Key Dates

Related Announcements

• June 6, 2024 - New eRA Human Subjects System Capabilities for Awarded NIH R&D Contract Vendors to Directly Enter Inclusion Data. See Notice NOT-OD-24-128.
• October 29, 2021 - Guidance electronic Research Administration (eRA) Research Performance Progress Report (RPPR) Submission Validations for Clinical Trial Registration and Results Reporting. See Notice NOT-OD-22-008.
• November 28, 2017 - Amendment: NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. See Notice NOT-OD-18-014.
• September 16, 2016 - NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information. See Notice NOT-OD-16-149.
•  October 9, 2001 - Amendment: NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research. See Notice NOT-OD-02-001.
• August 8, 2001 - NIH Policy on Reporting Race and Ethnicity Data: Subjects in Clinical Research. See Notice NOT-OD-01-053.
   

Issued by

NATIONAL INSTITUTES OF HEALTH (NIH)

Purpose

The purpose of this Notice is to inform the research community that NIH is revising the NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research to align with Executive Order 14168 “Defending Women from Gender Ideology Extremism and Restoring Biological Truth to the Federal Government.” Revisions are primarily focused on promulgating the use of “sex” instead of “sex/gender” and updating race and/or ethnicity information to align with Office of Management and Budget’s Statistical Policy Directive No. 15: Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity. The revised Policy is now titled, "NIH Policy and Guidelines on the Inclusion of Women and Members of Racial and/or Ethnic Minority Groups in Clinical Research."

Effective date

The Policy and Guidelines on the Inclusion of Women and Members of Racial and/or Ethnic Minority Groups in Clinical Research will apply to all grants, cooperative agreements, contracts, other transactions, and intramural studies 30 days after publication of this notice. The revised Policy is effective 30 days after the date of publication of this notice, at which time it will replace NOT-OD-18-014 and NOT-OD-02-001.

Background

The NIH Revitalization Act of 1993, PL 103-43, signed into law on June 10, 1993, directed the NIH to establish guidelines for inclusion of women and racial and/or ethnic minorities in clinical research.

 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 directed the NIH to establish guidelines to specify:
(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 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 racial and/or ethnic 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)

Exceptions to the requirement for inclusion of women and racial and/or ethnic minority groups 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)

The statute also requires reports of Institute or Center Advisory Councils, the required frequency of which was updated from biennial to triennial in the 21st Century Cures Act, enacted December 13, 2016:

The advisory council of each national research institute shall prepare triennial reports describing the manner in which the institute has complied with this section. 492B(f)

In 2004, NIH updated its peer review regulations [42 CFR 52h.8(f)] to reflect current statutes and NIH policies regarding inclusion (69 FR 275). The regulation specifies that scientific review groups must take into account, "The adequacy of plans to include both genders, minorities, children and special populations as appropriate for the scientific goals of the research." While, over time, the terms sex and gender have often been used interchangeably in the scientific literature, to ensure clarity moving forward and in alignment with EO 14168, NIH interprets the word "gender" to mean "sex" in the context of the regulation, unless otherwise specified.

Revised NIH Policy and Guidelines for Inclusion of Women and Members of Racial and/or Ethnic Minority Groups in Clinical Research (NIH Inclusion Policy)

A. Inclusion of Women and Members of Racial and/or Ethnic Minority Groups in Clinical Research

Through this Policy (herein referred to as the NIH Inclusion Policy), NIH sets the expectation that women and members of racial and/or ethnic minority groups and their subgroups must be included in all NIH-funded clinical research, unless a clear and compelling rationale and justification establishes to the satisfaction of the relevant Institute/Center/Office Director that inclusion is inappropriate with respect to the health of the participants[1] or the purpose of the research. Exclusion under other circumstances may be made by the Director, NIH, upon the recommendation of an Institute/Center/Office 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. This policy applies to research participants of all ages in all NIH-supported clinical research studies.

The inclusion of women and members of racial and/or ethnic minority groups and their subgroups must be addressed in developing a research design or contract proposal appropriate to the scientific objectives of the study. The research plan/proposal should describe the composition of the proposed study population in terms of sex and race and/or ethnicity groups, and provide a rationale for selection of such participants. Such a plan/proposal should contain a description of the proposed outreach programs for recruiting women and members of racial and/or ethnic minority groups as participants.

B. NIH-defined Phase 3 Clinical Trials: Planning, Conducting, and Reporting of Analyses for Sex and Race and/or Ethnicity Differences

When an NIH-defined Phase 3 clinical trial is proposed, evidence must be reviewed to show whether or not clinically important sex, race, and/or 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.

Investigators must consider the following when planning, conducting, analyzing, and reporting an NIH-Defined Phase 3 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 based on sex, racial and/or ethnic, and relevant subgroup comparisons, the primary question(s) to be addressed by the proposed NIH-defined Phase 3 clinical trial and the design of that trial must specifically accommodate this. For example, if males and females are thought to respond differently to an intervention, then the Phase 3 clinical trial must be designed to answer two separate primary questions, one for males and the other for females, with adequate sample size for each.

