[Federal Register Volume 59, Number 46 (Wednesday, March 9, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-5435]


[[Page Unknown]]

[Federal Register: March 9, 1994]


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Part IV





Department of Health and Human Services





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National Institutes of Health



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NIH Guidelines on the Inclusion of Women and Minorities as Subjects in 
Clinical Research; Notice
DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health
RIN 0905-ZA18

 
NIH Guidelines on the Inclusion of Women and Minorities as 
Subjects in Clinical Research

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.

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SUMMARY: The National Institutes of Health (NIH) is establishing 
guidelines on the inclusion of women and minorities and their 
subpopulations in research involving human subjects, including clinical 
trials, supported by the NIH, as required in the NIH Revitalization Act 
of 1993.

EFFECTIVE DATE: March 9, 1994.

ADDRESSES: Although these guidelines are effective on the date of 
publication, written comments can be sent to either the Office of 
Research on Women's Health, National Institutes of Health, Building 1, 
room 203, Bethesda, MD 20892, or to the Office of Research on Minority 
Health, National Institutes of Health, Building 1, room 255, Bethesda, 
MD 20892. During the first year of implementation, NIH will receive the 
comments and experience with the guidelines in order to determine 
whether modifications to the guidelines are warranted.

FOR FURTHER INFORMATION CONTACT: Programmatic inquiries should be 
directed to senior extramural staff of the relevant NIH Institute or 
Center named at the end of this notice.

SUPPLEMENTARY INFORMATION: NIH Guidelines on the Inclusion of Women and 
Minorities as Subjects in Clinical Research.

I. Introduction

    This document sets forth guidelines on the inclusion of women and 
members of minority groups and their subpopulations in clinical 
research, including clinical trials, supported by the National 
Institutes of Health (NIH). For the purposes of this document, clinical 
research is defined as NIH-supported biomedical and behavioral research 
involving human subjects. These guidelines, implemented in accordance 
with section 492B of the Public Health Service Act, added by the NIH 
Revitalization Act of 1993, Public Law. (Pub.L.) 103-43, supersede and 
strengthen the previous policies, NIH/ADAMHA Policy Concerning the 
Inclusion of Women in Study Populations, and ADAMHA/NIH Policy 
Concerning the Inclusion of Minorities in Study Populations, published 
in the NIH GUIDE FOR GRANTS AND CONTRACTS, 1990.
    The 1993 guidelines continue the 1990 guidelines with three major 
additions. The new policy requires that, in addition to the continuing 
inclusion of women and members of minority groups in all NIH-supported 
biomedical and behavioral research involving human subjects, the NIH 
must:
     Ensure that women and members of minorities and their 
subpopulations are included in all human subject research.
     For Phase III clinical trials, ensure that women and 
minorities and their subpopulations must be included such that valid 
analyses of differences in intervention effect can be accomplished;
     Not allow cost as an acceptable reason for excluding these 
groups; and,
     Initiate programs and support for outreach efforts to 
recruit these groups into clinical studies.
    Since a primary aim of research is to provide scientific evidence 
leading to a change in health policy or a standard of care, it is 
imperative to determine whether the intervention or therapy being 
studied affects women or men or members of minority groups and their 
subpopulations differently. To this end, the guidelines published here 
are intended to ensure that all future NIH-supported biomedical and 
behavioral research involving human subjects will be carried out in a 
manner sufficient to elicit information about individuals of both 
genders and the diverse racial and ethnic groups and, in the case of 
clinical trials, to examine differential effects on such groups. 
Increased attention, therefore, must be given to gender, race, and 
ethnicity in earlier stages of research to allow for informed decisions 
at the Phase III clinical trial stage.
    These guidelines reaffirm NIH's commitment to the fundamental 
principles of inclusion of women and racial and ethnic minority groups 
and their subpopulations in research. This policy should result in a 
variety of new research opportunities to address significant gaps in 
knowledge about health problems that affect women and racial/ethnic 
minorities and their subpopulations.
    The NIH recognizes that issues will arise with the implementation 
of these guidelines and thus welcomes comments. During the first year 
of implementation, NIH will review the comments, and consider 
modifications, within the scope of the statute, to the guidelines.

