NIH Guideline on The Inclusion of Women and
NOTE: Additional information concerning the NIH Policy on Inclusion of Women and Minorities as Subjects in Clinical Research is available at http://grants.nih.gov/grants/funding/women_min/women_min.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).
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).
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 guidelines with the noted changes in bold type:
NIH GUIDELINES ON THE INCLUSION OF WOMEN AND MINORITIES AS SUBJECTS IN CLINICAL RESEARCH
NIH GUIDE, Volume 23, Number 11, March 18, 1994
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
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:
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.
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;
B. members of minority groups are included in such research.
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)
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.
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.
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:
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.
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:
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.
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
Ms. Sharry Palagi