The Research Plan (for grant applications) or Proposal (for contract solicitations) must include a description of plans to conduct analyses to detect significant differences in intervention effect by sex, race and/or ethnicity, and relevant subgroups, if applicable. The final protocol(s) approved by the Institutional Review Board (IRB) must include these plans for analysis. The award will require that for each funded protocol, investigators must report in their annual Progress Report cumulative participant accrual and progress in conducting analyses for sex and race and/or ethnicity differences. If final analyses of sex and race and/or ethnicity are not available at the time of the Final Progress Report or Competing Continuation for the grant, a justification and plan ensuring completion and reporting of the analyses are required. If final analyses are required as part of the contract, these analyses must be included as part of the contract deliverables. These requirements will be cited in the terms and conditions of all awards for grants, cooperative agreements and contracts supporting NIH-defined Phase 3 clinical trials.

Inclusion of the results of sex, race and/or ethnicity and relevant subgroup analyses is strongly encouraged in all publication submissions. If these analyses reveal no differences, a brief statement to that effect, indicating the groups and/or subgroups 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(s) based on sex, race, and/or ethnicity and/or relevant subgroup comparisons, then sex and race and/or ethnicity will not be required as participant selection criteria. However, the inclusion and analysis of sex and/or racial or 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 based on sex, race and/or ethnicity, and relevant subgroup comparisons, then the NIH-defined Phase 3 clinical trial will be required to include sufficient and appropriate entry of women and racial and/or ethnic minority participants, so that valid analysis of the intervention effects can be performed. However, the trial will not be required to provide high statistical power for these comparisons.

The Research Plan (for grant applications) or Proposal (for contract solicitations) must include a description of plans to conduct valid analysis by sex, racial and/or ethnicity, and relevant subgroups, if applicable. The final protocol(s) approved by the Institutional Review Board (IRB) must include these plans for analysis. The award will require that for each funded protocol, investigators must report in their annual Progress Report cumulative participant accrual and progress in conducting analyses for sex and race and/or ethnic differences. If final analyses of sex and race and/or ethnicity are not available at the time of the Final Progress Report or Competing Continuation for the grant, a justification and plan ensuring completion and reporting of the analyses are required. If final analyses are required as part of the contract, these analyses must be included as part of the contract deliverables. These requirements will be cited in the terms and conditions of all awards for grants, cooperative agreements and contracts supporting NIH-defined Phase 3 clinical trials.

Inclusion of the results of sex, race and/or ethnic and relevant subgroup analyses is strongly encouraged in all publication submissions. If these analyses reveal no differences, a brief statement to that effect, indicating the groups and/or subgroups analyzed, will suffice.

For all three situations, cost is not an acceptable reason for exclusion of women and members of racial and/or ethnic minority populations from clinical trials.

C. Guidelines for Reporting Results of Valid Analyses in ClinicalTrials.gov

When registering in Clincialtrials.gov, NIH-defined Phase 3 applicable clinical trials must specify outcomes on sex and race and/or ethnic group(s). For NIH-defined Phase 3 applicable clinical trials, submissions of results to ClinicalTrials.gov must include results of valid analyses by sex and race and/or ethnicity, as required based on prior evidence.

The NIH Inclusion Policy is complementary to requirements outlined in the Clinical Trial Registration and Results Information Submission regulation at 42 CFR Part 11 and the accompanying NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information (NOT-OD-16-149). Applicable clinical trials are required to be registered in ClinicalTrials.gov not later than 21 calendar days after the enrollment of the first participant. Results information generally must be submitted no later than one year after the primary completion date, unless a certification of delay was submitted, a request for an extension for good cause was granted, or a request for a waiver of the requirements for submission of results information was granted.

Roles and Responsibilities

While the NIH Inclusion Policy applies to all applicants/offerors for NIH-supported clinical research, certain individuals and groups have special roles and responsibilities with regard to its implementation.

1. NIH Staff
The NIH staff provide educational opportunities for the extramural and intramural communities concerning this policy; monitor its implementation during the development, review, award and conduct of research; and manage the NIH research portfolio to comply with the policy.

2. Principal Investigators
Principal investigators should assess the theoretical and/or scientific linkages between sex, race and/or ethnicity, and their topic of study. Following this assessment, the principal investigator and the applicant/offeror institution will address the policy in each application and proposal, providing the required information on inclusion of women and racial and/or ethnic minority populations and their subgroups in clinical research projects, and any required justifications for exceptions to the policy.

For foreign awards and domestic awards with a foreign component, the NIH Inclusion Policy remains in effect. If there is scientific rationale for examining subgroup differences within the foreign population, investigators should consider designing their studies to accommodate these differences.

Investigators and their staff(s) are urged to develop appropriate and culturally sensitive outreach programs and activities commensurate with the goals of the study or objectives of the contract. The objective should be to actively recruit and retain the most appropriate and comprehensive 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) should take precautionary measures to ensure that ethical issues are considered, such that there is minimal possibility of coercion or undue influence on the incentives or rewards offered in recruiting into or retaining participants in studies.

