Late Guidance Push by Biden Administration Over Clinical Trial Diversity Faces New Obstacles From Recent Trump Executive Orders

Amongst the flurry of U.S. Food and Drug Administration (FDA) guidance documents issued in early January by the outgoing Biden administration were two draft guidances addressing the study and evaluation of sex and gender differences in medical product development: “Study of Sex Differences in the Clinical Evaluation of Medical Products” (the Sex Differences Draft Guidance)¹ and “Evaluation of Sex-Specific and Gender-Specific Data in Medical Device Clinical Studies” (the Sex- and Gender-Specific Data Draft Guidance).² Both of these draft guidances, in addition to FDA’s statutorily required guidance on Diversity Action Plans (the DAP Draft Guidance), were intended to provide recommendations for sponsors developing new products that may be required to submit information demonstrating safety and effectiveness across sexes and gender patient populations; the DAP Draft Guidance more generally provided guidance to sponsors conducting studies requiring Diversity Action Plans.³ Addressing clinical trial diversity has been a key FDA objective in recent years to address the historic underrepresentation of women and minorities in clinical studies of new drugs, biologics, and devices — and to ensure that clinical data supporting regulatory decision-making is representative of likely users of approved products.

However, by Friday, January 24, 2025, both the DAP Guidance and the Sex- and Gender-Specific Data Draft Guidance had been removed from FDA’s website, ostensibly as a result of new scrutiny in light of the Trump administration’s Executive Orders (EOs) rolling back actions on diversity, equity, and inclusion, and reversing positions with respect to sex and gender.⁴ (For now, the Sex Differences Draft Guidance remains available on FDA’s website.⁵) Other FDA links that appear to have been removed include ones to the agency’s “Health Equity Forum” podcast⁶ and a discussion paper on health equity in medical device trials.⁷

At this time, neither guidance has been formally withdrawn by FDA or the U.S. Department of Health and Human Services. Indeed, the guidance documents are still available on the U.S. government’s regulations.gov website, and the comment period remains open for the Sex- and Gender-Specific Data Draft Guidance through April 7, 2025. However, the removal of the documents from the website signals that FDA is likely to tread softly in this area in the coming years — and casts doubt over the implementation and enforcement of Diversity Action Plans and related requirements.⁸ This, in turn, raises questions for industry stakeholders, many of whom have already taken additional efforts to enroll more representative populations in clinical trials, which meet the diversity action plan requirements, under the assumption that FDA would begin enforcing those requirements in the summer of 2025. We discuss each of the guidances below.

Categorizing Participants Based on Sex in Clinical Investigations

FDA defined sex, for purposes of the draft guidances, to mean a biological construct based on anatomical, physiological, hormonal, and genetic (chromosomal) traits (referred to as male and female). Gender, on the other hand, was defined as a multidimensional construct encompassing self-identification across a continuum which may or may not correspond to a person’s sex (and which may be nonbinary and/or fluid for a person over time). At the time the draft guidances were published, it was not expected that the recommendations in either guidance would raise significant concern given the scientific community’s general acceptance that a well-controlled clinical trial must enroll a representative population to ensure the new product is studied in subjects of all backgrounds. In fact, FDA believed so strongly in this that the guidances in effect put sponsors on notice of FDA’s commitment to considering representative enrollment of patients across sexes in clinical trials, and even potentially placing clinical investigations under investigational new drugs (INDs) or investigational device exemptions (IDEs) on clinical hold or take other actions (e.g., requiring post-approval studies) when studies do not adequately enroll patients from both sexes.

Indeed, including robust representative populations from both sexes in clinical investigations is critical to avoiding product liability risks — risks that undoubtedly stifle innovation. Manufacturers are facing a plaintiff’s bar that is increasingly bullish about pursuing more creative and untraditional product liability theories. As technology continues to advance in the design and development of new medical products, it is plausible that plaintiffs will bring product liability claims, including for design defect and failure to warn, based on a manufacturer’s alleged failure to properly study and evaluate sex differences, gather data from an adequately diverse patient population, and utilize diverse data sets to dictate safe and effective use of medical products for all populations. Plaintiffs may argue that a lack of diversity in data skews outcomes and leads to treatments that are less effective. This is true for all types of medical products but could especially be a challenge for AI- and machine learning-enabled devices that rely on diverse data sets to make patient recommendations to healthcare providers. With respect to those devices, plaintiffs are likely to allege that failure to study representative populations can lead to inaccurate data input and result in a significant risk of data bias and less reliable algorithm predictions.

However, on day one of the new Trump administration, the president issued an EO stating that, as a matter of policy, there are only two sexes: male and female. Similarly, the EO restricted agencies from using the term “gender,” stating that “[s]ex is not a synonym for and does not include the concept of ‘gender identity.’” The EO went on to define “male” and “female” based on the person’s “belonging, at conception, to the sex that produces” either the large reproductive cell (i.e., egg) or the small reproductive cell (i.e., sperm).⁹ And, the EO ordered “agencies [to] remove all statements, policies, regulations, forms, communications, or other internal and external messages that promote or otherwise inculcate gender ideology.” Presumably in light of this, FDA removed the link to the Sex- and Gender-Specific Data Draft Guidance while maintaining the availability of the Sex Differences Draft Guidance, the latter of which does not address gender.

Summary of the Evaluating Sex Differences Draft Guidance

FDA’s draft guidance concerning sex differences in the clinical evaluation of medical products is most applicable to sponsors of products conducting clinical trials, typically under IND, that are intended to support submission of an application, e.g., new drug applications, abbreviated new drug applications, and biologics license applications. The draft guidance focuses on sex differences, noting that gender is not a required data variable.