II. Background

    The NIH Revitalization Act of 1993, PL 103-43, signed by President 
Clinton on June 10, 1993, directs the NIH to establish guidelines for 
inclusion of women and minorities in clinical research. This guidance 
shall include guidelines regarding--

    (A) the circumstances under which the inclusion of women and 
minorities as subjects in projects of clinical research is 
inappropriate * * *;
    (B) the manner in which clinical trials are required to be 
designed and carried out * * *; and
    (C) the operation of outreach programs * * * 492B(d)(1)

    The statute states that

    In conducting or supporting clinical research for the purposes 
of this title, the Director of NIH shall * * * ensure that--
    A. women are included as subjects in each project of such 
research; and
    B. members of minority groups are included in such research. 
492B(a)(1)

    The statute further defines ``clinical research'' to include 
``clinical trials'' and states that

    In the case of any clinical trial in which women or members of 
minority groups will be included as subjects, the Director of NIH 
shall ensure that the trial is designed and carried out in a manner 
sufficient to provide for valid analysis of whether the variables 
being studied in the trial after women or members of minority 
groups, as the case may be, differently than other subjects in the 
trial. 492B(C)

    Specifically addressing the issue of minority groups, the statute 
states that

    The term ``minority group'' includes subpopulations of minority 
groups. The Director of NIH shall, through the guidelines 
established * * * defines the terms ``minority group'' and 
``subpopulation'' for the purposes of the preceding sentence. 
492B(g)(2)

    The statute speaks specifically to outreach and states that

    The Director of NIH, in consultation with the Director of the 
Office of Research of Women's Health and the Director of the Office 
of Research on Minority Health, shall conduct or support outreach 
programs for the recruitment of women and members of minority groups 
as subjects in the projects of clinical research. 492B(a)(2)

    The statute includes a specific provision pertaining to the cost of 
clinical research and, in particular clinical trials.

    (A)(i) In the case of a clinical trial, the guidelines shall 
provide that the costs of such inclusion in the trial is (sic) not a 
permissible consideration in determining whether such inclusion is 
inappropriate. 492B(d)(2)
    (ii) In the case of other projects of clinical research, the 
guidelines shall provide that the costs of such inclusion in the 
project is (sic) not a permissible consideration in determining 
whether such inclusion is inappropriate unless the data regarding 
women or members of minority groups, respectively, that would be 
obtained in such project (in the event that such inclusion were 
required) have been or are being obtained through other means that 
provide data of comparable quality. 492B(d)(2)

    Exclusions to the requirement for inclusion of women and minorities 
are stated in the statute, as follows:

    The requirements established regarding women and members of 
minority groups shall not apply to the project of clinical research 
if the conclusion, as subjects in the project, of women and members 
of minority groups, respectively--
    (1) Is inappropriate with respect to the health of the subjects;
    (2) Is inappropriate with respect to the purpose of the 
research; or
    (3) Is inappropriate under such other circumstances as the 
Director of NIH may designate. 492B(b)
    (B) In the case of a clinical trial, the guidelines may provide 
that such inclusion in the trial is not required if there is 
substantial scientific data demonstrating that there is no 
significant difference between--
    (i) The effects that the variables to be studied in the trial 
have on a woman or members of minority groups, respectively; and
    (ii) The effects that variables have on the individuals who 
would serve as subjects in the trial in the event that such 
inclusion were not required. 492B(d)(2)

III. Policy

A. Research Involving Human Subjects

    It is the policy of NIH that women and members of minority groups 
and their subpopulations must be included in all NIH-supported 
biomedical and behavioral research projects involving human subjects, 
unless a clear and compelling rationale and justification establishes 
to the satisfaction of the relevant Institute/Center Director that 
inclusion is inappropriate with respect to the health of the subjects 
or the purpose of the research. Exclusion under other circumstances may 
be made by the Director, NIH, upon the recommendation of a Institute/
Center Director based on a compelling rationale and justification. Cost 
is not an acceptable reason for exclusion except when the study would 
duplicate date from other sources. Women of childbearing potential 
should not be routinely included from participation in clinical 
research involving human subjects is defined as clinical research. This 
policy applies to research subjects of all ages.
    The inclusion of women and members of minority groups and their 
subpopulations must be addressed in developing a research design 
appropriate to the scientific objectives of the study. The research 
plan should describe the composition of the proposed study population 
in terms of gender and racial/ethnic group, and provide a rationale for 
selection of such subjects. Such a plan should contain a description of 
the proposed outreach programs for recruiting women and minorities as 
participants.

