New draft guidance from the US Food and Drug Administration recommends improvements to medical device manufacturers’ clinical study designs in order to better assess safety and effectiveness of their products according to gender.
The guidance aims to suggest methods to enroll more women in clinical studies in order to better represent demographic distributions of particular diseases; identify statistical analyses of study data that take into account gender differences; emphasize the need to consider gender differences during manufacturers’ study design phases; and spell out expectations of the Center for Devices and Radiological Health (CDRH) for reporting of sex- and gender-related information in study summaries and labeling for approved or cleared devices.
“Certain medical products elicit different responses in women compared to men,” the guidance states, citing ventricular assist devices and cardiac resynchronization therapy defibrillators as examples of devices with significant differences in effectiveness between male and female patients.
“Many clinical studies do not enroll proportions of women that reflect the underlying disease distribution in the affected population… This has contributed to a substantial lack of available data regarding the risks and benefits of medical device use in women.”
Historical barriers to enrollment of women in clinical studies, according to the FDA, include fears of fetal consequences, avoidance of female subjects by study sponsors, and study inclusion or exclusion criteria that inadvertently exclude women. To reduce these challenges, study sponsors and manufacturers should examine screening logs in order to track reasons for non-enrollment of women as subjects.
What to include in submission documents
The guidance recommends inclusion of information such as sex-specific prevalence of the disease in question, sex-specific diagnosis and treatment patterns, identification of proportions for women included in past clinical studies, and identification of any known clinically significant sex differences in outcomes regarding safety or effectiveness.
For new and ongoing studies, manufacturers and sponsors should include the afore-mentioned data as components of the risk analysis sections of their investigational plans. Firms should also summarize this information in their study protocols and training materials.
For completed studies, this data should be included as part of your marketing application under clinical investigation results. A draft PMA Summaries of Safety and Effectiveness or 510(k) Summary should also include this information.
Finally, for postmarket studies, this information should be included in interim reports as well as the results sections of final reports.
Other Recommendations
In addition, the FDA guidance recommends clinical study investigators take into account how the influence of subjects’ sex affects primary endpoints for safety and effectiveness. Analysis of subgroups and testing for interaction or heterogeneity may also be necessary, according to the agency.
Statistical analysis must also address sex-specific issues, recommends the FDA. Any clinically significant sex differences should be reported and discussed with FDA personnel to see whether further investigations are required based on those findings. Sex-specific information should also be reflected more thoroughly in study summaries and labeling, according to the guidance.
