NIH policy states that all NIH-funded clinical research must include women and members of minority groups and their subpopulations. The NIH Director may make an exception to this policy if the investigator offers a clear and compelling rationale and justification for not including them. The investigator must establish to the satisfaction of the relevant Institute or Center director that inclusion is inappropriate with respect to the subjects’ health or to the purpose of the research. Cost is not an acceptable reason for exclusion of women and minorities except when the study would duplicate data from other sources. Women of childbearing potential should not routinely be excluded from participating in clinical research. This policy applies to research subjects of all ages in all NIH-supported clinical research studies.
The ORWH Inclusion of Women and Minorities in Clinical Research web page includes an overview of NIH policy on inclusion and provides links to many useful resources. Information on implementing this policy is available on the Office of Extramural Research Grants & Funding website at the Inclusion of Women and Minorities as Participants in Research Involving Human Subjects—Policy Implementation Page.
When preparing applications or technical proposals, investigators conducting NIH-defined clinical research must describe their plans for inclusion, justify exclusions, and provide an enrollment form breaking down the planned sample by sex/gender, race, and ethnicity, as explained in G.500 Section 2.4 for applications after January 25, 2019 of the General Application Guide for NIH and Other PHS Agencies. In addition, investigators’ annual progress reports must include updates on enrollment progress.
Although this inclusion policy applies to all NIH-supported clinical research, the policy imposes certain extra requirements on Phase III clinical trials. When proposing a Phase III clinical trial, investigators must review their evidence to show whether they expect the intervention to produce clinically relevant differences based on sex/gender and race/ethnicity. 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.
When preparing applications or technical proposals for a Phase III clinical trial, investigators must also provide in their inclusion plans a description of their strategies for conducting a valid analysis by sex/gender and race/ethnicity, as explained in G.500 Section 2.4 for applications after January 25, 2019 of the General Application Guide for NIH and Other PHS Agencies. In addition, investigators’ annual progress reports must include updates on the progress of these analyses.
For example, prior research might suggest that men and women respond to an intervention in ways that measurably and differentially affect their health or well-being. In this case, the investigators must design the Phase III clinical trial to answer two primary questions—one pertaining to men and the other pertaining to women, with a sample size adequately powered for each. The application must include plans for how the investigators will evaluate any potential group differences. Further information about what constitutes a valid analysis and policy requirements is available in the full policy statement.
NIH does not require analyses by sex or gender if the prior data give compelling evidence that no clinically relevant differences can be expected in the intervention effects by sex or gender. Nonetheless, NIH strongly encourages inclusion of both women and men in the trial and analyses by sex or gender.
If prior studies neither support nor negate the possibility of significant differences in intervention effects by sex or gender, the Phase III clinical trial must enroll sufficient numbers of women and men to provide valid data analyses on the effects of the intervention by sex or gender. Although encouraged by NIH, the study’s investigators will not be required to enroll the number of participants necessary to provide high statistical power for these comparisons.
Inclusion across the Lifespan Policy under 21stCCAct & Common Rule 2017 Amendment
Section 2038(H) of the 21st Century Cures Act (21stCCAct) requires NIH to update guidelines for the inclusion of women and minorities in clinical research to reflect individuals of all ages included in NIH clinical research. Applicants should justify the proposed age range of the participants in clinical research, with specific attention to justifying the inclusion/exclusion of individuals of all ages (including children, defined as individuals under the age of 18, and older adults, defined as individuals 65 and older). Exclusions based on age must be scientifically or ethically justified. Applicants should report participants’ age of enrollment in progress reports. More information on Inclusion Across the Lifespan is available on ORWH policy page the official NIH policy implementation page.
Inclusion of Pregnant Women in Clinical Research
NIH strongly encourages including pregnant women in clinical research in all circumstances in which their inclusion is scientifically valid and ethically permissible. The ORWH Strategic Plan, Moving into the Future with New Dimensions and Strategies: A Vision for 2020 for Women’s Health Research (link is to an external PDF) (PDF, 1.3MB), describes this issue in detail in Goal 3:
- Objective 3.3. Encourage research on safe and effective interventions for conditions affecting pregnant women.
- Objective 3.4. Expand research on pregnancy and related conditions, such as preeclampsia, diabetes, and hypertension, on the subsequent health of women and their offspring.
Legal authority for including pregnant women in clinical research is found at 45 CFR 46, Subpart B. As suggested by its title, Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in Research, Subpart B itemizes protections and requirements for including pregnant women in clinical research. The two primary conditions are:
- Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses.
- The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means.
As stated under 45 CFR 46.207, investigators may include pregnant women in research that is undertaken specifically to test an intervention that is reasonably likely to alleviate a serious health condition that affects pregnant women, even if the intervention’s risk to the fetus is unknown and might be greater than minimal.