B. Clinical Trials

    Under the statute, when a Phase III clinical trial (see 
Definitions, Section V-A) is proposed, evidence must be reviewed to 
show whether or not clinically important gender or race/ethnicity 
differences in the intervention effect are to be expected. This 
evidence may include, but is not limited to, data derived from prior 
animal studies, clinical observations, metabolic studies, genetic 
studies, pharmacology studies, and observational, natural history, 
epidemiology and other relevant studies.
    As such, investigators must consider the following when planning a 
Phase III clinical trial for NIH support.
     If the data from prior studies strongly indicate the 
existence of significant differences of clinical or public health 
importance in intervention effect amount subgroups (gender and/or 
racial/ethnic subgroups), the primary question(s) to be addressed by 
the proposed Phase III trial and the design of that trial must 
specifically accommodate this. For example, if men and women are 
thought to respond differently to an intervention, then the Phase III 
trial must be designed to answer two separate primary questions, one 
for men and the other for women, with adequate sample size for each.
     If the data from prior studies strongly support no 
significant differences of clinical or public health importance in 
intervention effect between subgroups, then gender or race/ethnicity 
will not be required as subject selection criteria. However, the 
inclusion of gender or racial/ethnic subgroups is still strongly 
encouraged.
     If the data from prior studies neither support strongly 
nor negate strongly the existence of significant differences of 
clinical or public health importance in intervention effect between 
subgroups, then the Phase III trial will be required to include 
sufficient and appropriate entry of gender and racial/ethnic subgroups, 
so that valid analysis of the intervention effect in subgroups can be 
performed. However, the trial will not be required to provide high 
statistical power for each subgroup.
    Cost is not an acceptable reason for exclusion of women and 
minorities from clinical trials.

C. Funding

    NIH funding components will not award any grant, cooperative 
agreement or contract or support any intramural project to be conducted 
or funded in Fiscal Year 1995 and thereafter which does not comply with 
this policy. For research awards that are covered by this policy, 
awardees will report annually on enrollment of women and men, and on 
the race and ethnicity of research participants.

IV. Implementation

A. Date of Implementation

    This policy applies to all applications/proposals and intramural 
projects to be submitted on and after June 1, 1994 (the date of full 
implementation) seeking Fiscal Year 1995 support. Projects funded prior 
to June 10, 1993, must still comply with the 1990 policy and report 
annually on enrollment of subjects using gender and racial/ethnic 
categories as required in the Application for Continuation of a Public 
Health Service Grant (PHS Form 2590), in contracts and in intramural 
projects.

B. Transition Policy

    NIH-supported biomedical and behavioral research projects involving 
human subjects, with the exception of Phase III clinical trial projects 
as discussed below, that are awarded between June 10, 1993, the date of 
enactment, and September 30, 1994, the end of Fiscal Year 1994, shall 
be subject to the requirements of the 1990 policy and the annual 
reporting requirements on enrollment using gender and racial/ethnic 
categories.
    For all Phase III clinical trial projects proposed between June 10, 
1993 and June 1, 1994, and those awarded between June 10, 1993 and 
September 30, 1994, Institute/Center staff will examine the 
applications/proposals, pending awards, awards and intramural projects 
to determine if the study was developed in a manner consistent with the 
new guidelines. If it is deemed inconsistent, NIH staff will contact 
investigators to discuss approaches to accommodate the new policy. 
Administrative actions may be needed to accommodate or revise the 
pending trials. Institutes/Centers may need to consider initiating a 
complementary activity to address any gender or minority representation 
concerns.
    The NIH Director will determine whether the Phase III clinical 
trial being considered during this transition is in compliance with 
this policy, whether acceptable modifications have been made, or 
whether the Institute/Center will initiate a complementary activity 
that addresses the gender or minority representation concerns. Pending 
awards will not be funded without this determination.
    Solicitations issued by the NIH planned for release after the date 
of publication of the guidelines in the Federal Register will include 
the new requirements.

