On December 19 the FDA released a new draft guidance recommending improvements to medical device manufacturers’ clinical study designs that do a better job of evaluating the effectiveness of their products for women. The draft guidance can be read at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm283453.htm.
Entitled “Draft Guidance for Industry and Food and Drug Administration Staff Evaluation of Sex Differences in Medical Device Clinical Studies,” the document aims to correct the historic underrepresentation of women in clinical studies. A 2001 report by the U.S. Government Accountability Office (GAO) on FDA-reviewed drug studies found that while women represented 52 percent of study enrollees, 30 percent of study documents did not report outcomes by sex and nearly 40 percent did not report enrollment demographics. A 2009 study of cardiovascular device pre-market applications showed that pivotal studies that reported sex enrolled an average of 33.9 percent women.
The guidance is especially intended for devices that require clinical information in support of a marketing submission, whether a premarket notification (510(k)), premarket approval (PMA) application, or humanitarian device exemption (HDE) application. The recommendations also apply to post-approval study (PAS) submissions and post-market surveillance (PS) studies conducted in accordance with Section 522.
According to the FDA, the guidance further “outlines the Center for Devices and Radiological Health’s (CDRH) expectations regarding sex-specific patient enrollment, data analysis, and reporting of study information. The intent is to improve the quality and consistency of available data regarding the performance of medical devices in both sexes by ensuring appropriate representation by sex in clinical studies of devices, and that data from such studies is appropriately analyzed for sex differences. This information can be of benefit to patients and their medical providers, as well as clinical researchers and others.”
The specific objectives of this guidance are to:
- Provide recommendations for study design and conduct to encourage enrollment of women in proportions that are representative of the demographics of disease distribution
- Outline recommended statistical analyses of study data for sex differences, and to identify sex-specific questions for further study
- Encourage the consideration of sex and associated covariates during the study design stage
- Specify CDRH’s expectations for reporting sex-specific information in summaries and labeling for approved devices
- Women are less likely to enroll in clinical studies for a number of reasons, including:
- Fear of fetal consequences if the woman becomes pregnant
- Lack of understanding about differences in disease etiology and pathophysiology may lead to under-diagnosis and under-referral of women
- Avoidance of female patients by investigators and sponsors due to the perception that it takes more time and money to recruit them
- Inclusion/exclusion criteria that may not be necessary to define the study population may unintentionally exclude women (e.g., upper age limit)
- Family responsibilities which limit ability for time commitment to study follow-up
What to Include
MDMs need to include more sex-specific information in their applications, including the prevalence of the targeted disease or condition in women. Other valuable data to include are any sex-specific diagnosis and treatment options, known results for female populations from past clinical studies, and identified sex differences regarding the safety or effectiveness of the device.
For new and ongoing studies, include the above information as part of the risk analysis section of the investigational plan. The FDA recommends summarizing this information in the study protocol and investigator training materials to explain the importance of enrolling representative percentages of women. For studies which are already enrolling under an approved (or conditionally approved) IDE, this information be communicated to investigators via revised training materials or other regular communication.
For completed studies, include this information as part of the marketing application in sections containing results of clinical investigations. A summary of this information should also be included in the draft PMA summary of safety and effectiveness or 510(k) summary, and in labeling.
For postmarket studies, this information should be included in interim reports as well as the results sections of final reports. For PAS or 522 PS studies involving newly enrolled patients, include the analyses as part of a pre-specified statistical analysis plan in your protocol. “Furthermore,” states the FDA, “if results from sex-specific analyses of pre-market data suggest there may be a clinically meaningful difference in outcomes, you should carefully consult with the Division of Epidemiology to determine whether this should also be incorporated into the study design and hypothesis for your PAS.”
Women are often under-represented in clinical studies; the guidance suggests strategies for increasing enrollment of women in these studies. However, in fields where men may be under-represented (e.g., breast cancer diagnosis, bone density scans) the strategies can also be used to increase enrollment of men.
To achieve the most meaningful outcomes, develop and describe your plan to prospectively enroll proportions of women and men in your study which are consistent with the sex-specific prevalence of the type of disease or condition which your device is intended to treat or diagnose.
Certain medical products also elicit different responses in women compared to men. Differences may be attributable to intrinsic factors (genetics, hormones, body size, sex-specific physiology), extrinsic factors (diet, sociocultural issues, environment) or interactions between these factors. For example, there may be medical conditions that are unique to a certain sex, ethnic or racial group which should be considered in study recruitment and in reporting of results.
The historic under-representation or exclusion of women in many clinical studies has resulted in a lack of information available for women and their physicians regarding the risks and benefits of many medical treatments and diagnostic procedures.
“The FDA recommends that investigators and manufacturers strive to enroll representative proportions of both women and men in their device studies,” states Dr. Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health. “This draft guidance outlines what we recommend for obtaining and improving the quality and consistency of sex-specific data on devices.”
The 90-day comment period started December 19. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, Maryland 20852. Electronic comments may be submitted to http://www.regulations.gov. Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.