FDA proposes to modernize guidance on sex, gender in clinical trials
The US Food and Drug Administration (FDA) is proposing to update two guidance documents that clarify terminology around sex and gender of clinical trial participants in an effort to improve the understanding of medical products’ effects on women.Both documents are guidance updates to older documents and are open for public comment through 7 April 2025.
One of the new draft guidance documents – Study of Sex Differences in the Clinical Evaluation of Medical Products – will replace guidance on “gender differences” issued in July 1993 once finalized. The 20-page guidance draft applies to trials of drugs, biological products, or medical devices intended for humans, whereas the 1993 version was focused on the study of drugs.
A Federal Register notice stressed the need for sponsors to ensure generalizability of study results and shed light on sex-based differences.
“This guidance provides recommendations for increasing enrollment of females in clinical trials, analyzing and interpreting sex-specific data, and including sex-specific information in regulatory submissions of medical products,” FDA wrote.
The other draft document – Evaluation of Sex-Specific and Gender-Specific Data in Medical Device Clinical Studies – will replace guidance issued in August 2014 once finalized. The 30-page document applies to clinical studies conducted to support various medical device submissions, including 510(k), premarket approval, de novo requests, and humanitarian device exemption marketing submissions. (RELATED: CDRH outlines plan to understand sex and gender differences in medical devices, Regulatory Focus 21 January 2024).
“The purpose of this guidance is to encourage science-driven consideration of sex and/or gender, as appropriate for both the scientific question being addressed and the intended use of the device, when designing medical device clinical studies and reporting data from such studies in accordance with legal requirements,” FDA explained in a Federal Register announcement.
Defining sex, gender
While there are many similarities between the 2025 updates and the previous incarnations of the guidances, the use of terminology is a notable difference. The 1993 guidance for drugs addressed “gender differences,” refers to “both genders”, repeatedly uses the word “women,” and makes references to “childbearing potential”.
FDA’s 2014 guidance for devices is aimed at the evaluation of “sex-specific data”. “For the purposes of this guidance document we use the term sex, with the understanding that for most medical device studies gender is used as a surrogate for sex,” the agency wrote at the time.
The 2025 version on devices refers to “sex-specific” and “gender-specific” data in the title.
Both of the new draft guidances have a preference for using “females/women” and “males/men” instead of “women” or “men” alone. The FDA included the following definitions of sex and gender at the start of the draft documents, noting that the terms have evolved into “separate concepts with distinct definitions.”
- “Sex: A biological construct based on anatomical, physiological, hormonal, and genetic (chromosomal) traits. Sex is generally assigned based on anatomy at birth and is usually categorized as female or male, but variations occur. Variations of sex refers to differences in sex development or intersex traits.”
- “Gender: A multidimensional construct that encompasses how an individual self-identifies. Gender may be described across a continuum, may be nonbinary, and may change over the course of a lifetime. Gender may or may not correspond to a person’s sex assigned at birth.”
“While sex and gender are distinct, they are interrelated and are not necessarily mutually exclusive,” FDA explained in the draft guidance for medical devices. “Sex and gender and their interactions may drive epigenetic influences and resultant physiologic reactions, influence etiology and presentation of disease, and affect treatment outcomes.”
The agency also suggested that sponsors may want to include an intersex category in clinical research but added that this is beyond the scope of the new draft guidance.
Boosting women’s inclusion
Boosting participation of women in clinical research has been a longtime goal of the agency and other organizations as products have different effects depending on sex, which can translate to differences in safety and efficacy. In the new general product guidance, the FDA cited studies showing disparities in effects of treatments for HIV and hepatitis C. The device draft guidance notes women are at higher risk compared to men in a range of therapeutic scenarios, for example stroke with ventricular assist devices, device wear and/or adverse local tissue reactions during hip transplants, and more microvascular cardiac disease.
The level of participation of females/women has improved but is still lacking. To remedy the current situation, the new draft guidance documents offer recommendations for statistical design, data analysis, and boosting enrollment. Among other ideas, FDA suggested including females of different ages/hormonal statuses in trials, using mobile technologies, and providing childcare during trial visits.
“Identification of a clinically relevant difference by sex may inform a benefit-risk assessment and inform product labeling,” the agency advised in the guidance for medical products. “Assessment of sex differences should occur throughout drug development, and in Phase 1 studies, females should be enrolled to determine if there are PK differences by sex that warrant further study.”
Reporting data based on sex and gender is also a big priority for regulatory officials. In the guidance document on devices, the agency noted that sex- and gender-specific analyses are submitted confidentially to FDA but that provision of this information in publicly available documents for products with premarket authorization is inconsistent.
“Despite the differences, it is important for generalizability, scientific understanding, and patient and health care professional understanding that both confidential submissions and public documents contain appropriate sex- and gender- specific information,” the FDA wrote.