C. Roles and Responsibilities

    While this policy applies to all applicants for NIH-supported 
biomedical and behavioral research involving human subjects, certain 
individuals and groups have special roles and responsibilities with 
regard to the adoption and implementation of these guidelines.
    The NIH staff will provide educational opportunities for the 
extramural and interamural community concerning this policy; monitor 
its implementation during the development, review, award and conduct of 
research; and manage the NIH research portfolio to address the policy.
1. Principal Investigators
    Principal investigators should assess the theoretical and/or 
scientific linkages between gender, race/ethnicity, and their topic of 
study. Following this assessment, the principal investigator and the 
applicant institution will address the policy in each application and 
proposal, providing the required information on inclusion of women and 
minorities and their subpopulations in research projects, and any 
required justifications for exceptions to the policy. Depending on the 
purpose of the study, NIH recognizes that a single study may not 
include all minority groups.
2. Institutional Review Boards (IRBs)
    As the IRBs implement the guidelines, described herein, for the 
inclusion of women and minorities and their subpopulations, they must 
also implement the regulations for the protection of human subjects as 
described in title 45 CFR part 46, ``Protection of Human Subjects.'' 
They should take into account the Food and Drug Administration's 
``Guidelines for the Study and Evaluation of Gender Differences in the 
Clinical Evaluation of Drugs,'' Vol. 58 Federal Register 39406.
3. Peer Review Groups
    In conducting peer review for scientific and technical merit, 
appropriately constituted initial review groups (including study 
sections), technical evaluation groups, and intramural review panels 
will be instructed, as follows:
     To evaluate the proposed plan for the inclusion of 
minorities and both genders for appropriate representation or to 
evaluate the proposed justification when representation is limited or 
absent,
     To evaluate the proposed exclusion of minorities and women 
on the basis that a requirement for inclusion is inappropriate with 
respect to the health of the subjects,
     To evaluate the proposed exclusion of minorities and women 
on the basis that a requirement for inclusion is inappropriate with 
respect to the purpose of the research,
     To determine whether the design of clinical trials is 
adequate to measure differences when warranted,
     To evaluate the plans for recruitment/outreach for study, 
participants, and
     To include these criteria as part of the scientific 
assessment and assigned score.
4. NIH Advisory Councils
    In addition to its current responsibilities for review of projects 
where the peer review groups have raised questions about the 
appropriate inclusion of women and minorities, the Advisory Council/
Board of each Institute/Center shall prepare biennial reports, for 
inclusion in the overall NIH Director's biennial report, describing the 
manner in which the Institute/Center has complied with the provisions 
of the statute.
5. Institute/Center Directors
    Institute/Center Directors and their staff shall determine whether: 
(a) The research involving human subjects, (b) the Phase III clinical 
trials, and (c) the exclusions meet the requirements of the statute and 
these guidelines.
6. NIH Director
    The NIH Director may approve, on a case-by-case basis, the 
exclusion of projects, as recommended by the Institute/Center Director, 
that may be inappropriate to include within the requirements of these 
guidelines on the basis of circumstances other than the health of the 
subjects, the purpose of the research, or costs.
7. Recruitment Outreach by Extramural and Intramural Investigators
    Investigators and their staff(s) are urged to develop appropriate 
and culturally sensitive outreach programs and activities commensurate 
with the goals of the study. The objective should be to actively 
recruit the most diverse study population consistent with the purposes 
of the research project. Indeed, the purpose should be to establish a 
relationship between the investigator(s) and staff(s) and populations 
and community(ies) of interest such that mutual benefit is derived for 
participants in the study. Investigator(s) and staff(s) should take 
precautionary measures to ensure that ethical concerns are clearly 
noted, such that there is minimal possibility of coercion or undue 
influence in the incentives or rewards offered in recruiting into or 
retaining participants in studies. It is also the responsibility of the 
IRBs to address these ethical concerns.
    Furthermore, while the statute focuses on recruitment outreach, NIH 
staff underscore the need to appropriately retain participants in 
clinical studies, and thus, the outreach programs and activities should 
address both recruitment and retention.
    To assist investigators and potential study participants, NIH staff 
have prepared a notebook, ``NIH Outreach Notebook On the Inclusion of 
Women and Minorities in Biomedical and Behavioral Research.'' The 
notebook addresses both recruitment and retention of women and 
minorities in clinical studies, provides relevant references and case 
studies, and discusses ethical issues. It is not intended as a 
definitive text on this subject, but should assist investigators in 
their consideration of an appropriate plan for recruiting and retaining 
participants in clinical studies. The notebook is expected to be 
available early in 1994.
8. Educational Outreach by NIH to Inform the Professional Community
    NIH staff will present the new guidelines to investigators, IRB 
members, peer review groups, and Advisory Councils in a variety of 
public educational forums.
9. Applicability to Foreign Research Involving Human Subjects
    For foreign awards, the NIH policy on inclusion of women in 
research conducted outside the U.S. is the same as that for research 
conducted in the U.S.
    However, with regard to the population of the foreign country, the 
definition of the minority groups may be different than in the U.S. If 
there is scientific rationale for examining subpopulation group 
differences within the foreign population, investigators should 
consider designing their studies to accommodate these differences.

