On August 22, 2014, FDA issued a final guidance addressing the collection and analysis of sex-specific data in medical device clinical trials, entitled “Evaluation of Sex-Specific Data in Medical Device Clinical Studies.”  The guidance outlines “FDA’s expectations regarding sex-specific patient enrollment, data analysis, and reporting of study information.”  According to the guidance, studying both sexes is crucial because clinical study outcomes can be affected by the different responses of women and men—whether attributable to intrinsic differences such as body size, hormones, or the arrangements of sex organs, or extrinsic differences such as diet or environment.

Historically, women have been underrepresented in device trials, leading to a lack of information on the risks and benefits for women of many medical devices.  The guidance is in part a response to pressure from Congress—including section 907 of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), requiring FDA to investigate and enhance the availability of demographic subgroup data in medical product applications—and special interest groups such as National Women’s Health Network.  The guidance applies to devices that require clinical information to support a marketing submission, whether a premarket notification (510(k)), premarket approval (PMA), de novo request, or humanitarian device exemption (HDE) application.  The guidance focuses on sex—classification as male or female based on chromosomal complement—rather than on gender, defined by the guidance as a person’s self-representation as male or female or by the response of social institutions to that person.

The guidance does not clearly define the consequences for non-compliance with its recommendations.  Nevertheless, the guidance indicates that sex-specific data can be relevant to questions such as whether data are poolable across sex, and whether sex-specific outcome differences should be included in labeling.  By satisfying FDA’s expectations for enrollment and data analysis, sponsors may be able to avoid delay in FDA approval or clearance of medical devices or the expense of follow-up trials.  While some devices may be intended for one sex only and thus may be studied in one sex (e.g., gynecology products), FDA expects that devices intended for use in both sexes will be studied in both sexes.

The guidance includes steps that sponsors can take to meet FDA’s expectations and potentially ease FDA’s review process, including the following:

• Enroll proportions of men and women consistent with disease prevalence.  For example, it could be appropriate that 75% of study subjects are women if women are three times as likely as men to suffer from the disease under investigation.

• Target investigational sites where more women might be recruited (e.g., women’s clinics) and consider incentives to increase recruitment and retention.

• Analyze the data for possible sex-specific differences, including pre-specified analyses in the statistical analysis plan for new or ongoing studies, or exploratory post hoc analyses of data from completed studies in the marketing application.

FDA’s FDASIA Action Plan was also released in late August 2014, citing the guidance and making clear that FDA plans to quickly incorporate recommendations of the guidance into its review of medical device notifications and applications.  Reaction to the Action Plan has generally been positive, though some have criticized the plan for not doing enough to ensure the participation of minorities and pregnant women in clinical trials.