U.S. Food and Drug Administration

Protecting and Promoting Your Health

Document issued on August 22, 2014.

The draft of this document was issued on December 19, 2011

For questions regarding this document, contact CDRH at 301-796-5900 or Kathryn O’Callaghan

(kathryn.ocallaghan@fda.hhs.gov); for Office of Device Evaluation specific questions, Jismi

Johnson (jismi.johnson@fda.hhs.gov); for Statistics specific questions, Lilly Yue

(lilly.yue@fda.hhs.gov); for Office of In Vitro Diagnostics and Radiological Health specific

questions, Robert Becker (robertl.becker@fda.hhs.gov); or for Epidemiology specific questions,

Nilsa Loyo-Berrios (nilsa.loyo-berrios@fda.hhs.gov).

For questions about this document regarding CBER regulated devices, contact the Office of

Communication, Outreach and Development (OCOD) by calling 1-800-835-4709 or240-402-7800.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health

Center for Biologics Evaluation and ResearchContains Nonbinding Recommendations

Preface

Public Comment

You may submit written comments and suggestions at any time for Agency consideration to

the Division of Dockets Management, Food and Drug Administration, 5630 Fishers Lane,

rm. 1061, (HFA-305), Rockville, MD, 20852. Submit electronic comments to

http://www.regulations.gov. Identify all comments with the docket number FDA-2011-D-

0817. Comments may not be acted upon by the Agency until the document is next revised or

updated.

Additional Copies

Additional copies are available from the Internet. You may also send an e-mail request to

CDRH-Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document

number 1727 to identify the guidance you are requesting.

Additional copies of this guidance document are also available from the Center for Biologics

Evaluation and Research (CBER) by written request, Office of Communication, Outreach and

Development 10903 New Hampshire Ave., Silver Spring, MD 20993, Bldg. 71, Rm. 3128,

1-800-835-4709 or240-402-7800, by email, ocod@fda.hhs.gov, or from the Internet at

http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/d

e fault.htm. Contains Nonbinding Recommendations

TABLE OF CONTENTS

I. INTRODUCTION ..................................................................................................................................... 1

II. SCOPE ........................................................................................................................................................ 2

III. BACKGROUND ........................................................................................................................................ 2

A. WHY CONSIDER SEX DIFFERENCES? .......................................................................................................... 3

B. PARTICIPATION OF WOMEN IN CLINICAL STUDIES .................................................................................... 5

1. Lack of Available Data for Women ................................................................................................... 5

2. Barriers to Enrollment of Women ..................................................................................................... 7

IV. RECOMMENDATIONS FOR ACHIEVING APPROPRIATE ENROLLMENT ............................. 9

A. CONSIDERATION OF POTENTIAL SEX DIFFERENCES .................................................................................. 9

1. For New or Ongoing Studies (IDE study design/early enrollment stage)........................................ 9

2. For Completed Studies (marketing application stage)....................................................................10

3. For Postmarket Studies (PAS or 522 PS stage)...............................................................................10

B. STUDY DESIGN AND CONDUCT ...............................................................................................................10

1. For New or Ongoing Studies (IDE study design/early enrollment stage)......................................10

2. For Completed Studies (marketing application stage)....................................................................11

3. For Postmarket Studies (PAS or 522 PS stage)...............................................................................12

V. CONSIDERING SEX IN STUDY DESIGN AND DATA INTERPRETATION ..............................14

A. STATISTICAL CONCEPTS FOR ASSESSING HETEROGENEITY ACROSS SEX GROUPS ..................................14

1. For New or Ongoing Studies (IDE study design/early enrollment stage)......................................15

2. For Completed Studies (marketing application stage)....................................................................16

3. For Postmarket Studies (PAS or 522 PS stage)...............................................................................16

B. RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL ELEMENTS IN STUDY DESIGN .............................16

When Sex Group Differences are Anticipated ............................................................................................16

Pre-specifying Assessment of Heterogeneity Across Sex Groups in Study Design .....................................17

Additional Considerations for Particular Study Design Types ..................................................................18

Special Considerations for Diagnostic Devices ..........................................................................................18

C. RECOMMENDATIONS FOR ANALYSIS AND INTERPRETATION OF SEX-SPECIFIC DATA IN COMPLETED

STUDIES............................................................................................................................................................19

Sex-Specific Analysis ..................................................................................................................................19

Additional Considerations for Data Analysis in Particular Study Design Types .......................................19

D. INTERPRETATION OF SEX-SPECIFIC DATA...............................................................................................21

VI. RECOMMENDATIONS FOR REPORTING SEX-SPECIFIC INFORMATION IN

APPLICATIONS AND PUBLIC DOCUMENTS ...........................................................................................21

A. ENROLLMENT DEMOGRAPHICS, BASELINE CHARACTERISTICS & CO-MORBIDITIES ...............................21

1. For New or Ongoing Studies (IDE study design/early enrollment stage)......................................22

2. For Completed Studies (marketing application stage)....................................................................22

3. For Postmarket Studies (PAS or 522 PS stage)...............................................................................22

B. SEX-SPECIFIC OUTCOMES (SAFETY OR EFFECTIVENESS) ........................................................................22

1. For Completed Studies (marketing application stage)....................................................................23

2. For Postmarket Studies (PAS or 522 PS stage)...............................................................................23

APPENDIX 1 – DECISION FRAMEWORK ..................................................................................................24

RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL DESIGN ....................................................24Contains Nonbinding Recommendations

RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL ANALYSES FOR COMPLETED STUDIES

- ONE –ARM STUDIES ..................................................................................................................................25

RECOMMENDATIONS FOR SEX-SPECIFIC STATISTICAL ANALYSES FOR COMPLETED STUDIES

- COMPARATIVE STUDIES ............