3. Institutional Review Boards (IRBs)
It is the responsibility of the IRBs to address the ethical issues as outlined in Section IV(2) for Principal Investigators. As the IRBs implement the regulation for the protection of human subjects as described in Title 45 CFR Part 46, "Protection of Human Subjects", https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46 they must also attend to the guidelines for the inclusion of women and members of racial and ethnic minority populations and their subgroups in clinical research. 

 
4. 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 are instructed, as follows:

• to evaluate the proposed plan for the inclusion of women and members of racial and/or ethnic minority populations for appropriate representation or to evaluate the proposed justification when representation is limited or absent,
• to evaluate the proposed exclusion of members of racial and/or ethnic minority populations and women on the basis that a requirement for inclusion is inappropriate with respect to the health of the participants,
• to evaluate the proposed exclusion of members of racial and/or ethnic minority populations 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 valid analysis for NIH-defined Phase 3 clinical trials,
• to evaluate the plans for recruitment/outreach for study participants, and to include these criteria as part of the scientific assessment and evaluation

For contracts, the Scientific Review Officer or contracting officer will provide instructions for contract reviewers. 

5. NIH Advisory Councils
In addition to other responsibilities for review of projects where the peer review groups have raised questions about the appropriate inclusion of women and racial and/or ethnic minority populations, the Advisory Council/Board of each Institute/Center/Office shall prepare triennial reports, for inclusion in the overall NIH Director's triennial report, describing the manner in which the Institute/Center has complied with the provisions of the statute.

6. Institute/Center/Office Directors
Institute/Center/Office Directors and their staff shall ensure compliance with the policy.

7. NIH Director

The NIH Director may approve, on a case-by-case basis, the exclusion of projects, as recommended by the Institute/Center/Office Director, that may be inappropriate to include within the requirements of these guidelines on the basis of circumstances other than the health of the participants, the purpose of the research, or costs.

Definitions

Throughout the section of the statute pertaining to the inclusion of women and racial and/or ethnic minority populations, 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 Research
Clinical research is defined as:

Research with human participants that is:

(1) Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. It includes: (a) mechanisms of human disease, (b), therapeutic interventions, (c) clinical trials, or (d) development of new technologies; or

(2) Epidemiological and behavioral studies; or

(3) Outcomes research and health services research

B. NIH-defined Clinical Trial

For the purpose of the NIH Inclusion Policy, an NIH-defined "clinical trial" is a broadly based prospective Phase 3 clinical investigation, usually involving several hundred or more human participants, 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.

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 participants. 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 sexes (males and females) and different racial or 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 sex and racial and/or 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

The Public Health Service Act section 492B(g)(2) requires the NIH Director define the terms "minority group" and "subpopulations" in reference to the requirements for inclusion described in that section.

 
1. Racial and/or Ethnic Minority Group

 A minority group is a readily identifiable subset of the U.S. population that is distinguished by racial, ethnic, and/or cultural heritage. The Office of Management and Budget (OMB) Statistical Policy Directive No. 15 defines minimum standards for maintaining, collecting and presenting data on race and ethnicity for all Federal reporting. NIH is required to use these definitions to allow comparisons to other federal databases, especially the census and national health databases. The categories in this classification are social-political constructs and should not be interpreted as anthropological in nature. When an investigator is planning data collection on race and ethnicity, these categories shall be used. The collection of greater detail is encouraged. However, more detailed items should be designed in a way that they can be aggregated into these required categories.

For the purposes of this policy, NIH considers racial and/or ethnic minority populations to include American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, Middle Eastern or North African, and Native Hawaiian or Pacific Islander. 

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 populations" and "minority subgroups" are meant to be inclusive, rather than exclusive, of these heterogeneous categories.

2. Subgroups (Subpopulations)
 

NIH defines "subpopulations" as subgroups of racial and/or ethnic populations that 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/or ethnic subgroup data. The subgroup to which an individual is assigned depends on self-reporting of specific origins and/or cultural heritage. Attention to subgroups also applies to individuals who self-identify with more than one race and/or ethnicity. Researchers should be cognizant of the possibility that these racial and/or ethnic combinations may have biomedical, behavioral, and/or social-cultural implications related to the scientific question(s) 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 the involvement of other individuals and organizations relevant to the populations and communities of interest, e.g., family, religious organizations, community leaders and members, 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. Applicable Clinical Trial

Applicable clinical trial is the term used in Title VIII of the Food and Drug Administration Amendments Act (FDAAA) of 2007 (P.L. 110-85) to designate the scope of clinical trials that may be subject to the registration and results reporting requirements in FDAAA. Clinical trials that are subject to the statute and its implementing regulation (42 CFR Part 11) are, in general, clinical trials of drug, biological, and device products regulated by the U.S. Food and Drug Administration (FDA). A pediatric post-market surveillance study of a device product required by the FDA is also subject to the statute and regulation.

[1] For the purposes of the NIH Policy and Guidelines on the Inclusion of Women and Members of Racial and/or Ethnic Minority Groups in Clinical Research, “participant” has the same definition as provided for “human subject” found at 45 CFR 46.102(e)(1).

Inquiries

Please direct all inquiries to:

Office of Policy for Extramural Research Administration (OPERA)
Division of Grants Policy
[email protected]