FDA Issues Draft Guidance: Study Of Sex Differences In The Clinical Evaluation Of Medical Products
By Liz Johnson, Clarkston Consulting

The U.S. FDA recently released a draft guidance on the Study of Sex Differences in the Clinical Evaluation of Medical Products,1 which deduced that individuals whose sex is assigned as “female” at birth are underrepresented in clinical trials for drugs and medical devices as well as some therapeutic areas. This often occurs where the disease or condition affects both males and females, making it challenging to evaluate the benefits and risks of medical products for females, including dosing requirements. The FDA published updated guidance to provide insight on:
- increasing enrollment of females in clinical trials and non-interventional studies to help ensure the generalizability of results
- analyzing and interpreting sex-specific data
- including sex-specific information in regulatory submissions of medical products.
Summary Of FDA Guidance
When designing and conducting clinical trials, it is important to follow the definition of sex and gender as defined in the guidance. Studies should use sex, which is assigned at birth; however, gender may refer to an individual’s chosen identity. In many cases, sex and gender are the same, but this is not always the case.
Per the guidance: “Although sex and gender are distinct concepts, they may both influence etiology and presentation of disease and affect treatment and patient-reported outcomes.” Another consideration is including a separate category for intersex in clinical trials and non-interventional studies as well as collecting data on individuals for whom the development of chromosomal, gonadal, or anatomic sex is atypical.
It is important to characterize the impact of sex as part of medical product development to determine if there may be differences in PK (pharmacokinetics), PD (pharmacodynamic relationships), effectiveness, and/or safety associated with use of the medical product that should be included in labeling instructions. Sponsors need to evaluate whether the demographic distribution of the potential trial population changes after screening, after consent, and at other follow up points in time. If the proportion of female participants drops significantly, the FDA recommends evaluating the trial inclusion/exclusion criteria and removing unnecessary criteria that may limit the number of female participants in the trial.
The FDA also recommends using methods to find potential female candidates for enrollment. This includes identifying clinical or social media sites2 that target women, providing flexibility in follow-up scheduling, choosing an array of geographic locations where patients receive their healthcare, and leveraging mobile medical professionals to visit patients at their locations.
Other recommendations include using digital health technology3 to collect information directly from the patient in their location, providing childcare or eldercare during visits, and including females of different races, ethnicities, and hormonal function, as applicable. The FDA recommends that for the enrollment of females of reproductive potential, they must be provided with the appropriate risk mitigation efforts (e.g., contraception) to avoid pregnancy during the clinical study to mitigate risks if the drug or device could potentially harm the fetus. Further, arbitrary exclusion criteria that prohibit participation based on sex for diseases or conditions that can occur in both females and males — but rarely occur in one of the sexes — should be avoided.
Where sex differences are anticipated, there should be sufficient numbers to inform reliable benefit-risk assessments in male and female participants. Sponsors should consult with the appropriate FDA review division to consider target enrollment of female and male participants. The trial should consider analyzing data to assess whether observed sex differences are the result of differences in PK, PD, adherence, comorbidities, or other factors.
Trial protocols should collect information on other variables such as smoking, age, and weight that may be important in evaluating and understanding sex differences, as these variables may affect drug absorption, distribution, metabolism, and excretion. Sponsors should consider the benefits and risks of enrolling pregnant or lactating participants at various stages of the development program for products not being developed for pregnancy-specific or lactation-specific indications. When there is justification for excluding pregnant participants, consider including PK sampling to inform drug dosing for females who become pregnant during the trial.
Statistical Analysis
It may be appropriate in a study to use different statistical approaches to characterize potential differences in treatment effects between sexes as opposed to estimating the treatment effect within a given sex. Differential treatment effects by sex may also be due to other factors associated with sex, including age and weight where these vary in males and females.
The FDA recommends analyses for:
- differences in treatment between females and males, including a calculation of an estimated difference in treatment effects such as a confidence interval and a quantitative interaction of treatment for females versus males.
- estimating treatment effects in female and males. In the past, only data from a given sex have been used when estimating the treatment effect size for that sex. Sponsors should consider prespecified statistical approaches that incorporate the data from all participants when estimating the treatment effect within a given sex.
The FDA recommends that sponsors report the number and proportion of study participants by sex — and gender as appropriate — who were treated or diagnosed with a device as part of a clinical study. Where statistical significance is achieved for an average treatment effect for the overall population, the results for each subgroup by sex should be examined to understand whether the finding for the overall population was driven by the results in only one of the sexes. The FDA should be made aware of any difference by sex.
Other Considerations
The FDA provides some additional guidance on trial design and post-market:
- If important differences in the treatment effect by sex are anticipated at the trial design stage, sponsors need to ensure there are an adequate number of participants from each sex to conduct an informative benefit-risk assessment.
- When evidence collected during clinical development identifies potential sex differences, they should be explored as much as possible in clinical trials and, if justified, in a study after approval.
- The FDA can require a post-marketing study when criteria are met, including assessing when data indicates the potential for a serious risk, including for individuals who are pregnant or lactating.
- When clinically significant differences in safety or effectiveness between female and male participants are detected, the applicant should propose how to address those differences through, for example, different recommended dosages in females and males or more frequent monitoring, in their marketing application.
- Post-market studies and surveillance efforts should note whether safety signals differ by sex; these differences could lead to further investigation.
The FDA is accepting comments on the guidance document for Study of Sex Differences in the Clinical Evaluation of Medical Products through April 7, 2025. More information can be found on the FDA’s website here.
References
- U.S. Food & Drug Administration. (2025, January). Study of Sex Differences in the Clinical Evaluation of Medical Products. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/study-sex-differences-clinical-evaluation-medical-products
- Parks Murray, E. & Stone, L. (2023, May 26). Leveraging Digital Marketing Tactics to Increase Diversity in Clinical Trial Recruitment. https://clarkstonconsulting.com/insights/digital-marketing-tactics-clinical-trial-recruitment/
- Epperson, E. & Stone, L. (2025, January 23). Strategizing And Implementing Your Clinical Trial Technologies. https://www.clinicaltechleader.com/doc/strategizing-and-implementing-your-clinical-trial-technologies-0001
About The Author:
Liz Johnson is a senior manager with Clarkston Consulting, specializing in program and project management and organizational change management across the life sciences and consumer products industries. She is passionate about helping organizations successfully navigate change experienced during transformations.