NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research

Summary

This notice updates the NIH policy on the inclusion of women and minorities as subjects in clinical research. It supercedes the 1994 Federal Register notice (/grants/guide/notice-files/not94-100.html) and the August 2000 notice in the NIH Guide to Grants and Contracts (/grants/guide/notice-files/NOT-OD-00-048.html). It incorporates the definition of clinical research as reported in the 1997 Report of the NIH Director's Panel on Clinical research. Also, this notice provides additional guidance on reporting analyses of sex/gender and racial/ethnic differences in intervention effects for NIH-defined Phase III clinical trials. The guidelines ensure that all NIH-funded clinical research will be carried out in a manner sufficient to elicit information about individuals of both sexes/genders and diverse racial and ethnic groups and, particularly in NIH-defined Phase III clinical trials, to examine differential effects on such groups. Since a primary aim of research is to provide scientific evidence leading to a change in health policy or 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.

In June 2001, NIH adopted the definition of clinical research as: (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. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, and (d) development of new technologies; (2) Epidemiologic and behavioral studies; and (3) Outcomes research and health services research http://www.nih.gov/news/crp/97report/execsum.htm.

I. Legislative 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 minorities in clinical research.
The statute states that:

The statute defines "clinical research" to include "clinical trials" and states that:

Specifically addressing the issue of minority groups, the statute states that:

The statute speaks specifically to outreach and states that:

The statute includes a specific provision pertaining to the cost of clinical research and, in particular clinical trials.

Exceptions to the requirement for inclusion of women and minorities are stated in the statute, as follows:

II. Policy

A. Inclusion of Women and Minorities as Subjects in Clinical Research

It is the policy of NIH that women and members of minority groups and their subpopulations 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 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. This policy applies to research subjects of all ages in all NIH-supported clinical research studies.

The inclusion of women and members of minority groups and their subpopulations must be addressed in developing a research design or contract proposal appropriate to the scientific objectives of the study/contract. The research plan/proposal 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/proposal should contain a description of the proposed outreach programs for recruiting women and minorities as participants.

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

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

Investigators must consider the following when planning, conducting, analyzing, 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 based on sex/gender, racial/ethnic, and relevant subpopulation comparisons, the primary question(s) to be addressed by the proposed NIH-defined 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 (for grant applications) or Proposal (for contract solicitations) must include a description of plans to conduct analyses to detect significant differences in intervention effect (see DEFINITIONS - Significant Difference) by sex/gender, racial/ethnic groups, and relevant subpopulations, 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 subject accrual and progress in conducting analyses for sex/gender and race/ethnicity differences. If final analyses of sex/gender and race/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 deliverables. These requirements will be cited in the terms and conditions of all awards for grants, cooperative agreements and contracts supporting NIH-defined Phase III clinical trials.

Inclusion of the results of sex/gender, race/ethnicity and relevant subpopulations 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 based on sex/gender, racial/ethnic and/or relevant subpopulation comparisons, then sex/gender and 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 based on sex/gender, racial/ethnic, and relevant subpopulation comparisons, then the NIH-defined Phase III clinical trial will be required to include sufficient and appropriate entry of sex/gender and racial/ethnic 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 (see DEFINITIONS - Valid Analysis) by sex/gender, racial/ethnic groups, and relevant subpopulations, 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 subject accrual and progress in conducting analyses for sex/gender and race/ethnicity differences. If final analyses of sex/gender and race/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 deliverables. These requirements will be cited in the terms and conditions of all awards for grants, cooperative agreements and contracts supporting NIH-defined Phase III clinical trials.

Inclusion of the results of sex/gender, race/ethnicity and relevant subpopulations 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 minorities from clinical trials.

III. Roles and Responsibilities

While this 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/gender, race/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 minorities and their subpopulations 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 policy on inclusion of women and minority groups in research is the same as that for research conducted 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.

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 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) should take precautionary measures to ensure that ethical issues are considered, 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.

