive Director, IRM Policy and Management
potential for ethnically variable enzymatic Office Building, Washington, DC 20503. Division.
conversion. FORFURTHERINFORMATIONCONTACT:
 High intersubject variation in Wayne Eddins, Reports Management Title of Proposal: Public and Indian
bioavailability. Officer, Department of Housing and Housing: Demolition/Disposition/
 Low bioavailability, thus more Urban Development, 451 7th Street, Conversion/Taking of Units or Property.
susceptible to dietary absorption effects.
 High likelihood of use in a setting of Southwest, Washington, DC 20410, Office: Public and Indian Housing.
multiple co-medications. telephone (202) 7081305. This is not a OMB Approval Number: 25770075.
 High likelihood for inappropriate use , toll-free number. Copies of the proposed
e.g., analgesics and tranquilizers. forms and other available documents Description of The Need For The
Dated: May 25, 1998. submitted to OMB may be obtained Information and Its Proposed Use: The
from Mr. Eddins. purpose of the Housing Authorities
William K. Hubbard,
Associate Commissioner for Policy SUPPLEMENTARYINFORMATION: The request is to seek HUD approval of a
Coordination. Department has submitted the proposal change in a public housing development
[FR Doc. 9815408 Filed 6998; 8:45 am] for the collection of information, as application from what was originally
described below, to OMB for review, as authorized under the Annual
BILLING CODE 416001F
required by the Paperwork Reduction Contributions Contract.
Act (44 U.S.C. Chapter 35). Form Number: 52860.
DEPARTMENT OF HOUSING AND The Notice lists the following Respondents: State, Local, or Tribal
URBAN DEVELOPMENT information: (1) The title of the Governments.
information collection proposal; (2) the
[Docket No. FR4349N23] office of the agency to collect the Frequency of Submission:
information; (3) the OMB approval Recordkeeping and Annually.
Submission for OMB Review:
number, if applicable; (4) the Reporting Burden:
Comment Request
description of the need for the
AGENCY: Office of the Assistant information and its proposed use; (5)
Secretary for Administration, HUD. the agency form number, if applicable;
Number of  Frequency of  Hours per = Burden hours
respondents response response
Application .................................................................................. 120 1 16 1920
Recordkeeping ........................................................................... 120 1 1 120
Total Estimated Burden Hours: 2,040. DEPARTMENT OF HOUSING AND ACTION: Announcement of funding
Status: Reinstatement, with no URBAN DEVELOPMENT awards.
changes.
Contact: Virginia Mathis, HUD, (202) [Docket No. FR4181N06] SUMMARY: In accordance with section
102(a)(4)(C) of the Department of
7081640; Joseph F. Lackey, Jr., OMB,
Public and Indian Housing Drug Housing and Urban Development
(202) 3957316.
Elimination Program Announcement of Reform Act of 1989, this announcement
Dated: June 4, 1998. Funding Awards for FY 1997 notifies the public of funding decisions
[FR Doc. 9815478 Filed 6998; 8:45 am] made by the department in competition
BILLING CODE 421001M AGENCY: Office of the Assistant for funding under the Notice of Funding
Secretary for Public and Indian Availability (NOFA) for the Public and
Housing, HUD. Indian Housing Drug Elimination