Please see updated Guidelines at:
   
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html

NIH GUIDELINES ON THE INCLUSION OF WOMEN AND MINORITIES AS SUBJECTS IN CLINICAL 
RESEARCH - UPDATED AUGUST 2, 2000.

Release Date:  August 2, 2000

NOTICE:  OD-00-048

National Institutes of Health

NOTE: A complete copy of the updated Guidelines is available at
https://grants.nih.gov/grants/funding/women_min/guidelines_update.htm 

INTRODUCTION

In March, 1994, NIH issued a policy on the inclusion of women and minorities 
as subjects in clinical research 
(https://grants.nih.gov/grants/guide/notice-files/not94-100.html).  
NIH experience has indicated that inclusion has been accomplished, but that 
results of planned analyses of NIH defined Phase III clinical trials need to be 
more consistently reported.  This document updates and provides further guidance 
on planning, conducting, and reporting the analysis of sex/gender and/or 
race/ethnicity differences in the intervention effect in NIH Phase III clinical 
trials (see Definitions, Section V-A below).  

The following reference published since the 1994 Guidelines provides 
additional background information.  "Inclusion of Women and Minorities in 
Clinical Trials and the NIH Revitalization Act of 1993 - The Perspective of NIH 
Clinical Trialists." Freedman, et.al., Controlled Clinical Trials, 16:277 
(1995).

Effective Date:

This policy update is effective immediately for active grants, cooperative 
agreements and contracts.  Beginning with the October, 2000 receipt date, grant, 
cooperative agreement and contract submissions must adhere to the updated policy.

The following is a restatement of the policy and definitions from the 
guidelines with the noted changes in bold type: 

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 sex/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.  NIH Phase III Clinical Trials

Under the statute, when an NIH defined Phase III clinical trial (see 
Definitions, Section V-A) is proposed, evidence must be reviewed to show whether 
or not clinically important sex/gender and/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.

Section III.B. of these Guidelines (NIH Phase III Clinical Trials Policy) 
will be cited in the terms and conditions of all awards for grants, cooperative 
agreements and contracts supporting NIH Phase III clinical trials.

Cost is not an acceptable reason for exclusion of women and minorities from 
clinical trials.

Investigators must consider the following when planning, conducting, and 
reporting an NIH Defined Phase III clinical trial. Based on prior 
studies, one of the three situations below will apply:

1. Prior Studies Support the Existence of Significant Differences

If the data from prior studies strongly support the existence of 
significant differences of clinical or public health importance in intervention 
effect among subgroups (sex/gender and/or racial/ethnic subgroups), the 
primary question(s) to be addressed by the proposed NIH Phase III 
clinical 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 clinical trial must be designed to 
answer two separate primary questions, one for men and the other for women, with 
adequate sample size for each.

The Research Plan in the application or proposal must include a description 
of plans to conduct analyses to detect significant differences in intervention 
effect.  The final protocol approved by the Institutional Review Board (IRB) 
must include these plans for analysis.  The award will require that the results 
of subset analyses must be reported to NIH in Progress Reports, Competitive 
Renewal Applications (or Contract Renewals/Extensions), and in the required 
Final Progress Report.  

Inclusion of the results of subset analyses is strongly encouraged in all 
publication submissions. If the analysis reveals no subset differences, a brief 
statement to that effect, indicating the subsets analyzed, will suffice. 

2. Prior Studies Support No Significant Differences
If the data from prior studies strongly support no significant 
differences of clinical or public health importance in intervention effect 
between subgroups, then sex/gender and/or race/ethnicity will not 
be required as subject selection criteria.  However, the inclusion and 
analysis of sex/gender and/or racial/ethnic subgroups is still 
strongly encouraged.

3. Prior Studies Neither Support nor Negate Significant Differences 
If the data from prior studies neither strongly support nor strongly negate 
the existence of significant differences of clinical or public health importance 
in intervention effect between subgroups, then the NIH Phase III 
clinical trial will be required to include sufficient and appropriate 
entry of sex/gender and/or 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.

The Research Plan in the application or proposal must include a description 
of plans to conduct the valid analyses of the intervention effect in subgroups.  
The final protocol approved by the IRB must include these plans for analysis. 
The award will require that the results of subset analyses must be reported to 
NIH in Progress Reports, Competitive Renewal Applications 
(or Contract Renewals/Extensions), and in the required Final Progress Report.

Inclusion of the results of subset analyses is strongly encouraged in all 
publication submissions. If the analysis reveals no subset differences, a brief 
statement to that effect, indicating the subsets analyzed, will suffice.

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.  NIH Defined Clinical Trial

For the purpose of these guidelines, an NIH defined "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 sexes/genders (males and 
females) and 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 sex/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.


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