V. Definitions

    Throughout the section of the statute pertaining to the inclusion 
of women and minorities, terms are used which require definition for 
the purpose of implementing these guidelines. These terms, drawn 
directly from the statute, are defined below.

A. Clinical Trial

    For the purpose of these guidelines, a ``clinical trial'' is a 
broadly based prospective Phase III clinical investigation, usually 
involving several hundred or more human subjects, for the purpose of 
evaluating an experimental intervention in comparison with a standard 
or control intervention or comparing two or more existing treatments. 
Often the aim of such investigation is to provide evidence leading to a 
scientific basis for consideration of a change in health policy or 
standard of care. The definition includes pharmacologic, non-
pharmacologic, and behavioral interventions given for disease 
prevention, prophylaxis, diagnosis, or therapy. Community trials and 
other population-based intervention trials are also included.

B. Research Involving Human Subjects

    All NIH-supported biomedical and behavioral research involving 
human subjects is defined as clinical research under this policy. Under 
this policy, the definition of human subjects in title 45 CFR part 46, 
the Department of Health and Human Services regulations for the 
protection of human subjects applies: ``Human subject means a living 
individual about whom an investigator (whether professional or student) 
conducting research obtains: (1) Data through intervention or 
interaction with the individual, or (2) identifiable private 
information.'' These regulations specifically address the protection of 
human subjects from research risks. It should be noted that there are 
research areas (Exemptions 1-6) that are exempt from these regulations. 
However, under these guidelines, NIH-supported biomedical and 
behavioral research projects involving human subjects which are exempt 
from the human subjects regulations should still address the inclusion 
of women and minorities in their study design. Therefore, all 
biomedical and behavioral research projects involving human subjects 
will be evaluated for compliance with this policy.

C. Valid Analysis

    The term ``valid analysis'' means an unbiased assessment. Such an 
assessment will, on average, yield the correct estimate of the 
difference in outcomes between two groups of subjects. Valid analysis 
can and should be conducted for both small and large studies. A valid 
analysis does not need to have a high statistical power for detecting a 
stated effect. The principal requirements for ensuring a valid analysis 
of the question of interest are:
     Allocation of study participants of both genders and from 
different racial/ethnic groups to the intervention and control groups 
by an unbiased process such as randomization,
     Unbiased evaluation of the outcome(s) of study 
participants, and
     Use of unbiased statistical analyses and proper methods of 
inference to estimate and compare the intervention effects among the 
gender and racial/ethnic groups.

D. Significant Difference

    For purposes of this policy, a ``significant difference'' is a 
difference that is of clinical or public health importance, based on 
substantial scientific data. This definition differs from the commonly 
used ``statistically significant difference,'' which refers to the 
event that, for a given set of data, the statistical test for a 
difference between the effects in two groups achieves statistical 
significance. Statistical significance depends upon the amount of 
information in the data set. With a very large amount of information, 
one could find a statistically significant, but clinically small 
difference that is of very little clinical importance. Conversely, with 
less information one could find a large difference of potential 
importance that is not statistically significant.

E. Racial and Ethnic Categories

1. Minority Groups
    A minority group is a readily identifiable subset of the U.S. 
population which is distinguished by either racial, ethnic, and/or 
cultural heritage.
    The Office of Management and Budget (OMB) Directive No. 15 defines 
the minimum standard of basic racial and ethnic categories, which are 
used below. NIH has chosen to continue the use of these definitions 
because they allow comparisons to many national data bases, especially 
national health data bases. Therefore, the racial and ethnic categories 
described below should be used as basic guidance, cognizant of the 
distinction based on cultural heritage.
    American Indian or Alaskan Native: A person having origins in any 
of the original peoples of North America, and who maintains cultural 
identification through tribal affiliation or community recognition.
    Asian or Pacific Islander: A person having origins in any of the 
original peoples of the Far East, Southeast Asia, the Indian 
subcontinent, or the Pacific Islands. This area includes, for example, 
China, India, Japan, Korea, the Philippine Islands and Samoa.
    Black, not of Hispanic Origin: A person having origins in any of 
the black racial groups of Africa.
    Hispanic: A person of Mexican, Puerto Rican, Cuban, Central or 
South American or other Spanish culture or origin, regardless of race.
2. Majority Group
    White, not of Hispanic Origin: A person having origins in any of 
the original peoples of Europe, North Africa, or the Middle East.
    NIH recognizes the diversity of the U.S. population and that 
changing demographics are reflected in the changing racial and ethnic 
composition of the population. The terms ``minority groups'' and 
``minority subpopulations'' are meant to be inclusive, rather than 
exclusive, of differing racial and ethnic categories.
3. Subpopulations
    Each minority group contains subpopulations which are delimited by 
geographic origins, national origins and/or cultural differences. It is 
recognized that there are different ways of defining and reporting 
racial and ethnic subpopulation data. The subpopulation to which an 
individual is assigned depends on self-reporting of specific racial and 
ethnic origin. Attention to subpopulations also applies to individuals 
of mixed racial and/or ethnic parentage. Researchers should be 
cognizant of the possibility that these racial/ethnic combinations may 
have biomedical and/or cultural implications related to the scientific 
question under study.

