Such efforts should be directed not only with regard to women, but also to the underrepresentation of men in areas such as breast cancer and bone-density loss research, where the majority of affected subjects tend to be women, according to the guidance report.
Sex-specific statistical analysis should also be part of the study designs, and there are reporting and language recommendations for sex-specific information in summaries and labeling of devices.
Good Intentions Not Enough?
FDA guidance documents do not establish legally enforceable responsibilities, according to the agency; instead, they describe the current thinking on a topic and should be viewed only as recommendations unless specific statutory or regulatory requirements are cited.
The FDA document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials, according to an editorial comment by Dr. Sanket S. Dhruva and Dr. Rita F. Redberg of the University of California, San Francisco, published online Feb. 29 in JAMA (doi:10.1001/jama.2012.254).
"Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women," they said.
"By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. ... The recommendations in this draft guidance may help ensure safe and effective medical devices in both sexes," they added.
However, despite the FDA’s laudable attempts to expand the participation of women patients in clinical trials of medical devices, according to Dr. Dhruva and Dr. Redberg, there is the inevitable problem of creating "nonbinding" guidelines in an era when the expense of conducting clinical trials is already considered one of the main barriers to developing and deploying new drugs and medical devices.
Nonbinding means nonparticipation, they added, citing as proof the example of the National Institutes of Health. The NIH developed sex bias guidelines in the late 1980s, and first adopted them as nonbinding encouragement for enrollment of women patients in all federally funded research. A few years later, the NIH noted that little progress had been made, and in the early 1990s, inclusion of women became a requirement for NIH funding, and annual progress reports were required. These changes led to a substantial increase in the number of women included in studies.
"The FDA should return device applications that have not enrolled sufficient numbers of women (or justified the reason for insufficient enrollment of women) or performed sex-specific analyses per the guidance document," wrote Dr. Dhruva and Dr. Redberg. Specifically, sex-specific analyses "should be performed for primary effectiveness end points, primary safety end points, and key secondary end points," they said.
In addition, the FDA should require transparency. "The practice of keeping sex-specific analyses ‘confidential’ must end," they said. And postmarketing analyses of outcomes must be performed in women as well as men, with penalties for noncompliance.
They concluded that it was time to ensure that FDA approval of medical devices be "based on data that they are safe and effective in both women and men."
Dr. Dhruva and Dr. Redberg stated that they had no conflicts of interest.
Final Note: A Question of Sexual Identity?
In formulating its guideline, the FDA felt the need to indulge in some elementary sex education – specifically by addressing the confusion regarding sex and gender that occurs in the literature and in medical device parlance. The agency referred to a 2001 consensus report published by the Institute of Medicine titled "Exploring the Biological Contributions to Human Health: Does Sex Matter?"which indicated that the terms have distinct definitions that should be used consistently to describe research results.
Sex refers to differences associated with biological difference, and as such is of greatest interest to the Center for Devices and Radiological Health, the FDA indicated. Gender refers to a person’s self-representation as male or female or how that person is responded to by social institutions based on the individual’s gender presentation. Gender, though rooted in biology, is shaped by environment and experience, the report stated.
The FDA noted that most medical device studies have used gender as a surrogate for sex. However, the agency said that its guidance "is focused on addressing potential differences in study design, conduct, and interpretations that should be considered to ensure sex-specific issues are adequately addressed in clinical studies."