NIH policy states that all NIH-funded clinical research must include women and members of racial and/or ethnic 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 participants’ 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. Information on implementing this policy is available on the Office of Extramural Research Grants & Funding website on the Inclusion of Women and Minorities as Participants in Research Involving Human Subjects webpage.

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, race and/or ethnicity, as explained in G.500 Section 2.4 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 NIH-defined Phase III clinical trials. When proposing an NIH-defined Phase III clinical trial, investigators must review their evidence to show whether they expect the intervention to produce clinically relevant differences based on sex, race and/or 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 an  NIH-defined Phase III clinical trial, investigators must also provide in their inclusion plans a description of their strategies for conducting a valid analysis by sex, race and/or ethnicity, as explained in G.500 Section 2.4 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 in the Project Outcomes section of the report. Examples are available on the Sample Project Outcomes website.

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 NIH-defined 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 if the prior data give compelling evidence that no clinically relevant differences can be expected in the intervention effects by sex. Nonetheless, NIH strongly encourages inclusion of both women and men in the trial and analyses by sex.

If prior studies neither support nor negate the possibility of significant differences in intervention effects by sex, the NIH-defined 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. 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. 

NIH strongly encourages including pregnant women in clinical research in all circumstances in which their inclusion is scientifically valid and ethically permissible.  

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  summarizes a number of reasons for including pregnant women in clinical research. Briefly, these reasons include:

• The need for effective treatments for pregnant women. 
• Concern about fetal exposure to medicine. 
• Clinician reticence to treat pregnant women for fear of harming the fetus. 

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 in  45 CFR 46.111(a)(3).

To briefly summarize the discussion of this principle found in Enrolling Pregnant Women: Issues in Clinical Research, non-inclusion 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. 
 

The Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) Recommendations and Implementation Plan

PRGLAC was established by the 21st Century Cures Act (see below) to advise the secretary of Health and Human Services (HHS) on activities related to identifying and addressing gaps in knowledge and research on safe and effective therapies for pregnant women and lactating women.
This Task Force developed a report that included 15 recommendations to improve the inclusion of pregnant women and lactating women in clinical research. In 2023, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) formed the PRGLAC Implementation Working Group of Council to put the PRGLAC recommendations into practice. The group release its report on implementation progress in July 2024. 

 

NIH is committed not only to supporting rigorous science that advances fundamental biomedical knowledge but also to using that knowledge to improve health outcomes. Since FY 2018, women have consistently comprised more than half of all NIH-supported clinical research  participants.

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. As a response to this concern, in June 2015, NIH published 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 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.
 

Inclusion Across the Lifespan Policy

The NIH Inclusion Across the Lifespan Policy (IAL) aims to ensure individuals are included in clinical research in a manner appropriate to the scientific question under study so that the knowledge gained from NIH-funded research is applicable to all populations affected by the diseases and conditions being researched. The policy, implemented across all NIH Institutes, Centers and Offices (ICOs) in 2017, expands the longstanding Inclusion of Children in Clinical Research Policy to include individuals of all ages, including children (defined as an individual under the age of 18 years) and older adults (defined as an individual 65 years of age or older.) The policy also requires that the age at enrollment of each participant be collected in progress reports. 

IAL Policy Requirements

In 2016, the 21st Century Cures Act included new requirements to examine NIH inclusion guidelines and report the demographics of participants in NIH research. Prior to the enactment of the Cures Act, the long-standing NIH policy had been that children must be included in all human subjects research conducted or supported by NIH, unless there are scientific or ethical reasons not to include them. The Cures Act mandated that NIH convene a workshop on age groupings and age exclusions in clinical research, publish guidelines addressing consideration of age in clinical research, and publish the number of children in NIH studies by research, condition, or disease category.

To implement the requirements of the Cures Act, on June 1–2, 2017, NIH held a workshop on Inclusion Across the Lifespan to discuss barriers and opportunities for participation of children and older adults in clinical research studies. In addition, NIH issued a Request For Information (RFI) to solicit input from the wider scientific community and general public regarding appropriate inclusion of pediatric and older populations in research studies involving human subjects. NIH considered the input and reviewed current policies to identify opportunities to align NIH policies with the goal of ensuring that the distribution of study participants reflects the population needed to accomplish the scientific goals of the study.  

The resulting IAL policy requires that applications address inclusion of individuals across the lifespan (including children and older adults). Awardees must also report de-identified individual-level participant data in progress reports. NIH also collects the planned age range of participants in its grant application package and uses an electronic system, Human Subjects System, that allows submission of participant demographic data. To help scientific investigators understand and comply with the policy, NIH has developed several resources, including an infographic, video presentations, and case studies, which are available online.