Reasons for including pregnant women in research
Despite legal limitations and strictures and well-founded concern about harming the fetus, a strong ethical case exists for enrolling pregnant women in clinical research.
An ORWH Research Forum report titled Enrolling Pregnant Women: Issues in Clinical Research (link is to an external PDF) (PDF, 2.6MB) summarizes a number of reasons for including pregnant women in clinical research. Briefly, these reasons include:
- The need for effective treatments for pregnant women. Because pregnant women historically have been excluded from clinical research, health care professionals and clinical researchers need to increase their knowledge substantially in providing safe and effective treatments for pregnant women. Few drugs are approved for use in pregnant women, and limited pharmacokinetic and pharmacodynamic research is available to inform clinical treatment guidelines.
- Concern about fetal exposure to medicine. Fetal exposure to medicine is widespread because many pregnant women already use prescription drugs. In most cases, investigators and physicians know little about these drugs’ teratogenicity or other risks that they may pose to the fetus. Clinical research that includes pregnant women is essential to reduce this gap in knowledge.
- Clinician reticence to treat pregnant women for fear of harming the fetus. Unfortunately, this reticence among clinicians can lead to undertreatment of pregnant women, which may pose greater risks than treatment with appropriate medications. To name just one example, untreated depression is associated with maternal suicide, premature delivery, and small-for-gestational-age infants.
Physicians are unlikely to feel comfortable prescribing medications to pregnant women until they know much more about safe and effective dosages and the effects that these medications have on the fetus. The current treatment approach has resulted in significant knowledge gaps and harmful effects. Pregnant women are left with two unacceptable options: either take a drug of unknown safety and efficacy or refrain from treating a condition, both of which pose potentially negative consequences. Pregnant women deserve better.
A final reason for including pregnant women in clinical research is the equitable distribution of the burdens and the benefits of research, which is integral to the Common Rule, the overarching ethical regulations (45 CFR 46) that govern all NIH-supported clinical research. Equitable selection of subjects is mandatory for clinical research to proceed, as stated at 45 CFR 46.111(a)(3).
To briefly summarize the discussion of this principle found in Enrolling Pregnant Women: Issues in Clinical Research (link is to an external PDF) (PDF, 2.5MB), noninclusion of pregnant women in clinical research:
- Denies pregnant women the direct benefits of research participation.
- Underrepresents the health interests of pregnant women in the research enterprise.
- Imposes a disproportionate burden on pregnant women because of the resulting clinician reticence to treat their conditions.
- Denies pregnant women their right to be treated both with dignity and as deserving of equal moral concern as women who are not pregnant.
NIH continues to work toward the goal of easier and safer participation in clinical research for pregnant women. Blehar, Spong, Grady, Goldkind, Sahin, and Clayton (2013)20 have discussed the pertinent issues, and more information is available in Enrolling Pregnant Women: Issues in Clinical Research (link is to an external PDF) (PDF, 2.5MB). Other investigators have recently examined the challenges associated with recruiting and retaining pregnant women in clinical trials.21
Considering Sex as a Biological Variable
NIH is committed not only to supporting rigorous science that advances fundamental biomedical knowledge but also to using that knowledge to improve health outcomes. During fiscal year 2014, about half of all NIH-supported clinical research participants were female.
Scientists have become increasingly aware that sex is an important biological variable in determining how health and disease processes differ among people. This awareness has led to growing concern that not considering sex as a biological variable in research could actually undermine the rigor, transparency, and generalizability of research findings. In response to this concern, NIH published in June 2015 Notice Number NOT-OD-15-102, titled Consideration of Sex as a Biological Variable in NIH-funded Research. NIH then followed up with formal guidance (link is to an external PDF) (PDF, 76KB) on the new policy.
NIH now expects sex to be considered as a biological variable in all NIH-funded vertebrate animal and human studies. The policy requires that investigators account for the possible role of sex as a biological variable, beginning with the development of the research questions and study design and continuing through data analyses and reporting. Applications proposing to study only one sex must support the exclusion of the other sex with strong justification from the relevant scientific literature, preliminary data, or other pertinent considerations.
The new policy pertains to all applications for support of vertebrate animal and human studies starting with submissions for the January 25, 2016, due date.
- Blehar, M. C., Spong, C., Grady, C., Goldkind, S. F., Sahin, L., & Clayton, J. A. (2013). Enrolling pregnant women: Issues in clinical research. Women’s Health Issues, 23(1), e39–e45. PMC: 3547525
- Frew, P. M., Saint-Victor, D. S., Isaacs, M. B., Kim, S., Swamy, G. K., Sheffield, J. S., … Ault, K. (2014). Recruitment and retention of pregnant women into clinical research trials: An overview of challenges, facilitators, and best practices. Clinical Infectious Diseases, 59(Suppl. 7), S400–S407. PMID: 25425718