Please see updated Guidelines at:
    http://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 http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm

In March, 1994, NIH issued a policy on the inclusion of women and minorities as subjects in clinical research (http://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).

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:

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.

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.

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.

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.