F. Outreach Strategies

    These are outreach efforts by investigators and their staff(s) to 
appropriately recruit and retain populations of interest into research 
studies. Such efforts should represent a thoughtful and culturally 
sensitive plan of outreach and generally include involvement of other 
individuals and organizations relevant to the populations and 
communities of interest, e.g., family, religious organizations, 
community leaders and informal gatekeepers, and public and private 
institutions and organizations. The objective is to establish 
appropriate lines of communication and cooperation to build mutual 
trust and cooperation such that both the study and the participants 
benefit from such collaboration.

G. Research Portfolio

    Each Institute and Center at the NIH has its own research 
portfolio, i.e., its ``holdings'' in research grants, cooperative 
agreements, contracts and intramural studies. The Institute or Center 
evaluates the research awards in its portfolio to identify those areas 
where there are knowledge gaps or which need special attention to 
advance the science involved. NIH may consider funding projects to 
achieve a research portfolio reflecting diverse study populations. With 
the implementation of this new policy, there will be a need to ensure 
that sufficient resources are provided within a program to allow for 
data to be developed for a smooth transition from basic research to 
Phase III clinical trials that meet the policy requirements.

VI. Discussion--Issues in Scientific Plans and Study Designs

A. Issues in Research Involving Human Subjects

    The biomedical and behavioral research process can be viewed as a 
stepwise process progressing from discovery of new knowledge through 
research in the laboratory, research involving animals, research 
involving human subjects, validation of interventions through clinical 
trials, and broad application to improve the health of the public.
    All NIH-supported biomedical and behavioral research involving 
human subjects is defined broadly in this guidance as clinical 
research. This is broader than the definition provided in the 1990 NIH 
Guidance and in many program announcements, requests for applications, 
and requests for proposals since 1990.
    The definition was broadened because of the need to obtain data 
about minorities and both genders early in the research process when 
hypotheses are being formulated, baseline data are being collected, and 
various measurement instruments and intervention strategies are being 
developed. Broad inclusion at these early stages of research provides 
valuable information for designing broadly based clinical trials, which 
are a subset of studies under the broad category of research studies.
    The policy on inclusion of minorities and both genders applies to 
all NIH-supported biomedical and behavioral research involving human 
subjects so that the maximum information may be obtained to understand 
the implications of the research findings on the gender or minority 
group.
    Investigators should consider the types of information concerning 
gender and minority groups which will be required when designing future 
Phase III clinical trials, and try to obtain it in their earlier stages 
of research involving human subjects. NIH recognizes that the 
understanding of health problems and conditions of different U.S. 
populations may require attention to socioeconomic differences 
involving occupation, education, and income gradients.