To assist investigators and potential study participants, NIH staff have prepared educational materials, including a notebook titled the, "NIH Outreach Notebook On the Inclusion of Women and Minorities in Biomedical and Behavioral Research." The notebook as well as the Frequently Asked Questions document, are located at the following URL: /grants/funding/women_min/women_min.htm

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", http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html they must also attend to the guidelines for the inclusion of women and minorities and their subpopulations in clinical research. 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 http://www.fda.gov/cder/guidance/old036fn.pdf.

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 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 valid analysis for NIH-defined Phase III 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.

The review instructions for grants are available on line at the following URL: /grants/peer/hs_review_inst.pdf

For contracts, the contracting officer will provide instructions for contract reviewers. Further information on instructions for contracts may be obtained at the following URL: http://oa.od.nih.gov/oamp/index.html.

Or contact:
National Institutes of Health
Division of Acquisition Policy and Evaluation
Office of Acquisition Management and Policy
6100 Executive Boulevard, Room 6C01
Phone: 301-496-6014
Fax: 301- 402-1199

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 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.

6. Institute/Center Directors
Institute/Center 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 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.

IV. 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 Research
Clinical research is defined as:

(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. Patient-oriented research includes: (a) mechanisms of human disease, (b) therapeutic interventions, (c) clinical trials, and (d) development of new technologies, (2) Epidemiologic and behavioral studies, (3) Outcomes research and health services research.
http://www.nih.gov/news/crp/97report/execsum.htm

B. 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.

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 sexes/genders (males and females) and 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 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.

E. Racial and Ethnic Categories 
1. Minority Groups

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) Directive No. 15 http://www.whitehouse.gov/omb/fedreg/ombdir15.html 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. Using respondent self-report or self-identification to collect an individual's data on ethnicity and race, investigators should use two separate questions with ethnicity information collected first followed by the option to select more than one racial designation. Respondents shall be offered the opportunity to select more than one racial designation. When data are collected separately, provision shall be made to report the number of respondents in each racial category who are Hispanic or Latino.

The following definitions apply for ethnic categories.

Hispanic or Latino - a person of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture or origin, regardless of race. The term "Spanish origin" can also be used in addition to "Hispanic or Latino."

Not Hispanic or Latino
The following definitions apply for racial categories.

American Indian or Alaska Native - a person having origins in any of the original peoples of North, Central, or South America, and who maintains tribal affiliations or community attachment.

Asian - a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific Islanders in previous data collection strategies.)

Black or African American - a person having origins in any of the black racial groups of Africa. Terms such as "Haitian" or "Negro" can be used in addition to "Black or African American."

Native Hawaiian or Other Pacific Islander - a person having origins in any of the original peoples of Hawaii, Guam, Samoa, or other Pacific Islands.

2. Majority Group

White - a person having origins in any of the original peoples of Europe, the Middle East, or North Africa.

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 racial and ethnic group contains subpopulations 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 ethnic subpopulation data. The subpopulation to which an individual is assigned depends on self-reporting of specific origins and/or cultural heritage. Attention to subpopulations also applies to individuals who self identify with more than one race or ethnicity. Researchers should be cognizant of the possibility that these racial/ethnic combinations may have biomedical, behavioral, and/or social-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.

V. 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. Paulette Gray
National Cancer Institute
6116 Executive Boulevard, Suite 8001
Bethesda, MD 20892-8327
Telephone: (301) 496-5147
Email: [email protected]

Dr. Lore Anne McNicol
National Eye Institute
Executive Plaza South
6120 Executive Boulevard, Room 350
Rockville, MD 20892
Telephone: (301) 496-5301
Email: [email protected]

Ms. Sharry Palagi
National Heart, Lung and Blood Institute
Building 31
31 Center Drive, Room 5A-07
Bethesda, MD 20892
Telephone: (301) 402-3424
Email: [email protected]

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

Dr. Eleanor Hanna
National Institute on Alcohol Abuse and Alcoholism
Willco Building
6000 Executive Boulevard, Suite 514
Rockville, MD 20892
Telephone: (301) 594-6231
Email: [email protected]

