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Evaluation of Sex-Specific 

Data in Medical Device 

Clinical Studies -

Final Guidance for Industry 

and FDA Staff

Jismi Johnson, M.S.

Kathryn O’Callaghan, B.S.

Lilly Yue, Ph.D.

Danica Marinac-Dabic, M.D., Ph.D.

August 25, 2014

2
Overview

• Guidance Objectives, Scope and Background 

• Major Comments Received on Draft Guidance

• Major Revisions Made to Final Guidance

• Content of Guidance

• Decision Framework

• Question & Answer

3
Introduction

• Intended to improve quality and consistency of available data 

regarding device performance in both sexes

• Objectives

– 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

• 2 public workshops helped to develop policy

– June 2, 2008

– December 9, 2008

4
Scope

• Focus on sex but can also be applicable for other 

demographic variables(e.g., age, race, ethnicity)

• Recommendations may not applicable in all cases 

(e.g., OB/GYN and urology devices intended for 

single-sex, de-identified IVD devices)

5
Comments Received on Draft 

Guidance

• Statistical Comments

– Clarification on statistical concepts

– When should studies be powered for sex difference?

– When would additional data be needed? 

– Primary effectiveness analyses followed by subgroup analyses

– Poolability questions 

• Statistical Section updated -“Considering Sex in Study Design and Data 

Interpretation”

– Discussion of statistical concepts for sex-specific differences

– Considerations when designing clinical study

– Considerations for analyzing data from one-arm and comparative studies

– Considerations for diagnostic devices

– Recommendations for interpreting sex-specific data

6
Background

• Sex/Gender Definitions

– Sex refers to classification of living things, generally as male or 

female according to their reproductive organs and functions 

assigned by chromosomal complement. 

– Gender refers to 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. 

7
Why Consider Sex Differences?

• Certain medical products elicit different responses in women 

compared to men

• Ventricular Assist Devices (VADs)

– Women observed to have higher incidence of strokes [18% vs. 6%], but 

strokes did not have significant effect on their overall survival 

compared with men

– Trends toward higher incidence of bleeding and infection events 

observed in women than men

• Cardiac Resynchronization Therapy Defibrillators (CRT-D)

– Both men and women experienced a CRT-D benefit; however, women 

received a greater benefit than men [77% vs. 42%]

• Metal-on-Metal Hips

– Higher revision rates in females when compared to males [e.g. 0-

27.6% vs. 1.4-8.97%]

8
Participation of Women in 

Clinical Studies

• Lack of available data for women

– 1970s: Women “of child-bearing potential” be excluded from 

drug studies

– 1992: GAO report concluded that women were significantly 

underrepresented; sex-specific data analysis was performed in 

<50% of drug studies

– 1994: CDRH discusses addressing possibility of “gender bias” in 

submissions and review documentation for new medical devices

– 2013: FDA Report shows participation rates for women varied 

widely by device product area

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Participation of Women in 

Clinical Studies

• Barriers to Enrollment of Women in Clinical Studies

– Lack of understanding about main obstacles to participation of women in 

clinical research

– Inclusion/exclusion criteria potentially not needed to define study population 

may unintentionally exclude women 

– Lack of understanding about differences in disease etiology and 

pathophysiology may lead to under-diagnosis and under-referral of women

– Device manufacturing limitations to accommodate anatomical differences 

between women and men

– Fear of fetal consequences if female participant becomes pregnant

– Investigators and sponsor avoidance of female patients due to perception that 

it takes more time and money to recruit them

– Family responsibilities limiting women’s ability to commit time for study 

follow-up

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Achieving Appropriate 

Enrollment

• Intent is to provide context based on disease science

– Sponsors should investigate and report whether sex differences may or 

may not exist for disease or condition which device is intended to 

treat or diagnose

• Methods to increase enrollment, for example: 

– Target sites where recruitment of women is easier

– Consider revising enrollment criteria, when appropriate, or consider 

parallel cohorts for collecting data on device use in women

– Investigate reasons for under-enrollment or non-enrollment of women 

or other key demographic groups 

• Sponsor and Investigator responsibilities to avoid or minimize 

loss-to-follow up

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Considering Sex in Study Design 

and Data Interpretation

• Important to consider variation in data across sex in both study 

design and interpretation of study data

• Statistical concepts for assessing heterogeneity across sex 

groups

– Identifies and define statistical terms and tests

– Includes recommendations for new or ongoing studies, completed 

studies, and for postmarketing studies

• Recommendations for Study Design:

– When sex group differences are anticipated

– Prespecifying assessment of heterogeneity across sex groups in study 

design

– One-arm studies and comparative studies

– Diagnostic devices 12
Considering Sex in Study Design 

and Data Interpretation (cont’d)

• Recommendations for Analysis and Interpretation

– Analysis for clinically meaningful sex differences

– Specific considerations for one-arm studies and comparative studies

• Interpretation of Sex-Specific Data

– Discuss with FDA to determine if additional data are needed

• Insufficient data à additional data pre-market or post-market may be 

needed to address potential sex-specific questions

– Clinically meaningful differences between sexes observed may lead to 

(rare cases):