B. Issues in Clinical Trials

    The statute requires appropriate representation of subjects of 
different gender and race/ethnicity in clinical trials so as to provide 
the opportunity for detecting major qualitative differences (if they 
exist) among gender and racial/ethnic subgroups and to identify more 
subtle differences that might, if warranted, be explored in further 
specifically targeted studies. Other interpretations may not serve as 
well the health needs of women, minorities, and all other 
constituencies.
    Preparatory to any Phase III clinical trial, certain data are 
typically obtained. Such data are necessary for the design of an 
appropriate Phase III trial and include observational clinical study 
data, basic laboratory (i.e. in vitro and animal) data, and clinical, 
physiologic, pharmacokinetic, or biochemical data from Phase I and 
Phase II studies. Genetic studies, behavioral studies, and 
observational, natural history, and epidemiological studies may also 
contribute data.
    It is essential that data be reviewed from prior studies on a 
diverse population, that is, in subjects of both genders and from 
different racial/ethnic groups. These data must be examined to 
determine if there are significant differences of clinical or public 
health importance observed between the subgroups.
    While data from prior studies relating to possible differences 
among intervention effects in different subgroups must be reviewed, 
evidence of this nature is likely to be less convincing than that 
deriving from the subgroup analyses that can be performed in usual-
sized Phase III trials. This is because the evidence from preliminary 
studies is likely to be of a more indirect nature (e.g. based on 
surrogate endpoints), deriving from uncontrolled studies (e.g. non-
randomized Phase II trials), and based on smaller numbers of subjects 
than in Phase III secondary analyses. For this reason, it is likely 
that data from preliminary studies will, in the majority of cases, 
neither clearly reveal significant differences of clinical or public 
health importance between subgroups of patients, nor strongly negate 
them.
    In these cases, Phase III trials should still have appropriate 
gender and racial/ethnic representation, but they would not need to 
have the large sample sizes necessary to provide a high statistical 
power for detecting differences in intervention effects among 
subgroups. Nevertheless, analyses of subgroup effects must be conducted 
and comparisons between the subgroups must be made. Depending on the 
results of these analyses, the results of other relevant research, and 
the results of meta-analyses of clinical trials, one might initiate 
subsequent trials to examine more fully these subgroup differences.

C. Issues Concerning Appropriate Gender Representation

    The ``population at risk'' may refer to only one gender where the 
disease, disorders, or conditions are gender specific. In all other 
cases, there should be approximately equal numbers of both sexes in 
studies of populations or sub-populations at risk, unless different 
proportions are appropriate because of the known prevalance, incidence, 
morbidity, mortality rates, or expected intervention effect.

D. Issues Concerning Appropriate Representation of Minority Groups and 
Subpopulations in All Research Involving Human Subjects Including Phase 
III Clinical Trials

    While the inclusion of minority subpopulations in research is a 
complex and challenging issue, it nonetheless provides the opportunity 
for researchers to collect data on subpopulations where knowledge gaps 
exist. Researchers must consider the inclusion of subpopulations in all 
stages of research design. In meeting this objective, they should be 
aware of concurrent research that addresses specific subpopulations, 
and consider potential collaborations which may result in complementary 
subpopulation data.
    At the present time, there are gaps in baseline and other types of 
data necessary for research involving certain minority groups and/or 
subpopulations of minority groups. In these areas, it would be 
appropriate for researchers to obtain such data, including baseline 
data, by studying a single minority group.
    It would also be appropriate for researchers to test survey 
instruments, recruitment procedures, and other methodologies used in 
the majority or other population(s) with the objective of assessing 
their feasibility, applicability, and cultural competence/relevance to 
a particular minority group or subpopulation. This testing may provide 
data on the validity of the methodologies across groups. Likewise, if 
an intervention has been tried in the majority population and not in 
certain minority groups, it would be appropriate to assess the 
intervention effect on a single minority group and compare the effect 
to that obtained in the majority population. These types of studies 
will advance scientific research and assist in closing knowledge gaps.
    A complex issue arises over how broad or narrow the division into 
different subgroups should be, given the purpose of the research. 
Division into many racial/ethnic subgroups is tempting in view of the 
cultural and biological differences that exist among these groups and 
the possibility that some of these differences may in fact impact in 
some way upon the scientific question. Alternatively, from a practical 
perspective, a limit has to be placed on the number of such subgroups 
that can realistically be studied in detail for each intervention that 
is researched. The investigator should clearly address the rationale 
for inclusion or exclusion of subgroups in terms of the purpose of the 
research. Emphasis should be placed upon inclusion of subpopulations in 
which the disease manifests itself or the intervention operates in an 
appreciable different way. Investigators should report the 
subpopulations included in the study.
    An important issue is the appropriate representation of minority 
groups in research, especially in geographical locations which may have 
limited numbers of racial/ethnic population groups available for study. 
The investigator must address this issue in terms of the purpose of the 
research, and other factors, such as the size of the study, relevant 
characteristics of the disease, disorder or condition, and the 
feasibility of making a collaboration or consortium or other 
arrangements to include minority groups. A justification is required if 
there is limited representation. Peer reviewers and NIH staff will 
consider the justification in their evaluations of the project.
    NIH interprets the statute in a manner that leads to feasible and 
real improvements in the representatives of different racial/ethnic 
groups in research and places emphasis on research in those 
subpopulations that are disproportionately affected by certain diseases 
or disorders.

