[Federal Register Volume 59, Number 59 (Monday, March 28, 1994)]
[Unknown Section]
[Page ]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-5435]
[Federal Register: March 28, 1994]
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Part VIII
Department of Health and Human Services
_______________________________________________________________________
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
Editorial Note: This document was originally published at 59 FR
11146, March 9, 1994, and is being reprinted in its entirety because
of typesetting errors.
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 review 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 affect 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 inclusion, 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 women 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 data from other sources. Women of childbearing potential
should not be routinely excluded from participation in clinical
research. All NIH-supported biomedical and behavioral 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 among 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 intramural 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 representativeness 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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