You should submit comments and suggestions regarding this draft document within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. Submit electronic comments to Identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.

For questions regarding this document, contact Kathryn O’Callaghan at 301-796-6349, or via email at


U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health


Confidential submissions to FDA contain detailed analyses of clinical study data, which may include a variety of sex-specific analyses. However, public documents on medical devices approved in the past are inconsistent with regard to the degree of information available on device performance in demographic subgroups. Although sponsors may be most interested in the generalizability of the findings, individual patients and their medical providers can benefit from more data regarding effectiveness and potential adverse events associated with device use in a particular demographic subgroup.

A. Enrollment Demographics, Baseline Characteristics & Co-Morbidities

The strength of the conclusions of your clinical study program with respect to device performance in women and men is linked to the representation of each sex in your study(s). FDA recommends that you report the number and proportion of subjects by sex who were treated or diagnosed with your device as part of a clinical study as follows:

  • You should report study demographics in terms of proportion enrolled by subgroup. You should discuss whether the proportions enrolled are consistent with the sex-specific prevalence of disease. For studies with multiple arms, you should report enrollment proportions for each sex in each arm.
  • If co-morbidities and/or other baseline characteristics are reported, we recommend that you report important baseline characteristics and co-morbidities by demographic subgroup as well as overall.
  • For per protocol analyses, we recommend a comparison and discussion of sex-specific differences in follow-up compared to at enrollment, for the overall study sample and for each study arm.

You may choose to adapt the example language below, or you may use similar language which incorporates the contents described above.

Example Language:

Women represented [34%] of the total patients enrolled in the overall study. This is similar to the prevalence of [coronary artery disease] in the general U.S. population [citation]. The proportion of women included in the treatment and control arms did not differ significantly (treatment: 33% vs. control: 34%).

Women were more likely to have diabetes compared to men (35% vs. 22%) and less likely to have prior history of myocardial infarction (24% vs. 36%).

Additionally, we recommend that you include this type of information in any applicable tables and charts.

1. For New or Ongoing Studies (IDE study design/early enrollment stage)

You should report this information as part of your annual progress reports.

2. For Completed Studies (marketing application stage)

You should report this information as part of your marketing application in sections containing results of clinical investigations. A summary of this information should also be included in your draft PMA Summary of Safety and Effectiveness or 510(k) Summary.

3. For Postmarket Studies (PAS or 522 PS stage)

You should report this information in interim reports and in the results section of your final report.

B. Sex-Specific Outcomes (Safety or Effectiveness)

The results of sex-specific outcomes analyses should be presented in the labeling, regardless of whether the analyses are pre-specified or post hoc. If analyses suggest a possible sex difference in an endpoint or event with clinical significance, but statistical significance is not reached, you should report the findings descriptively. If results of these analyses suggest no sex differences in outcomes, you should report which analyses were conducted and that no differences were found.

1. For Completed Studies (marketing application stage)

When presenting results of prespecified sex analyses, we recommend the following:

  • Clearly state which analyses were conducted
  • Specify statistical methods used to assess for heterogeneity of treatment differences by sex (as described above)
  • You may include inferential statistics, including p-values and/or confidence intervals.

When presenting results of post hoc sex-specific analyses, we recommend the following:

  • Clearly state that the analyses were unplanned
  • Clearly state which analyses were conducted
  • Specify statistical methods used to assess for heterogeneity of treatment differences by sex (as described above)
  • Use descriptive statistics only (mean, standard deviation, etc.). Results in confidential submissions to PMA can include inferential statistics, with a disclaimer that these are from post hoc analyses.
2. For Postmarket Studies (PAS or 522 PS stage)

When presenting results of sex-specific analyses of PAS or 522 PS data, the recommendations above should also apply.

If a clinically significant signal is detected in interim reports, FDA may recommend changes to your previously approved labeling and summaries, to communicate the newly observed sex difference.

If a clinically significant signal is detected in your final analysis, this information should be summarized in your revised labeling which you submit with your final study report.



3 Institute of Medicine, Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter? National Academy of Sciences, 2001.

4 Sex refers to the classification of living things, generally as male or female according to their reproductive organs and functions assigned by chromosomal complement.

5 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 is rooted in biology, and shaped by environment and experience.

6 U.S. Department of Health, Education, and Welfare, "General Considerations for the Clinical Evaluation of Drugs, HEW (FDA) 77-3040" (Government Printing Office, Washington, September 1977).

7 Women's health. Report of the Public Health Service Task Force on Women's Health Issues. Public Health Rep. 1985 Jan-Feb; 100(1): 73-106.

8 United States General Accounting Office. Women’s Health. FDA Needs to Ensure More Study of Gender

Differences in Prescription Drug Testing. (Accessed April 2, 2010 at

9 CDRH ODE Annual Report FY1994.

11 United States General Accounting Office. Women’s Health. Women Sufficiently Represented in New Drug Testing, but FDA Oversight Needs Improvement. (Accessed April 2, 2010 at, ed,: 2001).

11 Evelyn B, Toigo T, Banks D, Pohl D, Gray K, Robins B, Ernat J. Women's Participation in Clinical Trials and Gender-Related Labeling: A Review of New Molecular Entities Approved 1995-1999. June 2001. (Accessed September 28, 2010 at ForPatientAdvocates/ParticipatinginClinicalTrials/ucm197788.htm.)

12 Kramer D B , Mallis E, Zuckerman B D , Zimmerman BA, Maisel WH. Premarket Clinical Evaluation of Novel Cardiovascular Devices: Quality Analysis of Premarket Clinical Studies Submitted to the Food and Drug Administration 2000-2007. Am J Therapeutics. 2009.

13 See Report to Congress; Food and Drug Administration Amendments Act (FDAAA) of 2007, Public Law No. 110-85 Section 901 of the Federal Food, Drug, and Cosmetic Act; Direct-to-Consumer Advertising’s Ability to Communicate to Subsets of the General Population; Barriers to the Participation of Population Subsets in Clinical Drug Trials. Available online at: FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/ FoodandDrugAdministrationAmendmentsActof2007/FDAAAImplementationChart/UCM213016.pdf.

14 NIH Office of Research on Women’s Health has a number of publications available which provide advice on inclusion criteria, an overview of key elements in recruitment and retention, and a number of practical applications for conducting human subjects research, including ethical considerations. Available online at:

15 The National Institute of Mental Health developed a resource document which outlines common issues that can impact clinical recruitment and retention, and strategies to address these issues. Available online at: grants/recruitment-points-to-consider-6-1-05.pdf.

16 The National Cancer Institute developed an online resource designed for practicing professionals to support clinical trial accrual needs. The Web site is a repository for literature and other resources and serves as a 'community of practice' to encourage dialog and discussion. Available online at:

17 We also recommend the provision of race-specific information for each of these bullets to facilitate understanding of difference related to race relevant to the clinical evaluation of your device.

18 CDRH Guidance on IDE Policies and Procedures (1998): GuidanceDocuments/ucm080202.htm.

19 J. Hays, et al. The Women’s Health Initiative Recruitment Methods and Results. Ann Epidemiol 2003;13:S18-S77.

20 Committee on Understanding the Biology of Sex and Gender Differences. Exploring the Biological Contributions to Human Health: Does Sex Matter? Institute of Medicine, National Academies of Science. 2001.