• Additional confirmatory studies in one or both sexes

• Implementation of specific pre- or post-approval study conditions

• Modification of the design of subsequent studies

– Limitations in interpreting clinically meaningful differences in small 

data sets

13
Reporting Sex-Specific Information in 

Applications and Public Documents

• Report enrollment demographics, baseline 

characteristics, and co-morbidities

– Refer to guidance for example language

• Report sex-specific outcomes (safety or 

effectiveness) in labeling and review summaries

– If results are statistically significant and clinically meaningful, 

report results of outcome analyses

– If results suggest a sex difference in endpoint or event that is 

clinically meaningful, but statistical significance is not 

reached, report findings descriptively

– If results suggest no sex differences in outcomes, report which 

analyses were conducted and that no differences were found 14
Decision Framework

• Concern that recommendations applied to every 

clinical study

• Uncertainty on when additional data would be 

needed

• Decision trees created to illustrate and assist in 

determining when recommendations apply

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Recommendations for Sex-Specific Statistical Design

Follow recommendations associated with study design 

*For ongoing studies, provide descriptive statistics. For new studies, provide 

statistical inferences

**Applicable when sex-subgroup differences are anticipated

All Clinical Studies YES

Is the product’s use/design intended to be limited 

to one sex? (e.g., pregnancy test, PSA testing)

YES No separate sex analyses required.

NO

START

RECOMMENDATIONS

•Reporting by sex should be pre-specified*

•Provide strategy to recruit appropriate representation of 

women ideally matching disease prevalence by sex

•Report whether previous studies, disease science, etc. 

suggest a clinically meaningful difference by sex

•Follow recommendations in box above for “All Clinical 

Studies”

•Provide strategy for assessing heterogeneity

•May consider sex-specific Objective Performance Criteria 

(OPC) or Performance Goal (PG)**

YES

NO

NO

One-Arm Study

Non-Randomized Controlled Trial 

(concurrent control, historical control)

•Follow recommendations in box above for “All Clinical 

Studies”

•Control Overall Type 1 error rate if seeking multiple claims

•Pre-specify interaction testing

•May consider powering for sex-specific claims**

•Follow recommendations in boxes above for “All Clinical 

Studies” and “Comparative Study”

•May consider sex as stratification variable in randomization 

process when appropriate**

Randomized Controlled Trial (RCT) YES

Comparative Study YES

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Note: In some cases, the sex difference could be statistically significant but not clinically meaningful or clinically meaningful but not statistically 

significant. In these cases, discussion with FDA is advised. 

Recommendations for Sex-Specific Statistical Analyses for Completed Studies

One-Arm Studies (Objective Performance Criterion, Performance Goal, Observational Study)

Is sex difference clinically meaningful and 

statistically significant after adjusting for other 

covariates?

Determine whether there is a significant 

difference between sexes NO

Is overall treatment effect statistically significant 

and clinically meaningful?*

NO Analysis raises questions about data to support marketing 

application. 

YES

START

RECOMMENDATIONS

Data may be poolable across sex

Data may not be poolable across sex. Additional data 

may be required.

YES

NO

Data may be poolable across sex

YES

*Subgroup analyses are not recommended if overall treatment effect is not statistically significant and clinically meaningful.

17
Note: In some cases, the interaction effect could be statistically significant but not clinically meaningful or clinically meaningful but not statistically 

significant. In these cases, discussion with FDA is advised. 

Recommendations for Sex-Specific Statistical Analyses for Completed Studies

Comparative Studies

Is interaction effect clinically meaningful and 

statistically significant after adjusting for other 

covariates?

Determine whether there is a significant 

interaction effect between sex and treatment 

group for the outcome of interest

NO

Is overall treatment effect statistically significant 

and clinically meaningful?*

NO Analysis raises questions about data to support marketing 

application. 

YES

START

RECOMMENDATIONS

Data may be poolable across sex

Data may not be poolable across sex. Additional data 

may be required.

YES

NO

Data may be poolable across sex

YES

Describe qualitative or quantitative nature of interaction 

and clinical significance of any differences. Other 

subgroup analyses may be needed.

*Subgroup analyses are not recommended if overall treatment effect is not statistically significant and clinically meaningful.

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Questions?

CDRH/Office of the Center Director: Kathryn O’Callaghan 

(kathryn.ocallaghan@fda.hhs.gov)

CDRH/Office of Device Evaluation: Jismi Johnson 

(jismi.johnson@fda.hhs.gov)

CDRH/Office of In Vitro Diagnostics and Radiological 

Health: Robert Becker (robertl.becker@fda.hhs.gov) 

CDRH/Division of Biostatistics: Lilly Yue (lilly.yue@fda.hhs.gov) 

CDRH/Division of Epidemiology: Nilsa Loyo-Berrios (nilsa.loyoberrios@fda.hhs.gov)

CBER/Office of Communication, Outreach and Development: 

1-800-835-4709 or240-402-7800 

CDRH/Division of Industry and Consumer Education: 

DICE@fda.hhs.gov

CDRHQuestions@fda.hhs.gov 19