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Published 8/1/2015
Laura M. Bruse Gehrig, MD

Sex-Specific Data in Clinical Studies

FDA issues final guidance document

Over the years, clinical research has shown that certain medical devices elicit different responses in females compared to males. For example, according to study data on metal-on-metal (MoM) implants and resurfacing presented at the June 2012 meeting of the U.S. Food and Drug Administration’s (FDA) Orthopaedic and Rehabilitation Devices Advisory Panel, women have higher revision rates after MoM total hip arthroplasty and hip resurfacing than men. (See “Men, Women, and MoM.”) The reasons include a wide array of intrinsic and extrinsic factors, including genetics, hormonal differences, diet, and environmental factors, as well as the natural history of a device based on the activity level.

However, despite the evident differences between males and females, females continue to be underrepresented or excluded from clinical studies. The result is a lack of adequate information for women and their physicians on the risks and benefits of medical treatments and diagnostic procedures.

Guidance document
The FDA sought to remedy these information gaps for women by implementing a guidance document. In 2008, it held two public workshops for stakeholders to discuss ways to overcome barriers to understanding the impact of sex differences on clinical outcomes, with a focus on clinical studies and statistical analysis. In December 2011, the FDA released a draft guidance and requested comments from the public.

The FDA’s final guidance document on sex-specific data in medical device clinical studies was issued in August 2014. It outlines the FDA’s expectations regarding sex-specific patient enrollment, data analysis, and the reporting of study information. The document also aims to improve the quality and consistency of available data regarding the performance of medical devices in both sexes, especially as the data relate to devices that require clinical information as part of marketing submissions or post-approval/post-market surveillance submissions.

The final guidance document has the following goals:

  • encourage consideration of sex and associated covariates during study design stage
  • provide recommendations for study design and conduct to encourage enrollment of each sex
  • outline recommended sex-specific statistical analyses of study data with framework for considering sex-specific data when interpreting overall study outcomes
  • specify expectations for reporting sex-specific information in summaries and labeling for approved or cleared devices

The guidance document provides instruction on achieving appropriate enrollment, designing studies and data interpretation, and reporting information in applications and public documents. Furthermore, the guidance document applies to new and ongoing studies, completed studies, and post-market studies. Additionally, the document includes a decision framework for statistical analyses.

According to the guidance document, the consideration of sex during enrollment is best achieved during study design and conduct, which includes the incorporation of information into the risk analysis section of the investigational plan. Specific recommendations for improving the collection and interpretation of sex-specific data include revising the enrollment criteria, examining alternative communication strategies, planning for a continued access study, involving community or local healthcare providers, and exploring flexibility in follow-up visit scheduling that may include provision for child care or elder care services. The guidance document also provides general best practices for avoiding or minimizing the number of individuals lost to follow-up.

Additional data collection efforts
Other demographic variables also may affect device performance. Some of the recommendations provided by the FDA’s guidance document can be used to promote enrollment and data analysis with demographics such as age, race, and ethnicity.

Coinciding with the issuance of the final guidance document, the FDA released an Action Plan that describes its approach to enhance the collection and availability of demographic subgroup data in clinical trials. The Action Plan aims to do the following:

  • improve the completeness and quality of demographic subgroup data collection, reporting, and analysis
  • identify barriers to subgroup enrollment in clinical trials and employ strategies to encourage greater participation
  • make demographic subgroup data more available and transparent

Congress is also interested in ensuring that sex differences are factored into medical research. Last year, Rep. Jim Cooper (R-Tenn.) introduced the Research for All Act of 2014. This bill would have directed the FDA to review and develop policies to ensure that the design and size of most clinical trials are sufficient to determine the safety and effectiveness of the products for men and women, using subgroup analysis. Additionally, the bill would have amended the Public Health Services Act to require the director of the National Institutes of Health to determine when it would be appropriate for basic research to include both male and female cells, tissues, and animals. This bill attracted bipartisan support from 13 members of Congress before expiring in December at the end of the 113th Congress.

Looking ahead
The medical research community will have to wait to see how effective the FDA’s guidance document on sex-specific data will be, because the guidance is purely voluntary. Specifically, it will be interesting to see how the final guidance document will influence study design in medical device trials, and how it will impact data collection and enrollment in medical device studies.

Improving the quality and consistency of sex-specific performance data for medical devices will lead to better orthopaedic care for everyone. The AAOS Women’s Health Issues Advisory Board will continue to monitor the impact of this guidance with the assistance of the AAOS office of government relations.

Laura M. Bruse Gehrig, MD, chairs the AAOS Women’s Health Issues Advisory Board.

Men, Women, and MoM
The significance of sex-specific data was underscored in an analysis of data on metal-on-metal (MoM) hip implants. Results from studies presented to the FDA in 2012 showed that revision rates appeared higher among females at 3-to-5 years after the index surgery.

Sex-specific revision rates in total hip arthroplasty studies ranged between 2.7 percent and 19.8 percent for females and between 0 percent and 14.6 percent for males. In resurfacing studies, the revision rate was between 0 percent and 27.6 percent in females and between 1.4 percent and 8.97 percent in males.

Based on this information, the FDA was able to recommend to orthopaedic surgeons that females may be at higher risk for increased device wear and/or adverse local tissue reactions and should be followed more closely.

Putting sex in your orthopaedic practice
This quarterly column from the AAOS Women’s Health Issues Advisory Board and the Ruth Jackson Orthopaedic Society provides important information for your practice about issues related to sex (determined by our chromosomes) and gender (how we present ourselves as male or female, which can be influenced by environment, families and peers, and social institutions). It is our mission to promote the philosophy that male and female patients experience and react to musculoskeletal conditions differently; when it comes to patient care, surgeons should not have a one-size-fits-all mentality.