Personalized medicine may use devices and assays that identify sex-related differences. For example, a device or an assay may determine if a cancer patient harboring a particular genetic variance will or will not respond to a particular cancer therapy. In some instances, the prediction of clinical outcome is related not only to the genetic variance but also to the sex of the patient.

The Food and Drug Administration (FDA) recently issued a new guidance for industry and FDA staff that may be relevant in the design and development of medical devices that serve personalized medicine, especially those that categorize patients into responders and non-responders. “Evaluation of Sex-Specific Data in Medical Device Clinical Studies” (Guidance) should be carefully reviewed by clinical device manufacturers, especially manufacturers of devices that separate individuals into two or more groups, such as those that respond to a particular treatment and those that do not respond. The Guidance is intended for devices that require clinical information in support of a marketing submission, whether a premarket notification (510(k)), premarket approval (PMA), a de novo request, or a humanitarian device exemption application. The recommendations reported in the Guidance also apply to post-approval study submissions and postmarket surveillance.

Sex Versus Gender

Sex as defined by the Guidance, is the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement. Guidance, page 3. In contrast, gender is defined as a persons self-representation as male or female or how social institutions respond to that person.

The Guidance notes that the recommendations suggested therein do not create or confer any rights for or on any person and does not operate to bind the FDA or the public. The Guidance represents the FDAs current expectations regarding sex-specific patient enrollment, data analysis, and reporting of study information. The stated primary intent is to improve the quality and consistency of available regarding the performance of medical devices in both sexes by encouraging appropriate enrollment by sex in clinical studies of devices, and that data from such studies is appropriately analyzed by sex. Guidance, page 1.

Does Sex Make a Difference?

The Guidance acknowledges that certain medical products elicit different responses in women as compared to men. These differences may be attributed to intrinsic factors (such as genetics, hormones or body size) or extrinsic factors (such as diet, sociocultural issues or environment) or an interaction between these. It is also known that men and women report outcomes such as pain, differently. Moreover, fewer women historically have been enrolled in many clinical studies that have led to a lack of information available for women and their doctors regarding the risks and benefits of medical treatments and diagnostic procedures.

Recommendations for Clinical Studies

Sponsors of clinical studies for medical devices are encouraged to enroll representative proportions of women and men to achieve an unbiased estimate of treatment effect in the general population. However, where disease science or prior clinical study results suggest treatment effects for a medical device or treatment in only one sex, then sponsors are encouraged to intentionally enroll sufficient numbers of patients to support a valid analysis.

The Guidance suggests that sponsors of medical device clinical studies investigate whether sex differences may or may not exist for the disease or conditions that the device is intended to treat or diagnose in the following areas:

• Sex-specific prevalence;
• Sex-specific diagnosis and treatment patterns;
• Identification of proportions of women included in past studies for the target indication; and
• Identification of any known clinically meaningful sex differences in outcome related to either safety or effectiveness.

Guidance, page 9.

The Guidance recommends the use of sex-specific information in the design and conduct of clinical trials in several scenarios: for new or ongoing studies of medical devices; in the marketing application; and in any post market studies of the device. Investigation of heterogeneity across sex group should be conducted to account for any differences in how a device performs in women versus men in terms of safety and effectiveness.

Special Consideration for Diagnostic Assays and Devices That May Be Used for Personalized Medicine

Personalized medicine may use diagnostic devices and assays that use a cutoff. The Guidance notes that an assay or device involves a cutoff whenever a continuous or ordinal measurement is used to separate patients into two or more categories (for example, responders and non-responders). The Guidance recommends that separate cutoffs for men and women should be used only when there is reason to believe separate cutoffs are needed based on prior evidence.

Recommendations for Analysis and Interpretation in Completed Studies

The Guidance also recommends that in general, all studies should report descriptive statistics for outcomes of interest, e.g., the estimate of variance or standard deviation (as applicable), by sex. Sponsors are encouraged to examine data for clinically meaningful sex differences in each of: primary effectiveness endpoint(s); primary safety endpoint(s); and key secondary endpoints.

Implementation and Comment

Detailed information for the reporting sex-specific information in device applications can be found in the Guidance as well as recommendations for analysis and interpretation of sex-specific data.

The public may submit written comments and suggestions at any time for the FDA’s consideration to the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. Electronic comments may be submitted to http://www.regulations.gov. All documents must be identified with the docket number FDA-2011-D-0817.

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