Dr. John McGowan
National Institute of Allergy and Infectious Diseases
6700 B Rockledge
6700 Rockledge Drive
Bethesda, MD 20817
Telephone: (301) 496-7291
Email: [email protected]

Dr. Julia Freeman
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building
Building 45, Room 5AS19F
Bethesda, MD 20892
Telephone: (301) 594-4543
Email: [email protected]

Dr. Susan Streufert
National Institute of Child Health and Human Development
6100 Executive Boulevard
Building 61EB, Room 4A05
Bethesda, MD 20892
Telephone: (301) 435-6856
Email: [email protected]

Dr. Julie Gulya
National Institute on Deafness and Other Communication Disorders
Executive Plaza South
6120 Executive Boulevard, Room 400D-7
Rockville, MD 20892
Telephone: (301) 435-4085
Email: [email protected]

Dr. Norman S. Braveman
National Institute on Dental and Craniofacial Research
Natcher Building
Building 45, Room 4AN24C
Bethesda, MD 20892
Telephone: (301) 594-2089
Email: [email protected]

Dr. Robert Hammond
National Institute of Diabetes and Digestive and Kidney Diseases
2 Democracy Boulevard, Room 715
Bethesda, MD 20892
Telephone: (301) 594-8834
Email: [email protected]

Dr. Teresa Levitin
National Institute on Drug Abuse
Neuroscience Building
6001 Executive Boulevard, Room 3158
Bethesda, MD 20852
Telephone: (301) 443-2755
Email: [email protected]

Dr. Anne P. Sassaman
National Institute of Environmental Health Sciences
P.O. Box 12233, MD EC-30
Research Triangle Park, NC 27709
Telephone: (919) 541-7723
Email: [email protected]

Mr. Gary Marlowe
National Institute of General Medical Sciences
Natcher Building
Building 45, Room 2AN12L
Bethesda, MD 20892
Telephone: (301) 594-5143
Email: [email protected]

Dr. Richard Nakamura
National Institute of Mental Health
Neuroscience Building
6001 Executive Boulevard, Room 8235
Bethesda, MD 20852
Telephone: (301) 443-3675
Email: [email protected]

Ms. Lynn Morin
National Institute of Neurological Disorders and Stroke
Neuroscience Building
6001 Executive Boulevard, Room 2152
Bethesda, MD 20892
Telephone: (301) 496-3102
Email: [email protected]

Dr. Mark Guyer
National Human Genome Research Institute
Building 31
31 Center Drive, Room B2B07
Bethesda, MD 20892
Telephone: (301) 496-7531
Email: [email protected]

Dr. Carole Hudgings
National Institute of Nursing Research
Natcher Building
45 Center Drive, Room 3AN-12
Bethesda, MD 20892
Telephone: (301) 594-5976
Email: [email protected]

Dr. Christine Goertz
National Center for Complementary and Alternative Medicine
Building 31
31 Center Drive, Room 5B-58
Telephone: (301) 402-1030
Email: [email protected]

Dr. Geoffrey Cheung
National Center for Research Resources
Rockledge Centre I
6705 Rockledge Dr, Rm 6118
Bethesda, MD 20817
Telephone: (301) 435-0768
Email: [email protected]

Dr. Kenneth Bridbord
Fogarty International Center
Building 31
31 Center Drive, Room B2C39
Bethesda, MD 20892
Telephone: (301) 496-2516
Email: [email protected]

Dr. Joan T. Harmon
National Institute of Biomedical Imaging and Bioengineering
Room 697
6707 Democracy Boulevard
Bethesda, MD 20892
Telephone: (301) 594-8813
Email: [email protected]

Dr. Eric Bailey
National Center for Minority Health and Health Disparities
2 Democracy Boulevard, Suite 800
Bethesda, MD 20817
Telephone: (301) 402-1366
Email: [email protected]