Please see updated Guidelines at:
  http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html

NIH GUIDELINES ON THE INCLUSION OF WOMEN AND MINORITIES AS SUBJECTS IN CLINICAL RESEARCH

NIH GUIDE, Volume 23, Number 11, March 18, 1994

P.T. 34

Keywords:
  Grants Administration/Policy+ 

National Institutes of Health

The following is a reprint of the Notice of the NIH Guidelines that
was published as a separate Part IV in the Federal Register of March
9, 1994 (59 FR 11146-11151).

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.

SUPPLEMENTAL 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
(PL) 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, Vol. 19, No. 31, August 24, 1990 and Vol. 19,
No. 35, September 28, 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:

o  ensure that women and members of minorities and their
subpopulations are included in all human subject research;

o  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;

o  not allow cost as an acceptable reason for excluding these groups;
and,

o  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...
define 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 on 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 the 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 an
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.

o  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.

o  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.

o  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 and 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:

o  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,

o  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,

o  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,

o  to determine whether the design of clinical trials is adequate to
measure differences when warranted,

o  to evaluate the plans for recruitment/outreach for study
participants, and

o  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.
Research involving the collection or study of existing data,
documents, records, pathological specimens, diagnostic specimens, or
tissues which are individually identifiable also is included within
the term "research involving human subjects."

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:

o  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,

o  unbiased evaluation of the outcome(s) of study participants, and

o  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 subpopulations at risk, unless different
proportions are appropriate because of the known prevalence,
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 appreciably 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
Executive Plaza North, Room 600A
6130 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-5147

Dr. Richard Mowery
National Eye Institute
Executive Plaza South, Room 350
6120 Executive Boulevard
Rockville, MD   20892
Telephone:  (301) 496-5301

Dr. Lawrence Friedman
National Heart, Lung and Blood Institute
Federal Building, Room 212
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-2533

Dr. Miriam Kelty
National Institute on Aging
Gateway Building, Room 2C218
7201 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-9322

Dr. Cherry Lowman
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard
Rockville, MD  20892
Tel: (301) 443-0796

Dr. George Counts
National Institute of Allergy and Infectious Diseases
Solar Building, Room 207P
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-8214

Dr. Michael Lockshin
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Building 31, Room 4C32
Bethesda, MD  20892
Telephone:  (301) 496-0802

Ms. Hildegard Topper
National Institute of Child Health and Human Development
Building 31, Room 2A03
Bethesda, MD  20892
Telephone:  (301) 496-0104

Dr. Earleen Elkins
National Institute on Deafness and Other Communication Disorders
Executive Plaza South, Room 400
6120 Executive Boulevard
Rockville, MD  20892
Telephone:  (301) 496-8683

Dr. Norman S. Braveman
National Institute on Dental Research
Westwood Building, Room 509
Bethesda, MD  20892
Telephone:  (301) 594-7648

Dr. Walter Stolz
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 657
Bethesda, MD  20892
Telephone:  (301) 594-7527

Ms. Eleanor Friedenberg
National Institute on Drug Abuse
Parklawn Building, Room 10-42
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-2755

Dr. Gwen Collman
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4980

Dr. Lee Van Lenten
National Institute of General Medical Sciences
Westwood Building, Room 905
Bethesda, MD  20892
Telephone:  (301) 594-7744

Dr. Dolores Parron
National Institute of Mental Health
Parklawn Building, Room 17C-14
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-2847

Dr. Constance Atwell
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1016
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-9248

Dr. Mark Guyer
National Center for Human Genome Research
Building 38A, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-0844

Dr. Teresa Radebaugh
National Center for Nursing Research
Westwood Building, Room 754
Bethesda, MD  20892
Telephone:  (301) 594-7590

Dr. Harriet Gordon
National Center for Research Resources
Westwood Building, Room 10A03
Bethesda, MD  20892
Telephone:  (301) 594-7945

Dr. David Wolff
Fogarty International Center
Building 31, Room B2C39
Bethesda, MD  20892
Telephone:  (301) 496-1653


Return to 1994 Index

Return to NIH Guide Main Index


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