VII. NIH Contacts for More Information

    The following senior extramural staff from the NIH Institutes and 
Centers may be contacted for further information about the policy and 
relevant Institute/Center programs:

Dr. Marvin Kalt, National Cancer Institute, 6130 Executive Boulevard, 
Executive Plaza North, room 600A, Bethesda, Maryland 20892, Tel: (301) 
496-5147.
Dr. Richard Mowery, National Eye Institute, 6120 Executive Boulevard, 
Executive Plaza South, room 350, Rockville, Maryland 20892, Tel: (301) 
496-5301.
Dr. Lawrence Friedman, National Heart, Lung and Blood Institute, 7550 
Wisconsin Avenue, Federal Building, room 212, Bethesda, Maryland 20892, 
Tel: (301) 496-2533.
Dr. Miriam Kelty, National Institute on Aging, 7201 Wisconsin Avenue, 
Gateway Building, room 2C218, Bethesda, Maryland 20892, Tel: (301) 496-
9322.
Dr. Cherry Lowman, National Institute on Alcohol Abuse and Alcoholism, 
6000 Executive Boulevard, Rockville, Maryland 20892, Tel: (301) 443-
0796.
Dr. George Counts, National Institute of Allergy and Infectious 
Diseases, 6003 Executive Boulevard, Solar Building, room 207P, 
Bethesda, Maryland 20892, Tel: (301) 496-8214.
Dr. Michael Lockshin, National Institute of Arthritis and 
Musculoskeletal and Skin Diseases, 9000 Rockville Pike, Building 31, 
room 4C32, Bethesda, Maryland 20892, Tel: (301) 496-0802.
Ms. Hildegard Topper, Bethesda, National Institute of Child Health and 
Human Development, 9000 Rockville Pike, Building 31, room 2A-03, 
Bethesda, Maryland 20892, Tel: (301) 496-0104.
Dr. Earleen Elkins, National Institute of Deafness and Other 
Communication Disorders, 6120 Executive Boulevard, Executive Plaza 
South, room 400, Rockville, Maryland 20892, Tel: (301) 496-8683.
Dr. Norman S. Braveman, National Institute on Dental Research, 5333 
Westbard Avenue, Westwood Building, room 509, Bethesda, Maryland 20892, 
Tel: (301) 594-7648.
Dr. Walter Stolz, National Institute of Diabetes and Digestive and 
Kidney Diseases, 5333 Westbard Avenue, Westwood Building, room 657, 
Bethesda, Maryland 20892, Tel: (301) 594-7527.
Ms. Eleanor Friedenberg, National Institute on Drug Abuse, 5600 Fishers 
Lane, Parklawn Building, room 10-42, Rockville, Maryland 20857, Tel: 
(301) 434-2755.
Dr. Gwen Collman, National Institute of Environmental Health Sciences, 
P.O. Box 12233, Research Triangle Park, North Carolina 27709, Tel: 
(919) 541-4980.
Dr. Lee Van Lenten, National Institute of General Medical Sciences, 
5333 Westbard Avenue, Westwood Building, room 905, Bethesda, Maryland 
20892, Tel: (301) 594-7744.
Dr. Dolores Parron, National Institute of Mental Health, 5600 Fishers 
Lane, Parklawn Building, room 17C-14, Rockville, Maryland 20857, Tel: 
(301) 443-2847.
Dr. Constance Atwell, National Institute of Neurological Disorders and 
Stroke, 7550 Wisconsin Ave., Federal Building, room 1016, Bethesda, 
Maryland 20892, Tel: (301) 496-9248.
Dr. Mark Guyer, National Center for Human Genome Research, 9000 
Rockville Pike, Building 38A, room 605, Bethesda, Maryland 20892, Tel: 
(301) 496-0844.
Dr. Teresa Radebaugh, National Center for Nursing Research, 5333 
Westbard Avenue, Westwood Building, room 754, Bethesda, Maryland 20892, 
Tel: (301) 594-7590.
Dr. Harriet Gordon, National Center for Research Resources, 5333 
Westbard Avenue, Westwood Building, room 10A03, Bethesda, Maryland 
20892, Tel: (301) 594-7945.
Dr. David Wolff, Fogarty International Center, 9000 Rockville Pike, 
Building 31, room B2C39, Bethesda, Maryland 20892, Tel: (301) 496-1653.

    Dated: March 3, 1994.
Harold Varmus,
Director, NIH.
[FR Doc. 94-5435 Filed 3-8-94; 8:45 am]
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