Most of FDA’s recommendations are common sense, though a few may foreshadow what FDA plans to look at when determining whether regulatory action is warranted. In order to evaluate sex differences, FDA recommends:

• Evaluating demographic distribution across different time points to assess, for example, whether inclusion criteria should be adjusted to increase enrollment of females
• Consulting places focused on women’s health to help increase female enrollment and retention
• Employing remote monitoring or other digital health technologies where appropriate
• In studies where exclusion of pregnant females are justified, performing PK sampling

FDA also recommends that sponsors evaluate other variables that may affect drug absorption or metabolism differently based on a person’s sex, such as the person’s smoking status, age, or weight.

Importantly, the draft guidance is clear that FDA intends to evaluate data disaggregated by sex when determining whether a clinical study allows for a positive benefit-risk assessment of the product. Moreover, sponsors should be aware that FDA is attuned to looking at whether data from males can estimate effectiveness or safety in females and vice versa based on how similar the data is based on enrollment.

Summary of the Short-Lived Study of Sex and Gender Differences in Medical Device Clinical Studies Draft Guidance

Similar to the Sex Differences Draft Guidance, the Sex- and Gender-Specific Data Draft Guidance did not significantly depart from past recommendations. Instead, it provided insight into FDA’s likely focal points and explained why evaluating product performance across sex and gender is critical to ensuring the reasonable safety and effectiveness of medical devices approved by FDA.

For clinical studies intended to support medical device applications and submissions, FDA recommends that specific information concerning sex and gender be included in the IDE study design, at the time of the premarket submission, or in post-market clinical studies:

• Sex- and/or gender-specific differences should be included in the risk analysis of the investigational plan during the design and early enrollment stage for an IDE study.
• For studies that have already begun enrollment but where enrollment is not adequate with respect to sex and/or gender, the sponsor should discuss its plans with FDA.
• Premarket submissions should include data from such studies in addition to previous studies suggesting there is a clinically meaningful sex- and/or gender-specific difference.
• In cases where a post-approval study is required, sponsors should include sex- and/or gender-specific data in the interim reports when the evidence shows there may be a difference based on such markers.

Based on any of the above information, FDA may request that a sponsor revise product labeling to ensure patients and healthcare personnel are appropriately informed or FDA may require additional studies in one sex or other genders as warranted.

With respect to in vitro diagnostic devices, FDA recommends that sponsors include data from both males/men, females/women, and other study participants at the cutoff selection and cutoff validation stages. Further, sensitivity, specificity, and positive and negative predictive values (among other metrics as appropriate) should be evaluated by sex and/or gender. This device-specific guidance goes on to explain where such information should be included, e.g., in the labeling, summary, or in a specific part of the submission and provides example language sponsors can model for describing representative enrollment.

As noted above, this guidance has since been removed from FDA’s website and its status is currently uncertain though we anticipate FDA may revise the guidance to eliminate references to “gender” given the recent EO.

Removal of the DAP Draft Guidance: What Does This Mean Going Forward?

Unlike the other two guidances in question, the DAP Draft Guidance was specifically required by Congress as part of the Clinical Trial Diversity and Modernization provisions of FDORA.¹⁰ FDORA added a clear statutory requirement that sponsors of certain clinical investigations of drugs and devices must submit a diversity action plan that includes the sponsor’s goals for enrollment, the rationale for such goals, and an explanation of how the sponsor intends to meet such goals.¹¹ The “form and manner” of these diversity action plans was to be established in guidance by FDA within a specified time period. FDA was late issuing the draft guidance (which was issued on June 26, 2024) and was expected to issue the final guidance in late June of this year.¹² Importantly, the DAP requirement only applies to clinical investigations that begin enrollment more than 180 days after the publication of the final guidance.¹³

Now that the draft guidance has been taken down, FDA and stakeholders must grapple with how to move forward with the diversity action plan statutory requirements — many of which stakeholders had already been adopting as good practice in advance of FDA’s final guidance. If the new administration prohibits FDA from issuing such guidance, either because it views the guidance as violating the EO on Sex, or the “Ending Radical and Wasteful Government DEI Programs and Preferencing” EO, then the DAP requirement arguably will not take effect. We are also monitoring the changing landscape to see whether manufacturers that already practice principles related to clinical trial diversity may be at risk if they, for example, use federal grants to fund an investigation or rely on an NIH clinical site.

It remains to be seen how FDA will handle currently ongoing clinical studies involving action plans (and currently pending marketing applications including such clinical studies). The possibility of litigation exists on both sides: the agency may be open to challenges if it denies an application or places an IND, for example, on clinical hold on the basis that the study is not well controlled because it lacks a meaningfully representative population. On the other hand, manufacturers have good reason to include representative patient populations in their clinical studies — from the importance of generating appropriate labeling to guarding against potential product liability suits.

Conclusion

This is an unusual case where the actions beyond the guidance documents speak more than the recommendations from FDA itself. We, along with many in industry, await further direction from FDA on whether these draft guidances will be reissued with revisions or formally withdrawn. The effect on FDA’s statutory authorities likewise remains to be seen.

Arnold & Porter is monitoring closely the impact of the recently issued Trump administration Executive Orders on life sciences manufacturer operations, including clinical trials and compliance practices. The comment period on the Sex Differences Draft Guidance is open until April 7, 2025 and may become a central hub of comments in light of these recent developments. If you have any questions about the content discussed in this Advisory or would like more information, please reach out to one of the authors or your existing Arnold & Porter contact.

© Arnold & Porter Kaye Scholer LLP 2025 All Rights Reserved. This Advisory is intended to be a general summary of the law and does not constitute legal advice. You should consult with counsel to determine applicable legal requirements in a specific fact situation.